Ambulatory Care Pharmacy Preparatory Review and Recertification Course 9781952291395, 0217999922

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Ambulatory care pharmacy preparatory review and r e c e r t i f i c a t i o n c o u r s e

2022

All 2022 Ambulatory Care Pharmacy activities are done in partnership with ASHP.

®

American College of Clinical Pharmacy and American Society of Health-System Pharmacists Ambulatory Care Pharmacy Preparatory Review and Recertification Course

American College of Clinical Pharmacy and American Society of Health-System Pharmacists Ambulatory Care Pharmacy Preparatory Review and Recertification Course 2022 Edition

Director, Professional Development & Marketing: Joanna Gillette Project Manager, Professional Development: Terra Shover Senior Medical Editor: Kimma Sheldon-Old, Ph.D. Cover Design: Dane Anderson; Layout: Holly Swayne For order information or questions, contact: American College of Clinical Pharmacy 13000 W. 87th St. Parkway Lenexa, KS 66215-4530 Phone: (913) 492-3311 Fax: (913) 492-0088 [email protected] http://www.accp.com Copyright © 2022 by the American College of Clinical Pharmacy and American Society of Health-System Pharmacists. All rights reserved. This book is protected by copyright. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic or mechanical, including photocopy, without prior written permission of the American College of Clinical Pharmacy and the American Society of Health-System Pharmacists. To properly cite this book: Author(s). Chapter name. In: Cardone KE, Crannage E, Durham SH, et al., eds. Ambulatory Care Pharmacy Preparatory Review and Recertification Course, 2022 ed. Lenexa, KS: American College of Clinical Pharmacy, year:pages. Note: The authors and publisher of the Ambulatory Care Pharmacy Preparatory Review and Recertification Course recognize that the development of this material offers many opportunities for error. Despite our very best efforts, some errors may persist into print. Drug dosage schedules are, we believe, accurate and in accordance with current standards. Readers are advised, however, to check other published sources to be certain that recommended dosages and contraindications are in agreement with those listed in this book. This is especially important for new, infrequently used, or highly toxic drugs. ISBN 13: 978-1-952291-39-5 Errata When possible, corrections to this publication are included in the 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course Errata, which will be available beginning April 27, 2022, at www.accp.com/docs/products/apc22/errata.pdf Continuing Pharmacy Education: The American College of Clinical Pharmacy and the American Society of Health-System Pharmacists are accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The Universal Activity Numbers are: Ambulatory Care Pharmacy Preparatory Review and Recertification Course for home study, 2022 Edition: Trial Design and Biostatistics, Activity No. 0217-9999-22-050-H04-P; 2.5 contact hours; Endocrine Disorders, Activity No. 0217-9999-22-051-H01-P; 1.5 contact hours; Cardiology I, Activity No. 0217-9999-22-052-H01-P; 1.5 contact hours; Cardiology II, Activity No. 0217-9999-22-053-H01-P; 1.5 contact hours; Bone/Joint and Rheumatology, Activity No. 0217-9999-22-054-H01-P; 1.0 contact hour; Diabetes Mellitus, Activity No. 0217-9999-22-055-H01-P; 1.5 contact hours; Obstetrics/Gynecology, Activity No. 0217-9999-22-056-H01-P; 1.0 contact hour; Pulmonary Disorders, Activity No. 0217-9999-22-057-H01-P; 1.5 contact hours; Practices and Processes of Care, Activity No. 0217-9999-22-058-H04-P; 1.0 contact hour; Communication Strategies in Pharmacy, Activity No. 0217-9999-22-059-H04-P; 1.0 contact hour; Developing and Managing a Clinical Practice, Activity No. 0217-9999-22-060-H04-P; 1.5 contact hours; Psychiatric Disorders, Activity No. 0217-9999-22-061-H01-P; 1.5 contact hours; Neurology, Activity No. 0217-9999-22-062-H01-P; 1.0 contact hour; Gastrointestinal Disorders, Activity No. 0217-9999-22-063-H01-P; 1.5 contact hours; Infectious Diseases I, Activity No. 0217-9999-22-064-H02-P; 1.0 contact hour; Infectious Diseases II, Activity No. 0217-9999-22-065-H01-P; 1.0 contact hour; Nephrology, Activity No. 0217-9999-22-066-H01-P; 1.0 contact hour; Dermatologic and Eyes, Ears, Nose, and Throat, and Immunologic Disorders, Activity No. 0217-9999-22-067-H01-P; 1.0 contact hour; Genitourinary, Electrolytes, and Nutritional Deficiencies/Supplementation in Older Adults, Activity No. 0217-9999-22-049-H01-P; 1.0 contact hour. To earn continuing pharmacy education credit for the home-study version of the 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course, you must either successfully complete and submit the web-based posttest associated with each module within the course or submit the attestation statement no later than April 11, 2025. Statements of continuing pharmacy education credit will be available at CPE Monitor within 2 -3 business days after the successfully completed web-based posttest is submitted (for participants enrolled in the BCACP recertification version of the course) or successful submission of the attestation statement. To earn BCACP recertification credit for the home-study version of the 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course, you must successfully complete and submit the web-based posttest associated with each program within the course no later than April 11, 2023. To learn more about the Board of Pharmacy Specialties (BPS) specialty exams, please visit their website: www.bpsweb.org. The American College of Clinical Pharmacy (ACCP) and the American Society of Health-System Pharmacists (ASHP) have compiled the materials in this course book for pharmacists to use in preparing for the Board of Pharmacy Specialties (BPS) Ambulatory Care Pharmacy Specialty certification examination. There is no intent or assurance that all the knowledge on the examination will be covered in the ACCP/ ASHP process. Although ACCP/ASHP use the BPS Content Outline in creating the material for this course, ACCP/ASHP do not know the specific content of any particular BPS examination. BPS guidelines prohibit any overlap of individuals writing the examination and developing preparatory materials. To maintain its strict, independent standards for certification, BPS does NOT endorse or provide review information, preparatory courses, or study guides for Board Certification Examinations.

Program Goals and Target Audience

Program Goals and Target Audience Ambulatory Care Pharmacy Preparatory Review and Recertification Course is designed to help pharmacists who are preparing for the Board of Pharmacy Specialties certification examination in Ambulatory Care Pharmacy as well as those seeking a general review and refresher on disease states and therapeutics. The program goals are as follows: 1. To present a high-quality, up-to-date overview of disease states and therapeutics; 2. To provide a framework to help attendees prepare for the specialty certification examination in ambulatory care pharmacy; and 3. To offer participants an effective learning experience using a case-based approach with a strong focus on the thought processes needed to solve patient care problems in each therapeutic area.

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Faculty

Faculty *Designates Content Matter Experts for the Course Katie E. Cardone, Pharm.D., FCCP, FASN, FNKF, BCACP Associate Professor Albany College of Pharmacy and Health Sciences Albany, New York

Adam B. Jackson, Pharm.D., BCACP* Clinical Pharmacy Specialist in Drug Utilization Management Pharmacy Department Kaiser Permanente Colorado Denver, Colorado

Erica Crannage, Pharm.D., FCCP, BCPS, BCACP Associate Professor St. Louis College of Pharmacy at The University of Health Sciences & Pharmacy; Clinical Pharmacist Mercy Clinic Family Medicine St. Louis, Missouri

Joel C. Marrs, Pharm.D., M.P.H., FCCP, FAHA, FASHP, FNLA, BCACP, BCCP, BCPS, CHC, CLS Associate Professor Department of Clinical Pharmacy University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences Aurora, Colorado

Spencer H. Durham, Pharm.D., BCPS, BCIDP Associate Clinical Professor Department of Pharmacy Practice Auburn University Harrison School of Pharmacy Auburn, Alabama

Michelle T. Martin, Pharm.D., FCCP, BCPS, BCACP Clinical Pharmacist University of Illinois Hospital & Health Sciences System; Assistant Professor University of Illinois at Chicago College of Pharmacy Chicago, Illinois

Jessica Farrell, Pharm.D. Clinical Pharmacist The Center for Rheumatology, LLC; Associate Professor of Pharmacy Practice Albany College of Pharmacy and Health Sciences Albany, New York

Jamie L. McConaha, Pharm.D., BCACP* Assistant Professor of Pharmacy Practice Division of Pharmacy Practice Duquesne University Pittsburgh, Pennsylvania

Alicia B. Forinash, Pharm.D., FCCP, BCPS, BCACP Clinical Pharmacy Specialist Maternal Fetal Care Center/WISH Center SSM Health St. Mary’s; Professor of Pharmacy Practice St. Louis College of Pharmacy at The University of Health Sciences and Pharmacy St. Louis, Missouri

Emily K. McCoy, Pharm.D., BCACP Associate Clinical Professor Auburn University Harrison School of Pharmacy Mobile, Alabama Molly G. Minze, Pharm.D., FCCP, BCACP Associate Professor of Pharmacy Practice Regional Director of Student Affairs and Admissions Abilene Campus Texas Tech University Health Sciences Center Jerry H. Hodge School of Pharmacy Abilene, Texas

Nicole M. Hahn, Pharm.D., BCACP* Clinical Pharmacy Specialist – Neurology Kaiser Permanente Denver, Colorado

Jean Y. Moon, Pharm.D., FCCP, BCACP Associate Professor PGY1 Residency Program Director College of Pharmacy University of Minnesota Minneapolis, Minnesota

Diana Isaacs, Pharm.D., FCCP, FADCES, BCPS, BCACP, BC-ADM, CDCES Endocrine Clinical Pharmacy Specialist CGM and Remote Monitoring Program Coordinator Cleveland Clinic Endocrinology & Metabolism Institute Cleveland, Ohio

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Faculty Melissa C. Palmer, Pharm.D., BCPS, BCPP Clinical Pharmacy Specialist – Mental Health Alaska VA Healthcare System Anchorage, Alaska Katie J. Suda, Pharm.D., M.S., FCCP Professor Department of Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Jessica Tilton, Pharm.D., BCACP Clinical Assistant Professor Clinical Pharmacist Medication Therapy Management Clinic; Clinical Coordinator University of Illinois at Chicago College of Pharmacy Chicago, Illinois Elizabeth Van Dril, Pharm.D., BCPS, BCACP, CDCES Clinical Assistant Professor University of Illinois at Chicago College of Pharmacy Chicago, Illinois

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Disclosures

Faculty Disclosures Consultant/Member of Advisory Board: Katie E. Cardone (AstraZeneca, Vifor, Otsuka, Wolters Kluwer), Spencer H. Durham (Shionogi, Theratechnologies), Jessica Farrell (Cumberland Pharmaceuticals, Boehringer Ingelheim), Diana Isaacs (Lilly, Sanofi), Michelle T. Martin (AbbVie), Molly G. Minze (Wolters Kluwer) Grant Funding/Research Support: Jessica Farrell (Janssen), Michelle T. Martin (Gilead, Merck), Melissa C. Palmer (Telehealth ECHO) Speaker’s Bureau: Jessica Farrell (Pfizer, AbbVie), Michelle T. Martin (AbbVie), Diana Isaacs (Abbott, Bayer, Dexcom, Dexcom, Insulet, Medtronic, Nova Nordisk, Xeris) Minor Shareholder: Michelle T. Martin (AbbVie, Gilead, Merck), Jessica Tilton (Pfizer, Moderna, Viatris) Other: Alicia B. Forinash (royalties from Wolters Kluwer) Nothing to Disclose: Erica F. Crannage, Nicole M. Hahn, Adam B. Jackson, Joel C. Marrs, Jamie McConaha, Emily K. McCoy, Jean Y. Moon, Katie J. Suda, Elizabeth Van Dril

Reviewer Disclosures Consultant/Member of Advisory Board: Frank Fanizza (Guidepoint) Reviewers not listed above have nothing to disclose. All relevant financial relationships listed have been mitigated.

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Acknowledgments

Acknowledgments Jacquelyn L. Bainbridge, Pharm.D., FCCP Professor Department of Clinical Pharmacy Department of Neurology in the School of Medicine University of Colorado Denver Aurora, Colorado

L. Brian Cross, Pharm.D., BCACP, CDE Associate Professor Gatton School of Pharmacy East Tennessee State University Mountain Home, Tennessee Spencer H. Durham, Pharm.D., BCPS, BCIDP Associate Clinical Professor Department of Pharmacy Practice Auburn University Harrison School of Pharmacy Auburn, Alabama

Sally Y. Barbour, Pharm.D., BCOP, CPP Clinical Oncology Pharmacist Duke Comprehensive Cancer Center Duke University Medical Center Durham, North Carolina

Jessica Farrell, Pharm.D. Clinical Pharmacist The Center for Rheumatology, LLC; Associate Professor of Pharmacy Practice Albany College of Pharmacy and Health Sciences Albany, New York

Ashley Branham, Pharm.D., BCACP Director of Clinical Services Moose Pharmacy Concord, North Carolina Katie E. Cardone, Pharm.D., FCCP, FASN, FNKF, BCACP Associate Professor Albany College of Pharmacy and Health Sciences Albany, New York

Edward F. Foote, Pharm.D., FCCP, BCPS Professor and Chair of Pharmacy Practice Nesbitt College of Pharmacy and Nursing Wilkes University Wilkes-Barre, Pennsylvania

Mariann D. Churchwell, Pharm.D., BCPS Associate Professor University of Toledo College of Pharmacy Toledo, Ohio Nathan Clark, Pharm.D., FCCP, BCPS, CACP Supervisor Clinical Pharmacy Anticoagulation and Anemia Services Kaiser Permanente Colorado Aurora, Colorado

Alicia B. Forinash, Pharm.D., FCCP, BCPS, BCACP Clinical Pharmacy Specialist Maternal Fetal Care Center/WISH Center SSM Health St. Mary’s; Professor of Pharmacy Practice St. Louis College of Pharmacy at The University of Health Sciences & Pharmacy St. Louis, Missouri

Elizabeth A. Coyle, Pharm.D., FCCM, BCPS Clinical Associate Professor of Infectious Diseases University of Houston College of Pharmacy; Director of the Infectious Diseases Pharmacy Residency University of Texas MD Anderson Cancer Center Houston, Texas

Wendy A. Gattis Stough, Pharm.D. Assistant Consulting Professor in Medicine Department of Medicine Division of Cardiology Duke University Medical Center Durham, North Carolina

Erica F. Crannage, Pharm.D., FCCP, BCPS, BCACP Associate Professor St. Louis College of Pharmacy at The University of Health Sciences & Pharmacy; Clinical Pharmacist Mercy Clinic Family Medicine St. Louis, Missouri

Shellee A. Grim, Pharm.D., BCPS Clinical Assistant Professor University of Illinois at Chicago Chicago, Illinois Nicole M. Hahn, Pharm.D., BCACP Clinical Pharmacy Specialist – Neurology Kaiser Permanente Denver, Colorado

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Acknowledgments Ila M. Harris, Pharm.D., FCCP, BCPS Associate Professor Medical School Department of Family Medicine and Community Health, University of Minnesota Bethesda Family Medicine St. Paul, Minnesota

William A. Kehoe, Pharm.D., FCCP, BCPS Professor of Clinical Pharmacy and Psychology Chair of the Department of Pharmacy Practice, University of the Pacific Stockton, California Mary Ann Kliethermes, Pharm.D. Director of Medication Safety and Quality American Society of Health-System Pharmacists Bethesda, Maryland

Rachel M. Heilmann, Pharm.D., BCPS Clinical Pharmacy Specialist in Primary Care Kaiser Permanente Colorado Denver, Colorado

Sunny A. Linnebur, Pharm.D., FCCP, BCPS, CGP Associate Professor University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Aurora, Colorado

Sheryl J. Herner, Pharm.D., BCPS, CPPS Clinical Pharmacy Specialist in Medication Safety Kaiser Permanente Colorado Denver, Colorado Diana Isaacs, Pharm.D., FCCP, BCPS, BCACP, BC-ADM, CDCES, ADCES Endocrine Clinical Pharmacy Specialist CGM and Remote Monitoring Program Coordinator Cleveland Clinic Endocrinology & Metabolism Institute Cleveland, Ohio

Daniel S. Longyhore, Pharm.D., BCACP Associate Professor Wilkes University Wilkes-Barre, Pennsylvania; Ambulatory Care Pharmacist St. Luke’s Hospital & Health Network Bethlehem, Pennsylvania

Adam B. Jackson, Pharm.D., BCACP Clinical Pharmacy Specialist in Drug Utilization Management Pharmacy Department Kaiser Permanente Colorado Denver, Colorado

Joel C. Marrs, Pharm.D., MPH, FCCP, FNLA, FAHA, FASHP, BCACP, BCCP, BCPS, CHC, CLS Ambulatory Pharmacy Clinical Coordinator Billings Clinic; Clinical Associate Professor Department of Pediatrics University of Colorado School of Medicine Aurora, Colorado

Samuel G. Johnson, Pharm.D., FCCP, BCPS-AQ Cardiology Clinical Pharmacy Specialist – Cardiology Kaiser Permanente Colorado Region Denver, Colorado

Karen F. Marlowe, Pharm.D., BCPS, CPE Assistant Dean and Associate Department Head James T. and Anne Klein Davis Endowed Professor Harrison School of Pharmacy Auburn University Mobile, Alabama

Tiffany E. Kaiser, Pharm.D., FCCP, BCPS Associate Professor of Medicine Assistant Director of the PGY2 Transplant Specialty Residency University of Cincinnati Medical Center Cincinnati, Ohio

Michelle T. Martin, Pharm.D., FCCP, BCPS, BCACP Clinical Pharmacist University of Illinois Hospital & Health Sciences System; Assistant Professor University of Illinois at Chicago College of Pharmacy Chicago, Illinois

Michael P. Kane, Pharm.D., FCCP, BCPS, BCACP Professor of Pharmacy Practice Albany College of Pharmacy and Health Sciences; Clinical Pharmacy Specialist Albany Medical Center Division of Community Endocrinology Albany, New York

Jamie L. McConaha, Pharm.D., BCACP Assistant Professor of Pharmacy Practice Division of Pharmacy Practice Duquesne University Pittsburgh, Pennsylvania

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course vi

Acknowledgments Karen J. McConnell, Pharm.D., FCCP, BCPS-AQ Cardiology Clinical Pharmacy Specialist in Cardiology Kaiser Permanente Colorado; Clinical Associate Professor University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences; Adjunct Professor of Pharmacy Practice Regis University School of Pharmacy Denver, Colorado

Carol A. Ott, Pharm.D., BCPP Clinical Associate Professor of Pharmacy Practice College of Pharmacy Purdue University; Clinical Pharmacy Specialist in Psychiatry Wishard Health Services and Midtown Community Mental Health Indianapolis, Indiana Melissa C. Palmer, Pharm.D., BCPS, BCPP Clinical Pharmacy Specialist – Mental Health Alaska VA Healthcare System Anchorage, Alaska

Emily K. McCoy, Pharm.D., BCACP Associate Clinical Professor Auburn University Harrison School of Pharmacy Mobile, Alabama

Ann M. Philbrick, Pharm.D., BCPS, BCACP Associate Professor University of Minnesota; Clinical Pharmacist Bethesda Family Medicine St. Paul, Minnesota

Molly G. Minze, Pharm.D., FCCP, BCACP Associate Professor of Pharmacy Practice Regional Director of Student Affairs and Admissions Abilene Campus Texas Tech University Health Sciences Center Jerry H. Hodge School of Pharmacy Abilene, Texas

Theresa Prosser, Pharm.D., FCCP, BCPS Professor St. Louis College of Pharmacy St. Louis, Missouri

Jean Y. Moon, Pharm.D., FCCP, BCACP Associate Professor PGY1 Residency Program Director College of Pharmacy University of Minnesota Minneapolis, Minnesota

Frank Romanelli, Pharm.D., MPH, BCPS Associate Dean Professor of Pharmacy, Health Sciences, and Medicine University of Kentucky Lexington, Kentucky

Bruce A. Mueller, Pharm.D., FCCP Professor of Pharmacy and Chair Department of Clinical, Social and Administrative Sciences College of Pharmacy University of Michigan; Pharmacy Assistant Director Department of Pharmacy Services University Hospital University of Michigan Health Systems Ann Arbor, Michigan

J. Mark Ruscin, Pharm.D., BCPS Professor Department of Pharmacy Practice Southern Illinois University Edwardsville Edwardsville, Illinois Wendy L. St. Peter, Pharm.D., FCCP, FASN, FNKF, BCPS Professor College of Pharmacy University of Minnesota; United States Renal Data System & Chronic Disease Research Group Minneapolis, Minnesota

Edith A. Nutescu, Pharm.D., FCCP Director of the Antithrombosis Service Associate Professor Department of Pharmacy Practice University of Illinois at Chicago Chicago, Illinois

Sarah L. Scarpace, Pharm.D., BCOP Associate Professor and Assistant Dean for Pharmacy Professional Affairs Albany College of Pharmacy and Health Sciences; Clinical Pharmacy Specialist Stratton Veterans’ Affairs Medical Center Albany, New York

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course vii

Acknowledgments Tiffany Scott-Horton, Pharm.D., BCACP Clinical Assistant Professor, Pharmacy Practice MTMC Operations Coordinator Ambulatory Pharmacy Services University of Illinois at Chicago Chicago, Illinois

Andrea N. Traina, Pharm.D., BCPS, BCACP Assistant Professor of Pharmacy Practice St. John Fisher College Wegmans School of Pharmacy; Clinical Pharmacy Specialist Endocrine-Diabetes Care and Resource Center Rochester General Health System Rochester, New York

Mansi Shah, Pharm.D., BCACP, CDE Assistant Professor University of Illinois at Chicago College of Pharmacy Chicago, Illinois

Elizabeth Van Dril, Pharm.D., BCPS, BCACP, CDCES Clinical Assistant Professor University of Illinois at Chicago College of Pharmacy Chicago, Illinois

Kevin M. Sowinski, Pharm.D., FCCP Professor of Pharmacy Practice Purdue University College of Pharmacy; Adjunct Professor of Medicine Indiana University School of Medicine Indianapolis, Indiana

Joseph P. Vande Griend, Pharm.D., BCPS, CGP Assistant Professor University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences Aurora, Colorado

Sarah A. Spinler, Pharm.D., FCCP, BCPS Professor of Clinical Pharmacy Department of Pharmacy Practice and Pharmacy Administration Philadelphia College of Pharmacy University of the Sciences Philadelphia, Pennsylvania

Orly Vardeny, Pharm.D., BCACP Associate Professor of Pharmacy University of Minnesota Minneapolis, Minnesota Anna Vaysman, Pharm.D., BCPS Clinical Assistant Professor University of Illinois at Chicago College of Pharmacy Chicago, Illinois

Katie J. Suda, Pharm.D., M.S., FCCP Professor Department of Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Valerie A. Vuylsteke, Pharm.D., BCACP Pharmacy Clinical Specialist – Ambulatory Care PGY2 Transitions of Care Pharmacy Residency Program Director Methodist Dallas Medical Center – Golden Cross Academic Clinic Dallas, Texas

Michael C. Thomas, Pharm.D., BCPS Clinical Associate Professor and Vice Chair Department of Pharmacy Practice Western New England University College of Pharmacy Springfield, Massachusetts

Daniel M. Witt, Pharm.D., FCCP, BCPS Sr. Manager Clinical Pharmacy Research & Applied Pharmacogenomics Kaiser Permanente Central Support Services – Pharmacy Administration Kaiser Permanente Aurora, Colorado

Jessica Tilton, Pharm.D., BCACP Clinical Assistant Professor Clinical Pharmacist Medication Therapy Management Clinic; Clinical Coordinator University of Illinois at Chicago College of Pharmacy Chicago, Illinois

Pei Shieen Wong, Pharm.D., BCPS Neurology Clinical Research Fellow Department of Clinical Pharmacy Department of Neurology in the School of Medicine University of Colorado Denver Aurora, Colorado

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Reviewers Kristin Zimmerman, Pharm.D. Associate Professor Department of Pharmacotherapy and Outcomes Science Virginia Commonwealth University School of Pharmacy Richmond, Virginia

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Reviewers

Reviewers The American College of Clinical Pharmacy, and the American Society of Health-System Pharmacists, and the authors would like to thank the following individuals for their review of the Ambulatory Care Pharmacy Preparatory Review and Recertification Course. Jennifer Banks, Pharm.D., BCPS, BCACP, BCGP, BC-ADM, BCMTM, CDCES, CDP, CPh, AE-C Manager, Well Managed Programs WellDyne Lakeland, Florida

Scott Pearson, Pharm.D., BCACP Assistant Professor Department of Clinical Pharmacy Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Aurora, Colorado

Craig J. Beavers, Pharm.D., FCCP, FACC, FAHA, BCCP, BCPS-AQ Cardiology, CACP Director of Cardiovascular Services Baptist Health Paducah Nashville, Tennessee

Ann M. Philbrick, Pharm.D., FCCP, BCPS, BCACP Associate Professor Department of Pharmaceutical Care and Health Systems Department of Family Medicine and Community Health University of Minnesota Minneapolis, Minnesota VA Northeast Ohio Healthcare System Cleveland, Ohio

Wiyanna K. Bruck, Pharm.D., BCIDP Assistant Professor of Pharmacy Practice South College; Clinical Pharmacy Specialist Parkwest Medical Center South College School of Pharmacy Knoxville, Tennessee

Melanie K. Proffitt, Pharm.D., MHA, BCACP, BCMTMS Manager of Outpatient Pharmacy Operations Methodist Dallas Medical Center Dallas, Texas

Ashley N. Crowl, Pharm.D., BCACP Clinical Associate Professor University of Kansas School of Pharmacy Lawrence, Kansas

Shelly L. Rutledge, Pharm.D., BCACP, INHC Senior Clinical Pharmacy Specialist – Managed Care Providence Health Plan Beaverton, Oregon

Frank A. Fanizza, Pharm.D., BCACP, AAHIVP Ambulatory Care Clinical Pharmacist LMH Health Lawrence, Kansas

Lindsay M. Saum, Pharm.D., BCPS, BCGP Associate Professor of Pharmacy Practice Butler University College of Pharmacy and Health Sciences; Clinical Pharmacy Specialist Ascension - St. Vincent Hospital Indianapolis, Indiana

Melissa Lipari, Pharm.D., BCACP Associate Professor Wayne State University Eugene Applebaum College of Pharmacy and Health Sciences; Clinical Pharmacy Specialist – Ambulatory Care Ascension St. John Detroit, Michigan

Kyle V. Sheffer, Pharm.D., BCACP Clinical Pharmacist CDR – United States Public Health Service Santa Fe, New Mexico

Sarah A. McGill, Pharm.D., BCACP Clinical Pharmacist Rapid City, South Dakota

Andrew J. Sowles, Pharm.D., BCPS, BCACP, BC-ADM Clinical Pharmacist CDR – United States Public Health Service Santa Fe, New Mexico

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Table of Contents Sonal A. Taylor, Pharm.D., BCACP Manager Ambulatory Care Clinical Pharmacy Services Salem Health Hospitals and Clinics Salem, Oregon Kris Denzel T. Tupas, Pharm.D., BCPS, BCACP Assistant Professor of Clinical Sciences Roosevelt University of Clinical Sciences; Clinical Pharmacist Advocate Medical Group Sykes Outpatient Center Chicago, Illinois Hilary Weismantel, Pharm.D., BCACP Clinical Integration Pharmacist St. Luke’s University Health Network Bethlehem, Pennsylvania Susan R. Winkler, Pharm.D., FCCP, BCPS Professor and Chair Department of Pharmacy Practice Midwestern University Chicago College of Pharmacy Downers Grove, Illinois In addition to the reviewers above, all chapters were reviewed by one or more of ACCP/ASHP’s Course Content Matter Experts.

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Table of Contents

TABLE OF CONTENTS Trial Design and Biostatistics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Types of Studies; Case Reports/Case Series; Cross-Sectional Study Design; Case-Control Study; Randomized Controlled Trials; Noninferiority Trial Analysis; Systematic Review; Meta-Analysis; Reporting Guidelines for Clinical Studies;Pharmacoeconomic Studies; Sensitivity, Specificity, Predictive Value; Levels of Measure; Types of Statistics; Population Distributions; Confidence Intervals; Hypothesis Testing; Decision Errors; Parametric Tests; Nonparametric Tests; Correlation; Regression; Survival Analysis

Endocrine Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Obesity; Thyroid Disease; Polycystic Ovary Syndrome; Pituitary Disease; Adrenal Disease; Male Hypogonadism

Cardiology I. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Primary Prevention; Hypertension: Hyperlipidemia; Myocardial Infarction; Stroke/TIA; Peripheral Arterial Disease

Cardiology II. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

Cardiovascular Disease; Venous Thromboembolism, Atrial Fibrillation; Heart Failure, Ventricular Tachycardia, Pulmonary Hypertension

Bone/Joint and Rheumatology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

Osteoporosis; Rheumatoid Arthritis; Psoriatic Arthritis; Osteoarthritis; Fibromyalgia; Systemic Lupus Erythematosus; Gout and Hyperuricemia

Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

Classification; Diagnosis; Screening; Prediabetes; Diabetes Pathophysiology; Treatment; Point-of-Care Testing; NewDrug Treatment Requirements; Prevention and Management of Diabetes Complications; Diabetes Credentialing

Obstetrics and Gynecology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425

Contraception; Infertility; Pregnancy and Lactation; Menstrual Disorders; Endometriosis; Menopausal Symptoms; Women’s Health Resources

Pulmonary Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497

Asthma; Chronic Obstructive Pulmonary Disease; Smoking Cessation; Public Health Issues; Practice Management Issues; Patient Advocacy

Practices and Processes of Care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563

Pharmacist Scope of Practice; Clinical Pharmacy Practice Models; Medication Therapy Management; Comprehensive Medication Management; Collaborative Drug Therapy Management; Credentialing and Privileging; Pharmacists’ Patient Care Process; Immunizations; Federal Drug Administration and Other Medication Safety Organizations; Medication Safety; Medication Reconciliation; Transitions of Care; Pharmacy and Therapeutics Committees; Formulary Management; Medicare Part D; Patient Assistance; Regulatory Requirements for Point-of-Care Testing

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Table of Contents

Communication Strategies in Pharmacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615

Communicating Verbally with Patients and Caregivers, Selecting Written Patient Education Materials; Alternative Methods of Communicating with Patients; Communicating with Other Health Care Professionals; Documenting in the Medical Record; Opportunities for Patient Advocacy Outside the Health Care System

Developing and Managing a Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659

Identifying the Need for Ambulatory Care Services; Preparing Service Proposals; Creating a Service Model; Timeline for Establishing a Practice; Ongoing Management; Maintaining an Effective Team; Measuring Program Quality; Ensuring Continued Staff Competency; Reimbursement for Pharmacy Services in Ambulatory Care; Billing; Sustaining Your Practice for the Future

Psychiatric Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735

Anxiety Disorders; Sleep Disorders; Major Depression; Bipolar Disorder; Schizophrenia; Attention-Deficit/Hyperactivity Disorder; Substance Use Disorders

Neurology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819

Epilepsy Clinical Presentation; Known Causes of Seizures; Epilepsy Prognosis and Treatment; Patient Education and Special Populations; Types of Headache; Cluster Headache; Tension Headache; Migraine; Multiple Sclerosis Clinical Presentation and Course of Illness; Approach to Treatment; Neuropathy; Parkinson Disease; Dementia; Myasthenia Gravis; Tremors

Gastrointestinal Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 933

Gastroesophageal Reflux Disease; Peptic Ulcer Disease; Complications of Chronic Liver Disease; Viral Hepatitis; Malabsorption Syndrome; Diarrhea; Constipation; Nausea and Vomiting; Irritable Bowel Syndrome; Inflammatory Bowel Disease

Infectious Diseases I. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015 Sexually Transmitted Diseases; HIV; Non-HIV Viral Infections; Fungal Infections

Infectious Diseases II. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1071

Urinary Tract Infections; Community-Acquired Pneumonia; Tuberculosis; Upper Respiratory Tract Infections; Conjunctivitis/Ophthalmic Infections; Uncomplicated Skin and Soft Tissue Infections; Tickborne Infections/Lyme Disease; Infective Endocarditis; Infectious Diarrhea/Gastrointestinal Infections; Clostridium difficile; Central Nervous System Infections; Bone and Joint Infections; Antimicrobial Stewardship

Nephrology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111

Kidney Function; Classification of Kidney Failure; Diabetes Treatment in Chronic Kidney Disease; Hypertension Treatment in CKD; Nutritional Considerations; Anemia Management; Metabolic Bone Disease; Pharmacokinetic Changes in Kidney Disease; RRT; Kidney Stones

Dermatologic and Eyes, Ears, Nose, and Throat, and Immunologic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1151

Macular Degeneration; Glaucoma; Dry Eyes; Vertigo; Allergic Rhinitis; Psoriasis; Urticaria; Angioedema; Acne; Psoriasis; Infestations; Minor Burns; Decubitus Ulcers

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course xiii

Genitourinary, Electrolytes, and Nutritional Deficiencies/ Supplementation in Older Adults. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221

Benign Prostatic Hyperplasia; Urinary Incontinence; Erectile Dysfunction; Electrolyte Abnormalities; Nutritional Deficiencies and Nutritional Supplementation

Additional Resources Oncology Supportive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1269

Antiemetics; Pain Management; Treatment of Febrile Neutropenia; Use of CSFs for prevention of Febrile Neutropenia; Thrombocytopenia; Anemia and Fatigue; Chemoprotectants; Oncology Emergencies; Miscellaneous Antineoplastic Pharmacotherapy

American College of Clinical Pharmacy and American Society of Health-System Pharmacists Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Trial Design and Biostatistics Katie J. Suda, Pharm.D., M.S., FCCP University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Trial Design and Biostatistics

Trial Design and Biostatistics Katie J. Suda, Pharm.D., M.S., FCCP University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 3

Trial Design and Biostatistics

Learning Objectives 1. Describe hypothesis testing and state the meaning of and distinguish between p values, confidence intervals, and measures of central tendency and data spread. 2. Define, compare, and contrast the concepts of internal and external validity, causation, association, bias, and confounding in trial design. Select strategies to eliminate or control for bias and improve internal and external validity. 3. Compare and contrast the advantages and disadvantages of various study designs (e.g., prospective, retrospective, case-control, cohort, cross-sectional, randomized controlled clinical trials, systematic review, and meta-analysis). 4. Determine why a statistical test is appropriate or not appropriate, given the sample distribution, data type, and study design. Interpret statistical and clinical significance for results from commonly used statistical tests. 5. Define and evaluate odds ratio, risk/incidence rate, relative risk, number needed to treat, number needed to harm, and other risk estimates.

Abbreviations in This Chapter ANCOVA ANOVA CDI CI GOLD HCV HR NNT OR PPI QI RCT RR SD SEM

• Outliers: Extremely low or extremely high numbers in the data set • Population: Particular group that you would like to use to generalize your study results (e.g., all patients with diabetes; all patients with communityacquired pneumonia; all U.S. residents) • Prospective: Begins in the present and progresses forward; involves collecting data from patients or subjects whose outcomes lie in the future • Randomization: Each subject has an equal chance of being assigned to one of the study groups; tries to balance observed and unobserved variables • Retrospective: Begins and ends in the past; involves collecting information about events that occurred in the past • Sample: Subset of individuals from the population; the sample should have similar characteristics as the population of interest; usually, a random sample is considered optimal • Subjects: Individuals participating in the study • Statistically significant result: Result that is unlikely to have occurred by chance based on a preset probability of what is statistically significant (e.g., p < 0.05) • Variable: Any characteristic or numerical value that can be measured (e.g., a count [pain score], measurement [age], or category [sex])

Analysis of covariance Analysis of variance Clostridium difficile infection Confidence interval Global Initiative for Chronic Obstructive Lung Disease Hepatitis C virus Hazard ratio Number needed to treat Odds ratio Proton pump inhibitor Quality improvement Randomized controlled clinical trial Relative risk Standard deviation Standard error of the mean

Basic Terminology • 2×2 (or two by two) table: Organizes subjects (or observations) into groups based on the exposure and the resultant outcomes for two categorical variables (e.g., previous antibiotic exposure [yes or no] and C. difficile infection [yes or no]) • Model: General name for a function that you can use to describe what outcome will occur depending on given information about one or more related variables

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Trial Design and Biostatistics

Self-Assessment Questions Answers and explanations to these questions can be found at the end of this chapter.

Questions 4 and 5 pertain to the following case: A retrospective case-control study was conducted to assess peripheral neuropathy in patients taking fluoroquinolone antibiotics. Risk factors for neuropathy were not assessed (however, both the cases and the controls of this study had identical diagnostic evaluations and were stratified according to the duration of quinolone use before the onset of neuropathy).

1. A quality improvement (QI) initiative is implemented to decrease falls in patients recently discharged from the hospital. As the pharmacist champion at a pharmacy benefit manager (PBM), you have worked with the formulary team to ensure that medications with a high risk of falls have criteria for use. Which factor will be most important in showing the effectiveness of this QI initiative?

4. Which type of bias is this study design most susceptible to? A. B. C. D.

A. Obtaining informed consent for participation in the QI initiative. B. Identifying patients at risk for falls. C. Creating a community advertising campaign to bring awareness to the initiative. D. Determining the social value of the QI initiative.

5. Which factor will be most affected by the type of bias likely to occur in this study? A. B. C. D.

2. A study seeks to determine the impact of adverse drug events on patient outcomes in FDA-approved drugs. Which would be the best approach to conducting this study?

External validity Internal validity Assessment of exposure Number of patients needed for the study

6. When describing the results of an RCT, the investigators report using an intention-to-treat analysis to analyze their data. The results of their investigation comparing two antivirals for influenza-like illness show no difference in the number of hospitalizations for influenza between the treatment groups. Given their method of data analysis, which statement is most appropriate?

A. A randomized controlled clinical trial (RCT) with a test for continuous variables to determine the difference in outcomes. B. A retrospective case-control study with a test for proportions to determine the difference in outcomes. C. A prospective observational study with survival analysis to determine the difference between cohorts. D. A retrospective cohort study with a test for proportions to determine the difference in outcomes.

A. May be susceptible to issues regarding recall bias. B. Provides a good measure of effectiveness under typical clinical conditions. C. Cannot estimate the method’s effectiveness. D. May overestimate the actual treatment effect.

3. A case-control study is conducted to determine whether proton pump inhibitor (PPI) use is associated with an increased risk of developing C. difficile infection (CDI). The final analysis shows the odds ratio (OR) for CDI with PPI exposure to be 1.3 (95% confidence interval [CI], 0.8–1.5). Which best describes the results? A. B. C. D.

Confounding by indication Recall bias Diagnostic bias Misclassification

PPI exposure increases the risk of CDI by 130%. PPI exposure reduces the risk of CDI by 20%. PPI exposure increases the risk of CDI by 30%. PPI exposure is not associated with an increased risk of CDI.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 5

Trial Design and Biostatistics

A. B. C. D.

Questions 7 and 8 pertain to the following case: A prospective randomized study compared furosemide with hydrochlorothiazide when treating patients with newly diagnosed hypertension. One of the study’s end points was myocardial infarction one year after treatment initiation. The following table summarizes myocardial infarction rates in all patients.

All patients, n (%)

Furosemide 17/332 (5.1)

10. You are evaluating a randomized, double-blind, parallel group-controlled trial that compares four different antihypertensive regimens for their effect on systolic blood pressure in patients with refractory hypertension:

Hydrochlorothiazide

• Regimen 1: hydrochlorothiazide/diltiazem/ metoprolol • Regimen 2: furosemide/diltiazem/metoprolol • Regimen 3: diltiazem/metoprolol/enalapril • Regimen 4: hydrochlorothiazide/metoprolol/ enalapril

21/274 (7.7)

7. The 95% CI for the difference in myocardial infarction rates between the two groups was −3.2% to 10.3%. Which conclusion is most appropriate?

A. Furosemide is superior to hydrochlorothiazide. B. Superiority of furosemide could not be established over hydrochlorothiazide. C. Hydrochlorothiazide is not inferior to furosemide. D. No conclusion can be drawn because p values are unavailable.

The authors conclude that regimen 1 is better than regimen 2 (p 5 half-lives) so that the effects of the first treatment do not persist during the second treatment. Use of multiple crossover periods helps overcome the obstacle in the variability of exacerbations and periods of remission. Not appropriate for certain types of treatment questions (e.g., effect of treatment on a disease that worsens quickly over time or worsens during the study period). Example: Treatment of genital herpes outbreaks in patients not taking antivirals for suppression therapy Active

END Placebo

Figure 7. RCT: Parallel design. ACTIVE Group 1 (gray dashes) starts with the active arm PLACEBO

PLACEBO

WASHOUT

After a washout period, Group 1 ends with placebo ACTIVE Group 2 ends with the active arm

Group 2 (gray dots) starts with the placebo arm

Figure 8. RCT: Crossover design.

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Trial Design and Biostatistics

J. Factorial-Design RCTs: Tests two or more treatments compared with controls in one study; treatments can be for different diseases. Factorial-designed studies are informative and efficient but are also very complex, and there can be difficulty with subject adherence and polypharmacy. The analysis also must account for potential statistical interactions between treatments. An interaction means that the outcome differs depending on the presence or absence of another variable. This variable can be a disease or another intervention. An outcome is more likely to occur when the two variables are expected to have related mechanisms of action. For example, patients with cardiovascular disease and diabetes are more likely to have a myocardial infarction (vs.patients with cardiovascular disease alone). K. Advantages and Disadvantages 1. Determines a causal relationship; provides a direct measure of risk; controls for selection bias and confounding; blinding; detailed information on subjects; may allow for subgroup analyses 2. Expensive; time-consuming; can be complex and difficult to conduct; adherence to study protocol can be poor; incomplete follow-up of study subjects; guidelines/practice may have changed since the initiation of the trial; subjects may differ from the population of interest (external validity)

VIII.  ADDITIONAL TRIAL DESIGN CONSIDERATIONS A. Subgroup Analysis 1. Important part of controlled clinical trials (if set a priori) because they can evaluate the applicability of the study results across patient subgroups 2. Can be listed in the primary or secondary study objectives or just included in the results section 3. Subgroup analyses are less reliable than analyses that are based on all study subjects when not planned a priori. Thus, post hoc subgroup analyses are commonly overused and over-interpreted, leading to misinterpretation of results. 4. Issues with subgroup analyses: a. Failure to consider several comparisons or to adjust p values b. Problems with subgroup sample size (power), multiple comparisons, and classification and lack of assessment of interactions B. Composite End Points 1. Combines several end points into a single analysis 2. Use of composite end points is often criticized. 3. Advantages a. No single primary outcome b. Alleviates issues with multiple comparisons c. Increases the number of events, which decreases sample size and study time and cost 4. Disadvantages a. There may be difficulties in interpreting composite end points, especially when combining subjective (e.g., symptoms) and objective (e.g., death) outcomes. b. Impact of individual end points when combined i. Only one of the end points in the composite end point may have a significant result. ii. “Averaging” of overall effect (if individual end points move in different directions) iii. The results for each individual end point should be reported separately so that the results from the composite end point can be put in context.

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Trial Design and Biostatistics

C. Stopping a Clinical Trial Early After an Interim Analysis 1. There are several examples of clinical trials being stopped early because of benefit, harm, or lack of benefit. 2. Trials that are stopped early should have an independent data safety monitoring board, independent analysis of the interim study results, and predefined stringent boundaries for discontinuing the study. The investigators should put the results in the context of the literature and safety of the study subject while safeguarding public health to premature efficacy claims. D. Surrogate End Points 1. An outcome measure used as a substitute for a clinically meaningful outcome (i.e., cholesterol and cardiovascular disease) but does not always predict clinical outcomes 2. Using surrogate end points decreases the sample size and study duration but may not be large enough to detect uncommon adverse events. E. Nonrandomized Controlled Trials 1. Subjects are assigned to two or more groups nonrandomly. Thus, the baseline characteristics are likely not comparable between groups at baseline. 2. Advantages: Low cost; simplicity; can consider subject preference in treatment selection 3. Disadvantages: Groups may not be comparable, bias 4. Not a substitute for RCT that determines whether one intervention is truly better than another 5. Use of historical controls: A contemporary case group is compared with a control group from a previous population (obtained from the literature, data sets from previous studies, or search of health records). This nonrandomized study design may be useful when diagnosis and prognosis are well understood. a. Advantages: All current subjects can receive the treatment; conducting the study takes less time at a decreased cost. b. Disadvantages: Bias; timeliness of the control group; consistency of data collection c. Example: The initial study examining the efficacy of penicillin in patients with pneumonia. There were no other antibiotics available for the treatment of pneumonia. However, diagnosing pneumonia was established, and mortality without antibiotics was understood. F. Superiority vs. Equivalence vs. Noninferiority 1. A superiority trial is designed to detect a difference between experimental treatments. This is the typical design in a clinical trial. 2. An equivalence trial is designed to confirm the absence of a meaningful difference between treatments, neither better nor worse (both directions). The key is the definition of the specified margin. What difference is important? One example is a bioequivalence trial. 3. A noninferiority trial is designed to investigate whether a treatment is not clinically worse (not less effective than stated margin, or inferior) than an existing treatment.

IX.  NONINFERIORITY TRIAL ANALYSIS A. The traditional approach to RCTs seeks to establish novel treatment as superior to the established standard. Noninferiority trials seek to answer whether a competing treatment is no worse (or noninferior) than an active control (usually the established standard therapy). 1. Only shows noninferiority, but in reality, the intervention may be the most effective or it may have a similar effect.

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Trial Design and Biostatistics

2. Useful when placebo administration is not possible for ethical reasons 3. Important for pharmacists to understand this study design because it is increasingly being used in pharmacotherapy studies (Pharmacotherapy 2011;31:833-9) B. Noninferiority studies seek to determine similar efficacy while improving safety or reducing treatment burden (e.g., costs, inconvenience, labor). Should use equivalent drug doses, clinical conditions, and design. C. Adequate power is essential; larger sample sizes are usually required. D. Analytic Approach to a Noninferiority Trial 1. First step is to determine the marginal difference; determine an acceptable threshold for noninferiority. 2. What are the maximum allowable negative outcome events acceptable when comparing the treatment with standard therapy (the maximum increase in risk that you are willing to accept for a trade off in reducing treatment burden)? 3. The U.S. Food and Drug Administration (FDA) provides guidance for noninferiority thresholds as follows: a. Establish the smallest plausible benefit of the existing standard therapy. b. Insist on some preservation of the treatment effect of the standard therapy. The FDA recommends that 50% of the standard treatment effect be preserved when evaluating mortality for thrombolytic trials and 30% of the treatment effect for urinary tract infection trials. E. Examples of Threats to Meaningful Comparisons to Establishing Noninferiority: 1. Effect of standard treatment was not preserved; suboptimal standard treatment administered. Example: Heparin infusion does not achieve therapeutic anticoagulation. 2. Intention-to-treat analysis (defined in the text that follows): Suboptimal administration of the standard treatment results in a large proportion of undertreated patients for comparison. F. Interpreting the Results of a Noninferiority Trial 1. Look for an acceptable difference between groups that can be plausibly described as “noninferior.” 2. Event rate can be established by existing literature and clinical practice.

X.  COMMON APPROACHES TO ANALYZING CLINICAL TRIALS A. Intention-to-Treat Analysis 1. Compares outcomes on the basis of initial group assignment or “as randomized.” The allocation to groups was how they were “intended to be treated,” even though they may not have taken the medication for the study duration, may have dropped out, and may not have adhered to the protocol. 2. Determines effect of treatment under usual conditions of use; analogous to routine clinical practice in which a patient receives a prescription but may not adhere to the prescribed drug regimen 3. Gives a conservative estimate of differences in treatments; may underestimate treatment benefits 4. Most common approach to assessing clinical trial results 5. This is the preferred type of analysis in a superiority trial. B. Per-Protocol Analysis 1. Subjects who do not adhere to allocated treatment are not included in the final analysis; only those who completed the trial and adhered to the protocol (based on some predetermined definition [e.g., 80% adherence])

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Trial Design and Biostatistics

2. Provides additional information about treatment efficacy and provides more generous estimates of differences between treatments 3. Subject to several issues because of factors such as lower sample size and definitions of adherence. Results are more difficult to interpret and would be validly applied only to adherent patients like those in the trial; not necessarily generalizable to all patients C. As-Treated Analysis 1. Subjects are analyzed by the actual intervention received. If subjects were in the active treatment group but did not take active treatment, the data would be analyzed as if they were in the placebo group. 2. This analysis essentially ignores/destroys the randomization process for those who did not adhere to the study design. Results should be interpreted with caution.

XI.  SYSTEMATIC REVIEWS/META-ANALYSES A. The number of these papers has dramatically increased. B. Systematic Review 1. Summary that uses explicit methods to perform a comprehensive literature search, critically appraise it, and synthesize the literature on a specific topic 2. Differs from a standard literature review (or a narrative review): The study results of a systematic review are more comprehensively synthesized and reviewed. 3. Systematic reviews provide detailed methods, including search terms to identify studies for inclusion, criteria for inclusion, and an objective, reproducible evaluation of the literature (narrative reviews typically consist of an evaluation of a select portion of the literature combined with opinion). 4. Some systematic reviews will try to statistically combine results from many studies. C. Meta-Analysis 1. Systematic review that uses statistical analyses to pool the results from many trials so that the aggregate findings may have greater statistical power and more certainty a. Typically includes results from RCT, but may be appropriate to include results from observational studies b. Example: In a meta-analysis of the impact of influenza antivirals on hospitalization using only RCTs, no difference was identified. The RCTs were conducted in patients who had influenza but were otherwise healthy. However, when RCTs were combined with observational studies, decreased hospitalizations occurred in the group that received influenza antivirals. This difference was secondary to the RCT inclusion criteria of younger, healthier patients (see https://www.cdc.gov/media/haveyouheard/stories/ Influenza_antiviral.html). 2. Increases the certainty of results in rare diseases, when there is variation in results between studies, and when several studies are available that had a small sample size. This may improve the calculation of effect size, increase the statistical power, assist in interpretation of disparate results, and reduce bias. 3. Issues with meta-analyses: a. Quality of original study design b. Quality of literature search to identify studies for inclusion c. Study heterogeneity i. Differences in inclusion/exclusion criteria among the individual studies ii. Differences in treatment dosages, control used (placebo vs. standard of care), and patient demographics between studies ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 23

Trial Design and Biostatistics

d. Restricting studies to those that meet specific criteria for high-quality studies may improve the internal validity of the studies used, but it increases concerns about external validity. e. Publication bias 4. Elements of meta-analysis methodology a. Identification of a well-designed research question b. Criteria for trial inclusion/exclusion c. Identification of available studies (including rigorous search of the literature) d. Data collection/abstraction e. Combine the studies statistically; result is reported as a forest plot f. Quality assessments g. Assessment of homogeneity and heterogeneity h. Example: A paper found an increased risk of death in pediatric patients with febrile neutropenia who received cefepime, compared with other β-lactams. However, the cause of the increased mortality was unclear. In a meta-analysis, cefepime was not shown to have increased adverse events or deaths in pediatric patients. In the forest plot, the aggregated result for each group is identified by a large black diamond. The black diamond overlaps the vertical line at 1 (indicating no difference). If the black diamond is to the left of 1, this indicates favoring cefepime. If the black diamond is to the right of 1, this indicates favoring the comparator. The forest plot is located in J Pediatr 2010;157:490-5, 495.e1.

XII.  SUMMARY MEASURES OF EFFECT A. Measures of Risk 1. Absolute risk: Probability of an event occurring (5 in 100 experience an adverse event = 5% absolute risk) 2. Absolute risk reduction (ARR): Absolute difference in rates of outcomes between the case and control groups; provides an overall estimate of the change in risk. ARR = absolute risk in controls – minus absolute risk in cases. 3. Number needed to treat (NNT) a. NNT is another method to calculate differences in absolute risk. b. Number of patients that would need to be treated to prevent/cause one outcome c. Helps to understand the magnitude of the impact of the study treatment (based on the study results). NNT can be calculated with statistically significant categorical outcomes (e.g., alive/dead). d. NNT = 1/ARR (round to the next highest whole number). e. A low number signifies an effective treatment; a high number indicates a less effective therapy. f. Caution: Assumes the baseline risk is the same for all patients (or that it is unrelated to RR) B. Number Needed to Harm (NNH) 1. Quantifies the associated harm after exposure to a treatment 2. NNH = 1/attributable risk (AR). a. AR: Difference in incidence between the exposed group and the nonexposed group (AR = risk in the exposed group minus risk in the unexposed group) b. For NNH, a low number signifies a harmful treatment; a high number indicates a safer d r u g.

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Trial Design and Biostatistics

XIII.  REPORTING GUIDELINES FOR CLINICAL STUDIES A. Consolidated Standards of Reporting Trials (CONSORT) 1. Created in an effort to improve, standardize, and increase the transparency of the reporting of clinical trials and to facilitate the improvement of literature evaluation 2. Available at www.consort-statement.org B. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement 1. A guide to the conduct and dissemination of observational studies 2. Available at www.strobe-statement.org C. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 1. Evidence-based minimum set of items for reporting systematic reviews and meta-analyses 2. Available at www.prisma-statement.org D. Enhancing the Quality and Transparency of Health Research (EQUATOR) Network 1. International initiative that seeks to improve the reliability and value of health research literature by promoting transparent and accurate reporting and wider use of robust reporting guidelines 2. Does not have its own statements but promotes the use of key reporting guidelines and suggests which guideline to use for which type of study design 3. Available at www.equator-network.org

XIV.  PHARMACOECONOMIC STUDIES A. Cost-Minimization Analysis 1. Differences in cost among comparable therapies are evaluated. 2. Only useful to compare therapies that have similar outcomes B. Cost-Effectiveness Analysis 1. Outcome: Clinical units or cost per unit health outcome (outcome examples: years of life saved, number of symptom-free days) 2. Useful to measure the cost impact when health outcomes are improved C. Cost-Utility Analysis 1. Assigns utility weights to outcomes so that the impact can be measured in relation to the cost (outcome example: quality-adjusted life-years) 2. Compares outcomes related to mortality when mortality may not be the most important outcome D. Cost-Benefit Analysis 1. Monetary value is placed on both therapy costs and beneficial health outcomes. 2. Allows analysis of both the cost of treatment and the costs saved with beneficial outcomes

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Trial Design and Biostatistics

XV.  SENSITIVITY/SPECIFICITY/PREDICTIVE VALUES A. Sensitivity: Proportion of true positives that are correctly identified by a test; a test with a high sensitivity means that a negative test can rule out the disorder (the test is reliable to detect disease when it is actually present). A test with a low percentage of false-negative results is said to have high sensitivity (see Table 4). B. Specificity: Proportion of true negatives that are correctly identified by a test; a test with high specificity means that a positive test can rule in the disorder (the test is reliable to detect no disease when it is not present). A test with a low percentage of false-positive results is said to have high specificity (See Table 4). C. An optimal test is highly sensitive and highly specific. D. Positive Predictive Value (PPV): Proportion of patients who actually have the disease when the test is positive (See Table 4) E. Negative Predictive Value (NPV): Proportion of patients who actually do not have the disease when the test is negative (See Table 4) Table 4. Relationship Between Test and Correct Diagnosis Identified by Disease Disease

Test

Disease Present

Disease Absent

Total

True negative (TN)

TN + FN

Test positive

True positive (TP)

False positive (FP)

Total

TP + FN

FP + TN

Test negative 1. 2. 3. 4. 5. 6.

False negative (FN)

TP + FP Total

Sensitivity = TP/(TP + FN) Specificity = TN/(TN + FP) PPV = TP/(TP + FP) NPV = TN/(TN + FN) Positive likelihood ratio = sensitivity/(1 minus specificity) Negative likelihood ratio = (1 minus sensitivity)/specificity

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Trial Design and Biostatistics

PART 2 – BIOSTATISTICS

I.  INTRODUCTION TO STATISTICS A. Method for Collecting, Classifying, Summarizing, and Analyzing Data B. Statistics describe or make inferences about a population from a smaller sample of that population. C. Examples of Online Statistical and Study Design Tools 1. www.graphpad.com/quickcalcs/ 2. http://statpages.info 3. https://www.cdc.gov/epiinfo/index.html 4. Note that you can get slightly different results with these packages compared with more robust statistical analysis software (e.g., SAS, STATA). 5. Think of these programs as tools. If results obtained from poorly designed studies are analyzed, p values will still be derived, but they will not allow for correct application to the population of interest. In addition, statistical software does not tell you if you are using the correct test or the clinical significance of the result. D. Levels of Measure (a.k.a. Types of Data) 1. Continuous: Data can take on any value within a given range. For example, data that can be put in chronological order (e.g., 7.0, 7.1, 7.2, 7.3). a. Interval: Data are ranked in a specific order with a consistent change in magnitude between units; the zero point is arbitrary (e.g., 0 °F does not mean “no heat”). b. Ratio: Like “interval” but with an absolute zero; when the variable equals 0, there is none of that variable (e.g., heart rate, blood pressure, time, distance); you can calculate the ratio of two measurements with ratio variables 2. Nominal data a. Categories or groups for data without a rank (e.g., race, sex, presence/absence of a disease) b. Classified into groups in an unordered manner and with no indication of relative severity (e.g., male sex or female sex) c. Also called binary variables and dichotomous variables if two categories are studied 3. Ordinal data a. Groups represented by scale, rank, or natural order b. Ranked in a specific order but with no consistent level of magnitude of difference between ranks (e.g., Likert scales typically used in surveys, pain score) c. Central tendency expressed as median and quartiles; in most cases, means and standard deviations (SDs) should not be reported with ordinal data 4. Nominal and ordinal data are collectively called categorical data.

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II.  TYPES OF STATISTICS A. Descriptive Statistics: Used to summarize and describe data that are collected or generated in research studies. This is done both visually and numerically. 1. Visual methods of describing data a. Frequency distribution: Counts of the number of participants with that variable of interest; can be shown in a table or a histogram b. Histogram: Graph showing the shape of the data i. Symmetric: Bell-shaped curve, normal distribution (parametric) ii. Skewed to either side: Nonparametric, if the tail of the graph (shorter bars) is on the left side of the graph, this is referred to as “skewed to the left” or “skewed left” (negative skew) c. Scatterplot: Graph showing the possible association of two variables (or correlation) i. Positive slope (“uphill”): Positive linear relationship (as one variable increases, the other variable increases) ii. Negative slope (“downhill”): Negative linear relationship (as one variable increases, the other variable decreases) iii. Scatterplots are important for correlation and regression when a line is best fit to the study data points. d. Boxplot: Graph showing the minimum value, 25th percentile, 50th percentile (median), 75th percentile, and maximum value i. Can indicate whether the data have a normal distribution (median is in the middle of the box) ii. Skewed data: Nonparametric, the median cuts the box into two unequal pieces; if the longer part of the box is to the right for a horizontal boxplot (or above for a vertical boxplot), the data are “skewed to the right” or “skewed right” 2. Measures of central tendency a. Arithmetic mean (i.e., average) i. Sum of all values divided by the total number of values ii. Should generally be used only for continuous and normally distributed data (parametric data) iii. Very sensitive to outliers and tend toward the tail, which has the outliers iv. Most commonly used and most understood measure of central tendency v. Geometric mean: Product of n numbers (as opposed to arithmetic mean, which uses their sum), take the nth root of the product; minimizes the effect of extreme values in a nonparametric distribution vi. Population mean: Mean of the entire population vii. Sample mean: Mean of the sample (the mean you derived in your study population) b. SD (see additional discussion that follows under Measures of Data Spread and Variability) i. Used for continuous, parametric data ii. Describes variability (or spread) around the mean iii. General rule: If the SD is larger than the mean, report the median (alone or in addition to the mean). c. Median i. Midpoint of the values in the study data set when placed in order from highest to lowest. Half of the observations are above and half are below. When there is an even number of observations, it is the mean of the two middle values. ii. Also called the 50th percentile iii. Can be used for ordinal or continuous data (especially good for nonparametric skewed populations) iv. Insensitive to outliers d. Mode i. Value occurring most often in a distribution ii. Can be used for nominal, ordinal, or continuous data

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Trial Design and Biostatistics

iii. Sometimes, there may be more than one mode in a data set (e.g., bimodal, trimodal). iv. Does not help describe meaningful distributions with a large range of values, each of which occurs infrequently 3. Measures of data spread and variability a. SD i. Measure of the variability (or spread) around the mean; most common measure used to describe data spread ii. Affected by outliers iii. Square root of the variance (average squared difference of each observation from the mean); returns variance back to original units (non-squared) iv. A small SD indicates that the study values in the data set are relatively close to the mean; a large SD expresses values farther from the mean, indicating higher variability in the data set. In reality, high variability may be expected: Consider the salaries for all health care professionals (high variability) compared with those of ambulatory care pharmacists (smaller variability). v. Appropriately applied only to continuous data that are normally or near-normally distributed or that can be transformed to be normally distributed b. Range: Describes spread of data, minimum to maximum values i. Difference between the smallest and largest values in a data set does not give a tremendous amount of information by itself. ii. Easy to compute (simple subtraction) iii. Size of range is very sensitive to outliers. iv. In the health sciences, range is often reported as the actual values rather than the difference between the two extreme values. v. By the empiric rule for normal distributions, 68% of the sample values are found within ± 1 SD, 95% are found within ± 2 SD, and 99% are found within ± 3 SD. c. Percentiles i. Point (value) in a distribution in which a value is larger than some percentage of the other values in the sample; can be calculated by ranking all data in a data set ii. The 75th percentile lies at a point at which 75% of the other values are smaller. iii. Does not assume the population has a normal distribution (or any other distribution) (a) Interquartile range: Describes the values of the 25th–75th percentiles and is not affected by outliers (b) Median represents the 50th percentile (because the median is in the middle of the data set). (c) Example: Your NAPLEX score was 90%. This indicates that 90% of the other people who took the test scored lower than you did and that 10% scored higher than you did. 4. Presenting data using only measures of central tendency can be misleading without some idea of data spread. Studies that report only medians or means without their accompanying measures of data spread should be closely scrutinized. B. Inferential Statistics 1. Conclusions or generalizations made about a population (large group) from the study of a sample of that population 2. Choosing and evaluating statistical methods depend, in part, on the type of data used. 3. An educated statement about an unknown population is commonly called an inference in statistics. 4. Statistical inference can be made by estimation or hypothesis testing.

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Trial Design and Biostatistics

III.  POPULATION DISTRIBUTIONS A. Discrete Distributions 1. Binomial distribution: Distribution that has two possible outcomes (dead/alive) 2. Poisson distribution: Distribution of the number of events occurring within a given time interval; typically used when events are rare 3. Hypergeometric distribution: Distribution of two possible outcomes without replacement (binomial allows replacement); commonly used for subpopulations that are over- or under-represented in a sample B. Normal (Gaussian) Distribution 1. Most common model for population distributions 2. Symmetric or bell-shaped frequency distribution 3. When a random variable is measured in a large-enough sample of any population, some values will occur more often than others. 4. A visual check of a distribution can help determine whether it is normally distributed (whether it appears symmetric and bell shaped). Need the data to perform these checks a. Frequency distribution and histograms (visually look at the data; you should do this anyway) b. Median and mean will be about equal for normally distributed data (most practical and easiest to use). c. Can also calculate p values to test for normality such as with the Kolmogorov-Smirnov test (K-S test or KS test), d. More challenging to evaluate this when we do not have access to the data (when we are reading an article) because most articles do not present all data or both the mean and the median. 5. The parameters’ mean and SD define a normally distributed population. 6. Probability: Likelihood that any one event will occur, given all the possible outcomes 7. Estimation and sampling variability a. One method that can be used to make an inference about a population parameter b. Separate samples (even of the same size) from a single population will give slightly different estimates. c. The distribution of means from random samples approximates a normal distribution. i. The mean of this “distribution of means” is equal to the unknown population mean, µ. ii. The SD of the means is estimated by the standard error of the mean (SEM). iii. As in any normal distribution, 95% of the sample means lie within ± 2 SEM of the population mean. d. The distribution of means from these random samples is about normal regardless of the underlying population distribution (central limit theorem). Expect slightly different mean and SD values each time you repeat this experiment. e. The SEM is estimated with a single sample by dividing the SD by the square root of the sample size (n). The SEM quantifies uncertainty in the estimate of the mean, not variability in the sample. Important for hypothesis testing and 95% CI estimation f. Why is all this information about the difference between the SEM and the SD worth knowing? i. Calculation of CIs (95% CI is about equal to the mean ± 2 times the SEM) ii. Hypothesis testing iii. Deception (e.g., misusing SEM instead of SD can make results look less “variable,” especially when used in graphic format)

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Trial Design and Biostatistics

IV.  CONFIDENCE INTERVALS (CI) A. Commonly Reported as a Way to Describe a Point Estimate Within the Study Population 1. In the medical literature, 95% CIs are the most commonly reported CIs. In repeated samples, 95% of all CIs include the true population value (i.e., the likelihood or confidence [or probability] that the population value is contained within the interval). In some cases, 90% or 99% CIs are reported. A CI represents a range of likely values for the population parameter, depending on your sample statistic. 2. CIs offer a more descriptive interpretation of the data. a. Magnitude of difference between groups b. Range of values (possible spread of point estimates). Large CIs indicate great variability in the population being studied. c. A range with a 95% CI has a 0.95 probability of containing the true mean. 3. The differences between the SD, SEM, and CIs should be noted when interpreting the literature because they are often used interchangeably. Although it is common for CIs to be confused with SDs, the information each provides is quite different and must be assessed correctly. B. Estimates derived from categorical data such as risk, risk differences, and risk ratios should always be presented with the CI. C. CIs Instead of Hypothesis Testing 1. Hypothesis testing and calculation of p values tell us (ideally) whether there is a statistically significant difference between groups, but they tell us nothing about the magnitude of the difference. 2. CIs give us an idea of the magnitude of difference between groups and the statistical significance. 3. CIs help us determine the importance of a finding or findings, which we can apply to a situation. 4. CIs are a range of data, together with a point estimate of the difference. 5. Wide CIs a. Many results are possible, either larger or smaller than the point estimate provided by the study. b. All values contained in the CI are statistically plausible. 6. If the estimate is the difference between two continuous variables, a CI that includes zero (no difference between two variables) can be interpreted as not statistically significant (p≥0.05). There is no need to show both the 95% CI and the p value. 7. Interpretation of CIs for ORs and RRs is somewhat different. In that case, a value of 1 indicates no difference in risk (or odds), and if the CI includes 1, there is no statistical difference. (See the discussion of case-control/ cohort in other sections for how to interpret CIs for ORs and RRs.)

V.  HYPOTHESIS TESTING A. Hypothesis testing helps determine whether any observed differences between groups can be explained by chance (there is no difference) or are statistically significant. B. Null and Alternative Hypotheses 1. Null hypothesis (H0): No difference between groups being compared (treatment A equals treatment B). Not rejecting the null hypothesis (or accepting the null hypothesis) means that no difference exists between groups. 2. Alternative hypothesis (HA or H1): e.g., states that there is a difference between groups being compared (treatment A does not equal treatment B) ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 31

Trial Design and Biostatistics

3. Results of the hypothesis testing will indicate whether enough evidence exists for H0 to be rejected. a. If H0 is rejected: Statistically significant difference between groups (unlikely attributable to chance) b. If H0 is not rejected (or fails to reject): No statistically significant difference between groups (any apparent differences may be attributable to chance). Note that we are not concluding that the treatments are equal. c. Types of hypothesis testing. These are situations in which two groups (or more) are being compared. These procedures can be applied to many other examples of situations (Table 5). C. To determine what is sufficient evidence to reject H0, set a priori significance level (α) and generate the decision rule. 1. Developed after the research question has been stated in hypothesis form 2. Used to determine the level of acceptable error caused by a false positive (also known as level of significance, or type I error) a. Convention: The a priori significance level (α) is usually 0.05. b. Critical value is calculated, capturing how extreme the sample data must be to reject H0. D. Perform the experiment and estimate the test statistic - A test statistic is calculated from the observed data in the study, which is compared with the critical value. 1. Depending on this test statistic’s value, H0 is not rejected (often called “fails to reject”) or rejected. 2. In general, the test statistic and critical value are not presented in the literature; instead, probability values (p values) are generally reported and compared with the a priori value to assess statistical significance. P value is the probability of obtaining a test statistic and critical value as extreme as or more extreme than the one actually obtained 3. All hypothesis tests ultimately use a p value to weigh the strength of the evidence: a. A small p value (typically p0.05) indicates weak evidence against the null hypothesis, so you fail to reject it. 4. Because computers are used in these tests, this step is often transparent; the p value estimated in the statistical test is compared with the a priori p value (usually p=0.05), and the decision is made.

VI.  DECISION ERRORS A. Type I Error: The probability of making this error is defined as the significance level (α). 1. Type I error is concluding that there is a difference when there is truly no difference. Thus, the H0 is rejected when, in fact, it is true. 2. Typically, α is set at 0.05 (this is your decisional threshold). The value represents the likelihood that a type I error will be made (i.e., rejecting the H0 when the H0 should not be). An α of 0.05 indicates that, 1 in 20 times, a type I error will occur when the H0 is rejected. Thus, 5% of the time, a researcher will conclude that there is a statistically significant difference when one does not actually exist. 3. The calculated chance that a type I error has occurred is called the p value. 4. The p value tells us the likelihood of obtaining a given test result if the H0 is true. When the level is set a priori, the H0 is rejected when p is less than the value set a priori (usually 0.05). I.e., the p value tells us the probability of being wrong when we conclude that a true difference exists (false positive). 5. A lower p value does not mean the result is more important or more meaningful but only that it is statistically significant and not likely to be attributable to chance.

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Trial Design and Biostatistics

B. Type II Error: The probability of making this error is called beta (β). 1. A type II error concludes that no difference exists when one truly does exist. With hypothesis testing, a type II error is when the H0 is not rejected when there is a difference between groups (i.e., the H1 is true). 2. It has become standard to set β at 0.10–0.20. 3. Typically, the decisional threshold for a type II error is set at 0.20 (this is your β). (1 minus β) equals your power, or the ability to detect a difference if one truly exists. Therefore, 1 minus 0.2 = 0.80, or 80% of cases detect a difference when there is a difference. A study with high power has a small chance for a type II error. a. Power is contingent on sample size, effect size (anticipated size of the difference between groups), anticipated variability for the primary outcome, decisional thresholds set a priori for α and β, and planned study design (e.g., matching) and statistical analyses. b. If β is set at 0.10, power = 1 minus 0.1 = 0.90, or 90% of cases detect a difference when there is a difference. 4. Statistical significance vs. clinical significance a. As stated earlier, the size of the p value is not necessarily related to the clinical importance of the result. Smaller values mean only that chance is less likely to explain observed differences. b. Statistically significant does not necessarily mean clinically significant. c. Lack of statistical significance does not mean that results are not clinically important. d. When considering nonsignificant findings, consider sample size, estimated power, and observed variability. Table 5. Summary of Decision Errors Underlying Truth or Reality

Test Result

H0 is true (no difference)

H0 is false (difference)

Reject H0 (difference)

Type I error (α)

No error (correct decision)

Accept H0 (no difference)

No error (correct decision)

Type II error (β)

H0 = null hypothesis.

VII.  CHOOSING A STATISTICAL TEST A. Statistical tests are generally classified as bivariate or multivariate tests. 1. Bivariate: One predictor variable and one outcome (e.g., t-test) 2. Multivariate: a. Multivariate: Two or more dependent outcomes or variables; usually for longitudinal data for which an outcome is measured for the same individual at multiple time points (repeated measures), modeling of nested/clustered data when multiple individuals are in each cluster b. Multivariable: Multiple variables on the right side of the model equation (response or independent variables) B. Information Needed to Choose the Appropriate Statistical Test 1. Type of data (nominal, ordinal, or continuous) 2. Distribution of data (e.g., normal) 3. Number of groups (e.g., two or more than two) 4. Study design (e.g., case-control, RCT parallel, RCT crossover)

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Trial Design and Biostatistics

5. Presence of confounding variables 6. One-tailed vs. two-tailed (usually two-tailed) a. One-tailed test: Hypothesis mean is on one side of the null hypothesis mean. b. Two-tailed test: Hypothesis mean can be on either side of the null value; more conservative because area of rejection is on both sides 7. Parametric vs. nonparametric tests a. Parametric tests assume the following: i. Data being investigated have an underlying distribution that is normal or close to normal. ii. Data measured are continuous data, measured on either an interval or a ratio scale. iii. Parametric tests assume that the data being investigated have variances that are homogeneous between the groups investigated. This is often called homoscedasticity. iv. Nonparametric tests are used when data are not normally distributed or do not meet other criteria for parametric tests (e.g., discrete data).

VIII.  STATISTICAL TESTS: PARAMETRIC TESTS (see summary tables 7 and 8 at the end of the chapter) A. T-Tests 1. Used for continuous data (e.g., age) 2. Student t-test: Comparison of means between two independent (unpaired) groups a. Also called the independent t-test or the two-sample t-test b. If you used matched pairs, such as in matching cases to controls, your sample is paired, and a Student t-test is not appropriate (see paired t-test in the text that follows). Comparing before and after measurements in the same patient is also considered paired data (“before-and-after studies” or “repeated measures studies”). In these studies, patients serve as their own control (e.g., evaluating blood pressure before and after antihypertensives were initiated). c. Unpaired data are derived from different patients (patients are divided into two or more groups and receive different treatments; outcomes between groups are compared). 3. Paired t-test: Comparison of means between two dependent (paired) groups. For most crossover studies, casecontrol studies in which cases were matched to controls and “before-and-after studies” that have paired data 4. Using multiple t-tests with more than two groups (e.g., group 1 vs. group 2; group 1 vs. group 3) increases type I error (the more comparisons done, the increased likelihood that you will find a significant difference). We call this multiple comparisons (or multiple testing). One simple method to adjust for multiple comparisons is to divide α by the number of tests to “adjust” for the additional comparisons (0.05/number of tests). The adjustment makes it more difficult to find a conclusion that is significant. There are also formal statistical tests to adjust for multiple comparisons. B. Analysis of Variance (ANOVA) 1. Used for continuous data 2. One-way ANOVA: Form of the Student t-test that can apply to more than two independent groups 3. Two-way ANOVA: Extends the one-way ANOVA to include a categorical variable that affects response (e.g., in patients getting the same digoxin dose, assessing the presence or absence of renal dysfunction and digoxin levels) 4. Repeated-measures ANOVA: Form of paired t-test for more than two dependent groups; can also be used when there are multiple measurements over time (e.g., a study that measures HgbA1c every 3 months for 5 years)

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5. A significant p value indicates that at least two means (of three or more groups) are significantly different from each other. To identify which groups are significantly different, see the section below on post hoc tests 6. Post hoc tests are used for ANOVA to determine which groups actually differ from each other (Bonferroni, Fisher LSD [least significant difference], Tukey test). C. Analysis of Covariance (ANCOVA) 1. Compares one variable in two or more groups, considering (or to correct for) the variability of other variables (called “covariates”) 2. Combines one- or two-way ANOVA with linear regression that allows for adjusting for a continuous variable (vs. categorical) 3. Explains the influence of a categorical variable (independent variable) on a continuous variable (dependent variable) while controlling for another continuous variable (that may be confounding variables)

IX.  STATISTICAL TESTS: NONPARAMETRIC TESTS A. Nonparametric tests use ordinal data and continuous data that do not meet the assumptions of parametric tests (e.g., Student t-test). Use parametric tests when assumptions are met because these tests are generally more robust. 1. Tests for independent samples a. Wilcoxon rank sum test, Mann-Whitney U test, or Wilcoxon Mann-Whitney test: Compare two independent samples (related to a Student t-test) b. Kruskal-Wallis test i. Compares three or more independent groups (nonparametric analog to one-way ANOVA) ii. Post hoc testing is usually done with the Wilcoxon rank sum test to determine which population is different (similar to ANOVA described earlier). 2. Tests for related or paired samples a. Wilcoxon signed-rank test: Compares two matched or paired samples (nonparametric analog of the paired t-test) for paired data and continuous data that are not normally distributed b. Friedman ANOVA by ranks: Compares three or more matched or paired groups, nonparametric analog of the repeated-measures ANOVA B. Nominal Data 1. Chi-square test: Compares expected and observed proportions between two or more independent groups, determines whether the proportion of events is different from expected to occur by chance; must have more than five observations per cell in the 2 × 2 contingency table (or 20% of the cells in larger matrices) and a total sample size of 20 or more per group 2. Fisher exact test: Specialized version of the chi-square test for two or more small groups (cells) containing fewer than five predicted observations or fewer than 20 subjects per group 3. McNemar test: Paired-samples analog of chi-square test 4. Mantel-Haenszel test: Controls for the influence of confounders in matched categorical data; allows for stratification in the data (e.g., sex) 5. Cochran Q test: Analog of the McNemar test for three or more groups with matched samples

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Trial Design and Biostatistics

X.  CORRELATION AND REGRESSION A. Introduction 1. Correlation examines the strength and direction of the association between two continuous variables. It does not necessarily assume that one variable is useful in predicting the other. 2. Correlation is the extent to which two numerical variables have a linear relationship: a relationship that increases or decreases at a constant rate. Correlation cannot explain why or how the relationship between two variables, x and y, exists; it can only explain that a relationship does exist. 3. Regression examines the ability of one or more variables to predict another variable. B. Pearson Correlation Coefficient 1. Measures the strength and direction of the linear relationship between two variables that are normally distributed, continuous data 2. Often called the degree of association between the two variables 3. Does not necessarily imply that one variable is dependent on the other (regression analysis will do that) 4. Pearson correlation coefficient (r) ranges from −1 to +1 and can take any value in between: a. (-1) = perfect negative linear relationship; when x is low, y is high b. (1) = perfect positive linear relationship; when x is high, y is low c. (0) = no linear relationship 5. Hypothesis testing determines whether the correlation coefficient is different from zero. This test is highly influenced by sample size. C. Spearman Rank Correlation: Nonparametric test that quantifies the strength of an association between two variables but does not assume a normal distribution of continuous data; can be used for ordinal data or nonnormally distributed continuous data D. Pearls About Correlation 1. The closer the magnitude of r to 1 (either + or −), the more highly correlated the two variables. The weaker the relationship between the two variables, the closer r is to 0. 2. There is no agreed-upon or consistent interpretation of the value of the correlation coefficient. It depends on the environment of the investigation (laboratory vs. clinical experiment). 3. Pay more attention to the magnitude of the correlation than to the p value because correlation is influenced by sample size. 4. A crucial point on the proper use of correlation analysis is interpreting the graphic representation of the two variables. Before using correlation analysis, a scatterplot must be generated of the two variables (x and y) to visually examine the relationship. This is important because r may indicate a strong linear relationship, but if the relationship is not linear graphically, the correlation may be misleading. E. Regression 1. Describes whether an independent variable can predict the dependent outcome. Can be used to describe the strength of the association (a relationship) between an independent variable (the predictor) and a dependent variable (the outcome) 2. Two main purposes of regression: Development of a prediction model and accuracy of prediction 3. Linear regression: Has one or more independent (predictor) variables and a continuous dependent (outcome) variable a. Simple linear regression: One continuous dependent variable (the outcome) and one continuous or categorical independent (predictor) variable b. Multiple linear regression: One continuous dependent variable and two or more continuous or categorical independent variables ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 36

Trial Design and Biostatistics

4. Logistic regression: Has one or more independent (predictor) variables and a categorical dependent outcome (e.g., dead/alive) a. Simple logistic regression: One categorical response (dependent) variable and one continuous or categorical explanatory (independent) variable b. Multiple logistic regression: One categorical response (dependent) variable and two or more continuous or categorical explanatory (independent) variables 5. Nonlinear regression: Variables are not linearly related. a. Polynomial regression: One dependent continuous variable and any number of independent variables with a curvilinear relationship (e.g., number of infections and patients with very low white blood count (WBC) and very high WBC would likely result in a U-shaped curve) b. Exponential regression: One dependent continuous variable and any number of independent variables with a hyperbola graph (starts low and stays low; then curves very high and vice versa) 6. Two conditions must be met before performing linear regression analyses: a. The scatterplot must form a linear pattern. b. The correlation coefficient (r) must be moderate to strong (some recommend between 0.50 and 1 and between -0.50 and -1, but this definition varies by area). 7. Prediction model: Making predictions of the dependent variable (y) from the independent variable (x); Y = mx + b (dependent variable = slope × independent variable + intercept) a. Y is also called the response or outcome variable. b. X is also called the explanatory or predictor variable. c. The equation identifies a line to be a model around which the data lie if a linear pattern exists. 8. Accuracy of prediction: Measures model fit or how well the independent variable predicts the dependent variable. Regression analysis determines the extent of variability in the dependent variable that can be explained by the independent variable(s). a. Coefficient of determination (r2) describes the proportion of variability explained by the linear relationship in the Y variable that is explained by, or because of, its relationship with the X variable in a sample of data. Values of r2 can range from 0 to 1. b. An r2 of 0.80 could be interpreted as saying that 80% of the variability in Y is explained by the variability in X. c. This does not provide a mechanistic understanding of the relationship between X and Y but rather a description of how clearly such a model (linear or otherwise) describes the relationship between the two variables (or how well the model fits the study data). d. Like with r, the interpretation of r2 depends on the scientific arena (e.g., clinical research, basic research, social science research) to which it is applied. 9. For models with multiple independent variables (multiple linear and multiple logistic regression analyses), models should be assessed for multicollinearity. Multicollinearity is when two (or more) x variables are highly correlated. This is problematic when determining r2 and determining model fit. When multicollinearity is present, include only one of the variables. 10. Regression is useful in constructing predictive models, of which there are many examples. Using a multiple linear regression prediction model, calculate your 10-year coronary risk at: https://reference.medscape.com/ calculator/37/acc-aha-cv-risk-calculator-2013.

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Trial Design and Biostatistics

XI.  SURVIVAL ANALYSIS/TIME-TO-EVENT ANALYSIS A. Studies the Time Until an Event (e.g., death, myocardial infarction in patients with uncontrolled hypertension) 1. A group of patients are “followed” until an event occurs; patients are censored when the event of interest occurs. 2. Adjusts data so that patients are not included (i.e., “censored”) in the analysis if they did not experience, or were not observed for, the event; considers that some subjects leave the study for reasons other than the event (e.g., lost to follow-up, end of study period) 3. Considers that all subjects do not enter the study at the same time 4. For a discussion of interrupted time-series analyses, please see Bernal, et al. International Journal of Epidemiology. 2017;46(1):348-355. B. Can Be Used for Prospective or Retrospective Studies C. Estimating the Survival Function 1. Kaplan-Meier method a. Uses survival times (or censored survival times) to estimate the proportion of people who would survive a given length of time under the same circumstances b. Allows the production of a table (life table) and a graph (survival curve) c. Survival curves are purely descriptive; need inferential statistics to draw conclusions 2. Log-rank test a. A nonparametric test that compares the survival distributions between two or more groups b. It is purely a test of significance and precludes an analysis of the effects of several variables or the magnitude of difference between groups or the CI. c. The log-rank test uses several assumptions. i. Random sampling and subjects chosen independently ii. Consistent criteria for entry or end point iii. Baseline survival rate does not change as time progresses. iv. Censored subjects have the same average survival time as uncensored subjects. 3. Cox proportional hazards model a. Describes the impact of several predictor variables on the time-to-event in two or more groups; reported (graphically) like Kaplan-Meier b. Compares the survival times between two or more groups after adjusting for other variables c. Results are reported as the hazard ratio (HR) with the 95% CI. i. HR is similar to RR; is a weighted average of the RR over time ii. Accounts for time to an event (survival, time to discharge, time to first CDI recurrence, time to progression to AIDS in patients with a diagnosis of HIV, time to microvascular complications in patients with diabetes) iii. Similar to RR and OR, there is no statistically significant difference if the 95% CI crosses 1.0 (Table 6). Table 6. Interpretation of the HR Hazard Ratio

Interpretation

1

Increased risk of the event

=1

No association (the event is equally likely)

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Trial Design and Biostatistics

XII.  SELECTED REPRESENTATIVE STATISTICAL TESTS Table 7. Summary Table of Statistical Tests

Data Type

Nonparametric Nominal

Parametric

Ordinal or nonparametric continuous, not normally distributed

Continuous, normally distributed

Two Groups (independent)

3+ Groups (independent)

Before and After a Single Treatment in the Same Subjects (two groups)

Multiple Treatments in the Same Subjects (3+ groups)

Chi-square; Fisher exact test (< 5 in any cell or n 15%b or > 10%c) • High colorectal cancer risk • Lower bleeding risk • Longer duration of aspirin use (> 5 yr)c

Discuss risk-benefit

• Intermediate ASCVD risk (7.5%–15%b or 7.5%–10%c)

Avoid initiation/discontinue

• Low ASCVD risk (< 7.5%) • Higher bleeding risk • Shorter duration of aspirin use (< 5 yr)d

Estimation of ASCVD risk and a review of individual risk factors can be done to further refine risk.

a

b

For initiating aspirin.

For continuing aspirin.

c

d

For discontinuing aspirin.

GI = gastrointestinal; MI = myocardial infarction.

II.  HYPERTENSION Guidelines 1. 2017 ACC/AHA multisociety guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the ACC/AHA Task Force on Clinical Practice Guidelines 2. 2021 ADA standards of care 3. 2021 KDIGO guidelines 4. 2017 ACP/AAFP pharmacologic treatment of HTN in adults 60 and older A. Classification of Blood Pressure for Adults (Domain 1) Table 5. Classification of Blood Pressure Blood Pressure Category

Systolic (mm Hg)

Normal

Diastolic (mm Hg)

Elevated

< 120

120–129

and

  Stage 1

130–139

or

80–89

> 180

and/or

> 120

Hypertension   Stage 2

  Hypertensive crisis

≥ 140

and

or

< 80 < 80

≥ 90

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B. Measurement of Blood Pressure: Accurate Measurement Important in the Diagnosis and Treatment of Hypertension (Table 6) (Domain 1) Table 6. Checklist for Accurate BP Measurement Key Steps for Proper BP Measurements

Specific Instructions

Step 2: Use proper technique for BP measurements

1. Use a BP measurement device that has been validated; ensure that the device is periodically calibrated 2. Support the patient’s arm 3. Position the middle of the cuff on the patient’s upper arm at the level of the right atrium (midpoint of sternum) 4. Use correct the cuff size; the bladder should encircle 80% of arm; and note whether and larger- or smaller-than-normal cuff is used 5. Either the diaphragm or the bell can be used for auscultatory readings

Step 3: Take the proper measurements needed for diagnosis and treatment of elevated BP/HTN

1. At the first visit, record BP in both arms. Use the arm that gives the higher reading for subsequent readings 2. Separate repeated measurements by 1–2 min 3. For auscultatory determinations, use a palpated estimate of radial pulse obliteration pressure to estimate SBP. Inflate cuff by 20–30 mm Hg above this level 4. For auscultatory readings, deflate the cuff pressure by 2 mm Hg/s and listen for Korotkoff sounds

Step 4: Properly document accurate BP readings

1. Record SBP and DBP. If using auscultatory technique, record SBP and DBP at onset of the first Korotkoff sound and disappearance of all Korotkoff sounds, respectively, and use the nearest even number 2. Note the time most recent BP medication taken before measurement

Step 5: Average the readings

Use an average of ≥ 2 readings obtained on ≥ 2 occasions to estimate an individual’s BP

Step 1: Properly prepare the patient

Step 6: Provide BP readings to the patient

1. Have the patient relax, sitting in a chair (feet flat on floor, back supported) for > 5 min 2. Patient should avoid caffeine, exercise, and smoking tobacco for at least 30 min before measurement 3. Ensure that patients have emptied their bladders 4. Neither patient nor the observer should talk during the rest period or during measurement 5. Remove all clothing covering location of cuff placement 6. Measurements made while the patient is sitting or lying on examination table do not fulfill criteria

Provide patients with the SBP/DBP in writing and verbally

DBP = diastolic blood pressure; HTN = hypertension; SBP = systolic blood pressure.

C. Out-of-Office Blood Pressure Measurements (Domain 1) 1. Out-of-office blood pressure measurements are recommended to confirm HTN and to titrate BP-lowering medications. 2. Blood pressure measurements taken in different settings with various devices should correspond (Table 7). ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 128

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3. Home BP monitoring (HBPM) a. Patient training should occur under medical supervision. b. Verify use of the automated validated device; auscultatory devices are generally not recommended. i. Monitors that can store readings in memory are preferred. ii. Verify appropriate cuff size. iii. Verify that inter-arm differences are insignificant; measure BP in the arm with the higher reading, if significant. c. Instructions on HBPM i. Remain still, avoid smoking tobacco and using caffeine, and exercise 30 minutes before measurement. ii. Ensure 5 minutes or more of rest before measurement. iii. Sit with back straight and supported with feet flat on floor. iv. Keep arm supported on flat surface with upper arm at heart level. Bottom of cuff should be placed above antecubital fossa (bend of elbow). v. Take at least two readings 1 minute apart before taking medications and in the evening before supper. vi. Optimally, measure and record BP daily. vii. Ideally, obtain weekly BP readings beginning 2 weeks after a change in treatment and during the week before the clinic visit. viii. Record all readings. 4. Ambulatory BP monitoring (ABPM) is preferred for out-of-office BP measurement, if available. a. Devices should meet validation standards (www.dableducational.org). b. Systolic ABPM statistically significantly predicts stroke and other CV outcomes independently of office blood pressure monitoring (Ann Intern Med 2015;162:192-204). c. Monitors are usually programmed to obtain readings every 15–30 minutes throughout the day and every 15 minutes to 1 hour during the night. d. ABPM allows for estimates of mean BP throughout the monitoring period and separately during nighttime and daytime, determines the daytime/nighttime BP ratio to identify the extent of nocturnal “dipping,” identifies the early-morning BP surge pattern, estimates SBP variability, and allows for recognition of symptomatic hypotension. e. Centers for Medicare & Medicaid Services and other agencies provide reimbursement for ABPM in patients with suspected white-coat HTN and suspected masked HTN (as of July 2019). Table 7. Corresponding BP Values Office BP, mm Hg

HBPM, mm Hg

Daytime ABPM, mm Hg

130/80

130/80

130/80

120/80 140/90

160/100

120/80 135/85

145/90

120/80 135/85

145/90

Nighttime ABPM, mm Hg 100/65 110/65

120/70 140/85

24-Hr ABPM, mm Hg 115/75

125/75

130/80 145/90

ABPM = ambulatory blood pressure monitoring; HBPM = home blood pressure monitoring.

D. Masked and White-Coat HTN (Domain 1) 1. White-coat HTN: Office BP elevated (130/80 mm Hg or greater to less than 160/100 mm Hg) but daytime APBM or HBPM less than 130/80 mm Hg a. Screen for white-coat HTN if SBP is greater than 130 mm Hg to less than 180 mm Hg or diastolic blood pressure (DBP) is greater than 80 mm Hg to less than 100 mm Hg with either ABPM or HBPM before diagnosing HTN. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 129

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b. In adults with white-coat HTN, periodic monitoring with ABPM or HBPM is reasonable to detect transition to HTN. c. If office BP readings are uncontrolled and HBPM suggests white-coat HTN, it can be confirmed with ABPM. 2. Masked HTN: Office BP 120–129/less than 80 mm Hg, but ABPM or HBPM of 130/80 mm Hg or greater a. Screen for masked HTN if untreated office SBP 120–129 mm Hg or DBP 75–79 mm Hg. b. It is reasonable to screen for white-coat HTN if patient is taking several drug therapies and office blood pressure is within 10 mm Hg above goal. c. It is reasonable to screen for masked uncontrolled HTN in patients with HTN if office blood pressure goal is controlled in the presence of target organ damage or increased overall CV risk. E. Patient Evaluation (Domain 1) 1. Screen for and manage modifiable risk factors. a. Modifiable risk factors i. Smoking, secondhand smoking ii. Diabetes mellitus iii. Dyslipidemia iv. Overweight or obesity v. Physical inactivity or low fitness vi. Unhealthy diet b. Relatively fixed risk factors i. CKD ii. Family history iii. Increased age iv. Low socioeconomic or educational status v. Male sex vi. Obstructive sleep apnea vii. Psychosocial stress c. Assess for identifiable causes of HTN when clinically indicated (see HTN guidelines for further discussion) i. Sleep apnea ii. Drug-induced or related causes (see section O.3.d for specific drugs) iii. CKD iv. Primary aldosteronism v. Renovascular disease vi. Chronic steroid therapy or Cushing syndrome vii. Pheochromocytoma viii. Coarctation of the aorta ix. Thyroid or parathyroid disease d. Assess for the presence of CVD or other target organ damage.

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Patient Case 2. M.P., a 52-year-old Asian woman, presents to the clinic to discuss her heartburn symptoms. Her primary care physician has been running late, and she was rushed back to her examination room a few minutes ago. Her BP is 151/84 mm Hg. She has no history of HTN, and the only drug she takes is over-the-counter (OTC) famotidine. Which is the next best action to take? A. B. C. D.

Recheck her blood pressure after she has been seated quietly for 5 minutes. Initiate hydrochlorothiazide 12.5 mg/day. Initiate lisinopril 10 mg/day. There is no need for concern with her BP because she does not have HTN.

F. Blood Pressure Goals – Variation in National Guidelines (Domains 1, 2) Table 8. BP Goals Across Guidelines Patient Population

ACC/AHA

Disease-Specific Guideline

Diabetes

< 130/80 mm Hg

ADA 2021 10-yr ASCVD risk ≥ 15% or established ASCVD: < 130/80 mm Hg 10-yr ASCVD risk < 15%: < 140/90 mm Hg

Uncomplicated HTN

< 130/80 mm Hg

CKD

< 130/80 mm Hg

Older adult

< 130 mm Hg

KDIGO 2021 With or without diabetes, not on dialysis: SBP < 120 mm Hg Kidney transplant: < 130/80 mm Hg ACP/AAFP Stroke/TIA or high CV risk: < 140 mm Hg General: < 150 mm Hg

ACC = American College of Cardiology; AHA = American Heart Association; CKD = chronic kidney disease; HTN = hypertension; KDIGO = Kidney Disease: Improving Global Outcomes.

1. Select trials comparing more with less intensive BP goals: A Randomized Trial of Intensive versus Standard Blood-Pressure Control (SPRINT Research Group)—2015 a. 9361 people 50 and older with SBP of 130–180 mm Hg with increased CV risk (clinical or subclinical CVD other than stroke, CKD, 10-year Framingham risk of 15% or higher, age 75 or older) were randomized to an SBP target of less than 120 mm Hg or less than 140 mm Hg. b. Intensive control had a reduction in primary outcome of composite MI, ACS, acute decompensated HF, death from CV causes (1.65% per year vs. 2.19% per year; HR 0.75; 95% CI, 0.64–0.89; p 3 yr in patients who had MI or ACS

Treatment with ARB can help prevent recurrence

• Asymptomatic aortic stenosis: Start at low doses and titrate gradually • Chronic aortic insufficiency: Avoid medications that slow heart rate β-Blocker

Treat similarly to those without PAD

Carvedilol, metoprolol succinate, or bisoprolol.

a

b

GDMT β-blockers: carvedilol, metoprolol tartrate, metoprolol succinate, nadolol, bisoprolol, propranolol, and timolol.

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; CCB = calcium channel blocker; CKD = chronic kidney disease; DHP = dihydropyridine; GDMT = guideline-directed management and therapy; GFR = glomerular filtration rate; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; ISA = intrinsic sympathomimetic activity; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; PAD = peripheral arterial disease; SIHD = stable ischemic heart disease.

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Table 10. Principles of Drug Therapy Drug Class

Clinical Usea

Key ADRs/CIs

Additional Considerations

• Non–African American patients • Diabetes and CKD and albuminuria • HF or LVEF of ≤ 40% • CAD • Recurrent stroke prevention • Add-on therapy for African American patients

• Increasing SCr ≤ 30% above baseline is acceptable • Hyperkalemia • Angioedema: Less with ARBs, but use with extreme caution if substituting ARB for ACE inhibitor–associated angioedema • Cough with ACE inhibitor • CI: Bilateral renal artery stenosis, pregnancy, angioedema

• Caution using in women during childbearing years • Consider starting at a lowerthan-average dose if the patient is an older adult, is receiving concomitant diuretic therapy, or has renal impairment • Reassess SCr and K 1–2 wk after initiation or dose titration

• Option as first-line agent for HTN • Useful in patients with stable angina

• Peripheral edema • Orthostasis • Reflex tachycardia

• Option as first-line agent for HTN • Useful in patients with concomitant AF or stable angina

• • • •

• Initiate at low doses for older adult patients • Can be used in Raynaud syndrome

• Option as first-line agent for HTN alone or in combination • Chlorthalidone preferred to HCTZ • Enhances efficacy of multidrug regimens

• Electrolyte abnormalities • Dehydration • Hyperuricemia, hyperglycemia (larger doses) • CI: Anuria

First-line drug therapy

ACE inhibitors ARBs

CCBs

DHP CCBs

Non-DHP CCBs

Thiazide/ thiazide-like diuretics

Bradycardia Heart block Constipation CI—heart block, sick sinus syndrome

• May be useful for migraine prophylaxis • Potent CYP inhibitors; caution with drug interactions • Avoid in HFrEF • Caution if using concomitant β-blocker • Ineffective with GFR < 30 mL/min/1.73 m2 • Monitor renal function, sodium, and potassium 7–10 days after initiation or titration • Slow demineralization in osteoporosis • Caution with gout or diabetes

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Table 10. Principles of Drug Therapy (continued) Drug Class

Clinical Usea

Second-line drug therapy

Aldosterone antagonists

• HFrEF or HFpEF • Resistant HTN

α1-Blockers

• Can be used in BPH • Typically fourth- of fifth -line therapy for HTN

α2-Agonists

Key ADRs/CIs

Additional Considerations

• Hyperkalemia • Gynecomastia/mastodynia (spironolactone) • Hirsutism (eplerenone) • CI: GFR < 30 mL/min/1.73 m2, K ≥ 5.0 mEq/L, anuria

• Monitor renal function and potassium at 3 days, 7 days, monthly for first 3 mo, and then periodically

• Dizziness and orthostasis

• Start very low dose and titrate slowly; consider taking at bedtime

• Resistant HTN • Beneficial for hypertensive urgency

• Dizziness and orthostasis • Drowsiness • Dry mouth

• Rebound HTN if withdrawn too quickly • Avoid in patients with HF

β-Blockers

• HF or LVSD with an LVEF ≤ 40% • Post-MI • CAD/SIHD • Can also be used in treatment of AF, tachyarrhythmias, angina, migraine prophylaxis, and essential tremor

• Bradycardia: Adjust doses for symptomatic bradycardia only • Heart block: Adjust doses for greater than first-degree heart block • Bronchospastic disease • Exercise intolerance, sexual dysfunction, fatigue • CI: Sinoatrial or AV node dysfunction, decompensated HF, severe bronchospastic disease

• Monitor heart rate regularly • Can negatively affect blood glucose and mask symptoms of hypoglycemia • Can cause depression • Caution with asthma or COPD, especially with higher doses and nonselective β-blockers

Direct renin inhibitor

No outcomes data available in specific patient populations demonstrating benefit

• Angioedema • Hyperkalemia if used concomitantly with ACE inhibitor • CI: Pregnancy, combination with ACE inhibitor or ARB in diabetes or in renal impairment

• Caution using in women during childbearing years • High-fat meals substantially decrease absorption • Patients with renal insufficiency excluded from trials

Direct vasodilator

• Resistant HTN • HF (hydralazine)

• Hydralazine: Tachycardia, drug- • Use with diuretic (both) and induced lupus-like syndrome, β-blocker (hydralazine) • Can be dosed 2–4 times daily fluid retention, headache • Minoxidil: Fluid retention, pericardial effusion, hirsutism

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Table 10. Principles of Drug Therapy (continued) Drug Class

Clinical Usea

Second-line drug therapy (continued)

Key ADRs/CIs

Additional Considerations • Ethacrynic acid can be useful for patients with allergic reactions to other loops caused by sulfa moiety • Monitor renal function, sodium, and potassium 7–10 days after initiation and titration

Loop diuretics

HTN management for patients with HF or CKD

• Electrolyte abnormalities • Dehydration • CI: Anuria

Potassiumsparing diuretics

Typically used in combination with thiazide diuretic for potassium balance

• Hyperkalemia • CI: Anuria, hyperkalemia, severe renal or hepatic disease

• Avoid if GFR < 10 mL/ min/1.73 m2 • Monitor renal function and potassium 7–10 days after initiation and titration

See references for list of evidence supporting recommended use.

a

ACE = angiotensin-converting enzyme; ADR = adverse drug reaction; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BPH = benign prostatic hyperplasia; CAD = coronary artery disease; CCB = calcium channel blocker; CI = contraindication; CKD = chronic kidney disease; CYP = cytochrome P450 ; DHP = dihydropyridine; GFR = glomerular filtration rate; HCTZ = hydrochlorothiazide; HF = heart failure; HFrEF = Heart failure with reduced ejection fraction; HFpEF = Heart failure with preserved ejection fraction; HTN = hypertension; LVEF = left ventricular ejection fraction; SCr = serum creatinine ratio; LVSD = left ventricular systolic dysfunction.

Patient Case 4. A 60-year-old white man with type 2 diabetes is new to your clinic. Today, his BP is 155/78 mm Hg, with a repeated measurement of 151/73 mm Hg. His heart rate is 80 beats/minute. He could not tolerate two different ACE inhibitors because of cough. He currently takes metformin 850 mg three times daily, glipizide 10 mg twice daily, hydrochlorothiazide 25 mg/day, and omeprazole as needed. Laboratory test results are as follows: SCr 1.5 mg/dL (CrCl [IBW] 54 mL/minute), A1C 6.8%, K 4.0 mEq/L, and microalbumin/creatinine 98.2 mg/g. His BMI is 31.6 kg/m2. Which would best address his elevated blood pressure? A. B. C. D.

No further treatment is needed. Initiate amlodipine 2.5 mg/day. Initiate losartan 25 mg/day. Initiate metoprolol succinate 25 mg/day.

H. Special Patient Groups (Domain 1) 1. Race and ethnicity a. Lowest BP control rates are in Mexican American and Native American people. b. Socioeconomic factors and lifestyle may be barriers to BP control. c. In African American patients without HF or CKD, initial therapy should include a thiazide-type diuretic or CCB. i. BP lowering efficacy of RAS inhibitors is attenuated in African American patients because of lower circulating renin concentrations.

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2.

3.

4. 5.

ii. Black patients also have a higher level of salt sensitivity, which is also associated with lower circulating renin concentrations. (a) The sympathetic nervous system can also play a role, given that decreased dopamine concentrations without a decrease in norepinephrine in response to salt loading in black patients has been seen; this promotes sodium retention. (b) Lower concentrations of kallikrein have also been found in salt-sensitive subjects. iii. Two or more antihypertensives are recommended to achieve a BP goal of less than 130/80 mm Hg in African American patients. Women and pregnancy a. Transition to methyldopa, nifedipine, or labetalol during pregnancy. b. Do not treat with ACE inhibitors, ARBs, or direct renin inhibitors. c. Oral estrogen-containing contraceptives can increase BP, and the risk can increase with the duration of use. d. The treatment goal for pregnant patients with chronic HTN is 120–160/80–105 mm Hg, according to the ADA and the American College of Obstetricians and Gynecologists. Older adults a. According to the 2017 ACC/AHA guideline i. An SBP goal less than 130 mm Hg is recommended for noninstitutionalized ambulatory communitydwelling adults 65 and older. ii. Do not recommend a specific DBP goal. iii. Clinical judgment, patient preference, and a team-based approach are reasonable in patients with a high burden of comorbidity and limited life expectancy. b. According to the 2016 ACP/AAFP guideline for treatment of HTN in adults 60 and older i. SBP goal less than 150 mm Hg ii. SBP goal less than 140 mm Hg if history of stroke (or TIA) and high CV risk iii. Insufficient evidence for targeting treatment according to DBP c. Evidence for lowering BP in older patients i. For patients older than 80, the Hypertension in the Very Elderly Trial (HYVET) showed that targeting a BP less than 150/80 mm Hg significantly decreases the risk of stroke and all-cause mortality. ii. SPRINT-SENIOR, an analysis of patients 75 and older enrolled in SPRINT, had a significant reduction in the primary composite outcome (HR 0.66; 95% CI, 0.51–0.85) without significant differences in rates of serious adverse events. Obesity (BMI 30 kg/m2 or greater) i. Prevalent risk factor for HTN and CVD ii. Intensive lifestyle modification recommended Postural hypotension i. Decrease in standing BP of more than 10 mm Hg, when associated with dizziness, is more common in older patients with systolic HTN and diabetes and in those taking diuretics, vasodilators, or psychotropic drugs. Orthostatic hypotension is a decrease in SBP of at least 20 mm Hg or a decrease in DBP of at least 10 mm Hg. ii. Use caution to avoid volume depletion and rapid-dose titration of antihypertensive drugs.

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Patient Case 5. A 58-year-old Hispanic woman with CAD and type 2 diabetes presents to the clinic with her home BP readings. She is frustrated because her BP is still not at goal. She currently takes HCTZ 25 mg/day, lisinopril 40 mg/day, amlodipine 10 mg/day, and metoprolol tartrate 25 mg twice daily. She tried clonidine but had to discontinue it because of orthostasis. Today, her BP is 148/79 mm Hg, with a repeated measurement of 145/81 mm Hg. Her HR is 58 beats/minute. Laboratory test results today show SCr 1.2 mg/dL (CrCl [adjusted body weight] 51.8 mL/minute), K 4.2 mEq/L, and Na 142 mEq/L. Her BMI is 27.5 kg/m2, and ejection fraction is 45%. Which regimen change, if any, would be best for this patient? A. B. C. D.

Initiate spironolactone 12.5 mg/day. Discontinue hydrochlorothiazide, and initiate chlorthalidone 25 mg/day. Increase metoprolol to 50 mg twice daily. No change in her current regimen is warranted.

I. Resistant HTN (Domain 1) 1. Definition: a. Elevated BP (130/80 mm Hg or greater) despite concurrent uses of three antihypertensive agents from different classes, including a long-acting CCB, a blocker of the renin-angiotensin system (ACE inhibitor, ARB), and a diuretic at maximally tolerated doses with appropriate dosing frequency b. Controlled BP (less than 130/80 mm Hg) with the use of four or more antihypertensives 2. Causes of resistant HTN a. Improper BP measurement b. Volume overload and pseudotolerance i. Excessive sodium intake ii. Volume retention from kidney disease iii. Inadequate diuretic therapy c. Drug-induced causes i. Antidepressants (monoamine oxidase inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants) ii. Nonsteroidal anti-inflammatory drugs iii. Cocaine, amphetamines iv. Sympathomimetics v. Oral contraceptives vi. Glucocorticoids, mineralocorticoids, cyclosporine, or tacrolimus vii. Epoetin viii. Licorice ix. Dietary supplements d. Nonadherence i. Ensure that regimen is affordable and well tolerated. ii. Decrease pill burden using combination products and once-daily dosing when available and clinically indicated. iii. Adjust treatments on the basis of cultural beliefs and attitudes. iv. Use all members of the health care team. e. Clinical inertia: Inadequate doses or inappropriate drug combinations f. Associated conditions i. Obesity ii. Alcoholism g. Identifiable causes of HTN (as previously described in section E and earlier) ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 139

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3. Evaluation of TRH (2017 ACC/AHA guideline and 2018 AHA scientific statement) (Domain 1) a. Exclude pseudoresistance i. Ensure accurate office BP measurements. ii. Assess for nonadherence to prescribed regimen. iii. Obtain home, work, or ambulatory BP readings to exclude white-coat HTN. iv. Identify and reverse contributing lifestyle factors (obesity, physical inactivity, excessive alcohol ingestion, high-salt/low-fiber diet, sleep quality/quantity). b. Discontinue or minimize interfering substances. c. Screen for secondary causes of resistant HTN. i. Primary aldosteronism (elevated aldosterone/renin ratio) ii. CKD (eGFR less than 60 mL/minute/1.73 m2) iii. Renal artery stenosis (young female, known atherosclerotic disease, worsening kidney function) iv. Renal parenchymal disease v. Pheochromocytoma (episodic HTN, palpitations, diaphoresis, headache) vi. Obstructive sleep apnea (snoring, witnessed apnea, excessive daytime sleepiness) vii. Cushing syndrome (mood disorders, menstrual irregularities, muscle weakness, weight gain, abdominal striae, hirsutism, dorsal and supraclavicular fat, fragile skin, hypertension, abnormal glucose) viii. Coarctation of the aorta ix. Hypothyroid (dry skin, cold intolerance, constipation, hoarseness, weight gain) x. Hyperthyroid (warm, moist skin, heat intolerance, nervousness, insomnia, weight loss, diarrhea, muscle weakness) 4. Treatment of resistant HTN (2018 AHA scientific statement. Hypertension 2018;72:e53-e90) a. Step 1 i. Exclude other causes of HTN (pseudoresistance, secondary causes of HTN). ii. Ensure low-sodium diet (less than 2400 mg/day). iii. Maximize lifestyle interventions. (a) Overall dietary pattern (b) Weight loss (c) Exercise (d) 6 or more hours of uninterrupted sleep iv. Optimize three-drug regimen. (a) Ensure adherence to three antihypertensive medications of different classes (renin angiotensin system blocker, CCB, diuretic) at maximal or maximally tolerated doses. (b) Diuretic type must be appropriate for kidney function. b. Step 2: Substitute an optimally dosed thiazide-like diuretic, such as chlorthalidone or indapamide for the prior diuretic. c. Step 3: Add an mineralocorticoid receptor antagonist (MRA; spironolactone or eplerenone). i. Spironolactone has been well studied in this setting and is reported to decrease SBP by up to 25 mm Hg and DBP by 12 mm Hg, with similar results in both those with and those without hyperaldosteronism. ii. The PATHWAY-2 trial compared spironolactone with doxazosin, bisoprolol, and placebo. Spironolactone reduced BP significantly more than than bisoprolol and doxazosin, though all three medications lowered BP more than placebo. iii. The ReHOT trial comparing spironolactone with clonidine found that they agents achieved similar BP control; however, spironolactone had a greater reduction in 24-hour and daytime ABPM.

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d. Step 4: Add a β-blocker if heart rate is greater than 70 beats/minute (metoprolol succinate, bisoprolol, labetalol, or carvedilol). i. Consider a central α-agonist if a β-blocker is contraindicated. ii. Consider once-daily diltiazem if an α-agonist is not tolerated. e. Step 5: Add hydralazine 25 mg three times daily and titrate it to the maximum dose. i. Combine with isosorbide mononitrate 30 mg/day if HF with reduced ejection fraction (HFrEF) ii. Requires concomitant use of β-blocker and diuretic f. Step 6: Substitute minoxidil 2.5 mg twice daily/three times daily for hydralazine; requires concomitant use of β-blocker and diuretic 5. Refer to a specialist. a. For known or suspected secondary causes of HTN b. If BP remains uncontrolled after 6 months of treatment J. Hypertensive crises (Domain 1, 2) 1. Hypertensive urgencies: Patients with markedly elevated BP (greater than 180/120 mm Hg) without acute target organ damage usually do not require hospitalization, but they should receive immediate combination oral antihypertensive therapy. Oral agents typically used include captopril, clonidine, and labetalol. a. Data are limited for managing asymptomatic elevations in HTN in the ambulatory care setting. b. Patients should be transferred to a quiet room for rest and observation on confirmation of hypertensive urgency. Thirty minutes of rest is sufficient to lower BP in one third of patients. c. BP should be reduced gradually over hours to days, depending on patient-specific factors. i. Decrease SBP by no more than 25% within the first hour because reducing BP too quickly can increase the risk of cerebrovascular accident, MI, or acute kidney injury. ii. If BP is stable, decrease further to 160/100 mm Hg within the next 2–6 hours. iii. Next, decrease BP to goal within the next 1–2 days. d. Underlying causes should be evaluated and treated appropriately. i. Underlying causes include undiagnosed HTN, white-coat HTN, nonadherence, abrupt withdrawal of antihypertensives such as β-blockers, illicit drug use, and excessive sodium intake. ii. Antihypertensive therapy should be initiated, reinitiated, or intensified. (a) Reinitiate existing antihypertensives and address adherence issues if they exist. (b) Use combination products, when possible, if adherence is an issue. (c) Can add another long-acting antihypertensive agent to the existing regimen e. Antihypertensives that can be used to treat urgency in the outpatient setting include those with a quicker onset of action. i. Captopril ii. Clonidine iii. Labetalol iv. Nicardipine v. Minoxidil 2. Hypertensive emergency: Markedly elevated BP (greater than 180/120 mm Hg) with acute target organ damage a. Not traditionally treated in an ambulatory care setting b. 2017 ACC/AHA guidelines recommend that patients be admitted to the intensive care unit (ICU) and treated with intravenous antihypertensive medications. K. Miscellaneous (Domain 2) 1. Behavioral and motivational strategies to achieve healthy lifestyle are recommended. 2. Team-based approach is recommended.

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3. Use of electronic health records and patient registries helps identify patients with undiagnosed or undertreated HTN and to guide quality-improvement efforts. 4. Telehealth strategies can be useful adjuncts to interventions. 5. Every adult with HTN should have a clear, detailed, and current evidence-based plan of care that ensures achievement of treatment and self-management goals, encourages effective management of comorbidities, prompts timely follow-up with the health care team, and adheres to CVD guideline-directed medical therapy. Patient Case 6. A 72-year-old white man is new to your clinic. He has not seen a health care provider for the past 7 years because of financial issues. Today, his BP is 175/100 mm Hg, with a repeated measurement of 169/99 mm Hg. He takes no medications, although he took a drug for his BP “years ago.” He has no symptoms of illness or of feeling bad. Today, laboratory test results are as follows: SCr 1.6 mg/dL (CrCl [adjusted body weight] 56.4 mL/minute), K 4.0 mEq/L, and Na 142 mEq/L. His BMI is 30.2 kg/m2. Which intervention would best treat this patient’s HTN? A. B. C. D.

Initiate lisinopril 10 mg/day. Initiate HCTZ 12.5 mg/day. Initiate lisinopril/HCTZ 10/12.5 mg/day. Send him to the emergency department for hypertensive emergency.

III.  DYSLIPIDEMIA Guidelines 1. 2018 AHA/ACC multisociety guideline on managing blood cholesterol (called 2018 AHA/ACC throughout this section) 2. 2021 ADA standards of medical care in diabetes 3. 2020 American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) consensus statement for managing dyslipidemia and preventing CVD 4. 2021 ACC expert consensus decision pathway on managing ASCVD risk reduction in patients with hypertriglyceridemia Patient Case 7. A 62-year-old white man who smokes 1 pack/day presents to your clinic taking no medications. His medical history includes an MI 5 years ago, at which time a stent was placed. The primary care physician will address the patient’s other drug-related problems but would like your help in addressing his cholesterol status. The patient would prefer to lower his cholesterol without medications, if possible. Fasting laboratory results are as follows: TC 187 mg/dL, TG 157 mg/dL, HDL 43 mg/dL, LDL 113 mg/dL, non-HDL 144 mg/dL, SCr 1.0 mg/dL, ALT 25 IU/L, Na 140 mEq/L, and K 4.7 mEq/L. His BMI is 32.5 kg/m2 and BP is 115/65 mm Hg. Which is the best recommendation to treat his cholesterol? A. B. C. D.

Diet, exercise, and weight loss only. Diet, exercise, weight loss, and simvastatin 40 mg/day. Diet, exercise, weight loss, and atorvastatin 80 mg/day. Diet, exercise, weight loss, and pravastatin 20 mg/day.

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A. Practice Guidelines (Domain 1) 1. 2018 AHA/ACC multi-guideline for managing blood cholesterol a. Update to the 2013 AHA/ACC guideline for treating blood cholesterol, which is endorsed by several organizations b. Measuring lipid concentrations i. In adults 20 and older not receiving lipid-lowering therapy, obtain a fasting or nonfasting lipid profile to estimate ASCVD risk and document baseline LDL. (a) Reasonable to measure fasting lipid profile initially if patient has a family history of premature ASCVD or genetic hyperlipidemia (b) If TG is greater than 400 mg/dL in an initial nonfasting lipid profile, repeat a fasting lipid panel. (c) Use of fasting lipid testing is preferred in order to: (1) Establish the diagnosis of metabolic syndrome because one of the diagnostic criteria is fasting TG 150 mg/dL or above (2) Identify lipid disorders in those without clinical ASCVD, but with a family history of premature ASCVD or genetic lipid disorders (3) Assess adherence to lifestyle and medical therapy in those being treated with lipid-lowering medication for ASCVD risk reduction (4) Identify those with TG 500 mg/dL or above and individuals at risk of hypertriglyceridemiainduced pancreatitis, and monitor their response to therapy ii. If LDL is less than 70 mg/dL, measure direct LDL or use a modified LDL estimate. iii. Other lipoproteins: (a) Apolipoprotein B (apoB) measurement can help to determine whether hypertriglyceridemia is an atherogenic condition. (1) A relative indication for measuring apoB is when TG is greater than 200 mg/dL. (2) A concentration greater than 130 mg/dL corresponds to an LDL of 160 mg/dL or greater. (b) Lipoprotein (a) is a modified form of LDL that can have atherogenic potential. (1) A relative indication for measuring lipoprotein (a) is a family history of premature ASCVD or a personal history of ASCVD not explained by major risk factors. (2) A lipoprotein (a) concentration of 50 mg/dL or greater can be considered a risk-enhancing factor. (3) Current evidence shows that it should be considered in women only in the presence of hypercholesterolemia. c. Assessing risk (see section I.D Aspirin Use.) i. Assess traditional ASCVD risk factors every 4–6 years in adults without ASCVD at 20–79 years of age: Age, sex, cholesterol, HTN, tobacco smoking ii. Estimate a 10-year ASCVD risk every 4–6 years in adults age 40–79 without ASCVD. iii. Assess a 30-year or lifetime risk in adults age 20–39 without ASCVD or adults age 40–59 with a 10-year ASCVD risk less than 7.5%. d. Treatment of hyperlipidemia i. Emphasize a heart-healthy lifestyle across the life course (www.heart.org/en/healthy-living/ healthyeating/eat-smart/nutrition-basics/aha-diet-and-lifestyle-recommendations). ii. Emphasize clinician-patient shared decision-making (Table 11). iii. Statin therapy is the cornerstone of treatment. (a) Moderate-intensity statins lower LDL by 30%–49% from baseline. (b) High-intensity statins lower LDL by 50% or more from baseline.

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Table 11. Checklist for Clinician-Patient Shared Decision-making for Initiating Therapy Checklist Item

ASCVD risk assessment

Lifestyle modifications Potential net clinical benefit of pharmacotherapy

Cost considerations

Shared decision-making

Recommendation

• Assign to statin benefit group • Use the PCE risk estimator plusa in primary prevention for adults age 40–75 with LDL ≥ 70 mg/dL • Assess other patient characteristics (risk-enhancing factors) that influence risk • Assess CAC if risk decision uncertain and additional information is needed to clarify ASCVD risk • Use decision tools to explain risk • Review lifestyle habits (diet, physical activity, weight, tobacco use) • Endorse healthy lifestyle • Provide relevant advice/materials/referrals • • • •

Recommend statins first line Consider combination of statin and nonstatin therapy in select patients Discuss potential risk reduction from lipid-lowering therapy Discuss potential adverse effects and drug interactions

• Discuss potential out-of-pocket cost of therapy to the patient

• Encourage patient to verbalize what was heard • Invite patient to ask questions, express values/preferences, state ability to adhere to lifestyle changes and medications • Refer patient to trustworthy materials to aid in understanding the issues regarding risk decisions • Collaborate with the patient to determine therapy and follow-up plan

Available at https://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/.

a

CAC = coronary artery calcium; LDL = low-density lipoprotein cholesterol; PCE = Pooled Cohort Equations.

iv. Recommend treatment in four patient management groups (Table 12) Table 12. Overview of Primary and Secondary ASCVD Prevention Patient Management Group

ASCVD Risk Scorea

Secondary Prevention Stable ASCVD N/A Very high-risk ASCVDb

N/A

Statin Intensity Recommended

Non-statin Recommendations

Age ≤ 75: High intensity Age > 75: Moderate or high intensity

Ezetimibe if LDL ≥ 70 mg/dL on maximally tolerated statin

High intensity

Ezetimibe if LDL ≥ 70 mg/dL on maximally tolerated statin PCSK9 inhibitor reasonable if LDL ≥ 70 mg/dL or non-HDL ≥ 100 mg/ dL on maximally tolerated statin + ezetimibe

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 144

Cardiology I

Table 12. Overview of Primary and Secondary ASCVD Prevention (continued) Patient Management Group

ASCVD Risk Scorea

Statin Intensity Recommended

Non-statin Recommendations

High intensity

Ezetimibe if < 50% LDL reduction or if LDL ≥ 100 mg/dL on maximally tolerated statin BAS may be considered if patient achieves < 50% LDL reduction on maximally tolerated statin + ezetimibe and TG < 300 mg/dL

Primary Prevention LDL ≥ 190 mg/dL Age ≥ 20 yr

N/A

PCSK9 inhibitor may be considered if LDL ≥ 100 mg/dL on maximally tolerated statin + ezetimibe

Age 30–75 with HeFH Age 40–75 with baseline LDL ≥ 220 mg/dL

PCSK9 inhibitor may be considered if LDL ≥ 130 mg/dL on maximally tolerated statin + ezetimibe

Diabetes, LDL 70–189 mg/dL Age 20–39

N/A

Moderate intensity if DM-specific enhancersc

Age 40–75

N/Ad

Age > 75 on statin therapy

N/A

Moderate intensity High intensity can be considered if several ASCVD risk factors (including elevated 10-yr risk score) or age 50–75 yr

Reasonable to continue statin therapy, if tolerated

N/A

Ezetimibe if on maximally tolerated statin and 10-yr ASCVD risk ≥ 20% to reduce LDL by ≥ 50% N/A

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Cardiology I

Table 12. Overview of Primary and Secondary ASCVD Prevention (continued) Patient Management Group

ASCVD Risk Scorea

Statin Intensity Recommended

Non-statin Recommendations

Primary Prevention (continued) LDL 70–189 mg/dL, without DM or ASCVD Age 20–39 Age 40–75

N/A; may assess None; conduct lifestyle and risk lifetime risk start- discussion ing at age 21

N/A

5% to < 7.5% (borderline risk)

N/A

< 5% (low risk)

≥ 7.5% to < 20% (intermediate risk)

Age > 75

≥ 20% (high risk) N/A

None; conduct lifestyle and risk discussion

N/A

Risk enhancerse present: Moderateintensity statin Presence of risk enhancers may favor intensification of statin therapy (e.g., high intensity) If uncertainty, measure CACf

• Ezetimibe or BAS (if TG< 300 mg/ dL) may be reasonable if patient would benefit from high intensity advised but not tolerated or not acceptable

Risk enhancerse present: Moderateintensity statin If uncertainty, may measure CACf

High intensity

Moderate-intensity statin may be N/A reasonable May be reasonable to discontinue statin therapy when functional decline, multimorbidity, frailty, or limited life expectancy limits potential benefits May be reasonable to measure CACf in those age 76–80

Calculated using the Pooled Cohort Equations (PCE) Risk Estimator Plus (https://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/).

a

b

History of several major ASCVD events or one major ASCVD event + several high-risk conditions.

DM-specific risk enhancers: Long duration (≥ 10 yr of type 2 DM; ≥ 20 yr of type 1 DM); albuminuria (30 mcg/mg); eGFR < 60 mL/min/1.73 m2; retinopathy; neuropathy; ABI < 0.9. c

d

It is reasonable to assess the 10-yr risk using the PCE to help stratify risk.

Risk enhancers: Family history of premature ASCVD, persistently elevated LDL ≥ 160 mg/dL, CKD, metabolic syndrome, conditions specific to women (e.g., preeclampsia, premature menopause), inflammatory disease (especially psoriasis, rheumatoid arthritis, or HIV), ethnicity, lipid/biomarkers; persistently elevated TG (≥ 175 mg/dL), if measured: hs-CRP ≥ 2.0 mg/L, Lp(a) concentrations ≥ 50 mg/dL, apoB ≥ 130 mg/dL especially at higher Lp(a) concentrations, ABI < 0.9. e

f

CAC 0: Withhold statin and reevaluate in 5–10 yr. CAC 1–99: Initiate statin therapy if ≥ 55 yr. CAC ≥ 100: Initiate statin.

ABI = ankle-brachial index; apoB = apolipoprotein B; BAS = bile acid sequestrant; CAC = coronary artery calcium; DM = diabetes mellitus; HeFH = heterozygous familial hypercholesterolemia; hs-CRP = high-sensitivity C-reactive protein; Lp(a) = lipoprotein(a); PCSK9 = proprotein convertase subtilisin/kexin type 9.

(a) Secondary ASCVD prevention: Clinical ASCVD is defined as ACS, or a history of MI, stable angina or UA, coronary or other arterial revascularization, stroke, TIA, or atherosclerotic PAD. (1) General points (A) In patients 75 and younger, high-intensity statin therapy should be initiated or continued with the aim of achieving a 50% or greater reduction in LDL. (B) If high-intensity therapy is contraindicated or not tolerated, moderate-intensity statin therapy should be used to achieve a 30%–49% LDL reduction. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 146

Cardiology I

(2) Very high-risk ASCVD (Table 13) (A) High-intensity (or maximally tolerated) statin recommended regardless of age (B) Adding ezetimibe is reasonable if the patient is taking a maximally tolerated statin and the patient’s LDL is 70 mg/dL or greater. (C) Adding a PCSK9 inhibitor is reasonable if the patient is taking a statin plus ezetimibe and the patient’s LDL is 70 mg/dL or greater or the non-HDL is 100 mg/dL or greater. (3) Stable clinical ASCVD (A) Age 75 or younger: High-intensity statin recommended; use moderate intensity if high intensity is not tolerated. (B) Older than 75 • If initiating: Moderate-intensity statin to lower LDL by 30%–49% from baseline recommended • If patient previously receiving high-intensity and tolerating therapy, reasonable to continue (C) Reasonable to add ezetimibe if LDL is 70 mg/dL or greater while receiving maximally tolerated statin therapy in those 75 and younger Table 13. Criteria for Very-High-Risk ASCVDa Category

Criteria

High-risk conditions

Age ≥ 65 Heterozygous familial hypercholesterolemia History of CABG or PCI Diabetes HTN CKD (GFR 15–59 mL/min/1.73 m2) Current smoking LDL ≥ 100 mg/dL despite statin plus ezetimibe History of congestive HF

Major ASCVD events

Recent (within past 12 mo) ACS History of MI History of ischemic stroke Symptomatic PAD

a Definition: Very high risk includes history of several major ASCVD events or one major ASCVD event and several high-risk conditions.

ACS = acute coronary syndrome; CABG = coronary artery bypass grafting; CKD = chronic kidney disease; HF = heart failure; HTN = hypertension; LDL = low-density lipoprotein cholesterol; MI = myocardial infarction; PAD = peripheral arterial disease; PCI = percutaneous coronary intervention.

(b) Primary prevention: Primary elevations of LDL greater than 190 mg/dL in patients age 20–75 (1) High-intensity statin to lower LDL by 50% or more from baseline is recommended (2) Ezetimibe can be considered if patients have less than a 50% LDL reduction while taking a maximally tolerated statin or have an LDL of 100 mg/dL or more while receiving statin therapy. (3) PCSK9 inhibitor can be considered: (A) In patients age 30–75 with heterozygous familial hypercholesterolemia (HeFH) with an LDL of 100 mg/dL or greater while using a statin plus ezetimibe (B) In patients age 40–75 with a baseline LDL of 220 mg/dL or greater who achieve an on-treatment LDL of 130 mg/dL or lower on a statin plus ezetimibe

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Cardiology I

(4) Bile acid sequestrants can be considered in patients age 20–75 whose fasting TG of 300 mg/dL or greater while taking a statin plus ezetimibe. (c) Primary prevention: Diabetes mellitus in adults age 40–75 without clinical ASCVD (1) Moderate-intensity statin therapy to lower LDL by 30%–49% from baseline is recommended, regardless of 10-year ASCVD risk. (2) High-intensity statin therapy to lower LDL by 50% or more from baseline is reasonable in patients at higher risk: (A) Those with multiple ASCVD risk factors (see below for diabetes-specific risk enhancers), including 10-year ASCVD risk score of 20% or more (B) Those age 50–75 (3) Consider adding ezetimibe (A) In patients receiving maximally tolerated statin therapy and who have a 10-year ASCVD risk of 20% or greater who have not had an LDL reduction 50% or more (B) To a moderate-intensity statin if high-intensity cannot be tolerated (4) May be reasonable to initiate moderate-intensity statin therapy in patients age 20–39 years with diabetes-specific risk enhancers of: (A) Long duration (10 years or more for type 2 diabetes or 20 years or more for type 1 diabetes) (B) Albuminuria of 30 mcg/mg or greater (C) eGFR less than 60 mL/minute/1.73 m2 (D) Retinopathy (E) Neuropathy (F) Ankle-brachial index (ABI) less than 0.9 (5) In patients older than 75 (A) It may be reasonable to initiate statin therapy after a clinic–patient discussion of potential benefit and risk. (B) It is reasonable to continue statin therapy if the patient is already taking statin therapy. (d) Primary prevention: No clinical ASCVD or diabetes with LDL of 70–189 mg/dL (1) Adults age 20–39: May consider statin therapy if family history of premature ASCVD and LDL 160 mg/dL or greater (2) Adults age 40–75 (A) Calculate the 10-year ASCVD risk score using the PCE risk calculator. (B) 10-year ASCVD less than 5%: low risk • Emphasize lifestyle to reduce risk factors. (C) 10-year ASCVD 5% to less than 7.5%: borderline risk • If risk-enhancing factors present, have risk discussion regarding moderate-intensity statin therapy (D) 10-year ASCVD risk of 7.5% to less than 20%: intermediate risk • Initiate moderate-intensity statin therapy if risk-enhancing factors present (see the text that follows) (E) 10-year ASCVD risk of 20% or greater: High risk • Initiate high-intensity statin therapy. (3) Risk-enhancing factors for clinician-patient risk discussion (A) Family history of premature ASCVD with onset before age 55 in a first-degree male relative or before age 65 in a first-degree female relative (B) Primary LDL of 160 mg/dL or greater or non-HDL of 190–219 mg/dL

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(C) Metabolic syndrome: Increased waist circumference, TG greater than 175 mg/dL, elevated blood pressure, elevated blood glucose, low HDL (less than 40 mg/dL in men, less than 50 mg/dL in women) (D) CKD (eGFR 15–59 mL/minute/1.73 m2) (E) Chronic inflammatory conditions (e.g., psoriasis, rheumatoid arthritis, HIV) (F) History of premature menopause (before age 40) and history of pregnancy-associated conditions that later increase ASCVD risk (e.g., preeclampsia) (G) High-risk race/ethnicities (e.g., South Asian) (H) Lipid biomarkers: • If TG are persistently (i.e., three or more measurements) elevated at 175 mg/dL or greater • If measured, high-sensitivity C-reactive protein greater than 2 mg/L, lipoprotein (a) of 50 mg/dL or greater, apoB of 130 mg/dL or greater, ABI less than 0.9 (4) If risk decision is uncertain in patients classified as intermediate risk or in those who are borderline (e.g., those without risk enhancing factors), consider measuring CAC. (A) CAC = 0: lowers risk; consider no statin unless presence of diabetes, family history of premature ASCVD, or tobacco smoking (B) CAC = 1–99: Favors statin, especially after age 55 (C) CAC = 100 plus or 75th percentile or above: initiate statin therapy (D) Measuring CAC not useful in patients already taking statins (E) CAC not typically covered by insurers; patients should be informed that testing will incur direct out-of-pocket costs ($50–$350) v. Adherence to medication and lifestyle, therapeutic response to statin therapy, and safety should regularly be assessed. e. Treatment of hypertriglyceridemia i. 2018 ACC/AHA Multisociety guidelines (a) For moderate hypertriglyceridemia (TG 175–499 mg/dL) (1) Adults 20 years and older: Recommend lifestyle therapies, secondary factors, and medications that increase TG (A) Lifestyle factors: Obesity, metabolic syndrome (B) Secondary factors: Diabetes, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism (2) Adults 40–75 years old with ASCVD of 7.5% or greater: initiate or intensity statin therapy (b) For severe hypertriglyceridemia (TG of 500 mg/dL or greater) (1) Adults 40–75 years old with ASCVD risk 7.5% or greater: initiate statin therapy (c) In adults with severe hypertriglyceridemia, especially if fasting TG concentrations are 1000 mg/dL or greater: (1) Address reversible causes. (2) Implement a very-low-fat diet (avoid carbohydrates and alcohol). (3) Initiate omega-3 fatty acids or fibrate therapy (fenofibrate if on statin) to prevent pancreatitis if necessary. ii. 2021 ACC expert consensus decision pathway on management of ASCVD risk reduction in hypertriglyceridemia (a) Persistent hypertriglyceridemia defined as fasting TG 150 mg/dL or above after at least 4–12 weeks of lifestyle intervention, a stable dose of maximally tolerated statin therapy when indicated, and evaluation and management of secondary causes of hypertriglyceridemia. When TG concentrations are 500 mg/dL and above, the primary goal is to reduce the risk of pancreatitis.

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(b) Before initiating medication therapy, clinicians should consider performing the following: (1) Evaluate and manage secondary causes, including diseases, diet/lifestyle, medications, and disorders of metabolism (2) Optimize diet/lifestyle interventions for hypertriglyceridemia (A) TG less than 500 mg/dL: sugar less than 6% of calories; total fat 30%–35% of calories; restrict alcohol (B) TG 500–999 mg/dL: sugar less than 5% of calories; total fat 20%–25% of calories; abstain from alcohol (C) TG 1000 mg/dL or above: eliminate all sugar; total fat 10%–15% of calories: abstain from alcohol (D) Weight loss goal 5%–10% for all patients with elevated TG (E) Aerobic activity of at least 150 minutes/week; moderate intensity or 75 minutes/week vigorous intensity (3) Optimize glycemic control (4) Monitor response to therapy and adherence (5) Conduct clinician-patient discussion of potential benefits-harms and patient preference (6) If TG concentrations remain elevated, consider referral to dietitian and addition of TG riskbased pharmacologic agent (c) Medication therapy (1) Option to pursue LDL risk-based therapy, TG risk-based therapy, or both; this depends on patient management group and risk (2) Statin therapy provides 10%–30% dose-dependent reduction in TG. (3) Ezetimibe, PCSK9 inhibitors, and bempedoic acid can be considered before initiation of TG risk-based therapy, depending on patient management group and risk. (4) Nonprescription fish oil products are classified as dietary supplements and are NOT interchangeable with prescription omega-3 products. (5) Icosapent ethyl is the only TG-based non-statin therapy approved for ASCVD risk reduction. (6) Prescription omega-3 carboxylic acid and omega-3 acid ethyl esters are indicated as adjuncts to diet to reduce TG concentrations in adults with severe hypertriglyceridemia (TG 500 mg/dL or above). (7) Fibrates (with preference to fenofibrate) may be used in severe hypertriglyceridemia to reduce the risk of pancreatitis. (d) Patient management groups (1) Secondary prevention patients with clinical ASCVD and fasting TG 150 mg/dL or above, non-fasting TG 175 mg/dL or above, and TG less than 500 mg/dL (Figure 2) (2) Adults 40 and older with diabetes, no ASCVD, fasting TG 150 mg/dL or above, non-fasting TG 175 mg/dL or above, and TG less than 500 mg/dL (Figure 3) (3) Adults 20 and older without ASCVD/diabetes, fasting TG 150 mg/dL or above, non-fasting TG 175 mg/dL or above, and TG less than 500 mg/dL (Figure 4) (4) Adults 20 and older with severe hypertriglyceridemia, TG 500 mg/dL or above, and especially TG 1000 mg/dL or above (Figure 5)

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Cardiology I

Rule out secondary causes and optimize lifestyle

LDL < 70 mg/dL

May consider IPE

TG risk-based approachb

Persistent fasting TG 150-499 mg/dL a

LDL 70-99 mg/dL

Shared decision-making

Combined TG/LDL risk-based approachc

LDL risk-based approach

Maximize statin therapy; optimize adherence

LDL ≥ 100 mg/dL

Consider LDL-guided non-statin therapy per 2018 AHA/ACC Multisociety cholesterol guidelined

Figure 2. ACC consensus pathway: Adults with ASCVD; fasting TG ≥ 150 mg/dL or non-fasting TG ≥ 175 mg/dL but < 500 mg/dL.

a If a patient has TG ≥ 150 mg/dL or non-fasting TG ≥ 175 mg/dL, rule out secondary causes, optimize lifestyle modifications and glucose control, maximize statin therapy, and optimize adherence. If the patient has persistent fasting hypertriglyceridemia, continue on the basis of LDL concentrations. b

Icosapent ethyl is preferred because of CVD risk reduction in this patient population.

Clinicians can use a TG risk-based approach once LDL concentrations are optimized, or vice versa.

c

d

Adding ezetimibe, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, or bempedoic acid is recommended before using a TG risk-based approach.

ASCVD = atherosclerotic cardiovascular disease; IPE = icosapent ethyl.

Age < 50 or ≥ 50 with no ASCVD risk-enhancing factors

Continue LDL risk-based approach

Age ≥ 50 with ≥ 1 ASCVD high-risk featuresb

Shared decision-making, patient preference

Persistent fasting TG 150-499 mg/dL a Can consider IPE

Figure 3. ACC consensus pathway: Adults ≥ 40 yr with DM and without ASCVD; fasting TG ≥ 150 mg/dL or nonfasting TG ≥ 175 mg/dL but < 500 mg/dL.

a If a patient has TG ≥ 150 mg/dL or non-fasting TG ≥ 175 mg/dL, first rule out secondary causes; optimize glycemic control and lifestyle modifications; optimize statin therapy, with preference for high-intensity statin; and maximize adherence. If the patient has persistent fasting hypertriglyceridemia, continue on the basis of age and ASCVD risk factors.

High-risk features include men ≥ 55, women ≥ 65, cigarette smoking, stopped smoking within 3 mo, hypertension or antihypertensive medication, HDL ≤ 40 mg/dL for men or ≤ 50 mg/dL for women, high-sensitivity CRP > 3.0 mg/L, renal dysfunction (CrCl > 30 and < 60 mL/min), retinopathy, albuminuria (≥ 30 mcg/mg), and anklebrachial index < 0.90 without symptoms of intermittent claudication.

b

DM = diabetes.

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Cardiology I

Optimize diet and lifestyle Low ASCVD risk (< 5%)

Persistent fasting TG 150-499 mg/dL a and age 40-75 yr

10-yr ASCVD risk assessment; consider other riskenhancing factorsb

Perform periodic 10-yr ASCVD risk assessment Borderlineintermediate ASCVD risk (5% to < 20%)

Shared decisionmaking, patient preference

Consider initiating or intensifying statin therapy

ASCVD risk ≥ 20%

Shared decisionmaking, patient preference

Initiate or intensify to high-intensity statin therapy

Figure 4. ACC consensus pathway: Adults ≥ 20 without ASCVD or DM; fasting TG ≥ 150 mg/dL or non-fasting TG ≥ 175 mg/dL but < 500 mg/dL.

a If patient is ≥ 20 yr without ASCVD or DM and has fasting TG ≥ 150 mg/dL or non-fasting TG ≥ 175 mg/dL, rule out secondary causes, optimize lifestyle modifications and glucose control, maximize statin therapy, and optimize adherence. If patient continues to have persistent fasting hypertriglyceridemia, continue on the basis of 10-yr risk assessment and other risk factors.

Family history of premature ASCVD, persistently elevated LDL ≥ 160 mg/dL, chronic kidney disease, metabolic syndrome, conditions specific to women (e.g., preeclampsia, premature menopause), inflammatory disease (especially psoriasis, rheumatoid arthritis, or HIV), ethnicity, lipid/biomarkers; persistently elevated TG (≥ 175 mg/dL), if measured: high-sensitivity CRP ≥ 2.0 mg/L, lipoprotein(a) ≥ 50 mg/dL, apolipoprotein B ≥ 130 mg/dL especially at higher lipoprotein(a) concentrations, ankle-brachial index < 0.9.

b

Rule out secondary causes TG 500-999 mg/dL

Persistent fasting TG 500-999 mg/dL in patients 20-39 yr, or 40-75 yr with a 10-yr ASCVD score < 5%, without ASCVD/DM

Emphasize low-fat diet Consider fibrate,a IPE, or omega-3 acid ethyl esters

Optimize diet/lifestyle

Emphasize low-fat diet

Optimize glycemic control Rule out secondary causes. Implement very-low-fat diet Optimize glycemic control

TG ≥ 1000 mg/dL

Persistent fasting TG 500-999 mg/dL in patients 40-75 yr with a 10-yr ASCVD risk ≥ 5%, ASCVD, or DM

Initiate or intensify statin therapy

Increase statin intensity and optimize adherence Consider fibrate,a IPE, or omega-3 acid ethyl esters

Consider fibrate,a IPE, or omega-3 acid ethyl esters Consider statin initiation or intensification depending on patient management group

Figure 5. ACC consensus pathway: Adults ≥ 20 yr with severe hypertriglyceridemia; TG ≥ 500 mg/dL and especially ≥ 1000 mg/dL. Fenofibrate is the preferred fibric acid derivative because it has a better safety profile and fewer drug interactions than gemfibrozil.

a

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Patient Case 8. A 62-year-old woman (height 64 inches, weight 81 kg) with a history of diabetes who underwent a three-vessel CABG 5 years earlier completes her fasting laboratory testing. Medications have been stable since her CABG and include simvastatin 80 mg/day, glipizide 5 mg twice daily, metoprolol SR 25 mg/day, and aspirin 81 mg/ day. During the past year, her renal function had steadily decreased (6 months ago, her SCr was 1.5 mg/dL). Laboratory results are as follows: TC 143 mg/dL, TG 160 mg/dL, HDL 42 mg/dL, LDL 63 mg/dL, non-HDL 101 mg/dL, SCr 2.3 mg/dL, CrCl (IBW) 21.9 mL/minute, ALT 45 IU/L, Na 144 mEq/L, K 4.9 mEq/L, and A1C 7.5%. Which is the best recommendation for this patient? A. B. C. D.

Add omega-3 fatty acids, with eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) at least 1 g/day. Add fenofibrate 160 mg/day. Continue simvastatin 80 mg/day. Change simvastatin to atorvastatin 20 mg/day.

2. 2020 AACE/ACE guidelines for managing dyslipidemia and preventing CVD (Table 14) a. Suggest targeting specific LDL, non-HDL, ApoB, and TG goals on the basis of patient risk. b. Non-HDL (total cholesterol minus HDL) reflects the total atherogenic burden, including particles contained within very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and LDL, as well as chylomicron remnants Lipoprotein (a)(Lp(A). i. More precise indicator of ASCVD risk than LDL. ii. The non-HDL goal is 25 to 30 above the LDL goal. c. ApoB refers to the total plasma concentration of apo B-100 and apo B-48. i. May be elevated in individuals with optimal LDL when small, dense LDL particles are present, such as those with insulin resistance who manifest diabetes, metabolic syndrome, obesity, or hypertriglyceridemia. ii. May provide more accurate assessment of atherogenicity because all atherogenic molecules contain 1 apo B-100 molecule. d. Low-HDL (130 mg/dL: add ezetimibe, colesevelam, bepedoic acid

Figure 6. AACE/ACE Recommendation for Treating LDL to Goal

LDL = low density lipoprotein; PCKS9i = proprotein convertase subtilisin/kexin type 9 inhibitor

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Cardiology I

Therapeutic Lifestyle Changes, Manage Secondary Causes

TG 135–499 mg/dL + CVD or DM + ≥2 RF

TG 1 qt/dayb

Use cautionb

CIb,c

Cardiology I

20 mgf

CIa

Pravastatin

Pitavastatin

Lovastatin CIa,c

Simvastatin

Itraconazole

20 mgc,f

Rosuvastatin

Fosamprenavir + ritonavir

Fluvastatin

Interacting Drug

Atorvastatin

Table 16. Statin Dosing with Interacting Drugs* (continued)

Use cautiond,c

CIb,c CIb

Ketoconazole

CIa

CIb

Nefazodone

CIa

CIb

CIa,c

CIb,c

Nelfinavir

40 mgf

Niacin (> 1 g/day)

Use cautionf

Lopinavir + ritonavir

Use lowest dosec,f

Posaconazole Ranolazine Rifampin

Simultaneous coadministrationf

Saquinavir + ritonavir Telaprevir

Telithromycin Ticagrelor

Tipranavir + ritonavir

Use cautionh

Use cautiona CIa,c

Use cautioni

Use cautiong

Use cautiond 10 mgc,d

CIa

Consider dose adjustmenta

Use cautionb CIb,c CIb 20 mgb

2 mgi

20 mgc,f

CIa,c

CIh,i

CIc,f

CIa,c

CIb,c

40 mgk

40 mgk

CIc,f

Verapamil

CIa

CIa,c

20 mga

CIb

Use cautionc,d

CIb,c

10 mgh

*Doses listed are the maximum recommended doses in combination with interacting medication.

Mevacor (lovastatin) tablets [prescribing information]. Whitehouse Station, NJ: Merck, February 2012.

a

Zocor (simvastatin) tablets [prescribing information]. Cramlington, Northumberland, UK: Merck Sharp & Dohme, February 2012.

b

U.S. Food and Drug Administration Drug Safety Communication (3-1-12): Interactions Between Certain HIV or Hepatitis C Drugs and Cholesterol-Lowering Statin Drugs Can Increase the Risk of Muscle Injury. Available at www.fda.gov/Drugs/DrugSafety/ucm293877.htm. Accessed May 1, 2012. c

Crestor (rosuvastatin calcium) tablets [prescribing information]. Wilmington, DE: AstraZeneca, February 2012.

d

Nexletol (bempedoic acid) tablets [prescribing information]. Ann Arbor, MI: Esperion, February 2020.

e

Lipitor (atorvastatin calcium) tablets [prescribing information]. New York: Pfizer, February 2012.

f

Pravachol (pravastatin sodium) tablets [prescribing information]. Princeton, NJ: Bristol-Myers Squibb, February 2012.

g

Lescol (fluvastatin sodium) capsules/Lescol XL (fluvastatin sodium) extended-release tablets [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals, February 2012.

h

Livalo (pitavastatin) tablets [prescribing information]. Montgomery, AL: Kowa Pharmaceuticals America, February 2012.

i

Multaq (dronedarone) tablets [prescribing information]. Bridgewater, NJ: Sanofi-Aventis U.S., January 2012.

j

Brilinta (ticagrelor) tablets [prescribing information]. Wilmington, DE: AstraZeneca, July 2011.

k

BID = twice daily; CI = contraindicated.

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Table 17. Characteristics of Nonstatin Medications Medication Class

Medication

Dosing

Impact on Lipid Concentrations

PCSK 9 inhibitors (note: subcutaneous administration)

Alirocumab

75–150 mg q2wk or 300 mg q4wk

Evolocumab

Bile acid sequestrants

Cholestyramine

140 mg q2wk or 420 mg q4wk

LDL ↓ 60% HDL ↑ 4%–7% TG ↓ 0%–17%

Cholesterol absorption inhibitor

Ezetimibe

Fish oil

Nicotinic acid ACL inhibitor

4–8 g BID

Colestipol

Tablets: 2–16 g/day Granules: 5–30 g/day

Colesevelam

3750 mg/day

Fenofibrate micronized

43–200 mg/day

Fenofibric acid

35–105 mg/day

Gemfibrozil

600 mg BID

Omega-3 acid ethyl esters

2–4 g/day

Fenofibrate

Fibrates

10 mg/day

Icosapent ethyl Omega-3 carboxylic acids Niacin IR Niaspan ER Slo-Niacin

Bempedoic acid

40–160 mg/day

1.5–3 g/day 1–2 g/day 1–2 g/day 180 mg/day

LDL ↓ 18%–20% HDL ↑ 1%–5% TG ↓ 10%

LDL ↓ 15%–26% HDL ↑ 3%–6% TG ↑ 0%–10%

LDL ↓ 5%–20% HDL­ ↑ 18%–22% TG ↓ 30%–50%

LDL ↑ 45% with omega-3 ethyl esters; otherwise NS HDL ↑ 0%–14% TG ↓ 20%–50% LDL ↓ 15%–26% HDL ↑ 15%–26% TG ↓ 20%–50%

LDL ↓ 15%–23% Non-HDL ↓ 11%–19% ApoB ↓ 9%–15% HDL ↓ 5%

ACL = adenosine triphosphate citrate lyase inhibitor; apoB = apolipoprotein B; ER = extended release; HDL = high-density lipoprotein cholesterol; IR = intermediate release; LDL = low-density lipoprotein cholesterol; NS - not significant; q = every; TG = triglycerides.

b. Ezetimibe i. Evidence (a) Combination therapy of simvastatin 40 mg and ezetimibe 10 mg significantly reduced CV events in patients after ACS in the IMPROVE-IT trial. (b) The ENHANCE trial showed no significant difference in carotid artery intima-media thickness in patients receiving simvastatin with or without ezetimibe in familial hypercholesterolemia despite significantly lower LDL concentrations. (c) The SHARP trial compared simvastatin 20 mg plus ezetimibe 10 mg/day versus matching placebo in patients with CKD (majority not using dialysis) with no known history of MI or coronary revascularization. Combination therapy reduced CV events.

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ii. Clinical use (a) Agent for LDL lowering used after statins maximized or not tolerated in patients with ASCVD, LDL 190 mg/dL, diabetes, or primary prevention if goal LDL reduction not achieved (see Table 11) (b) Can consider ezetimibe/simvastatin in patients with CKD iii. Contraindication: Active hepatic disease iv. Important ADRs: GI upset, potential elevation of LFTs when used in combination with statin c. PCSK9 inhibitors i. Evidence (a) Combination therapy with high-intensity statin therapy significantly reduced CV events in patients with ASCVD in both the FOURIER and the ODYSSEY OUTCOMES trials. (b) Prespecified analysis of ODYSSEY OUTCOMES indicated that alirocumab was more costeffective in patients with ACS, uncontrolled LDL, and diabetes. ii. Clinical use (a) Adjunct to diet, alone, or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe) for the treatment of adults with primary hyperlipidemia (including familial hypercholesterolemia) (b) To reduce the risk of MI, stroke, and coronary revascularization in adults with established CVD (Table 12) (c) Can be used in statin-intolerant patients (d) Use has been limited by cost, but both manufacturers have lowered price to $5800/year, which correlates to around $125,000/year to prevent one CV event every 2 years. iii. Contraindication: History of hypersensitivity reaction to either medication iv. Important ADRs: Allergic reactions, injection site reactions, nasopharyngitis, upper respiratory infection, myalgia, skeletal muscle pain, diarrhea, cough, elevated LFTs d. Bile acid sequestrants i. Evidence: Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) showed that cholestyramine monotherapy reduced coronary events. ii. Clinical use (a) Agent for LDL lowering used after maximally tolerated statins and ezetimibe (b) Colesevelam lowers glucose concentrations. iii. Contraindication: Complete biliary obstruction, TG greater than 300 mg/dL iv. Important ADRs: GI effects (e.g., constipation, obstruction), decreased drug absorption, increased TG concentrations e. Niacin (vitamin B3; examples include immediate-release (IR) niacin, Slo-Niacin, and Niaspan) i. Evidence: Has not been found to lower CV events when used in combination with statin therapy, and some trials have suggested possible harm with use ii. Clinical use not recommended for use in current 2018 ACC/AHA lipid guidelines iii. Contraindications (a) Active hepatic disease, active peptic ulcer, arterial hemorrhage (b) Caution in uncontrolled diabetes and gout iv. Important ADRs (a) Flushing or itching (1) Less common in controlled-release preparations (2) Food, aspirin 30 minutes before administration, nighttime administration, and slow-dose titration can improve symptoms. (3) ER products possibly better tolerated, but can cause more liver dysfunction than IR products; however, flushing is not as severe with ER products than with IR products (b) Elevated LFTs, hyperuricemia, hyperglycemia, upper GI distress ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 161

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f. Adenosine triphosphate citrate lyase inhibitor (ACL) inhibitors (bempedoic acid) i. Evidence (a) Bempedoic acid lowered LDL by 15%–25% in clinical trials and by up to 38% when used in combination with ezetimibe. (b) LDL, non-HDL, and apoB were significantly reduced when bempedoic acid was used in combination with maximally tolerated statin therapy (CLEAR HARMONY, CLEAR Wisdom) in statin-intolerant patients as monotherapy (CLEAR Serenity), in statin-intolerant patients in combination with ezetimibe (CLEAR Tranquility), and in combination with ezetimibe in patients with established ASCVD, HeFH, or several CV risk factors (Eur J Prev Cardiol 2020;27:593-603). (c) Ongoing CLEAR OUTCOMES trial will evaluate whether bempedoic acid can lower ASCVD events in statin-intolerant patients. ii. Clinical use (a) Adjunct to maximally tolerated statin therapy in adults with HeFH (b) Adjunct to diet and maximally tolerated statin therapy in adults with ASCVD (c) Can be used in statin-intolerant patients and in combination with ezetimibe g. Other OTC options i. Plant stanols or sterols (a) The National Cholesterol Education Program recommended these as adjuncts to diet. (b) 15%–20% LDL reduction is possible, if taken as directed (usually in large quantities). ii. Red yeast rice (a) Some red yeast rice products contain monacolin K, which is chemically identical to the active ingredient of lovastatin. (b) Caution is warranted because of lack of regulatory oversight and quality control (cases of hepatic failure, absence active drug). Patient Case 9. A 50-year-old African American woman who does not smoke and has no significant medical history presents for her annual well-woman examination. Her fasting laboratory test results are as follows: TC 157 mg/dL, TG 277 mg/dL, HDL 39 mg/dL, LDL 63 mg/dL, non-HDL 118 mg/dL, SCr 0.9 mg/dL, ALT 20 IU/L, Na 144 mEq/L, K 4.5 mEq/L, and FBG 99 mg/dL. Her BMI is 30.3 kg/m2 and BP is 110/60 mm Hg. Which is best to manage her elevated TG? A. B. C. D.

Diet, exercise, and weight loss. Fenofibrate 160 mg/day. Gemfibrozil 600 mg twice daily. Pravastatin 80 mg every evening.

2. TG-lowering drugs a. Fibrates (fenofibrate, gemfibrozil) i. Evidence (a) Reduces coronary events as monotherapy according to the Helsinki Heart Study, VA-HIT, and FIELD (b) Has not been found to reduce CV events in combination with statin therapy, except in subgroup with elevated TG and low HDL (ACCORD-LIPID) ii. Clinical use: In general, fibrates are reserved for patients with high TG values (greater than 500 mg/dL), despite implementation of lifestyle modifications. Gemfibrozil should not be used in combination with statin therapy because of the risk of myopathy (2018 AHA/ACC guidelines). ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 162

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iii. Contraindications (a) Significant renal or hepatic dysfunction (b) Gallbladder disease (c) Biliary cirrhosis iv. Important ADRs (a) Dyspepsia, gallstones, myalgia (b) More severe (but rarer) ADRs: Elevated LFTs, myopathy, increases in SCr v. Dosing and monitoring (a) Fasting lipid panel and ALT assessment 6–8 weeks after initiation or titration, patients should report unusual muscle pain or weakness immediately, and CK concentration should be assessed. (b) Assess renal function at baseline, within 3 months of initiation, and then every 6 months. (c) Adjust dose for renal insufficiency. (1) Fenofibrate should not be used when eGFR is less than 30 mL/minute/1.73 m2. (2) Fenofibrate dose should not exceed 54 mg if GFR is 30–59 mL/minute/1.73 m2. b. Fish oil: Prescription options include omega-3 acid ethyl esters (Lovaza), omega-3 carboxylic acid (Epanova), and icosapent ethyl (Vascepa). i. Evidence (a) Dietary supplementation with n–3 polyunsaturated fatty acids and vitamin E after MI: Results of the GISSI-Prevenzione trial show a significantly reduced risk of sudden death associated with the use of 850 mg/day of DHA/EPA combined. (b) REDUCE-IT: Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia trial (N Engl J Med 2019;380:11-22). Randomized 8179 participants with either ASCVD or diabetes plus one or more CV risk factors receiving moderate- to high-intensity statin therapy and TG 135–499 mg/dL to icosapent ethyl 2 g twice daily or placebo. Icosapent ethyl significantly reduced the primary CV outcome of CV death, nonfatal MI, stroke, coronary revascularization, or unstable angina (HR 0.75; 95% CI, 0.68–0.83). (c) JELIS trial (Lancet 2007;369:1090-8): 18,645 Japanese participants with hypercholesterolemia randomized to EPA 1.8 g daily plus low-intensity statin compared with low-intensity statin therapy alone. Major CV events were reduced by 19% in EPA group, with greatest benefit in those with TG 150 mg/dL or above and low HDL. (d) VITAL trial (N Engl J Med 2019;380:22-32): 25,871 primary prevention participants randomized to either active fish oil (1000-mg capsule with 840 mg of EPA plus DHA) or placebo. No significant difference in major CV events shown (e) OMEMI trial (Circulation 2021;143:528-39): Compared 1.8 g of omega-3 fatty acids (930 mg of EPA plus 660 mg of DHA) with placebo for secondary prevention in 1027 participants age 70– 82 years with recent (2–8 weeks) acute MI. No significant difference in CV outcomes shown (f) STRENGTH trial (JAMA 2020;324:2268-80): Randomized 13,078 patients with high CV risk (established CVD, diabetes with at least one additional risk factor, or men at least 50 years of age and women at least 60 years with at least one additional risk factor) to either 4 g of omega-3 carboxylic acids (550 mg of EPA plus 200 mg of DHA) or placebo. Trial was stopped early and showed no significant difference in CV events. (g) ASCEND trial (N Engl J Med 2018;379:1540-50): Evaluated 15,840 primary prevention participants with diabetes who were randomized to either 1 g of marine n-3 fatty acids (460 mg of EPA plus 380 mg of DHA) or placebo. No significant differences in CV events shown ii. Clinical use (a) Icosapent ethyl is now FDA approved as adjunctive therapy with statins to reduce the risk of CV events in patients with elevated TG (150 mg/dL or above) plus established ASCVD or diabetes and 2 or more ASCVD risk factors.

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(b) Omega-3 acid ethyl esters and omega-3 carboxylic acid contain both DHA and EPA and can increase LDL concentrations. (c) Icosapent ethyl contains only EPA and does not increase LDL. (d) Differences in CV outcomes may be a result of the different formulations (e.g., EPA alone vs. EPA and DHA combination). iii. Important ADRs (a) Fishy taste or burping (b) Antiplatelet effects (c) Atrial fibrillation or flutter iv. Contraindication: Hypersensitivity to fish v. Dosing and monitoring (a) OTC (choose concentrated products) and prescription products (discussed earlier) available; OTC versions often include omega-3 fatty acids and not as strong as prescription-strength formulations; these require more capsules per day to achieve the same dose as the prescription products (b) Base the dose on the amount of DHA/EPA per capsule. c. Niacin: See the previous section (B.1.e). 3. Other lipid-lowering medications a. Mipomersen i. Evidence: Studied in small trials, mainly in patients with familial hypercholesterolemia; LDL significantly lowered ii. Clinical use: Indicated for patients with homozygous familial hypercholesterolemia (a) Important ADRs: Injection site reactions, elevated LFTs (b) Dosing and monitoring: Given once weekly by subcutaneous injection b. Lomitapide i. Evidence: Studied in small trials, mainly in patients with familial hypercholesterolemia; LDL significantly lowered ii. Clinical use: Indicated for patients with homozygous familial hypercholesterolemia (a) Important ADRs: Black box warning for serious risk of liver toxicity, teratogenic, GI symptoms, including elevated LFTs iii. Dosing and monitoring (a) Dose by mouth once daily and titrate as tolerated. (b) This medication is very expensive. (c) LFTs and pregnancy tests (as indicated) must be done routinely. (d) Fat-soluble nutrients must be supplemented to avoid deficiency. C. Special Patient Populations (Domains 1, 3) 1. Older adults a. 2018 AHA/ACC guidelines b. It may be reasonable to initiate moderate-intensity statin therapy in patients 75 and older with an LDL of 70–189 mg/dL c. In adults 75 and older, it may be reasonable to discontinue statin therapy when functional decline, multimorbidity, frailty, or reduced life expectancy limit the potential benefits of statin therapy. d. In adults age 76–80 with an LDL of 70–189 mg/dL, it may be reasonable to measure CAC to reclassify those with a score of zero to avoid statin therapy. 2. HFrEF a. Follow the 2018 AHA/ACC guidelines. b. If HFrEF is attributable to ischemic heart disease and patients have a reasonable (3–5 years) life expectancy, consider initiating moderate-intensity statin therapy. c. CORONA trial showed reduced hospitalizations in patients receiving rosuvastatin 10 mg daily. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 164

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3. Chronic inflammatory disorders and HIV a. Follow the 2018 AHA/ACC guidelines. b. Chronic inflammatory disorders and HIV are risk-enhancing factors. c. For adults age 40–75 with LDL 70–189 mg/dL who have a 10-year ASCVD risk of 7.5% or higher, moderate- or high-intensity statin therapy is preferred. 4. Diabetes a. 2021 ADA standards of medical care in diabetes (note that the ADA does endorse the 2018 AHA/ACC guidelines) b. Statin recommendations i. Clinical ASCVD (a) High-intensity statin, regardless of age (b) If LDL is 70 mg/dL or greater despite the maximally tolerated statin dose, consider adding ezetimibe or a PCSK9 inhibitor. ii. No clinical ASCVD (a) 10-year ASCVD risk (using PCE) 20% or greater: Initiate high-intensity statin therapy. (b) Age younger than 40 (1) No statin therapy (2) Can consider moderate intensity depending on risk-benefit profile and presence of ASCVD risk factors: (A) Family history of premature ASCVD (B) HTN (C) Tobacco smoking (D) LDL of 100 mg/dL or greater (E) CKD (F) Albuminuria (c) Age 40–75 (1) Moderate-intensity statin therapy recommended (2) Can consider high-intensity statin therapy depending on risk-benefit profile and presence of ASCVD risk factors (d) Age older than 75 (1) If already on statin therapy, reasonable to continue statin treatment (2) May be reasonable to initiate after discussion of risk-benefit iii. If intended statin intensity not tolerated, use maximally tolerated statin dose 5. CKD a. 2018 AHA/ACC guidelines i. CKD is considered a risk-enhancing factor. ii. Adults age 40–75 with LDL 70–189 mg/dL who have a 10-year ASCVD risk of 7.5% or higher: Reasonable to initiate moderate-intensity statin or moderate-intensity statin in combination with ezetimibe iii. Reasonable to continue statin therapy in CKD patients who progress to dialysis, but not recommended to initiate statin therapy while patient is receiving dialysis b. KDIGO dyslipidemia guidelines 2013 (recommendations in addition to 2018 AHA/ACC guidelines) i. Patients older than 50 with an eGFR of less than 60 mL/minute/1.73 m2, but not treated with dialysis or kidney transplantation: Treatment with a recommended dosed statin or statin/ezetimibe combination is advised. ii. Patients older than 50 with CKD and an eGFR greater than 60 mL/minute/1.73 m2: Treatment with a recommended dosed statin is advised.

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iii. Statins should not be initiated for patients undergoing dialysis; however, if patients undergoing dialysis are already receiving statins or a statin/ezetimibe combination when dialysis is initiated, statins should be continued. iv. Statins should be used after kidney transplantation. v. In adults younger than 50 with CKD but not treated with dialysis or kidney transplantation, statin treatment is recommended if the patient has at least one of the following concomitant conditions: (a) Known coronary disease (MI or coronary revascularization) (b) Diabetes mellitus (c) Prior ischemic stroke (d) Estimated 10-year incidence of coronary death or nonfatal MI greater than 10% vi. Recommended statin doses in adults with stage 3a–5 CKD (including patients receiving dialysis or with a kidney transplant) are based on statins and doses that have been studied in this patient population. Dosing recommendations are as follows: (a) Atorvastatin 20 mg/day (b) Fluvastatin 80 mg/day (c) Lovastatin: Not studied (d) Pitavastatin 2 mg/day (e) Pravastatin 40 mg/day (f) Rosuvastatin 10 mg/day (g) Simvastatin 40 mg/day (h) Simvastatin/ezetimibe 20/10 mg/day c. Dose modifications that are based on package labeling may conflict with KDIGO recommendations. i. Estimated CrCl less than 30 mL/minute (a) Lovastatin 10–40 mg/day (b) Simvastatin 10–40 mg/day (c) Atorvastatin 10–80 mg/day (d) Rosuvastatin 5–10 mg/day (e) Pravastatin 10–80 mg/day (f) Pitavastatin 1–2 mg/day (g) Fluvastatin: No dosage adjustment necessary ii. Estimated CrCl of 30–60 mL/minute: Pitavastatin 1–2 mg/day iii. Estimated CrCl less than 50 mL/minute: Initiate lower-dose fenofibrate (54 mg/day) and gemfibrozil (300 mg twice daily), and titrate as needed. iv. No dose adjustment is needed for people receiving dialysis, except for pitavastatin (1–2 mg/day) and fenofibrate (avoid).

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Patient Cases 10. A 52-year-old man with a history of symptomatic atrial fibrillation, dyslipidemia, and hypothyroidism presents to the clinic. For the past month, he has been in atrial fibrillation, with unsuccessful cardioversion. His cardiologist initiated chronic amiodarone therapy today. His medications include simvastatin 40 mg/ day, levothyroxine 137 mcg/day, warfarin as directed, and metoprolol succinate 50 mg/day. Laboratory test results are as follows: TC 131 mg/dL, TG 100 mg/dL, HDL 32 mg/dL, LDL 79 mg/dL, non-HDL 99 mg/dL, SCr 1.1 mg/dL, CrCl 83 mL/ minute, ALT 52 IU/L, Na 142 mEq/L, K 4.8 mEq/L, INR 2.3, and TSH 4.32 mIU/mL. Which is the best treatment recommendation for this patient? A. Discontinue simvastatin because it cannot be used concomitantly with amiodarone. B. Increase simvastatin to 80 mg every evening because the patient’s LDL will increase once amiodarone therapy is begun. C. Lower simvastatin to 20 mg every evening to reduce the risk of a drug-drug interaction. D. Add niacin 500 mg twice daily to increase his HDL.

11. A 76-year-old man with a history of CAD and diabetes completes his fasting laboratory testing. For the past 2 months, he has been treated for a diabetic foot ulcer. While interviewing the patient, you discover that he helped his wife tear down her jewelry display at a convention and had been feeling achy during the past week. Medications include atorvastatin 80 mg/day, niacin 500 mg twice daily, fish oil supplement 1000 mg/ day, metoprolol succinate 25 mg/day, lisinopril 20 mg/day, and aspirin 81 mg/day. Laboratory test results are as follows: TC 148 mg/dL, TG 146 mg/dL, HDL 37 mg/dL, LDL 82 mg/dL, non-HDL 111 mg/dL, CK 1064 U/L, SCr 1.7 mg/ dL, CrCl 37 mL/minute, ALT 36 IU/L, Na 144 mEq/L, and K 5.0 mEq/L. Which is best to address his laboratory test results? A. Discontinue atorvastatin because of his elevated CK. The patient will be unable to take statin therapy in the future. B. Hold atorvastatin because of his elevated CK, and monitor his CK. C. Continue therapy because the elevated CK is likely caused by his diabetic foot ulcer and recent strenuous activity. D. Change his therapy to ezetimibe/simvastatin 10/80 mg/day because his LDL is not at goal.

IV.  SECONDARY PREVENTION OF MYOCARDIAL INFARCTION AND STABLE ISCHEMIC HEART DISEASE Guidelines 1. 2016 ACC/AHA guideline focused update on duration of DAPT 2. 2014 AHA/ACC guideline for treating patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS) 3. 2013 ACCF/AHA guideline for managing ST-segment elevation MI (STEMI) 4. 2012 ACCF/AHA guideline for diagnosing and managing stable ischemic heart disease (SIHD) 5. 2014 ACC/AHA guideline on perioperative CV management for noncardiac surgery 6. 2012 update to Society of Thoracic Surgeons guideline on antiplatelet drugs for patients having cardiac and noncardiac operations A. AHA 2017 Performance Measures for MI Applicable to the Outpatient Setting (Domains 1, 2) 1. Aspirin prescribed at discharge 2. P2Y12 receptor inhibitor prescribed at discharge

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3. β-Blocker prescribed at hospital discharge 4. High-intensity statin prescribed at discharge 5. ACE inhibitor or ARB for patients with left ventricular systolic dysfunction (LVSD) B. Lifestyle Counseling (Domains 1, 2, 5) 1. Diet and physical activity a. Same counseling as for primary prevention patient, except exercise as tolerated b. Encourage consumption of fish. c. Encourage smoking cessation. C. Referral to a Cardiac Rehabilitation Program (Domains 1, 2) 1. American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR): www.aacvpr.org/ 2. 2010 AACVPR/ACCF/AHA performance measures for cardiac rehabilitation and secondary prevention services a. All patients hospitalized for MI, PCI, or cardiac surgery should be referred before discharge. b. All outpatients who did not participate in a program within the past 12 months after hospitalization should be referred. 3. Core components of a cardiac rehabilitation program for secondary prevention of CHD (2007 AHA/ AACVPR) a. Patient assessment b. Nutritional counseling c. Lipid management d. Blood pressure management e. Smoking cessation f. Weight management g. Diabetes management h. Psychosocial management i. Physical activity counseling j. Exercise training D. Antiplatelets for Patients with ACS (Domains 1, 3) 1. DAPT with aspirin and a P2Y12 inhibitor is recommended for at least 12 months after ACS according to the most recent guidelines (Table 17). a. Aspirin is given at a preferred dose of 81 mg/day (75–100 mg/day). b. Aspirin monotherapy is continued after 12 months of DAPT. c. However, recent studies have suggested that shortening the duration of DAPT is safe and efficacious. Of importance, the following trials included mostly stable angina with elective PCI, UA, and/or NSTEMI (Table 18). 2. Choice of P2Y12 inhibitor a. For patients with NSTE-ACS who are treated with medical therapy alone (without revascularization or a fibrinolytic therapy– or ischemia-guided strategy) i. Clopidogrel and ticagrelor are preferred. ii. It is reasonable to choose ticagrelor over clopidogrel. b. For patients with ACS treated with PCI (invasive strategy) i. Clopidogrel, ticagrelor, and prasugrel are preferred. ii. Ticagrelor is reasonable in preference to clopidogrel for maintenance P2Y12 inhibitor therapy. iii. Prasugrel is reasonable in preference to clopidogrel for maintenance P2Y12 inhibitor therapy if the patient is not at high risk of bleeding complications and has no history of stroke or TIA.

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Table 17. P2Y12 Inhibitor Therapy for Secondary Prevention in Patients with Recent ACS (2016 ACC/AHA Focused Update) Therapy Duration (Class Recommendations)a

ACS

Clopidogrel

After CABG, resume P2Y12 inhibitor to complete 1 yr of DAPT (I)b

CABG

Medical therapy

At least 12 mo (I)b,d

Lytic (STEMI)

At least 14 days and up to 12 mo (I)b,d

PCI (BMS or DES)

Therapy Options

Ticagrelor

c

Prasugrel

Clopidogrel c

Clopidogrel

At least 12 mo (I)b,d

Clopidogrel Ticagrelor

75 mg/day

90 mg BID

10 mg/day; consider dose reduction to 5 mg/day orally for patients weighing < 60 kg (I); in general, not recommended for patients ≥ 75 (I); contraindicated in patients with prior stroke or TIA (III)

c

Ticagrelor

Doses

c

Prasugrel

c

75 mg/day

90 mg BID 75 mg/day 75 mg/day

90 mg BID

10 mg/day; consider dose reduction to 5 mg/day orally for patients weighing < 60 kg (I); in general, not recommended for patients ≥ 75 yr (I); contraindicated in patients with prior stroke or TIA (III)

Class recommendations refer to the 2016 ACC/AHA focused update.

a

Option to discontinue after 6 mo may be reasonable if high bleeding risks (those who have or who develop high risk of bleeding [e.g., treatment with oral anticoagulant therapy] or are at increased risk of severe bleeding complication [e.g., major intracranial surgery] or significant overt bleeding (IIb)).

b

It is reasonable to choose ticagrelor or prasugrel over clopidogrel for maintenance P2Y12 inhibitor therapy (IIa).

c

d

Option to continue beyond 12 mo if no high risk of bleeding and no significant overt bleeding on DAPT (IIb).

ACC = American College of Cardiology; ACS = acute coronary syndrome; AHA = American Heart Association; BMS = bare metal stent; CABG = coronary artery bypass grafting; DES = drug-eluting stent; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction; TIA = transient ischemic attack.

Table 18. Studies Comparing Shorter vs. Longer Duration of DAPT Trial

TWILIGHT

TICO

Patient Populations

Interventions

Major Outcomes

• 11 countries • DAPT (ticagrelor 90 mg BID + • Ticagrelor monotherapy • Patients (n=7119) aspirin 81–100 mg/day) × 3 mo noninferior to DAPT for primary undergoing DES PCI • Followed by ticagrelor vs. composite CV end point • ~30% stable angina, DAPT • Reduction in all bleeding 35% UA, 30% end points with ticagrelor NSTEMI monotherapy

• Korean patients • DAPT × 3 mo (n=3056) with ACS • Followed by ticagrelor 90 mg undergoing DES PCI BID monotherapy or 12 mo of • ~36% STEMI ticagrelor-based DAPT

• Significant reduction in primary CV end point with ticagrelor monotherapy vs. 12 mo of DAPT • Major bleeding reduced in monotherapy group

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Table 18. Studies Comparing Shorter vs. Longer Duration of DAPT (continued) Trial

SMART-CHOICE

STOPDAPT-2

GLOBAL LEADERS

ASET pilot study

Patient Populations

Interventions

Major Outcomes

• Japanese patients (n=3045) undergoing DES PCI • ~62% stable CAD, 38% ACS

• DAPT (clopidogrel 75 mg/day + aspirin 81–100 mg/day) × 1 mo • Followed by clopidogrel vs. DAPT

• Primary end point (composite CV and bleeding outcomes) significantly reduced with P2Y12 monotherapy, driven by reduction in bleeding

• Korean patients (n=2993) undergoing DES PCI • ~42% stable angina, 31% UA, 16% NSTEMI, 11% STEMI

• DAPT (clopidogrel 75 mg/ day, prasugrel 10 mg/day, or ticagrelor 90 mg BID + aspirin 100 mg/day) for 3 mo • Followed by P2Y12 monotherapy vs. DAPT

• P2Y12 monotherapy noninferior to DAPT for primary composite CV end point • Reduction in bleeding with P2Y12 monotherapy

• Patients (n=15,968) • Ticagrelor 90 mg BID + aspirin • Ticagrelor monotherapy failed undergoing DES PCI 75–100 mg/day for 1 mo, to show superiority to standard for stable CAD or followed by 23 mo of ticagrelor DAPT ACS monotherapy to standard DAPT with clopidogrel 75 (stable CAD) mg/day or ticagrelor 90 mg BID (ACS) + aspirin 75–100 mg/day for 12 mo, followed by aspirin monotherapy for 12 mo

• Patients (n=201) • Loading dose of aspirin 300 undergoing DES PCI mg and clopidogrel 600 mg at for stable CAD time of index PCI • Loading dose of prasugrel 60 mg then administered in catheterization laboratory (excluded in those already receiving prasugrel) • Followed by prasugrel 10 mg/ day monotherapy × 3 mo • After 3 mo, patients changed to either DAPT or aspirin monotherapy

• 98.5% of patients adherent to prasugrel • Primary ischemic and bleeding end points occurred in one patient (0.5%) • No stent thrombotic events occurred

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Table 18. Studies Comparing Shorter vs. Longer Duration of DAPT (continued) Trial

MASTER DAPT

Patient Populations

• Patients (n=4579) with symptomatic CAD at high risk of bleeding who had undergone PCI within the previous 30–44 days

Interventions

Major Outcomes

• Those without an indication for • 1 mo of DAPT was noninferior OAC to continuation of DAPT for at DAPT × 1 mo after PCI least 2 additional months; results Followed by SAPT vs. DAPT were consistent among those for 5 mo with and without an indication • Those with an indication for for OAC OAC • Abbreviated therapy was DAPT x 1 mo after PCI associated with significantly less Followed by SAPT vs. DAPT bleeding for 2 mo • Choice of P2Y12 inhibitor used and type of SAPT at discretion of investigator

ACS = acute coronary syndrome; BID = twice daily; CAD = coronary artery disease; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; NSTEMI = non– ST-segment elevation myocardial infarction; OAC = oral anticoagulant; PCI = percutaneous coronary intervention; SAPT = single antiplatelet therapy; STEMI = ST-segment elevation myocardial infarction; UA = unstable angina.

3. Efficacy and treatment goals for secondary prevention in patients not undergoing PCI a. NSTE-ACS i. Clopidogrel reduced the risk of death, MI, or stroke (composite end point) by 20% (similar to patients undergoing PCI, according to the subgroup analysis of the CURE trial. ii. Ticagrelor reduced the composite end point of death from CV causes, MI, or stroke significantly more than clopidogrel (HR 0.84; 95% CI, 0.77–0.92) in the PLATO trial. iii. The TRILOGY trial compared prasugrel with clopidogrel in patients with ACS not undergoing revascularization and found that prasugrel did not reduce the risk of CV events but did increase bleed risk. b. STEMI i. Clopidogrel reduced mortality by 7% and death, reinfarction, or stroke by 9% compared with placebo when added to aspirin and standard therapy in the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT). ii. Ticagrelor reduced the composite end point of death from CV causes, MI, or stroke significantly more than clopidogrel (HR 0.84; 95% CI, 0.77–0.92) in the PLATO trial. 4. Efficacy and treatment goals for patients undergoing PCI a. Prasugrel versus clopidogrel: Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 i. Studied only in patients undergoing PCI (NSTE-ACS and STEMI) ii. Prasugrel reduced the risk of the primary end point of CV death, MI, or stroke at 30 days and 15 months compared with clopidogrel. iii. Increased risk of bleeding, including life-threatening bleeding, with prasugrel in overall study (2.4% vs. 1.8%) at 15 months iv. Increased risk of bleeding in patients with low body weight (less than 60 kg) and in patients 75 and older v. Prasugrel contraindicated in patients with prior stroke or TIA vi. Subgroups in which benefit occurred without increased bleeding risk (a) STEMI (b) Diabetes mellitus ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 171

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vii. Core cohort of patients without history of stroke or TIA, weighing 60 kg or more, and younger than 75 (a) 26% reduction in CV death, MI, or stroke (b) No increased bleeding risk b. Prasugrel versus ticagrelor: ISAR-REACT 5 trial i. Studied in patients with ACS undergoing PCI ii. Prasugrel was associated with a 2.4% absolute risk reduction in the primary outcome of death, nonfatal MI, and stroke; this was driven primarily by a reduction in nonfatal MI. iii. Major bleeding was similar in both groups. c. Ticagrelor versus clopidogrel: PLATO trial i. Studied in both NSTE-ACS and STEMI in patients with intended medical management (results previously stated) and those with intended early coronary angiography or revascularization ii. Ticagrelor reduced CV death, MI, or stroke as a composite end point and individual end points of CV death, MI, and all-cause mortality compared with clopidogrel. iii. There was no difference in study-defined bleeding, but non–CABG-related major bleeding was higher with ticagrelor. 5. Extended duration of DAPT a. The DAPT study evaluated long-term use of DAPT (30 months) with clopidogrel or prasugrel plus aspirin after DES placement and showed a reduced rate of stent thrombosis and major adverse CV and cerebrovascular events, but moderate-severe bleeding was higher. i. A DAPT trial subanalysis introduced the DAPT score, which weighs bleeding risk beyond 1 year after PCI (Table 19). (a) For those with a DAPT score of 2 or greater, prolonged DAPT reduces net events. (b) For those with a DAPT score less than 2, there is an unfavorable risk-benefit ratio. (c) Limitations include modest discrimination, application only to the DAPT population, and the need for confirmation. b. The PEGASUS-TIMI 54 trial evaluated the long-term use of DAPT with ticagrelor and aspirin in patients with a prior MI (1–3 years before enrollment) and showed lower CV events in the prolonged therapy, but bleeding rates were higher with ticagrelor. 6. Triple antiplatelet therapy with vorapaxar: Competitive inhibitor of platelet protease-activated receptor on platelet surface; blocks thrombin-mediated platelet activation a. TRACER trial: compared vorapaxar with placebo in addition to standard therapy (91.1% taking clopidogrel) in patients with NSTE-ACS; vorapaxar did not achieve the primary end point compared with placebo but did reduce secondary end point of MI. However, bleeding was increased with vorapaxar. b. TRA 2P = TIMI 50 trial: compared vorapaxar added to aspirin and/or thienopyridine (most received clopidogrel; only 0.7% received prasugrel) as part of standard care, compared with placebo in patients with a history of ASCVD. Vorapaxar reduced the primary combined end point but increased bleeding. i. Net clinical benefit shown in patients with MI (reduction in primary end point) and PAD (reduction in hospitalization for limb ischemia and peripheral artery revascularization) ii. Stroke arm of the trial was discontinued early because of increased risk of intracranial hemorrhage. c. U.S. Food and Drug Administration (FDA) approval: Patients with a history of MI or PAD in adjunct to aspirin, clopidogrel, or both; contraindicated in patients with history of stroke, TIA, intracranial hemorrhage, or active bleeding i. Approved dose is 2.08 mg daily. ii. This dose is equivalent to 2.5 mg of vorapaxar sulfate. 7. Colchicine: Inhibits β-tubulin polymerization and NLRP3 inflammasome activation, reduces production of interleukin-6 and CRP inflammatory biomarkers, and stabilizes coronary plaque a. Circulating levels of acute-phase inflammatory biomarkers correlate with prognosis after an ACS.

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b. Trials evaluating use in patients with a recent MI i. COLCOT trial: Compared colchicine 0.5 mg/day with placebo in patients with a recent MI (30 days or less) for whom any planned PCI had been performed (a) Significantly reduced composite end point of CV death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization leading to coronary revascularization (HR 0.77; 95% CI, 0.61–0.96) (b) Efficacy was more pronounced for strokes (HR 0.26) and urgent hospitalizations requiring revascularization (HR 0.50). ii. COPS trial: Evaluated colchicine 0.5 mg twice daily for 30 days, followed by 0.5 mg/day for 11 months compared with placebo in patients with ACS and 30% or more luminal stenosis treated with either PCI or medical treatment alone (a) No significant difference found in composite end point (6.1% vs. 9.5%; p=0.09) (b) Lack of statistical significance, possibly because of a smaller-than-anticipated sample size and short duration of follow-up iii. CLEAR SYNERGY trial (NCT03048825): Aims to randomize 7000 participants with MI treated with PCI to colchicine 0.5 mg twice daily compared with placebo c. COLCHICINE_PCI trial i. Compared colchicine with placebo in patients undergoing PCI ii. Colchicine dosed at 1.2 mg given 1–2 hours before procedure, followed by 0.6 mg 1 hour after PCI iii. Numerical but not statistically significant reduction in MI related to PCI (57.3% with colchicine vs. 64.2% with placebo; p=0.19) Table 19. Dual Antiplatelet Therapy Scorea Variable

Points

Age ≥ 75

Age 65 to < 75 Age < 65

Current cigarette smoker Diabetes mellitus

MI at presentation

Prior PCI or prior MI

Stent diameter < 3 mm Paclitaxel-eluting stent CHF or LVEF < 30%

Saphenous vein graft PCI

−2 −1 0 1 1 1 1 1 1 2 2

A score ≥ 2 is associated with a favorable benefit-risk ratio for prolonged DAPT, whereas a score < 2 is associated with an unfavorable benefit-risk. a

CHF = congestive heart failure; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention.

E. Antiplatelet Therapy in Patients with Atrial Fibrillation Undergoing PCI (Please see the Cardiology II chapter for further information on atrial fibrillation) 1. 2020 ACC Expert Consensus Decision Pathway for Anticoagulant and Antiplatelet Therapy in Patients with Atrial Fibrillation or Venous Thromboembolism Undergoing Percutaneous Coronary Intervention or with Atherosclerotic Cardiovascular Disease (J Am Coll Cardiol 2021;77:629-58) a. Addresses use of anticoagulant and antiplatelet therapy in patients with atrial fibrillation or venous thromboembolism undergoing PCI or with ASCVD (Figure 8, Figures 9a and 9b) ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 173

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b. General principles i. Recommend against routine use of triple antithrombotic therapy for most patients. ii. Strongly recommend dual therapy with an oral anticoagulant plus a P2Y12 inhibitor. iii. If triple therapy is used, limit to the shortest duration possible (up to 30 days post-PCI). iv. For a recent PCI (6 months or less SIHD, 12 months or less ACS), a P2Y12 inhibitor is the preferred antiplatelet. v. Clopidogrel is the preferred P2Y12 inhibitor for combination antithrombotic therapy. vi. Aspirin dose should not exceed 100 mg/day. vii. If indefinite oral anticoagulant (OAC) therapy is not indicated, duration of antiplatelet therapy should follow the 2016 ACC/AHA DAPT guidelines. If indefinite OAC therapy is indicated, antiplatelet therapy should be continued for 1 year post-PCI; follow the 2016 ACC/AHA recommendations for duration of single antiplatelet therapy (SAPT) versus DAPT. viii. If at high risk of bleeding, may discontinue SAPT before recommended duration; should weigh risk of bleeding versus risk of stent thrombosis ix. If patient requires a vitamin K antagonist, reasonable to target INR 2.0–2.5 x. If patient is on two or more antithrombotic agents, start or continue a proton pump inhibitor or histamine-2 receptor antagonist, and avoid nonsteroidal anti-inflammatory drugs; may discontinue once the patient is on OAC monotherapy unless there are other indications for use xi. Cost and patient preference may be considered. 2. 2019 AHA/ACC/HRS focused update for treatment of patients with atrial fibrillation a. For patients with ACS and atrial fibrillation at increased risk of thromboembolism on the basis of a CHA2DS2-VASc risk score of 2 or greater, anticoagulation is recommended unless the bleeding risk outweighs the benefit. b. If triple therapy is prescribed for stenting with ACS, it is reasonable to choose clopidogrel in preference to prasugrel. c. Double therapy with the following is reasonable to reduce the risk of bleeding compared with triple therapy: i. P2Y12 inhibitor (clopidogrel or ticagrelor) and dose-adjusted warfarin, using a lower target INR of 2–2.5 ii. Clopidogrel and rivaroxaban 15 mg daily iii. Clopidogrel and dabigatran 150 mg twice daily d. If triple therapy is prescribed, a transition to double therapy with OAC and P2Y12 inhibitor at 4–6 weeks may be considered. 3. 2018 CHEST guidelines a. Assess stroke risk using CHA2DS2-VASc and bleed risk using HAS-BLED. b. Type and duration of antithrombotic therapy depend on: i. Bleed risk based on HAS-BLED (see Cardiology II for more information) ii. Emergency versus elective PCI c. Options include i. Triple therapy: DAPT plus OAC ii. Dual therapy: SAPT plus OAC iii. Monotherapy: OAC d. Clopidogrel is the preferred P2Y12 inhibitor for DAPT and is preferred for SAPT.

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Continue OAC Indefinitely PCI for SIHD (DES)

PCI for ACS (BMS/DES)

Continue P2Y12i for 6 mo

Continue P2Y12i for 12 mo

Either continue P2Y12i or change to ASA for months 6-12

Stop antiplatelet at month 12

Stop antiplatelet at month 12 Figure 8. Patients with established atrial fibrillation now needing percutaneous coronary intervention.

ACS = acute coronary syndrome; ASA = aspirin; BMS = bare metal stent; DES = drug-eluting stent; OAC = oral anticoagulant; PCI = percutaneous coronary intervention; P2Y12i = P2Y12 inhibitor; SIHD = stable ischemic heart disease.

SIHD No ACS, prior PCI

No ACS or revascularization

No ACS, prior CABG

Time from PCI

Start OAC

Time from CABG

DES: < 6 mo (BMS: < 1 mo)

DES: 6-12 mo (BMS: 1-12 mo)

> 12 mo (DES/BMS)

Start OAC

Start OAC

Stop ASA Continue P2Y12i

Continue ASA or P2Y12i

Stop P2Y12i once standard DAPT time period complete

Stop APT once standard DAPT time period complete

Stop APT

< 12 mo

> 12 mo

Start OAC

Start OAC

Start OAC

Stop APT

Continue ASA (< 100

Stop ASA

Figure 9a. Patients with SIHD on antiplatelet therapy with new atrial fibrillation diagnosis. APT = antiplatelet therapy; CABG = coronary artery bypass grafting.

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History of ACS Time from ACS ± PCI ≤ 12 mo

> 12 mo

Start OAC

Start OAC

Stop ASA Continue P2Y12i

Stop APT

Stop P2Y12i once standard DAPT period complete Figure 9b. Patients with a history of ACS on antiplatelet therapy with new atrial fibrillation diagnosis. Table 20. Antithrombotic Therapy in Atrial Fibrillation with PCI/Stent (2018 CHEST Guidelines) Bleed Risk

Elective PCI/Stent

ACS with Stent

High (HAS-BLED 3)

Triple therapy for 1 mo Dual therapy until 6 mo Monotherapy indefinitely

Triple therapy for 1–3 mo Dual therapy until 12 mo Monotherapy indefinitely

Low (HAS-BLED 0–2)

Unusually high (HAS-BLED 3 + recent bleed)

Triple therapy for 1–3 mo Dual therapy until 12 mo Monotherapy indefinitely

Dual therapy for 6 mo Monotherapy indefinitely

Triple therapy for 6 mo Dual therapy until 12 mo Monotherapy indefinitely

Dual therapy for 6–9 mo Monotherapy indefinitely

F. Antithrombotic Therapy for Patients with SIHD (Domains 1, 3) 1. Patients with a history of ACS for more than 1 year earlier who have remained free of recurrent ACS are considered to have transitioned to SIHD. 2. Aspirin 81 mg (75–100) mg daily should be continued indefinitely in the absence of contraindications. 3. DAPT in SIHD a. DAPT is not beneficial in patients with no history of ACS, coronary stent implantation, or CABG within the past 12 months. b. DAPT should be continued for at least 1 month after BMS and 6 months after DES if the patient is not at a high risk of bleeding. c. In patients being treated with DAPT or an MI that occurred 1–3 years earlier who have tolerated DAPT without a bleeding complication and who are not at high bleeding risk, further continuation may be reasonable. d. DAPT continuation for 12 months after CABG may be reasonable to improve vein graft patency. e. Clopidogrel is the P2Y12 inhibitor of choice. 4. Efficacy and treatment goals for patients with SIHD (Table 21): Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events (CHARISMA) a. Patients with stable CAD or otherwise at high risk of CV events (n=15,603) were randomized to either aspirin plus clopidogrel or aspirin monotherapy and were followed prospectively for CV events, including MI, stroke, or death attributable to CV causes. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 176

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b. After a median follow-up of 2.3 years, rates of composite outcome of MI, stroke, or CV-related death were similar between groups (6.8% vs. 7.3%) with a 0.4% absolute increase in severe bleeding. c. In a post hoc subgroup analysis of patients enrolled with a prior MI, DAPT produced a 1.7% absolute decrease in the composite end point of CV death, MI, or stroke. 5. Anticoagulation in stable ASCVD a. Rivaroxaban 2.5 mg is now indicated in combination with aspirin to reduce the risk of major CV events in patients with chronic CAD or PAD on basis of the COMPASS trial (see PAD for further discussion). b. Bleeding events higher in combination therapy than aspirin monotherapy. 6. Colchicine in stable CAD a. LoDoCo trial: Evaluated use of colchicine 0.5 mg/day in 532 patients with angiographically proven CAD i. Primary efficacy end point (composite of ACS, fatal and nonfatal out-of-hospital arrest, and noncardioembolic stroke) occurred less often in those receiving colchicine (HR 0.33; 95% CI, 0.18– 0.59). b. LoDoCo2 trial: Evaluated colchicine 0.5 mg/day in 5522 participants with stable CAD i. Reduced the risk of the primary composite end point of CV death, MI, ischemic stroke, or ischemiadriven coronary revascularization (HR 0.69; 95% CI, 0.57–0.83) ii. Rates of MI and ischemia-driven coronary revascularization were significantly lower with colchicine. iii. No significant difference in rates of ischemic stroke or death from any cause c. Can consider colchicine 0.5 mg/day in addition to standard of care in patients with stable CAD Table 21. P2Y12 Inhibitor Therapy in Patients with SIHD (2016 ACC/AHA Focused Update) SIHD

Therapy Duration (Class Recommendations)a

After CABG

12 mo may be reasonable (IIb)

DES

At least 6 mo (I)

BMS

At least 1 mo (I)b,c

Therapy Options

Doses

Clopidogrel

75 mg/day

c,d

For class recommendations, see the 2016 ACC/AHA focused update.

a

b

Option to continue after 1 mo may be reasonable if no high bleeding risk or significant overt bleeding (IIb).

Discontinuation after 3 mo may be reasonable if high bleeding risks (those who have or who develop high risk of bleeding [e.g., treatment with OAC therapy] or are at increased risk of severe bleeding complication [e.g., major intracranial surgery]) or significant overt bleeding (IIb)). c

d

Option to continue beyond 6 mo if not at high risk of bleeding and no significant overt bleeding on DAPT (IIb).

BMS = bare metal stent; CABG = coronary artery bypass graft; DES = drug-eluting stent; SIHD = stable ischemic heart disease.

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Table 22. Factors Associated with Increased Ischemic or Bleeding Risk Increased Ischemic Risk or Risk of Stent Thrombosisa

Increased Bleeding Riskb

  Advanced age

OAC therapy

Increased ischemic risk

History of bleeding

  ACS presentation

Female sex

  Several prior MIs

Advanced age (≥ 65)

  Extensive CAD

Low body weight (BMI < 18.5 kg/m2)

 DM

CKD

Increased risk of stent thrombosis

Anemia

 CKD

DM

  ACS presentation

Chronic steroid or NSAID therapy

 DM

  LVEF < 40%

  First-generation DES

  Stent undersizing or underdeployment   Small stent diameter   Greater stent length   Bifurcation stents

  In-stent restenosis May favor longer-duration DAPT.

a

b

May favor shorter-duration DAPT.

ACS = acute coronary syndrome; CAD = coronary artery disease; CKD = chronic kidney disease; DES = drug-eluting stent; DM = diabetes mellitus; LVEF = left ventricular ejection fraction; OAC = oral anticoagulant.

Patient Case 12. A 66-year-old man presents to the primary care clinic with a medical history of HTN and an MI first occurrence with coronary stent placement that was 4 mm in diameter 8 months ago. His current medications include aspirin 81 mg/day orally, prasugrel 10 mg/day orally, nitroglycerin 0.4-mg tablets sublingually as needed for chest pain, metoprolol succinate 75 mg/day orally, ramipril 10 mg/day orally, and atorvastatin 20 mg/day orally. The patient denies tobacco and alcohol use. He asks how long he will need to take prasugrel. Which is the best answer? A. B. C. D.

If you have a BMS, call your physician because you should be able to discontinue prasugrel now. If you have a DES, call your physician because you should be able to discontinue prasugrel now. You will need to take prasugrel indefinitely. You will need to take prasugrel for at least 1 year after your MI and stent placement.

G. Monitoring Antiplatelet Therapy for Adverse Effects (Domain 1) 1. Aspirin: GI bleeding and bruising; major bleeding about 2%–3% in first year 2. Clopidogrel: Bleeding, diarrhea, rash; an additional absolute risk of 1% for major (severe or life threatening) bleeding when added to aspirin (3%–4% per year in combination with aspirin) in first year; similar to aspirin alone after the first year in patients able to tolerate DAPT in the first year in a post hoc substudy of the CHARISMA trial

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3. Prasugrel: Bleeding, diarrhea, rash; an additional absolute risk of 0.6% major and 0.5% life-threatening bleeding compared with clopidogrel 4. Ticagrelor: Bleeding, bradycardia, heart block, dyspnea 5. Vorapaxar: Bleeding, anemia, depression, rashes, skin eruptions, exanthemata 6. Reduction of Atherothrombosis for Continued Health (REACH) bleeding risk score (Tables 23, 24) a. Tool used to predict bleeding risk in stable patients with atherosclerosis receiving long-term antiplatelet therapy; may assist in proper treatment modality and selection of stent type b. Nine clinical factors c. High risk of bleeding with score greater than 10 H. Clinical Considerations of Therapy (Domain 1) 1. Clopidogrel a. Nonuniform platelet activity, and only about 50% of patients achieve greater than 50% platelet inhibition with clopidogrel after a 600-mg loading dose; 30% of patients are estimated to have inadequate response b. Reduced effectiveness in carriers of reduced-function alleles, particularly CYP2C19*2 i. In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38), carriers had lower concentrations of active metabolite, diminished platelet inhibition, and increased rates of major CV events and stent thrombosis; however, this has not been confirmed in other studies. ii. Clinical trials have failed to show the ability to modulate clinical outcomes with genetic-based therapy. c. Proton pump inhibitors, specifically omeprazole, can interfere with metabolism and diminish in vitro platelet activity, but this does not appear to correlate to worse clinical outcomes; however, consider an alternative proton pump inhibitor such as pantoprazole, which has less interaction. 2. Prasugrel should not be used in patients with a history of stroke or TIA and was not beneficial in patients 75 and older or weighing less than 60 kg in the TRITON-TIMI 38 trial. 3. Ticagrelor should be used only with low-dose aspirin, with doses not to exceed 81 mg, according to the PLATO trial, which showed a smaller effect in North America. In addition, in this trial, the number of patients with prior strokes was small, which limited the ability to detect differences in rates of intracranial hemorrhage in this population. 4. Vorapaxar should not be used in patients with severe hepatic dysfunction because of bleeding risk, and it is contraindicated in patients with a history of stroke, TIA, or intracranial hemorrhage because of the increased risk of intracranial hemorrhage in this patient population. a. Vorapaxar should only be used with clopidogrel because it has not been studied with prasugrel or ticagrelor. b. Bleeding risk limits its use. 5. Colchicine should be avoided in patients with severe renal or hepatic disease.

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Table 23. REACH Bleeding Risk Score Factor

Value

Age, yr

45–54

Point(s) 1

55–64

0

65–74

Peripheral arterial disease

1

≥ 75

0

Yes

2

No

0

Heart failure

Yes

2

Diabetes mellitus

Yes

0

Hypercholesterolemia

No

2

Hypertension

No

1

No

4

Yes

1

Yes

0

No

Smoking

4

Current

0

Former

Antiplatelets prescribed

Oral anticoagulant prescribed

1

Never

0

≥2

1

Aspirin alone

2

Yes

2

0

Nonaspirin antiplatelet alone None

0

No

1

Table 24. Reduction of Atherothrombosis for Continued Health Scoringa Score 0–6

2-Yr Risk of Serious Bleeding, %

7–8

9–10

11–21

0.46 0.95

1.25 2.76

Sum the score associated with each of the nine factors.

a

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I. Management of DAPT in Patients Undergoing a Surgical Procedure (Domain 1) 1. Elective or nonurgent surgical procedures a. Cardiac: For patients with past ACS who are transitioning to nonurgent CABG surgery (2014 AHA/ACC NSTEMI guideline recommendation) i. Continue low-dose aspirin. ii. Discontinue clopidogrel or ticagrelor at least 5 days before surgery. iii. Discontinue prasugrel at least 7 days before surgery. b. Noncardiac i. Patients with PCI undergoing elective noncardiac surgery (2016 ACC/AHA guideline focused update) (a) Select BMS over DES for patients likely to undergo invasive procedures. (b) Elective noncardiac surgery should be delayed for 30 days after BMS implantation and optimally for 6 months after DES implantation (I). (1) Elective noncardiac surgery should not be done within 30 days after BMS implantation or within 3 months of DES implantation for patients whose DAPT will need to be discontinued perioperatively (III). (2) If it has been 3–6 months since DES implantation and delayed surgery risk is greater than stent thrombosis risk, proceeding with surgery may be considered (IIb). (c) In patients treated with DAPT after stent implantation who must undergo surgical procedures that mandate discontinuation of P2Y12 inhibitor therapy, aspirin should be continued, if possible, and the P2Y12 inhibitor should be reinitiated as soon as possible after surgery (I). 2. Urgent surgical procedures a. Cardiac: Urgent CABG (2013 ACCF/AHA STEMI and 2014 AHA/ACC NSTEMI guideline recommendations) i. Continue aspirin. ii. Discontinue clopidogrel or ticagrelor at least 24 hours before on-pump CABG surgery. iii. Urgent off-pump CABG surgery can be considered earlier than 24 hours after discontinuing clopidogrel or ticagrelor if the benefit of revascularization outweighs the bleeding risk. iv. Urgent CABG within 5 days of clopidogrel or ticagrelor or within 7 days of prasugrel can be considered if the benefit of revascularization outweighs the bleeding risk. b. Noncardiac (2014 ACC/AHA perioperative management guideline recommendation) i. In patients undergoing urgent noncardiac surgery during the first 4–6 weeks after BMS or DES implantation, continue DAPT unless the relative risk of bleeding outweighs the benefit of prevention of stent thrombosis. ii. If P2Y12 therapy must be discontinued, continue aspirin, if possible, and reinitiate the P2Y12 inhibitor as soon as possible after surgery. 3. 2012 Society of Thoracic Surgeons Guideline on Use of Antiplatelet Drugs in Patients Having Cardiac and Noncardiac Operations (Ann Thorac Surg 2012;94:1761-81) a. Elective cardiac surgery without ACS and no prior stent: discontinuing aspirin for a few days before surgery is “reasonable.” b. Noncardiac surgery and no prior stent: continue antiplatelet monotherapy (either aspirin or clopidogrel). c. Noncardiac surgery and prior stent: continue DAPT unless bleeding risk is prohibitive. d. Urgent surgery while undergoing DAPT i. Continue aspirin. ii. Delay surgery for 1–2 days after discontinuing the P2Y12 inhibitor, if possible. iii. If DES was placed less than 1 year ago, surgery should be done less than 5 days after discontinuing the P2Y12 inhibitor. e. Consider platelet aggregation testing, but the target level of platelet aggregation inhibition when surgery can commence safely has not been established. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 181

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J. Long-term Management Post-ACS (Domain 1, 3) 1. DAPT as discussed 2. High-intensity statin therapy (see Dyslipidemia) 3. β-Blockers a. Indicated for all patients unless contraindicated b. Continue for at least 3 years if EF is greater than 40%. c. Continue indefinitely for EF less than 40%: Carvedilol, bisoprolol, or metoprolol succinate d. Reasonable to continue as chronic therapy after 3 years in all patients with a history of MI or ACS e. Reasonable for patients with LVSD without HF or a prior MI f. Consider as long-term therapy for all other patients with coronary or other vascular disease. 4. ACE inhibitors a. Initiate and continue indefinitely in patients with EF less than 40%, HTN, diabetes, or CKD if no contraindications b. It is reasonable for all patients with ASCVD to continue indefinitely if no contraindications are present. c. Largest benefit is for patients with a reduced LVEF of less than 40%. 5. Angiotensin receptor blockers: initiate as alternative for patients intolerant of ACE inhibitor; same recommendations apply (as previously stated) a. PARADISE-MI trial: Combination of sacubitril/valsartan compared with ramipril in patients (n=5661) with acute MI within previous 7 days did not reduce primary end point of combined CV death, first HF hospitalization, or outpatient HF. 6. Aldosterone antagonists a. For patients after MI who are already receiving therapeutic doses of ACE inhibitor and a β-blocker and with an LVEF of 40% or less, HF, or diabetes b. Contraindications include GFR less than 30 mL/minute/1.73 m2 or SCr greater than 2.5 mg/dL in men or greater than 2.0 mg/dL in women, or K greater than 5.0 mEq/L 7. Nitrates a. ACCF/AHA guideline recommendations: not indicated for secondary prevention b. Do not reduce mortality but are indicated for treatment of chronic stable angina as an addition to a β-blocker or CCB c. Relieves symptoms of ischemia and pulmonary congestion and moderately effective for lowering arterial blood pressure d. Should be prescribed for angina symptoms when β-blockers are contraindicated or cause unwanted adverse effects or in combination with β-blockers if symptoms persist in patients with stable angina e. All patients who are post-ACS should be given sublingual or spray nitroglycerin with verbal and written instructions for use. f. Monitor for hypotension and tolerance; a nitrate-free interval of 10–12 hours is recommended. g. Avoid use with phosphodiesterase inhibitors because of the risk of severe hypotension. 8. Calcium channel blockers a. Do not use IR nifedipine (reflex tachycardia and hypotension). b. Are not indicated for secondary prevention of MI c. May relieve ischemia, lower blood pressure, or control ventricular response rate to atrial fibrillation in patients who are intolerant of β-blockers d. Are indicated for chronic stable angina in a patient with a contraindication to a β-blocker or in combination with a β-blocker for relief of symptoms e. Long-acting CCBs and nitrates are recommended in patients with coronary artery spasm. f. Caution is advised in patients with LVSD, particularly with non-dihydropyridine CCBs, because of negative inotropic effects. 9. Immunizations: Obtain annual influenza vaccine.

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10. Patients with systolic HF (Domain 1) (see the Cardiology II chapter) a. Other than the agents previously listed, hydralazine plus nitrate is recommended, particularly in African American patients, as an addition to ACE inhibitors, β-blockers (metoprolol succinate, carvedilol, bisoprolol), and diuretics. b. No trials have addressed which is preferred – an MRA or hydralazine plus nitrate – to add first to ACE inhibitor and β-blocker therapy; however, no MI studies have documented a mortality benefit with hydralazine plus nitrates, and less than 25% of patients enrolled in the African American Heart Failure Trial (AHeFT) had ischemic heart disease; this would suggest an MRA before hydralazine plus nitrate for a patient after MI.

V.  SECONDARY PREVENTION OF ATHEROSCLEROTIC (NON-CARDIOEMBOLIC ISCHEMIC) STROKE OR TRANSIENT ISCHEMIC ATTACK Guidelines 1. 2021 ACCF/AHA guideline for preventing stroke in patients with stroke and TIA 2. 2019 AHA/ASA guidelines for the early treatment of patients with acute ischemic stroke A. Antiplatelet Therapy 1. Antithrombotic therapy, including antiplatelet or anticoagulant agents, is recommended for almost all patients without contraindications. a. With few exceptions, a combination of antiplatelets and antithrombotic therapy is not indicated for secondary stroke prevention. b. DAPT is not recommended long term. 2. Antiplatelet options include: a. Aspirin (50–325 mg/day) monotherapy b. Aspirin 25 mg and ER dipyridamole 200 mg twice daily c. Clopidogrel 75 mg/day monotherapy d. Short-term DAPT with clopidogrel 75 mg/day and aspirin 81 mg/day for 21–90 days (see text that follows) 3. Minor ischemic stroke (NIHSS score 3 or less) or high-risk TIA (ABCD score 4 or greater): a. Initiate DAPT with aspirin plus clopidogrel early (ideally within 12–24 hours of symptom onset and at least within 7 days of onset). b. Continue for 21–90 days, followed by SAPT. c. The combination of aspirin and clopidogrel is not recommended for long-term use for secondary stroke prevention because of its potential to increase the risk of hemorrhage. d. Evidence for this is as follows: i. The CHANCE trial showed that clopidogrel (75 mg daily) plus aspirin (75 mg daily) for 21 days followed by clopidogrel alone to 90 days reduced recurrent stroke at 90 days (HR 0.68; 95% CI, 0.57–0.81; p 60 kg (initiated after at least 5 days of initial treatment with either UFH or LMWH) 30 mg PO daily for patients (1) with a CrCl 30–50 mL/minute, (2) with body weight ≤ 60 kg, (initiated after at least 5 days of initial treatment with either UFH or LMWH) Patients with an estimated CrCl < 30 mL/minute not studied.

a

BID = twice daily; LMWH = low-molecular-weight heparin; PO = by mouth; UFH = unfractionated heparin.

5. Therapy duration a. Patients should receive 3 months (treatment phase) of anticoagulation therapy after provoked VTE. b. For patients with unprovoked VTE or life-threatening PE, the long-term risks of anticoagulant use (bleeding) must be weighed against the risk of repeated thrombosis after completing a minimum of 3 months of anticoagulation therapy. Table 5. Duration of Anticoagulation Therapy in Patients with VTE (DVT and/or PE) Patient Characteristic Therapy Duration Comments

First episode of VTE 3 mo secondary to a transient (reversible) risk factor

Recommendation applies to both proximal DVT and PE

First episode of VTE and cancer

3 mo

First episode of unprovoked VTE

At least 3 mo

Continue PO anticoagulant therapy if patient is at low risk of bleeding and adherent to therapy Continue PO anticoagulant therapy for 3 mo in patients at high risk of bleeding The risk-benefit of indefinite therapy should be reassessed at periodic intervals (e.g., annually)

Apixaban, edoxaban, and rivaroxaban are recommended over LMWH for the initiation and treatment phase. Apixaban and LMWH are preferred if luminal GI malignancy

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Table 5. Duration of Anticoagulation Therapy in Patients with VTE (DVT and/or PE) (continued) Patient Characteristic Therapy Duration Comments

First episode of VTE with inherited or acquired thrombophiliaa

At least 3 mo

Second unprovoked VTE

Indefinite

Continue PO anticoagulant therapy if patient is at low risk of bleeding and adherent to therapy Several abnormalities or homozygous traits have at least additive risk The risk-benefit of indefinite therapy should be reassessed at periodic intervals Applies to patients at low or moderate risk of bleeding

Factor V Leiden; prothrombin G20210A; antiphospholipid antibody syndrome; excess factor VIII; deficiency in protein C, protein S, or antithrombin.

a

DOAC = direct oral anticoagulant; DVT = deep vein thrombosis; GI = gastrointestinal; LMWH = low-molecular-weight heparin; PE pulmonary embolism; PO = by mouth; VTE = venous thromboembolism.

Patient Case Questions 1–3 pertain to the following case. E.W., a 50-year-old man (height 70 inches, weight 75 kg), presents to his primary care clinic with swelling in his entire left lower extremity, which is tender to the touch. His left calf is 6 cm larger than his right calf. He reports no recent surgical procedures. He describes mild shortness of breath, but no chest pain. He has 3+ pitting edema in his lower left leg. His medical history includes HTN, type 2 diabetes, and chronic kidney disease. His medications are metformin 1000 mg orally twice daily, empagliflozin 25 mg orally daily, lisinopril 40 mg orally daily, hydrochlorothiazide 25 mg orally once daily, atorvastatin 80 mg orally daily, and aspirin 81 mg orally daily. His initial laboratory values include Hct 40% (normal 42%–52%), PT 11.2 seconds (normal 9.9–11.2 seconds), INR 1.0, aPTT 30.0 seconds (normal 24–36 seconds), Plt 300,000/mm3 (normal 150,000–300,000/mm3), and CrCl 50 mL/minute. 1. Which risk level most accurately reflects the clinical probability of this patient’s having a DVT? A. B. C. D.

Low. Moderate. High. Very high.

2. The decision is made to initiate anticoagulation therapy and treat E.W. for DVT in the outpatient setting. What is the best recommendation for an anticoagulant initiation regimen for this patient? A. B. C. D.

Apixaban 10 mg orally twice daily for 7 days and then 5 mg orally twice daily. Rivaroxaban 20 mg orally daily and enoxaparin 150 mg subcutaneously daily for 5 days. Rivaroxaban 20 mg orally once daily. Enoxaparin 100 mg subcutaneously daily and warfarin 5 mg/day orally adjusted to an INR of 2–3.

3. What is the best course of action regarding E.W.’s aspirin therapy taken for primary prevention of atherosclerotic cardiovascular disease? A. B. C. D.

Discontinue aspirin 81 mg orally daily. Continue aspirin 81 mg orally daily. Increase the aspirin dose to 325 mg orally daily. Discontinue aspirin while the patient is receiving anticoagulation.

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II.  ANTITHROMBOTIC THERAPY IN ATRIAL FIBRILLATION A. Stroke Prevention in Atrial Fibrillation (Domain 1, Tasks 1–7; Domain 3, Tasks 2, 3; Domain 2, Tasks 2, 3; Domain 5, Tasks 1, 2) 1. AF is a major risk factor for cardiogenic embolic stroke and systemic arterial thromboembolism (TE). 2. Approximately 90% of AF TE complications are stroke related, and the remaining 10% are systemic embolism. 3. Thromboembolic risks associated with AF: a. Stasis or turbulence of blood flow within the left atrial appendage leads to thrombus formation. b. Dysfunction of vascular endothelium predisposes to local or systemic hypercoagulability. c. Conversion to normal sinus rhythm (NSR), whether spontaneous or intentional, can dislodge any existing left atrial thrombi. 4. Morbidity and mortality associated with AF: a. 15% of all strokes occur in people with AF. b. The annual stroke risk in untreated patients with AF varies from 1% to greater than 10%. c. Stroke risk in AF increases with age. i. 1.5% in the 50–59-year age group ii. 23.5% in the 80–89-year age group 5. Classification of AF: a. Acute AF: Onset within previous 48 hours b. Paroxysmal AF: Terminates spontaneously within 7 days (may recur) c. Recurrent AF: More than one episode d. Persistent AF: Duration of more than 7 days without spontaneous termination e. Permanent AF: Persistence of AF despite electrical or pharmacologic cardioversion attempts 6. Tools for nonvalvular atrial fibrillation (NVAF) stroke risk stratification a. Various risk stratification schemes have been developed with the following goals: i. Identifying patients with AF having such a low stroke risk that anticoagulation-associated bleeding risk might outweigh stroke prevention benefit ii. Encouraging anticoagulation therapy use in patients at high risk of AF stroke b. CHA2DS2-VASc (congestive heart failure, HTN, age at least 75, diabetes, previous stroke or TIA, presence of vascular disease, age 65–74, and female sex) score Table 6. CHA2DS2-VASc Stroke Risk Factor Calculation CHA2DS2-VASc Stroke Risk Factora

Points

Congestive HF HTN

Age ≥ 75 years Diabetes

Previous stroke, TIA, systemic embolus

Vascular disease (previous MI, angina, PCI, PAD, CABG, or aortic plaque) Age 65–74 years

Sex category (female)

1 1 2 1 2 1 1 1

CHA2DS2-VASc score calculator is available at www.mdcalc.com/cha2ds2-vasc-score-for-atrial-fibrillation-stroke-risk/.

a

CABG = coronary artery bypass grafting; CHA2DS2-VASc = congestive heart failure, HTN, age at least 75, diabetes, previous stroke or TIA, presence of vascular disease, and age 65–74; HTN = hypertension; MI = myocardial infarction; PAD = peripheral arterial disease; PCI = percutaneous coronary intervention.

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Table 7. CHA2DS2-VASc Score and Recommended Antithrombotic Therapy CHA2DS2- Adjusted Stroke Rate, VASc Score %/Year Recommended Therapy (2019 AHA/ACC/HRS Guidelines) 0 1

0

1.3

No antithrombotic therapy

PO anticoagulant therapy may be reasonable for men

2

2.2

3

3.2

PO anticoagulant therapy (VKA INR 2–3, apixaban, dabigatran, edoxaban, or rivaroxaban) DOACs are preferred to VKA when no contraindications exist

6.7

Consider the patient’s preferences, values, and bleeding risk

9.6

Aspirin plus clopidogrel or aspirin alone may be considered in patients who refuse anticoagulation or cannot tolerate anticoagulants for any reason unrelated to bleeding

4

4.0

6

9.8

8

6.7

5 7 9

PO anticoagulant therapy recommended for men; may be reasonable for women

15.2

ACC = American College of Cardiology; AHA = American Heart Association; CHA2DS2-VASc = congestive heart failure, HTN, age at least 75, diabetes, previous stroke or TIA, presence of vascular disease, and age 65–74; CI = confidence interval; HRS = Heart Rhythm Society; HTN = hypertension; INR = international normalized ratio; PO = by mouth; VKA = vitamin K antagonist.

c. Risk stratification considerations i. No tool can incorporate all potential AF stroke risk factors. ii. Patient perspectives and preferences should also factor into clinical decision making. 7. Treatment considerations a. Rate versus rhythm control i. In clinical trials, ischemic events have occurred with similar frequency with either a rhythm control strategy or a rate control strategy. ii. Whether a rate or rhythm control strategy is used, patients with AF and thromboembolic risk factors should probably receive chronic therapeutic anticoagulation. b. Adjusted-dose warfarin versus aspirin therapy i. Aspirin alone provides, at best, a modest reduction in the risk of nonfatal stroke in AF. ii. A randomized comparison of warfarin versus clopidogrel plus aspirin was terminated early after showing the superiority of warfarin. iii. Adding aspirin to warfarin therapy increases the risk of major bleeding and does not provide further protection against ischemic stroke in patients with AF. c. Adjusted-dose warfarin versus newer anticoagulants i. Adjusted-dose warfarin has been compared with dabigatran (RE-LY trial), rivaroxaban (ROCKET AF), apixaban (ARISTOTLE), and edoxaban (ENGAGE-AF) for stroke prevention in AF.

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Table 8. Major Outcomes of New Anticoagulants versus Adjusted-Dose Warfarina

Outcome (RR ± 95% CI)

CHADS2 score Warfarin TTR Stroke/SEE

RE-LY (Dabigatran 150 mg BID)

ROCKET-AF (Rivaroxaban 20 mg/dayb)

ARISTOTLE (Apixaban 5 mg BIDc)

ENGAGE-AF (Edoxaban 60 mg/dayd)

64%

55%

62.2%

68.4%

2.1

3.5

2.1

0.65 (0.52–0.81)

0.88 (0.75–1.03)

0.79 (0.66–0.95)

0.79 (0.63–0.99)

0.26 (0.14–0.49)

0.59 (0.37–0.93)

0.51 (0.35–0.75)

0.54 (0.38–0.77)

0.42 (0.30–0.58)

0.47 (0.34-0.63)

Ischemic stroke

0.76 (0.59–0.97)

Major bleeding

0.93 (0.81–1.07)

1.04 (0.90–1.20)

0.69 (0.60–0.80)

0.85 (0.72–0.99)

0.89 (0.73–1.10)

0.89 (0.76–1.04)

Hemorrhagic stroke

Intracranial hemorrhage

0.40 (0.27–0.60)

All-cause mortality

0.88 (0.77–1.00)

CV mortality

2.8

0.94 (0.75–1.17)

0.67 (0.47–0.93) 0.85 (0.70–1.02)

0.92 (0.74–1.13)

0.89 (0.80–0.998)

1.00 (0.83–1.19) 0.80 (0.71–0.91)

0.92 (0.83–1.01)

0.86 (0.77–0.97)

Patients with CrCl < 30 mL/minute were excluded from RE-LY, ROCKET-AF, and ENGAGE-AF trials; patients with CrCl < 25 mL/minute were excluded from ARISTOTLE trial. Patients with mechanical heart valves were excluded from all trials. Patients with bioprosthetic valves were excluded from RE-LY, ROCKET-AF, and ARISTOTLE trials. a

b

Dose adjusted to 15 mg/day for CrCl 30–49 mL/minute.

Dose adjusted to 2.5 mg BID for two or more of the following: Age ≥ 80, SCr ≥ 1.5 mg/dL, body weight < 60 kg.

c

Dose adjusted to 30 mg/day if CrCl 30–50 mL/minute, body weight ≤ 60 kg, or concomitant use of verapamil, quinidine, dronedarone; concomitant use of azithromycin, clarithromycin, ketoconazole, itraconazole, cyclosporine, and ritonavir was prohibited.

d

BID = Twice daily; CI = confidence interval; CV = cardiovascular; RR = relative risk; SEE = systemic embolic event; TTR = therapeutic international normalized ratio range.

ii. The 2018 American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for Antithrombotic Therapy for Atrial Fibrillation recommend DOACs over warfarin, acknowledging that patient and caregiver preferences, cost, formulary considerations, anticipated medication adherence, or compliance with INR testing and dose adjustment should be incorporated into clinical decision making. DOACs are also recommended over warfarin in the 2019 AHA/ACC/HRS focused update to the 2014 guidelines. iii. An antidote is available for reversing the anticoagulant effect of dabigatran, rivaroxaban, and apixaban. iv. Routine laboratory monitoring is not required with the newer anticoagulants. v. When deciding which oral anticoagulant to use for patients with AF, consider individual clinical features, including the ability to adhere to the requirements of therapy, the availability of the anticoagulation management program, patient preferences, and cost. 8. Transthoracic echocardiography and transesophageal echocardiography (TEE) a. Can detect the presence of features associated with TE (and anticoagulation therapy in patients with these features reduces stroke risk; e.g., impaired left ventricular [LV] systolic function, left atrial thrombus, dense spontaneous echo contrast [or “smoke”]) or reduced velocity of blood flow in the left atrial appendage) b. Valuable for detecting rheumatic mitral valve disease i. Detection of a left atrial thrombus is a contraindication for cardioversion of AF. ii. TEE surpasses transthoracic echocardiography in the evaluation of cardiogenic risk factors in patients with AF. 9. Optimal intensity of anticoagulation for AF a. Optimal anticoagulation intensity involves a careful balance between maximizing protection against TE while minimizing bleeding risk. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 220

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b. The risk of ischemic stroke is low, at INR levels of 2.0 or higher. c. The risk of intracranial hemorrhage increases at INR levels of 3.5–4.0 and greater. d. An INR of less than 2.0 at admission for a new stroke substantially increases the likelihood of death and severe disability from an AF-related stroke. e. An INR target of 2.5 (range 2–3) should be used for most patients. Narrower target ranges have been suggested in certain instances (e.g., INR 2.0–2.5 has been recommended in patients requiring warfarin, aspirin, and clopidogrel after percutaneous coronary intervention). 10. Considerations during cardioversion a. Systemic embolism is the most serious complication of cardioversion. b. There is no evidence that cardioversion, followed by prolonged maintenance of NSR, effectively reduces TE in AF. i. At least 4 weeks of therapeutic anticoagulation is recommended after successful cardioversion. ii. Patients with risk factors for TE should continue anticoagulation beyond 4 weeks. c. Hemodynamically unstable patients requiring emergency cardioversion should receive therapeutic anticoagulation with intravenous UFH, LMWH, or a DOAC as soon as possible, followed by at least 4 weeks of therapeutic anticoagulation (limited/no evidence). d. During the RE-LY trial, 1983 cardioversions were performed in 1270 patients: 647, 672, and 664 in the dabigatran 110-mg twice-daily, dabigatran 150-mg twice-daily, and warfarin groups, respectively. The frequencies of stroke and major bleeding within 30 days of cardioversion in patients taking the two doses of dabigatran were low and comparable with those in patients taking warfarin with or without TEE guidance. e. During the ROCKET-AF trial, 320 patients had 460 cardioversions or AF ablations; 161 patients were treated with warfarin and 160 were treated with rivaroxaban. f. During the ARISTOTLE trial, 540 patients had 743 cardioversions; 275 patients were treated with warfarin, and 265 were treated with apixaban. No strokes or systemic emboli occurred during the 30day follow-up period. 11. Considerations during ablation procedures a. Patients with persistent AF who are in AF at the time of ablation should have TEE to screen for a thrombus, even if warfarin or DOAC anticoagulation was used before the procedure. b. The most common anticoagulation strategy is to continue therapeutic anticoagulation with warfarin and to add UFH during the procedure to inhibit activated clotting factors, because warfarin just prevents the formation of active clotting factors. If DOACs are the anticoagulation approach, they should be continued throughout the procedure. c. UFH is continued for 12–24 hours after the procedure, with a brief interruption for arterial sheath pull. After the sheath pull, anticoagulation is resumed for 12–24 hours for periprocedural stroke and PE prevention. d. If a DOAC is selected, the oral dose is typically reinitiated the morning after the procedure, once hemodynamic stability is ensured and intrapericardial bleeding is ruled out.

III.  ANTITHROMBOTIC AGENTS: PHARMACOLOGIC AND CLINICAL CONSIDERATIONS A. Unfractionated Heparin (Domain 1, Tasks 2, 3, 4, 7) 1. Pharmacology and pharmacokinetics a. Rapid-acting, parenterally administered anticoagulant b. UFH prevents the growth and propagation of a formed thrombus and allows the patient’s own thrombolytic system to degrade the clot. c. When UFH is administered intravenously, continuous infusion is preferable. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 221

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2. Dosing and administration a. When immediate and full anticoagulation are required, an intravenous bolus dose followed by continuous infusion is preferred (see Table 7; initial dose of 80 units/kg followed by 18 units/kg/ hour). b. Subcutaneous UFH is administered in an initial dose of 333 units/kg, followed by 250 units/kg every 12 hours. 3. Monitoring a. Administration of UFH by intravenous infusion requires close monitoring because of the unpredictable anticoagulant patient response. b. Tests are available to monitor UFH therapy in ambulatory patients. i. aPTT (a) aPTT is the most widely used test to determine the degree of therapeutic anticoagulation. (b) An institution-specific aPTT therapeutic range should be established that correlates with a plasma heparin concentration of 0.3–0.7 unit/mL by an amidolytic anti-factor Xa (anti-Xa) assay. (c) aPTT should be measured before therapy initiation to determine the patient’s baseline. (d) When monitoring an aPTT during subcutaneous injections, the therapy response should be measured at the mid-dosing interval two or three doses after therapy initiation or a dose change. c. Heparin resistance should be suspected in patients who require more than 35,000 units of UFH during a 24-hour period. In such cases, adjust the UFH dose according to anti-Xa concentrations. 4. Adverse effects a. Bleeding i. The presence of concomitant bleeding risks such as thrombocytopenia, the use of other antithrombotic therapy, and a pre-existing source of bleeding increase the risk of UFH-induced hemorrhage. ii. Recent surgery, hemostatic defects, heavy alcohol consumption, renal failure, peptic ulcers, and neoplasms also increase the risk of major bleeding while receiving UFH. b. Heparin-induced thrombocytopenia (HIT) i. A rare but serious drug-induced problem requiring immediate intervention ii. A baseline platelet count should be obtained before UFH therapy is initiated. iii. If the patient has received UFH within the previous 100 days, or if previous UFH exposure is uncertain, a repeated platelet count should be performed within 24 hours. iv. The incidence of HIT is greater than 1% in postoperative patients receiving prophylactic or therapeutic UFH doses. v. A Plt decrease of greater than 50% from baseline but not less than 20 × 109/L is most suggestive of HIT. B. Low-Molecular-Weight Heparin (Domain 1, Tasks 2, 3, 4, 7) 1. Pharmacology and pharmacokinetics a. Like UFH, the LMWHs prevent the growth and propagation of formed thrombi. b. Both UFH and LMWH inhibit both thrombin and factor Xa. UFH inhibits both equally, and LMWHs preferentially inhibit factor Xa. c. Compared with UFH, the LMWHs have a more predictable anticoagulation response. 2. Dosing and administration a. The LMWHs are given in fixed or weight-based doses according to the product and indication. i. VTE treatment indications or as bridging in AF, enoxaparin is administered as 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously once daily. ii. A reduced dose of 1 mg/kg once daily is recommended for patients with an estimated CrCl of less than 30 mL/minute.

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iii. LMWH are indicated for VTE prophylaxis. Enoxaparin is administered (40 mg once daily) for medical patients during acute illness, abdominal surgery, and following hip replacement surgery. An alternative dose of enoxaparin 30 mg twice daily can be administered following hip or knee replacement surgery. b. Doses should be based on actual body weight, and studies of patients with obesity indicate that full weight-based doses do not lead to elevated LMWH concentrations compared with patients with normal weight. 3. Therapeutic monitoring a. Because the LMWHs achieve a predictable anticoagulant response when given subcutaneously, routine laboratory monitoring is unnecessary to guide the dosing of these agents. b. Before initiating LMWH, a baseline complete blood cell count with a Plt and SCr measurement should be obtained. c. Although limited data support the use of laboratory monitoring to guide LMWH therapy, measuring anti-Xa activity has been suggested in patients who have significant renal impairment (e.g., CrCl less than 30 mL/minute), weigh less than 50 kg, have morbid obesity, or are pregnant (because of changing pharmacokinetic variables such as volume of distribution and renal function). i. UFH is preferred for patients with a CrCl less than 30 mL/minute. 4. Adverse effects a. Bleeding is the most common adverse effect of the LMWHs. i. Major bleeding incidence is less than 3% and varies among the LMWH preparations, their indication for use, the patient population, and the dose administered. ii. Minor bleeding, particularly at the injection site, occurs often with LMWH use. b. HIT i. The incidence of HIT is lower than with the use of UFH in the postoperative setting. The risk of HIT in patients treated for VTE is too low to discern a difference between UFH and LMWH. ii. LMWHs have almost 100% cross-reactivity with heparin antibodies in vitro; they should be avoided in patients with an established diagnosis or history of HIT. C. Indirect Factor Xa Inhibitor (synthetic pentasaccharide) (Domain 1, Tasks 2, 3, 4, 7) 1. Fondaparinux is the only commercially available synthetic pentasaccharide. 2. Pharmacology and pharmacokinetics a. Similar to UFH and the LMWHs, fondaparinux prevents thrombus generation and clot formation by indirectly inhibiting factor Xa activity through its interaction with antithrombin. b. Contraindicated in patients with severe renal function impairment (CrCl less than 30 mL/minute); use caution in moderate renal insufficiency (CrCl 30–50 mL/minute). 3. Dose and administration a. For VTE prevention, the fondaparinux dose is 2.5 mg injected subcutaneously once daily starting 6–8 hours after surgery if hemostasis has been established. b. For the treatment of DVT or PE, the fondaparinux dose is 7.5 mg given subcutaneously once daily. Patients who weigh more than 100 kg should be given 10 mg once daily, and those who weigh less than 50 kg should receive 5 mg/day. c. Similar to the LMWHs, fondaparinux is administered to the fatty tissue of the abdominal wall. 4. Therapeutic monitoring a. A complete blood cell count and SCr should be measured at baseline. b. Kidney function should be monitored closely in patients at risk of developing renal failure. c. Fondaparinux should be discontinued if the CrCl drops to less than 30 mL/minute. d. Signs and symptoms of bleeding should be monitored daily, particularly in patients with a baseline CrCl of 30–50 mL/minute. e. Fondaparinux does not alter coagulation tests such as the aPTT and PT. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 223

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5. Adverse effects a. Bleeding is the primary adverse effect associated with fondaparinux therapy. b. The rate of major bleeding in the VTE prophylaxis trials was around 2%–3%. c. Unlike UFH and the LMWHs, fondaparinux has not been associated with HIT and does not produce cross-sensitivity in vitro. Fondaparinux has been used in the treatment of HIT. Table 9. Comparison of UFH, LMWHs, and Fondaparinux Property

Molecular weight range Average molecular weighta Anti-Xa/antifactor IIa activity aPTT monitoring required Inactivation by platelet factor 4 Capable of inactivating platelet-bound factor Xa Inhibition of platelet function Increases vascular permeability Protein binding Endothelial cell binding Dose-dependent clearance Primary route of elimination a

Elimination half-life

UFH

3000–30,000 12,000–15,000 1:1 Yes Yes No ++++ Yes ++++ +++ Yes 1. Saturable binding processes and depolymerization 2. Renal 30–150 min

LMWH

Fondaparinux

2–6 hr

17 hr

1000–10,000 4000–5000 2:1–4:1 No No Yes ++ No + + No Renal

1728 1728 >100:1 No No Yes No No No No No Renal

Measured in Daltons.

a

LMWH = Low-molecular-weight heparin; UFH = unfractionated heparin.

D. Warfarin (Domain 1, Tasks 2, 3, 4, 5, 6, 7) 1. Warfarin is FDA approved for the prevention and treatment of VTE and for the prevention of thromboembolic complications associated with AF, heart valve replacement, and myocardial infarction (MI). 2. Because of its narrow therapeutic index, predisposition to drug and food interactions, and propensity to cause hemorrhage, warfarin requires continuous patient monitoring and education to achieve optimal outcomes. 3. Pharmacology and pharmacokinetics a. Warfarin exerts its anticoagulation effect by inhibiting vitamin K epoxide reductase, the enzyme responsible for the cyclic interconversion of vitamin K in the liver. b. Reduced vitamin K is a cofactor required for the carboxylation of the vitamin K–dependent coagulation proteins; factors II (prothrombin), VII, IX, and X; and the endogenous anticoagulant proteins C and S. c. Warfarin undergoes stereoselective metabolism by CYP 1A2, 2C9, 2C19, 2C8, 2C18, and 3A4 isoenzymes in the liver, with CYP2C9 as the main enzyme to modulate in vivo anticoagulant activity. d. Pharmacokinetic variables of warfarin, particularly hepatic metabolism, vary substantially between individuals, leading to large interpatient differences in dose requirements. e. Genetic variations in the gene that codes for the CYP2C9 isoenzyme, vitamin K epoxide reductase complex 1 (VKORC1), correlate with warfarin dose requirements. f. Warfarin dosing algorithms that incorporate pharmacogenetic information are being evaluated, but they have yet to show improved clinical outcomes (e.g., reduced bleeding).

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4. Dosing and administration a. The warfarin dose is patient specific, depending on the desired intensity of anticoagulation and the patient’s individual response. b. For most patients, initiating therapy with 5–10 mg/day and adjusting the dose according to the INR response will produce therapeutic INRs in 5–7 days. 5. Initiation dosing of warfarin therapy for outpatients; warfarin initiation using the average daily dosing method a. This nomogram is useful in outpatients for whom INR cannot be checked on a daily basis. b. The response to therapy should be measured every 1–3 days until the patient’s condition stabilizes. 6. Maintenance dosing of warfarin therapy a. When adjusting the warfarin dose, the clinician should allow sufficient time for changes in the INR to occur. b. Doses should be adjusted by calculating the weekly dose and reducing or increasing the weekly dose by 5%–20%. c. Use of dosing algorithms (computerized or paper-based) is strongly encouraged. d. The effect of dose changes might not become evident for 7 days or greater if alternate-day dosing is used. 7. Therapeutic monitoring a. Warfarin requires frequent laboratory monitoring to ensure optimal therapeutic outcomes and to minimize bleeding complications. b. The PT is used to monitor the anticoagulation effects of warfarin. c. The INR corrects for differences in thromboplastin reagents. d. Although the INR system has several potential problems, it is currently the best means available to interpret the PT and is the preferred method for monitoring oral anticoagulation therapy. e. The recommended target INR and associated goal range are based on the therapeutic indication. f. For most indications, the target INR is 2.5 with an acceptable range of 2.0–3.0. g. The target INR is higher for some patients with mechanical prosthetic heart valves (target INR 3.0, range 2.5–3.5). h. Once the patient’s dose response is established, an INR should be determined every 7–14 days until it stabilizes and, optimally, every 4–6 weeks thereafter. i. Recent evidence indicates INR recall intervals as long as 12 weeks can be used in patients with stable conditions. j. For patients with previously stable INR control, avoid changing the warfarin dose for mildly out-of-range INR (e.g., 1.5–3.5); instead, increase INR monitoring frequency and consider a one-time boost or held dose. 8. Patient assessment and treatment: With each INR, the patient should also be assessed for other factors that can influence the anticoagulant effect of warfarin. a. Verification of the warfarin dose administered or taken b. Changes in current medications (prescription, over-the-counter, herbal) c. Acute illnesses (nausea, vomiting, diarrhea) d. Changes in diet (especially foods rich in vitamin K or decreased oral intake) e. Binge alcohol use f. Signs and symptoms of TE g. Signs and symptoms of bleeding 9. Adverse effects a. Bleeding i. As with the other anticoagulants, bleeding is the most common adverse effect. ii. The GI tract and the nose are the most common sites of bleeding. Intracranial hemorrhage is the most serious and feared complication related to warfarin therapy. iii. The annual incidence of major bleeding ranges from 1% in highly selected patient populations who are carefully treated to greater than 10% in patients who are medically managed in less structured environments. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 225

Cardiology II

Box 2. Risk Factors for Major Bleeding While Taking Anticoagulation Therapy

Anticoagulation intensity (e.g., INR > 4.0) Therapy initiation (first few weeks) Unstable anticoagulation response (INR control) Age > 65 years Concurrent antiplatelet or NSAID use History of GI bleeding

Recent surgery or trauma High risk of fall or trauma Heavy alcohol use Renal failure Cerebrovascular disease Malignancy

GI = Gastrointestinal; INR = international normalized ratio; NSAID = nonsteroidal anti-inflammatory drug.

iv. Patients whose target INR is greater than 3.0 have twice the incidence of major bleeding compared with those whose target INR is 2.5. v. Unstable INR control also appears to be associated with an increased risk of bleeding. Table 10. Scoring Systems to Assess the Risk of Major Bleeding in Patients Taking Warfarin (validated only in patients with AF—Note also that CHADS2-VASc scores correlate with bleeding risk [i.e., higher scores = higher bleeding risk]) Scoring System

Outpatient bleeding risk index

HEMORR2HAGES scoring system

HAS-BLEDa

Criteria

Age > 65 years History of GI bleed History of stroke One or more of diabetes, Hct < 30%, SCr > 1.5 mg/dL, or recent MI Hepatic or renal disease Ethanol abuse Malignancy Older (age > 75) Reduced Plt or function Rebleeding risk HTN (uncontrolled) Anemia Genetic factors (CYP2C9 polymorphism) Excessive fall risk Stroke

Uncontrolled HTN (SBP > 160 mm Hg) Renal disease (SCr > 2.6 mg/dL, dialysis, transplantation) Hepatic disease (cirrhosis, bilirubin > 2 × ULN, AST/ALT > 3 × ULN) Stroke Prior major bleeding or predisposition Labile INR (< 60% time in range) Older adults (age > 65) Drugs (e.g., concomitant antiplatelets, NSAIDs)/ alcohol concomitantly

Point Scores Risk of Major Bleeding 1 1 1 1

Score MB/pt-yr Low: (0) 3% Intermediate: (1–2) 8% High: (3–4) 30%

1 1 1 1 1 2 1 1 1 1 1

Score MB/pt-yr Low: (0–1) 1.9%–2.5% Intermediate: (2–3) 5.3%–8.4% High: (≥4) 10.4%–12.3%

1 1 1

Score MB/pt-yr Low: (0) 0.9% Intermediate: (1–2) 3.7% High: (≥3) 6.7%

1 1 1 1 (1 each)

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Table 10. Scoring Systems to Assess the Risk of Major Bleeding in Patients Taking Warfarin (validated only in patients with AF—Note also that CHADS2-VASc scores correlate with bleeding risk [i.e., higher scores = higher bleeding risk]) (continued) Scoring System

ATRIA

Criteria

Point Scores Risk of Major Bleeding

Anemia Severe renal disease Age ≥ 75 Any prior hemorrhage diagnosis Diagnosed HTN

3 3 2 1 1

Score MB/pt-yr Low: (0–3) 0.76% Intermediate: (4) 2.62% High: (5–10) 5.76%

HAS-BLED calculator available at www.mdcalc.com/has-bled-score-for-major-bleeding-risk/.

a

AF = atrial fibrillation; AST/ALT = aspartate aminotransferase/alanine aminotransferase; GI = gastrointestinal; Hct = hematocrit; HTN = hypertension; MB = major bleeding; MI = myocardial infarction; Plt = platelet; pt-yr = patient-year; SBP = systolic blood pressure; SCr = serum creatinine; ULN = upper limit of normal.

vi. Serious bleeding, such as intracranial hemorrhage, necessitates holding warfarin and administering 10 mg of vitamin K by slow intravenous infusion for 1 hour and prothrombin complex concentrate (PCC) administration. Only the four-factor PCC (Kcentra) is FDA approved for warfarin reversal. The Kcentra dose is based on the patient’s INR, body weight, and factor IX concentration of the vial. b. Warfarin-induced skin necrosis i. This dermatologic reaction is uncommon (less than 1%) but serious. ii. It is characterized by a painful maculopapular rash and ecchymosis or purpura that progresses to necrotic gangrene. iii. Warfarin therapy should be reinitiated with extreme caution in patients having a history of skin necrosis, using small doses and gradual titration until a therapeutic INR has been achieved, if at all. 10. Drug and dietary interactions a. The pharmacokinetic and pharmacodynamic properties of warfarin, together with its narrow therapeutic index, predispose this agent to several clinically important drug and food interactions. b. Drug interactions i. Pharmacokinetic drug interactions with warfarin are primarily a result of alterations in hepatic metabolism or binding to plasma proteins. ii. Drugs that inhibit or induce the CYP 2C9, 1A2, and 3A4 isoenzymes have the greatest potential to significantly alter the response to warfarin therapy. iii. In most cases, increasing the frequency of INR monitoring and adjusting the warfarin dose as needed are preferable to preemptive empiric warfarin dose adjustment. c. Dietary interactions i. Vitamin K (a) Vitamin K can reverse warfarin’s pharmacologic activity, and many foods contain sufficient vitamin K to reduce the anticoagulation effect of warfarin if a patient consumes them in unusually large portions or repetitively within a short period. (b) Patients should be given a list of vitamin K–rich foods and instructed to maintain a relatively consistent intake. ii. Other dietary and herbal supplements (a) All patients receiving warfarin therapy should be questioned regarding the use of herbal drugs and dietary supplements. (b) Clinicians should advise patients receiving warfarin therapy to seek information about potential interactions with warfarin whenever they start to take a new drug product, whether it is prescribed or purchased over the counter.

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Table 11. Warfarin Drug–Disease State Interactions Clinical Condition Effect on Warfarin Therapy

Advanced age Pregnancy

Increased sensitivity to warfarin because of reduced vitamin K stores or lower plasma concentrations of vitamin K–dependent clotting factors Teratogenic; avoid exposure during pregnancy

Lactation

Not excreted in breast milk; can be used postpartum by nursing mothers

Alcoholism

Acute ingestion: Inhibits warfarin metabolism, with acute elevation in INR Chronic ingestion: Induces warfarin metabolism, with higher dose requirements

Liver disease Renal disease Heart failure

Cardiac valve replacement Nutritional status Use of tube feedings

Thyroid disease Smoking and tobacco use

May induce coagulopathy by decreased production of clotting factors, with baseline elevation in INR May reduce clearance of warfarin Reduced activity of CYP2C9, with lower warfarin dose requirements Reduced warfarin metabolism because of hepatic congestion

Enhanced sensitivity to warfarin postoperatively because of hypoalbuminemia, lower PO intake, decreased physical activity, and reduced clotting factor concentrations after cardiopulmonary bypass

Changes in dietary vitamin K intake (e.g., intentional or because of disease or surgery) alter response to warfarin, especially in patients with lower-than-average baseline dietary vitamin K intake Decreased sensitivity to warfarin, possibly caused by changes in absorption or vitamin K content of nutritional supplements Hypothyroidism: Decreased catabolism of clotting factors requiring increased dosing requirements Hyperthyroidism: Increased catabolism of clotting factors causing increased sensitivity to warfarin Smoking: May induce CYP1A2, increasing warfarin dosing requirements Chewing tobacco: May contain vitamin K, increasing warfarin dosing requirements

Fever

Increased catabolism of clotting factors, causing acute increase in INR

Diarrhea

Acute infection or inflammation Malignancy

Reduction in secretion of vitamin K by gut flora, causing acute increase in INR Increased sensitivity to warfarin

Increased sensitivity to warfarin by many factors; increased bleeding risk

E. DOACs: Dabigatran (Domain 1, Tasks 2–7; Domain 3, Tasks 2, 3) Table 12. Direct Oral Anticoagulant Characteristics Characteristic

Protein binding

Dabigatran

35%

Volume of distribution

50–70 L

Elimination half-life

CrCl ≥ 80 = 13 hr CrCl 50–80 = 15 hr CrCl 30–50 = 18 hr CrCl 15–30 = 27 hr

Time to maximal 1 (fasted) to 2 (fed) hr serum concentrations

Rivaroxaban

92%–95%

Apixaban

87%

Edoxaban

55%

50 L

21 L

21 L

2–4 hr

3–4 hr

2 hr

5–9 hr

12 hr

12 hr

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Table 12. Direct Oral Anticoagulant Characteristics (continued) Characteristic

Metabolism

Dabigatran

Prodrug dabigatran etexilate converted to active drug dabigatran by esterase hydrolysis

Renal excretion of unchanged drug

Conjugation

Dialyzable

80% (of the absorbed dose, < 7% of dabigatran etexilate absorbed)

Rivaroxaban

Oxidative metabolism by CYP3A4/5 66% of the total dose, 33% of the absorbed dose

Unlikely (because of high plasma protein binding)

Apixaban

Edoxaban

Oxidative metabolism primarily by CYP3A4

Oxidative metabolism primarily by CYP3A4, conjugation

Yes

No

27% of total dose 50% of total dose

Table 13. Dabigatran: Considerations for Use Category

Dosage availability

Dosage form

Dosing

75- and 150-mg capsules PO Do not chew, break, or open capsules; this can substantially increase the bioavailability (once open, the bottle expires in 4 mo) Capsules contain many drug pellets with a tartaric acid core (coated with dabigatran etexilate) that creates an acidic microenvironment to improve dissolution and absorption independently of gastric pH

Dosing

NVAF CrCl > 30 mL/minute: 150 mg PO BID CrCl 15–30 mL/minute: 75 mg PO BID CrCl < 15 mL/minute or receiving dialysis: Not recommended

Hemodialysis Instructions if missed dose Hepatic impairment Older adults Reversal

Converting dabigatran to warfarin

Removes a substantial amount of dabigatran (62% at 2 hr, 68% at 4 hr); may be considered if overdose

Take on the same day as soon as possible; skip the missed dose if it cannot be taken at least 6 hr before the next scheduled dose; dosing should not be doubled to make up for a missed dose No adjustment required

No significant PK differences in healthy older adults, but they may be at higher GI bleeding risk from dabigatran Idarucizumab (Praxbind) 5 g IV (available as 2.5 g/50 mL vials) can be injected with two consecutive infusions or bolus injections Activated charcoal can decrease absorption if used within 1–2 hr of ingestion Hemodialysis (see above)

Adjust the starting time of warfarin based on CrCl CrCl > 50 mL/minute: Initiate warfarin 3 days before discontinuing dabigatran CrCl 31–50 mL/minute: Initiate warfarin 2 days before discontinuing dabigatran CrCl 15–30 mL/ minute: Initiate warfarin 1 day before discontinuing dabigatran CrCl < 15 mL/minute: Not recommended Note: Dabigatran can elevate the INR; the INR will better reflect warfarin’s effect after dabigatran has been discontinued for at least 2 days

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Table 13. Dabigatran: Considerations for Use (continued) Category

Dosing

Converting warfarin to dabigatran

Discontinue warfarin and initiate dabigatran when the INR is < 2

Surgery or invasive procedures

Discontinue dabigatran 2 days (CrCl ≥ 50 mL/minute) or 4 days (CrCl 30–49 mL/minute) or 5 days (< 30 mL/minute) before invasive or surgical procedures, if possible, to reduce the risk of bleeding Note: Depending on the risk of bleeding, urgency of the procedure, and thrombosis risk, holding for a shorter period may be considered Longer holding periods to establish complete hemostasis may be considered for major surgery, spinal puncture, or placement of a spinal or epidural catheter or port If a delay in surgery is not possible, the increased risk of bleeding should be weighed against the urgency of intervention

Converting to or from a parenteral anticoagulant

Contraindications

Warnings and precautions Adverse reactions

When a parenteral anticoagulant is in use, initiate dabigatran 0–2 hr before the next subcutaneous dose of parenteral drug was to have been administered or when a continuously administered IV parenteral drug is discontinued For patients currently taking dabigatran, wait 12 hr (CrCl ≥ 30 mL/minute) or 24 hr (CrCl < 30 mL/minute) after the last dabigatran dose before initiating the parenteral (subcutaneous or IV) anticoagulant

Active bleeding History of serious hypersensitivity reaction to dabigatran CrCl < 15 mL/minute Mechanical heart valve Avoid dabigatran in patients taking P-gp inhibitors with a CrCl 15–30 mL/minute

Risk of bleeding: Dabigatran can cause serious and sometimes fatal bleeding; promptly evaluate signs and symptoms of blood loss Temporary discontinuation: Avoid lapses in therapy to minimize stroke risk Discontinuation places the patient at increased thrombosis risk GI AEs are the most common: Dyspepsia, nausea, vomiting, constipation

AE = adverse effect; BID = twice daily; CrCl = creatinine clearance; GI = gastrointestinal; INR = international normalized ratio; IV = intravenous; NVAF = nonvalvular atrial fibrillation; P-gp = P-glycoprotein; PK = pharmacokinetic; PO = by mouth; rFVIIa = recombinant factor VI.

Adapted from: 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017;69:871-98.

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Table 14. Direct Oral Anticoagulant Drug Interactions Impact

Dabigatran

Rivaroxaban

Apixaban

Increase serum concentration

• Amiodarone • Dronedarone (reduce dose to 75 mg BID if CrCl 30–50 mL/min) • Quinidine • Ketoconazole (reduce dose to 75 mg BID if CrCl 30–50 mL/min) • Verapamil

• Combined P-gp and strong CYP3A4 inhibitors (avoid use) • Ketoconazole • Itraconazole • Lopinavir/ritonavir • Ritonavir • Indinavir/ritonavir • Conivaptan

Decrease serum concentration

• Rifampin (interaction to avoid) • Taking P-gp inhibitor and CrCl 15–30 mL/min

Increase anticoagulation effect

• Other anticoagulants or antiplatelets • Salicylates • SSRIs or SNRIs

• Combined P-gp and strong CYP3A4 inducers (avoid use) • Carbamazepine • Phenytoin • Rifampin • St. John’s wort

• Combined P-gp and strong CYP3A4 inducers (avoid use) • Carbamazepine • Phenytoin • Rifampin • St. John’s wort

Weigh risk–benefit in patients with a CrCl 15–50 mL/min taking concomitant P-gp and weak or moderate CYP3A4 inhibitors

Verapamil: for VTE, reduce dose to 30 mg daily

Other

• Other anticoagulants or antiplatelets • NSAIDs • SSRIs or SNRIs

• Combined P-gp and strong CYP3A4 inhibitors (reduce 5-mg dose BID to 2.5 mg BID, and if 2.5 mg BID, avoid use) • Ketoconazole • Itraconazole • Lopinavir/ritonavir • Ritonavir • Indinavir/ritonavir • Clarithromycin

Edoxaban

• Combined P-gp and strong CYP3A4 inducers (avoid use) • Carbamazepine • Phenytoin • Rifampin • St. John’s wort

• Other anticoagulants or antiplatelets • NSAIDs • SSRIs or SNRIs

BID = twice daily; CrCl = creatinine clearance; NSAID = nonsteroidal anti-inflammatory drug; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.

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F. Direct Xa Inhibitors; Oral Xa Inhibitors: Rivaroxaban, Apixaban, Edoxaban (Domain 1, Tasks 2–7; Domain 3, Tasks 2, 3) 1. Rivaroxaban Table 15. Rivaroxaban: Considerations for Use Category

Dosing

Dosage Availability

10-, 15-, and 20-mg PO Film-coated Tablets

Dosing

NVAF CrCl > 50 mL/minute: 20 mg PO once daily with evening meal CrCl 15–50 mL/minute: 15 mg once daily with evening meal CrCl < 15 mL/minute or receiving dialysis: Avoid use VTE treatment CrCl ≥ 30 mL/minute: 15 mg once daily PO BID with a meal for 21 days; then 20 mg PO once daily with a meal thereafter CrCl < 30 mL/minute: Avoid use VTE prophylaxis CrCl ≥ 30 mL/minute: 10 mg once daily PO once daily with evening meal CrCl < 30 mL/minute: Avoid use

Hemodialysis

Instructions if missed dose

Hepatic impairment Older adults

Because of high plasma protein binding, not expected to be dialyzable

If a dose is not taken at the scheduled time, administer the dose as soon as possible on the same day Avoid use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy

No significant PK differences in healthy older adults, but older adults may be at higher GI bleeding risk from rivaroxaban

Reversal

Converting rivaroxaban to warfarin

Converting warfarin to rivaroxaban

Use of activated charcoal to reduce absorption in case of overdose may be considered FDAapproved reversal agent Andexxa (coagulation factor Xa [recombinant], inactivated-zhzo). Low-dose regimen is an initial IV bolus of 400 mg at a target rate of 30 mg/ min followed by an IV infusion of 4 mg/min for up to 120 minutes. Benefits of rFVIIa are unknown; limited evidence indicates four-factor PCCs (Kcentra) may reverse anticoagulant effect No clinical trial data are available to guide converting patients’ therapy from rivaroxaban to warfarin Rivaroxaban affects INR, so INR measurements made during coadministration with warfarin might not be useful for determining the appropriate warfarin dose Another (unproven) approach is based on CrCl: CrCl > 50 mL/minute: Initiate warfarin 4 days before discontinuing rivaroxaban CrCl 31–50 mL/minute: Initiate warfarin 3 days before discontinuing rivaroxaban CrCl 15–30 mL/ minute: Initiate warfarin 2 days before discontinuing rivaroxaban Discontinue warfarin and initiate rivaroxaban as soon as the INR is < 3.0 to avoid periods of inadequate anticoagulation

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Table 15. Rivaroxaban: Considerations for Use (continued) Category

Converting to or from anticoagulants other than warfarin

Surgery or invasive procedures Contraindications Warnings and precautions Adverse reactions

Dosing

Initiate rivaroxaban 0–2 hr before the next scheduled evening administration of the drug and omit administration of the other anticoagulant For UFH administered by continuous infusion, discontinue the infusion and initiate rivaroxaban at the same time For patients currently taking rivaroxaban and transitioning to an anticoagulant with rapid onset, discontinue rivaroxaban and give the first dose of the other anticoagulant (PO or parenteral) when the next rivaroxaban dose would have been taken Discontinue at least 24 hr before the procedure with low bleeding risk if CrCl > 30 mL/min and 48 hr before the procedure with moderate or high bleeding risk if CrCl > 30 mL/min; in deciding whether a procedure should be delayed until 24 hr after the last rivaroxaban dose, weigh the increased risk of bleeding against the urgency of intervention Active bleeding History of serious hypersensitivity reaction to rivaroxaban

Risk of bleeding: Rivaroxaban can cause serious and sometimes fatal bleeding; promptly evaluate signs and symptoms of blood loss Temporary discontinuation: Avoid lapses in therapy to minimize stroke risk Low incidence of adverse reactions other than bleeding

CrCl = creatinine clearance; FDA = U.S. Food and Drug Administration; INR = international normalized ratio; IV = intravenous; NVAF = nonvalvular atrial fibrillation; PCC = prothrombin complex concentrate; PO = by mouth; VTE = venous thromboembolism. Adapted from: 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017;69:871-98.

2. Apixaban Table 16. Apixaban – Considerations for Use Category

Dosing

Dosage Availability

2.5- and 5-mg Film-coated PO Tablets

Hemodialysis

Dialysis clearance 18 mL/min (compared with renal clearance in healthy normal volunteers of 11 mL/min), representing a 14% decrease in exposure compared with an off-dialysis period; 7% of dose removed by hemodialysis

Dosing

Instructions if missed dose

NVAF 5 mg PO BID for CrCl ≥ 15 mL/minute Reduce dose to 2.5 mg PO BID if two of the following are present: age ≥ 80, body weight ≤ 60 kg, SCr ≥ 1.5 mg/dL For patients receiving hemodialysis (excluded from trials), prescribing information recommends a dose of 5 mg BID unless one of the following is present: age ≥ 80, body weight ≤ 60 kg; then reduce dose to 2.5 mg PO BID VTE and PE treatment 10 mg PO BID for days 1−7, then 5 mg PO BID VTE prophylaxis 2.5 mg PO BID

If a dose is not taken at the scheduled time, administer the dose as soon as possible on the same day, and BID administration should be resumed

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Table 16. Apixaban – Considerations for Use (continued) Category

Hepatic impairment Reversal

Converting apixaban to warfarin Converting warfarin to apixaban

Converting to or from anticoagulants other than warfarin

Surgery or invasive procedures Contraindications Warnings and precautions Adverse reactions

Dosing

No dosage adjustment in mild hepatic impairment; avoid use in patients with severe hepatic impairment

Use of activated charcoal to reduce absorption in case of overdose can be considered FDAapproved reversal agent Andexxa (coagulation factor Xa [recombinant], inactivated-zhzo); low-dose regimen is an initial IV bolus of 400 mg at a target rate of 30 mg/ min followed by an IV infusion of 4 mg/min for up to 120 minutes Benefits of rFVIIa are unknown; limited evidence indicates four-factor PCCs (not available in the United States) may reverse anticoagulant effect

Apixaban affects INR; therefore, INR measurements made during coadministration with warfarin might not be useful for determining the appropriate warfarin dose One (unproven) approach is to discontinue apixaban and begin both a parenteral anticoagulant and warfarin when the next apixaban dose would have been taken Discontinue warfarin and initiate apixaban as soon as the INR is < 2.0 to avoid periods of inadequate anticoagulation

Initiate apixaban at the same time as the next scheduled dose and omit administration of the other anticoagulant For UFH administered by continuous infusion, discontinue the infusion and initiate apixaban at the same time For patients currently taking apixaban and transitioning to an anticoagulant with rapid onset, discontinue apixaban and give the first dose of the other anticoagulant (PO or parenteral) when the next rivaroxaban dose would have been taken Discontinue at least 24 hr before a procedure with a low bleeding risk if CrCl > 30 mL/min and at least 48 hr before a procedure with a moderate or high bleeding risk if CrCl > 30 mL/ min; reinitiate after the surgical or other procedures as soon as adequate hemostasis has been established Active bleeding History of serious hypersensitivity reaction to apixaban

Risk of bleeding: Apixaban can cause serious and sometimes fatal bleeding; promptly evaluate signs and symptoms of blood loss Temporary discontinuation: Avoid lapses in therapy to minimize stroke risk Low incidence of adverse reactions other than bleeding

BID = twice daily; CrCl = creatinine clearance; FDA = U.S. Food and Drug Administration; IV = intravenous; NVAF = nonvalvular atrial fibrillation; PE = pulmonary embolism; PO = by mouth; UFH = unfractionated heparin; VTE = venous thromboembolism. Adapted from: 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017;69:871-98.

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3. Edoxaban Table 17. Edoxaban: Considerations for Use Category

Dosing

Dosage Availability

30- and 60-mg Film-coated PO Tablets

Hemodialysis

A 4-hr hemodialysis session reduced total edoxaban exposure by < 7%

Dosing

Instructions if missed dose

Hepatic impairment Reversal

NVAF 60 mg PO daily for CrCl 50–95 mL/minute; use not recommended if CrCl > 95 mL/min Reduce dose to 30 mg PO daily if CrCl is 15–50 mL/minute Patients receiving hemodialysis (excluded from trials): Not recommended VTE and PE treatment VTE and PE treatment: 60 mg taken PO once daily after 5–10 days of initial therapy with a parenteral anticoagulant 30 mg once daily for patients with CrCl 15-50 mL/minute or body weight 60 kg or less, or who use certain P-gp inhibitors. Caution in patients with CrCl > 95 mL/min If a dose is not taken at the scheduled time, administer the dose as soon as possible on the same day, and once-daily administration should be resumed the next day

No dosage adjustment in mild hepatic impairment; avoid use in patients with moderate to severe hepatic impairment

Use of activated charcoal to reduce absorption in case of overdose may be considered No FDAapproved antidote is available Benefits of rFVIIa are unknown; limited evidence indicates four-factor PCCs (not available in the United States) may reverse anticoagulant effect (vitamin K, FFP, protamine, and aminocaproic acid are not expected to have any effect)

Converting edoxaban to warfarin

Decrease edoxaban to 30 mg daily and initiate warfarin; continue edoxaban until INR ≥ 2.0 OR, discontinue edoxaban and initiate warfarin (recommend parenteral anticoagulation until INR > 2)

Converting warfarin Initiate edoxaban when INR is ≤ 2.5 to edoxaban Converting to or from anticoagulants other than warfarin

Surgery or invasive procedures Contraindications Warnings and precautions Adverse reactions

Initiate edoxaban at the same time as the next scheduled dose and omit administration of the other anticoagulant For UFH administered by continuous infusion, discontinue the infusion and initiate edoxaban 4 hr later For patients currently taking edoxaban and transitioning to an anticoagulant with rapid onset, discontinue edoxaban and give the first dose of the other anticoagulant (PO or parenteral) when the next edoxaban dose would have been taken Discontinue at least 24 hr before invasive or surgical procedures if low bleeding risk and 48 hr before invasive or surgical procedures if at moderate or high bleeding risk; reinitiate after the surgical or other procedures as soon as adequate hemostasis has been established Active bleeding History of serious hypersensitivity reaction to edoxaban

Risk of bleeding: Edoxaban can cause serious and sometimes fatal bleeding; promptly evaluate signs and symptoms of blood loss Temporary discontinuation: Avoid lapses in therapy to minimize stroke risk Low incidence of adverse reactions other than bleeding

CrCl = creatinine clearance; FDA = U.S. Food and Drug Administration; FFP = fresh frozen plasma; NVAF = nonvalvular atrial fibrillation; PCC = prothrombin complex concentrate; PE = pulmonary embolism; VTE = venous thromboembolism. Adapted from: 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017;69:871-98.

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Patient Case Questions 4 and 5 pertain to the following case. C.S. is a 65-year-old woman (weight 65 kg) with a history of uncontrolled HTN, history of TIAs, and chronic NVAF. Her current medications include lisinopril 40 mg orally once daily, chlorthalidone 25 mg orally once daily, aspirin 81 mg once daily, and carvedilol 25 mg orally twice daily. Her SCr is 1.1 mg/dL and calculated CrCl is 52 mL/minute. 4. Which best describes C.S.’s CHADS2 -VASc score and classification for stroke risk? A. B. C. D.

2 (Moderate). 3 (Moderate). 4 (High). 5 (High).

5. Which treatment for thromboembolic prophylaxis is most appropriate for C.S.? A. B. C. D.

Apixaban 10 mg orally twice daily for 7 days and then 5 mg orally twice daily thereafter. Rivaroxaban 20 mg orally daily. Edoxaban 30 mg orally once daily. Warfarin 10 mg orally daily.

IV.  THERAPY PRECAUTIONS AND MANAGEMENT OF ADVERSE EVENTS (Domain 1, Tasks 2, 3, 4) Table 18. Reversal Considerations for LMWH or Fondaparinux LMWHs

Protamine can be used as a “partial” reversal agent for the effects of LMWH. Protamine neutralizes ~60% of the anti-Xa activity If LMWH was given in the previous 8 hr, then 1 mg of protamine should be administered for every 100 IU (or 1 mg) of the LMWH If the LMWH dose is given in the previous 8–12 hr, a 0.5-mg dose of protamine should be given for every 100 anti-Xa units Use of protamine sulfate is not recommended if the LMWH was administered > 12 hr earlier

Fondaparinux

No specific antidote exists

LMWH = Low-molecular-weight heparin.

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Table 19. Guidelines for Reversal of an Elevated INR in a Patient Taking Warfarin INR

Recommendation

75

Low

Bileaflet aortic valve CHADS2 score of 0–2 Single VTE occurred > 12 mo ago and no other prosthesis without AF and (no previous stroke or risk factors no other risk factors for TIA) stroke

AF = Atrial fibrillation; HTN = hypertension; TIA = transient ischemic attack; VTE = venous thromboembolism.

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D. Periprocedural Anticoagulation for Cardioversion (Domain 1, Tasks 2, 3, 4) Table 21. Guidelines for Anticoagulation for Early Cardioversion in Acute onset of NVAF or Atrial Flutter Guideline

American Heart Association/ America College of Cardiology/ Heart Rhythm Society American College of Chest Physicians

European Society of Cardiology Canadian Cardiovascular Society

Recommendation

AF or AFL of 48 hours’ duration or longer, or when the duration of AF is unknown, anticoagulation with warfarin (INR 2.0-3.0), a factor Xa inhibitor, or direct thrombin inhibitor is recommended for at least 3 weeks before and at least 4 weeks after cardioversion, regardless of the CHA2DS2-VASc score or the method (electrical or pharmacological) used to restore sinus rhythm AF of documented duration of < 48 hours undergoing elective cardioversion (electrical or pharmacologic), we suggest starting anticoagulation at presentation (LMWH or UFH at full VTE treatment doses) and proceeding to cardioversion rather than delaying cardioversion for 3 weeks of therapeutic anticoagulation or a TEE-guided approach Early cardioversion can be performed without TEE in patients with a definite duration of AF < 48 hours

Cardioversion of symptomatic AF or AFL without at least 3 weeks of previous therapeutic anticoagulation (or use of the TEE approach) reserved for patients with NVAF who present with a clear AF onset within 12 hours in the absence of recent stroke or transient ischemic attack (within 6 months) or in patients with a CHADS2 score < 2 who present after 12 hours but within 48 hours of AF onset

AF = atrial fibrillation; AFL = atrial flutter; INR = international normalized ratio; LMWH = low-molecular-weight heparin; NVAF = nonvalvular atrial fibrillation; TEE = transesophageal echocardiography; UFH = unfractionated heparin; VTE = venous thromboembolism.

Table 22. Guidelines for Anticoagulation after Cardioversion of Low-Risk Acute NVAF or Atrial Flutter Guideline

American Heart Association, American College of Cardiology, Heart Rhythm Society American College of Chest Physicians European Society of Cardiology Canadian Cardiovascular Society

Recommendation

AF or AFL of < 48 hours’ duration with a CHA2DS2-VASc score of 0 in men or 1 in women, administration of heparin, a factor Xa inhibitor, or a direct thrombin inhibitor, vs no anticoagulant therapy, may be considered before cardioversion, without the need for post cardioversion oral anticoagulation

After successful cardioversion to sinus rhythm, we recommend therapeutic anticoagulation (with VKA or full adherence to DOAC therapy) for at least 4 weeks rather than no anticoagulation, regardless of baseline stroke risk In patients without stroke risk factors, anticoagulation is recommended for 4 weeks after cardioversion

All patients who undergo cardioversion of AF/AFL receive at least 4 weeks of therapeutic anticoagulation (adjusted-dose warfarin or a DOAC) after cardioversion or in patients with a CHADS2 score < 2 who present after 12 hours but within 48 hours of AF onset

AF = Atrial fibrillation; AFL = ; DOAC = direct oral anticoagulation; VKA = ; vitamin K antagonist.

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Table 23. Warfarin to Parenteral Anticoagulant Bridge Therapy Guidelines for Invasive Procedures Thromboembolic Renal Riska Function

Low

All patients

High

CrCl > 30 mL/min

CrCl ≤ 30 mL/min

Bridge Therapy

Last dose of warfarin on day −6 before procedure Hold warfarin day from day −5 through day −1 Consider vitamin K 2.5 mg PO on day −2 or day −1 if INR ≥ 1.5 Resume warfarin 12–48 hr after procedure at usual maintenance dose (decision based on postoperative assessment of bleeding risk) In general, bridging is not recommended in patients with a low/moderate risk of TE in AF (BRIDGE trial). Anticoagulation can often be continued through low-bleedingrisk procedures such as dental extractions Last dose of warfarin on day −6 before procedure Hold warfarin day −5 through day −1 Start LMWH on day −3 (or when INR < lower limit of range) Consider vitamin K 2.5 mg PO on day 2 or day 1 if INR ≥ 1.5 Last dose of LMWH 24 hr before procedure (On day −1, give one-half dose of LMWH if patient is receiving once-daily LMWH) Resume warfarin 12–24 hr after procedure at usual maintenance dose (decision predicated on after procedure assessment of bleeding risk) Resume LMWH 24 hr after procedure (or 48–72 hr for major surgery or high bleeding risk procedure) and continue until INR > lower limit of therapeutic range

Last dose of warfarin on day –6 before procedure Hold warfarin day –5 through day –1 Consider vitamin K 2.5 mg PO or 1 mg IV × on day –2 or day –1 before procedure if INR ≥ 1.5 Admit on day –1 pre-procedure and begin IV UFH (70 units/kg bolus, 15 units/kg/hr infusion and adjust per inpatient protocol) Discontinue IV UFH 6 hr before procedure Resume warfarin 12–24 hr after procedure at the usual maintenance dose (decision based on postoperative assessment of bleeding risk) Resume IV UFH 24 hr after procedure (or 48–72 hr for major surgery or highbleeding-risk procedure) and continue until INR > lower limit of therapeutic range

The decision to bridge patients with a moderate risk of thromboembolism should be based on surgery and patient-related factors. Day 0 = day of procedure.

a

CrCl = creatinine clearance; INR = international normalized ratio; IV = intravenous; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin.

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VI.  CONSIDERATIONS FOR PATIENT SAFETY AND DELIVERY OF QUALITY PATIENT CARE A. Systematic Management (Domain 4, Task 1) 1. Anticoagulation therapy management services can: a. Improve the care of patients who take warfarin therapy. b. Provide structured and comprehensive patient education and evaluation. c. Improve the safety and effectiveness of warfarin therapy compared with “usual” medical care. d. Lower the overall cost of care by reducing the frequency of major bleeding and recurrent thromboembolic events. 2. However, the benefit of anticoagulation management services is not supported by high-quality evidence. B. National Quality Initiatives (Domain 5, Tasks 1, 2) 1. The recent national focus on quality health care has been emphasized by the call to accountability through The Joint Commission, the Institute of Medicine’s report on medical errors; the endorsed safe practices of the National Quality Forum (NQF); and the Leapfrog Group’s recommendations a. Organizations Monitoring Quality of VTE Care i. The Joint Commission: www.jointcommission.org ii. Leapfrog Group: www.leapfroggroup.org iii. National Quality Forum: www.qualityforum.org 2. The NQF has developed national consensus standards for VTE prevention and treatment that will apply to a variety of health care settings. a. Provide a framework for measuring the effective screening, prevention, and treatment of VTE. b. The NQF’s recommendations include developing organizational policies that address staff education, treatment protocols, and compliance measurements to improve VTE prevention in the hospital. c. NQF consensus standards goal is to facilitate the early promulgation of VTE policies, risk assessment, prophylaxis, diagnosis, and treatment services as well as patient education and organizational accountability. Table 24. The Joint Commission’s Performance Measures for the Prevention and Treatment of Venous Thrombosis Number 1

2

3

Description of Performance Measure

Assesses the number of patients who receive VTE prophylaxis or have documentation regarding why no VTE prophylaxis was given the day of or the day after hospital admission or surgery end date for surgeries that started the day of or day after hospital admission. Assesses the number of patients who receive VTE prophylaxis or have documentation regarding why no VTE prophylaxis was given the day of or the day after the initial admission (or transfer) to the ICU or surgery end date for surgeries that started the day of or day after ICU admission (or transfer).

Assesses the number of patients with diagnosed VTE during hospitalization (not present at admission) who did not receive VTE prophylaxis between hospital admission and the day before the VTE diagnostic testing order date.

ICU = intensive care unit; VTE = venous thromboembolism.

C. Useful Resources Involving Anticoagulation Therapy 1. American College of Chest Physicians (https://www.chestnet.org/Publications/CHEST-Publications/ Guidelines-Consensus-Statements) 2. Anticoagulation (www.acforum.org/) 3. ClotCare (www.clotcare.com/)

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HEART FAILURE VII.  DIAGNOSIS A. Symptoms Suggestive of HF (Domain 1, Task 2) 1. Dyspnea at rest or on exertion 2. Reduced exercise capacity 3. Unexplained fatigue 4. Orthopnea 5. Paroxysmal nocturnal dyspnea 6. Wheezing or coughing 7. Confusion or delirium 8. Depression 9. Early satiety, nausea, and vomiting 10. Weakness B. Physical Examination Findings (Domain 1, Task 2) 1. Elevated jugular venous pressure 2. S3 gallop 3. Rales 4. Ascites 5. Hepatojugular reflux 6. Narrow pulse pressure 7. Cardiac enlargement 8. Edema 9. Displaced apical pulse, or PMI (“point of maximum impulse”) 10. Cardiac murmurs suggesting valvular dysfunction 11. Cool Extremities C. Other Pertinent Diagnostic and Laboratory Findings (Domain 1, Tasks 2, 3) 1. Assessment of B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) concentration is recommended by guidelines, especially when the diagnosis is uncertain. 2. BNP greater than 100 pg/mL or a NT-proBNP of more than 450 pg/mL for patients younger than 50 years, more than 900 pg/mL for patients 50–74 years olf, and more than 1800 pg/mL for patients 75 years and older are predictive of HF. 3. Left ventricular ejection fraction (LVEF) less than 40% as determined by echocardiography, radionuclide angiography (multiple gated acquisition blood scan, considered the gold standard for LVEF measurement), or coronary angiography. D. Definitions (Domain 1, Task 2)

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Table 25. Classification of Heart Failure Classification I.

Heart failure with reduced ejection fraction (HFrEF)

II. Heart failure with preserved ejection fraction (HFpEF)

a. HFpEF, borderline b. HFpEF, improved

EF (%) Description ≤40 ≥50

Also referred to as systolic HF. Randomized controlled trials have mainly enrolled patients with HFrEF, and it is only in these patients that efficacious therapies have been demonstrated to date.

Also referred to as diastolic HF. Several different criteria have been used to further define HFpEF. The diagnosis of HFpEF is challenging because it is largely one of excluding other potential noncardiac causes of symptoms suggestive of HF. To date, efficacious therapies have not been identified.

41 to 49 These patients fall into a borderline or intermediate group. Their characteristics, treatment patterns, and outcomes appear to be similar to those of patients with HFpEF. >40

It has been recognized that a subset of patients with HFpEF previously had HFrEF. These patients with improvement or recovery in EF may be clinically distinct from those with persistently preserved or reduced EF. Further research is needed to better characterize these patients.

EF indicates ejection fraction; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; and HFrEF, heart failure with reduced ejection fraction.

Table 26. Clinical Classifications of Heart Failure Severity NYHA Functional Classification

Class I

Class II

Class III

ACC/AHA Stages of Heart Failure

Stage A

No limitation of physical activity; ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea

Stage B

Slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea

Marked limitation of physical activity; comfortable at rest, but less than ordinary activity results in fatigue, palpitation, or dyspnea

Stage C

Class IV Unable to carry on any physical activity without discomfort; symptoms present at rest; if any physical activity is undertaken, discomfort is increased

Stage D

At high risk of HF; no identified structural or functional abnormality; no signs or symptoms Developed structural heart disease that is strongly associated with the development of HF but without signs or symptoms

Symptomatic HF associated with underlying structural heart disease

Advanced structural heart disease and marked symptoms of HF at rest despite maximal medical therapy

ACC = American College of Cardiology; AHA = American Heart Association; HF = heart failure; NYHA = New York Heart Association. Reprinted with permission from: McMurray JJV. Systolic heart failure. N Engl J Med 2010;362:228-38.

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VIII.  STANDARD PHARMACOLOGIC MANAGEMENT STRATEGIES FOR HEART FAILURE WITH REDUCED LEFT VENTRICULAR EJECTION FRACTION (HFrEF) A. Angiotensin-Converting Enzyme (ACE) Inhibitors (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3) 1. ACE inhibitors are recommended in all patients with symptomatic HFrEF, unless contraindicated. Randomized controlled trials with ACE inhibitors in HF have shown the following: a. Reductions in mortality and morbidity (Reduced HF hospitalizations) 2. ACE inhibitors should be avoided in patients with the following: a. History of angioedema b. Bilateral renal artery stenosis c. Severe aortic stenosis d. Hypotension e. Pregnancy 3. ACE inhibitors should be used cautiously and with close monitoring in patients with a serum potassium concentration greater than 5.5 mmol/L because of the potential for hyperkalemia. 4. In acute HF and significant worsening of renal dysfunction, ACE inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs) can be temporarily dose reduced or discontinued. 5. Table 27 lists specific ACE inhibitors and recommended doses. In general, the benefits of ACE inhibitors are considered a class effect, and doses should be titrated to doses proven effective in randomized trials. 6. In the ATLAS (Assessment of Treatment with Lisinopril and Survival) trial, patients randomly assigned to receive high-dose lisinopril (32.5–35 mg/day) had a significantly lower risk of all-cause hospitalization than did patients randomly assigned to receive low-dose lisinopril (2.5–5 mg/day); all-cause mortality alone was not significantly different between the high- and low-dose groups. Table 27. ACE Inhibitors and Doses Generic Name

Trade Name

Initial Daily Dose

Target Dose

Mean Dose Achieved in Clinical Trials

Captopril

Capoten

6.25 mg TID

50 mg TID

122.7 mg/day

Fosinopril

Monopril

5–10 mg daily

80 mg daily

N/A

Enalapril

Lisinopril

Perindopril

Vasotec

Zestril, Prinivil Aceon

2.5 mg BID

10 mg BID

2.5–5 mg daily

20–40 mg daily

2 mg daily

16 mg daily

16.6 mg/day

4.5 mg/day (low-dose ATLAS)a 33.2 mg/day (high-dose ATLAS) N/A

Quinapril

Accupril

5 mg BID

80 mg daily

N/A

Trandolapril

Mavik

1 mg daily

4 mg daily

N/A

Ramipril

Altace

1.25–2.5 mg daily

10 mg daily

N/A

No difference in mortality between the high- and low-dose groups, but a 12% lower risk of death or hospitalization in the high- versus low-dose group.

a

ACE = angiotensin-converting enzyme; ATLAS = Assessment of Treatment with Lisinopril and Survival; N/A = not applicable; TID = three times daily.

Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-239.

7. Monitoring a. SCr and serum potassium assessed within 1–2 weeks after initiation and periodically thereafter b. Consider dose reduction or discontinuation if increase in SCr greater than 30% from baseline 8. Major adverse effects a. Angioedema, hyperkalemia, hypotension, worsening renal function, and nonproductive cough

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B. Angiotensin Receptor Blockers (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3) 1. ARBs for ACE inhibitor–intolerant patients a. An ARB is a useful alternative to an ACE inhibitor because of ACE inhibitor intolerance. i. ELITE II (Losartan Heart Failure Survival Study) trial showed no differences in all-cause mortality for patients randomly assigned to losartan versus captopril. ii. Candesartan in Heart Failure Assessment of Reduction in Morbidity and Mortality (CHARM) Alternative study, candesartan was associated with a 23% reduction (hazard ratio [HR] 0.77; 95% CI, 0.67–0.89, p=0.0004) compared with placebo for the primary end point of cardiovascular (CV) death or HF hospitalization in patients intolerant of ACE inhibitors. b. ARBs are routinely recommended for patients intolerant of ACE inhibitors because of cough. c. Patients intolerant of ACE inhibitors because of worsening renal function, hyperkalemia, or hypotension are likely to have similar effects with ARBs. d. Patients with ACE inhibitor angioedema should be considered for ARB therapy as there is a low risk of ARB induced angioedema if experience ACE inhibitor angioedema. Table 28. Angiotensin Receptor Blockers and Recommended Doses Generic Name

Trade Name

Initial Daily Dose

Target Dose

Mean Dose Achieved in Clinical Trials

Candesartan

Atacand

4–8 mg/day

32 mg daily

24 mg/day

Valsartan

Diovan

40 mg BID

160 mg BID

254 mg/day

Losartan

Cozaar

12.5–25 mg/day

150 mg/day

129 mg/day

BID = Twice daily.

Reprinted with permission from: Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-239.

2. Addition of an ARB to ACE inhibitor therapy a. Adding an ARB may be recommended for patients with HF who remain symptomatic despite optimal treatment with ACE inhibitors and β-blockers (unless contraindications are present) and for whom an MRA is not indicated or not tolerated. b. Several studies have evaluated adding an ARB to background ACE inhibitor therapy. i. The Valsartan Heart Failure Trial (Val-HeFT) showed a 13% reduction (relative risk [RR], 0.87; 97.5% CI, 0.77–0.97; p=0.009) in the combined end point of mortality and morbidity for patients randomly assigned to receive valsartan versus placebo. Mortality was similar between groups. ii. CHARM-Added trial, adding candesartan for patients with HF receiving background ACE inhibitor therapy provided a 15% reduction (HR, 0.85; 95% CI, 0.75–0.96; p=0.011) in the primary end point of CV death or HF hospitalization, compared with placebo. iii. The combination of ACE inhibitor and ARB has fallen out of favor clinically as there are better alternatives shown to add to an ACE inhibitor or ARB that reduces both morbidity and mortality (e.g., MRA). C. Angiotensin Receptor Neprilysin Inhibitor (ARNI) (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3) 1. Natriuretic peptides (NPs; atrial natriuretic peptides, BNPs, and C-type NPs), are responsible for natriuresis, and help maintain sodium (Na) and fluid balance. NPs are released in the setting of excess plasma volume and elevated left ventricular filling pressures. a. NPs are cleared through the natriuretic receptor and through peptide-mediated breakdown by neprilysin. b. Neprilysin also breaks down angiotensin II; therefore, an inhibitor of this enzyme must be combined with renin–angiotensin–aldosterone system blockade.

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2.

3. 4. 5. 6. 7. 8. 9.

c. Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor, which is a fixed-dose combination of the ARB valsartan and the neprilysin inhibitor sacubitril. In the Prospective Comparison of ARNI with ACE inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, patients with New York Heart Association (NYHA) FC II–IV and reduced LVEF of less than 40% (later changed to 35% or less) were randomly assigned to receive enalapril 10 mg twice daily or sacubitril/valsartan 200 mg twice daily. a. Sacubitril/valsartan reduced the primary composite end point of CV death or HF hospitalization by 20% compared with enalapril (HR, 0.80; 95% CI, 0.73–0.87; p15% (QTc should never exceed 0.5 s or 0.55 s in patients with baseline conduction system abnormality); if QTc prolongs by > 15% or 0.5 s in patients with baseline conduction abnormalities of baseline after any dosage adjustment, dofetilide must be discontinued and deemed treatment failure; before the patient is discharged, the health care facility must provide a free 7-day supply of dofetilide and the medication guide to patients or ensure the patient’s take-home prescription is filled. Inform the patient about the serious risks associated with dofetilide therapy (medication guide mandated). Mandates K+, magnesium, SCr, and 12-lead ECG monitoring at least every 3 mo

ADHF = acute decompensated heart failure; AE = adverse effect; AV = atrioventricular; BID = twice daily; CAD = coronary artery disease; CI = contraindication; CNS = central nervous system; CR = continuous release; CT = computed tomography; DI = drug interaction; Dis = disease; HCTZ = hydrochlorothiazide; GI = gastrointestinal; HF = heart failure; HRS = Heart Rhythm Society; IR = immediate release; LA = long acting; LFT = liver function test; LV = left ventricular; MI = myocardial infarction; MOA = mechanism of action; NYHA = New York Heart Association; PK = pharmacokinetics; PO = by mouth; QTc = corrected QT interval; REMS = Risk Evaluation and Mitigation Strategies; SR = sustained release; TdP = torsades de pointes; TIPS = Tikosyn In Pharmacy Systems; VF = ventricular fibrillation; VT = ventricular tachycardia.

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VALVULAR HEART DISEASE XIV.  THROMBOEMBOLISM PREVENTION A. Prevention of TE in Patients with Valvular Heart Disease or Prosthetic Heart Valves (Domain 1, Tasks 2, 3) 1. Patients with valvular AF are considered at “high risk” of cardioembolic stroke and should receive anticoagulation and, in some cases, added aspirin. 2. Patients with mechanical valve prosthesis without AF are at high risk of thromboembolic complications (mainly cardioembolic stroke and valve thrombosis) and require lifelong antithrombotic prophylaxis. 3. Prosthetic valves are made of various materials that differ in thrombogenicity. a. Newer materials reduce thrombogenicity, and future materials such as polymerics can reduce thrombogenicity even more. b. Bioprosthetic valves are less thrombogenic, but they are not as durable as mechanical valve prosthesis and are thus more prone to failure, requiring replacement. c. Because valve position, type, and materials affect thrombogenicity, correct use of anticoagulation therapy requires determining exactly which valves have been replaced and the type of prosthesis used so that mistakes in anticoagulation are avoided. 4. Risk factors for thrombosis a. Annual risk of TE is 4%–23% without prophylaxis. b. Prophylaxis reduces the risk of TE to less than 2% per year. c. Risk of TE is highest in the early postsurgical period because of exposed valvular components (e.g., suturing ring, valve surfaces). After about 3 months, endothelialization occurs and TE risk decreases. 5. Types of valves a. Mechanical prosthetic valves i. Three basic types of mechanical valves: caged-ball/disk, tilting disk, and bileaflet Table 36. Types of Mechanical Heart Valves Valve Type

Model

Caged-ball

Starr-Edwards

Bileaflet

St. Jude On-X Carbomedics Baxter TEKNA Duromedics Sorin Bicarbon

Tilting disk

Björk-Shiley Monostrut Medtronic-Hall Omniscience Omnicarbon Ultracor

ii. Older caged-ball and tilting disk valves more thrombogenic than bileaflet valves iii. Annual TE event rate in patients who receive anticoagulation treatment to an INR of 2.5–4.9 (a) Bileaflet 0.5% per year (b) Tilting disk 0.7% per year b. Bioprosthetic valves i. Bioprosthetic valves use a ring of material from an animal source (e.g., porcine, bovine). ii. Porcine valves use the tissue valve from pig hearts (usually aortic valves).

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iii. Pericardial valves use tissue from the bovine pericardium to make the valve leaflets, which are supported by a synthetic frame. iv. The valves are less thrombogenic and less durable than mechanical valves. Table 37. Bioprosthetic Valve Types Valve Type

Model

Porcine

Pericardial (bovine)

Hancock I Hancock II Intact Carpentier-Edwards Freestyle Bicor

Carpentier-Edwards Perimount Ionescu-Shiley Mitroflow

6. Position of valves: Valve position influences thrombogenicity. Mechanical mitral valves are more thrombogenic than mechanical aortic valves. 7. Antithrombotic prophylaxis a. Intravenous adjusted-dose UFH or subcutaneous LMWH can be used postoperatively after valve insertion as a transition to warfarin and continued until INR is therapeutic and stable. b. A recent observational study suggests that discontinuing warfarin after placing a bioprosthetic aortic valve is associated with an increased risk of TE and CV death; therefore, future guidelines may suggest anticoagulation after aortic bioprosthetic surgery, as they now do for mitral bioprosthetic valve placement (JAMA 2012;308:2118-25). c. The 2017 ACC/AHA valvular heart disease guideline states that it is reasonable to provide anticoagulation for 3–6 months after bioprosthetic mechanical valve replacement or aortic valve replacement [AVR]). d. In the only study reported with mechanical heart valves and a DOAC (phase 2, open-label, RE-ALIGN trial), patients who received dabigatran had increased thrombotic and bleeding risk compared with patients who received warfarin, and the trial was terminated prematurely. Dabigatran is the only newer oral agent that specifically carries a contraindication for use in patients with mechanical heart valves. e. All patients with a mechanical valve should receive lifelong warfarin therapy adjusted to the recommended INR range. f. Patients with bioprosthetic valves and AF should receive lifelong anticoagulation therapy. Although not contraindicated in current product labeling of dabigatran, rivaroxaban, and apixaban, these agents have not been adequately studied in this group of patients. g. Patients with either mitral stenosis or a bioprosthetic heart valve were enrolled in the ENGAGE-AF trial comparing edoxaban and warfarin, but results in this important subgroup have not yet been presented or published. h. In patients with AF and a bioprosthetic mitral valve in the RIVER trial, rivaroxaban was noninferior to warfarin with respect to the mean time until the primary outcome of death, major CV events, or major bleeding at 12 months.

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Table 38. Chest Guideline Recommendations for Antithrombotic Prophylaxis Valve Position

Aortic Mitral

Bioprosthetic

Mechanicala

Aspirinb

Warfarin (INR 2–3) for 3 mo, then aspirinb

Warfarin (INR 2–3)c

Warfarin (INR 2.5–3.5)

Recommend adding low-dose aspirin 50–100 mg by mouth daily for all patients with mechanical valves and low risk of bleeding.

a

b

Aspirin 50–100 mg/day. Recommend against giving aspirin to patients at high risk of bleeding (e.g., history of gastrointestinal bleed, age > 80).

American Collge of Cardiology/American Heart Association recommends INR 2.5–3.5 for all caged-ball and tilting disk valves.

c

8. Patients who develop systemic embolism despite a therapeutic INR a. If the patient was not previously taking aspirin, add aspirin 50–100 mg/day. b. Titrate warfarin to a higher INR range. Previous INR Range

2–3

2.5–3.5

Postsystemic Embolism INR Range

2.5–3.5

3.5–4.5

INR = International normalized ratio.

XV.  AORTIC STENOSIS (Domain 1, Tasks 2, 3; Domain 3, Task 2) A. Diagnosis is usually made auscultation of a heart murmur on physical examination. Typically, crescendodecrescendo systolic ejection murmur radiating to the neck and is confirmed with echocardiography. B. Severe Aortic Stenosis is defined by Doppler echocardiography as a maximum aortic jet velocity greater than 4 m/second, mean transvalvular pressure gradient greater than 40 mm Hg, and continuity equation valve area less than 1.0 cm2 or valve area index less than 0.6 cm.2 C. Pathophysiology: Pressure Overload Hypertrophy D. Signs and Symptoms 1. Three classic signs and symptoms are HF, syncope, and angina. 2. HF is caused by hypertrophy and the failure to eject blood effectively from the ventricles, leading to fluid overload, syncope secondary to diminished carotid blood flow, and angina secondary to diminished coronary flow to the hypertrophied heart. 3. Typically, patients are asymptomatic until late in the disease course. 4. Interval from the onset of symptoms to the time of death is around 2 years in patients with HF, 3 years in those with syncope, and 5 years in those with angina. E. Treatment of Severe Aortic Stenosis 1. Medical management of severe aortic stenosis has a mortality rate of 50% at 1 year. 2. Mechanical or bioprosthetic valve replacement surgery provides symptom relief and mortality reduction in appropriate candidates.

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3. Candidates are screened for surgical acceptability using the Society of Thoracic Surgeons score, which predicts operative and short-term postoperative survival, using a model of 24 variables. See http:// riskcalc. sts.org/STSWebRiskCalc273/de.aspx. 4. Transcatheter aortic valve replacement (TAVR) involves nonsurgical placement of a porcine or bovine aortic valve. 5. Aortic balloon valvuloplasty is used primarily as a bridge to TAVR or as palliation, because durability is short. Two valves are FDA approved: SAPIEN (Edwards) and CoreValve system (Medtronic). F. TAVR with SAPIEN Valve (Edwards): Placed Primarily Using a Transfemoral Approach and, Less Preferably, a Transapical Approach; FDA Approved According to the PARTNER Trial 1. The PARTNER (Placement of Aortic Transcatheter Valve) trial was a prospective, unblinded, multicenter randomized trial that compared medical management with TAVR in patients who were not considered surgical candidates (cohort B) and AVR patients deemed high-risk operable (cohort A). 2. Cohort B results compared with medical management of TAVR a. Reduced all-cause mortality by 38% at 1 year (p 2 drinks per day) 120 mL of wine, 30 mL of liquor, 260 mL of beer High caffeine intake RA CV disease Type 2 diabetes Celiac disease Vitamin D deficiency

Asthma/COPD Anorexia nervosa Autoimmune disorders Hepatic disease History of falls

Antiepileptic agents Immunosuppressants (cyclosporine) Lithium PPIs Systemic corticosteroids (see Figure 2) Selective serotonin reuptake inhibitors Excessive thyroid hormone supplementation Tricyclic antidepressants Warfarin or heparin (long-term use) Thiazolidinediones

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Table 1. Factors Associated with Decreased BMD and/or Osteoporotic Fractures (continued)

Sex-specific factors

Women Medroxyprogesterone depot use Excessive vitamin A intake GI malabsorption syndromes Parental history of osteoporosis Men Loop diuretic use Gonadotropin-releasing hormone agonists (prostate cancer) Psoriasis

BMD = bone mineral density; BMI = body mass index; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; GI = gastrointestinal; PPI = proton pump inhibitor; RA = rheumatoid arthritis. Adapted from: Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to preventions and treatment of osteoporosis. Osteoporosis Int 2014;25:2359-81.

Patient Case 1. F.R. is a 74-year-old woman with a history of a right hip replacement after a fall and fracture. In addition to her hip fracture, she has a history of type 2 diabetes (most recent hemoglobin A1C 7.3%) and hypothyroidism (current thyroid-stimulating hormone concentration [TSH] 0.1 mIU/L), for which she receives treatment. A dual-energy x-ray absorptiometry (DEXA) revealed F.R.’s T-score at her femoral neck as -2.7. The Z-score associated with her femoral neck T-score was -2.1. Her physician believes this was a fracture secondary to drug-induced bone density loss. Which medication most likely contributed to her bone mineral density (BMD) loss and fracture? A. B. C. D.

Metformin. Glipizide. Levothyroxine. Lovastatin.

Table 2. Fracture Prevention Counseling (all individuals age > 50) (Domain 1, Task 1, Knowledge 1 and Task 6, Knowledge 3)

Calcium intake

Vitamin D intake

Exercise and physical activity Social habit changes

NOF: Calcium 1000–1200 mg (elemental)/day from diet or supplementation* USPSTF: 1000 mg (elemental)/day from diet or supplementation* *Supplemental calcium not necessary if appropriate amount obtained through diet

NOF: 800–1000 units/day* USPSTF: 400 units/day* *Supplemental vitamin D not necessary if patient has adequate serum concentrations of 25(OH)D > 20 ng/mL; therefore, recommended amount can be obtained through diet Walking Aerobics (low impact) Strength training Multifactorial fall prevention assessment and management Smoking cessation/avoidance Limited to moderate alcohol intake (< 2 drinks/day) 120 mL of wine, 30 mL of liquor, or 260 mL of beer

25(OH)D = 25-hydroxyvitamin D.

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Table 3. Screening Recommendations (Domain 5, Task 2, Knowledge 1) American Association of Clinical Endocrinology (AACE 2020)

All postmenopausal women ≥ 50 yr should undergo clinical assessment for osteoporosis and fracture risk, including a detailed history and physical examination. Tools such as FRAX should be used, when available

U.S. Preventive Services Task Force (2018)

Women: ≥ 65 yr without known fractures or secondary causes of osteoporosis Postmenopausal women < 65 yr who are at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool

FRAX = Fracture Risk Assessment Tool; SD = standard deviation.

Table 4. Fracture Risk Assessment Tools (Domain 1; Tasks 2, 3; Knowledge 1)

WHO FRAX

Peripheral (Calcaneal) DEXA

Available online at www.sheffield.ac.uk/FRAX Developed to assess a 10-yr probability of hip or other major osteoporotic fracture For screening, results may be used to identify patients who require diagnostic evaluation with a DEXA scan, but is not a definitive tool for deciding to treat a patient For treatment, results may be used to determine whether patients with osteopenia require pharmacologic treatment (see Figure 1) Consider treatment with antiresorptive agent when 10-yr risk of any major osteoporotic fracture is ≥ 20% or hip fracture ≥ 3%; non-U.S. countries/regions may have different thresholds Useful tool found in many community screenings This method of screening/assessment is useful for identifying individuals with a low BMD but should not be used as a diagnostic tool to quantify the severity of bone loss Pharmacies using this form of outpatient DEXA should develop a policy and/or protocol for referring patients to a physician if the test results are abnormal and require additional investigation

DEXA = dual-energy x-ray absorptiometry.

B. Diagnostic Criteria 1. Dual-energy x-ray absorptiometry (DEXA) a. Definitions i. T-score: Reports how many standard deviations (SDs) separate a patient’s BMD compared with the BMD of a young adult reference population ii. Z-score: Reports how many SDs separate a patient’s BMD compared with the BMD of another patient matched for age, sex, and ethnicity; used when diagnosing secondary osteoporosis and/or in children, young adults, premenopausal women, and men younger than 50 b. Measures the lumbar spine (1–4) and femoral neck of nondominant hip c. T-scores are based on the mean BMD for a young, healthy adult of the same sex. i. “Normal”: 0 or 1 SD below the mean value ii. Osteopenia: 1–2.5 SDs below the mean value iii. Osteoporosis: Greater than 2.5 SDs below the mean value d. The lumbar spine T-score is reported as the average of L1–L4. Consider a diagnosis of osteoporosis if two individual lumbar spine measurements are greater than 2.5 SDs below the mean, regardless of the lumbar spine average. e. If a patient’s Z-scores are greater than 2 SDs below the mean, the result usually indicates accelerated bone loss unrelated to menopause and/or aging.

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2. A clinical diagnosis of osteoporosis can be made in the presence of: a. Fragility fracture, particularly at the spine, hip, wrist, humerus, rib, and pelvis OR b. T-score of -2.5 or less SDs at any site according to BMD measurement by DEXA 3. Quantitative computed tomography: Can predict fracture risk, but with greater radiation exposure than DEXA; helpful in clinical scenarios when joint replacements prevent DEXA Table 5. Additional Tests to Consider When Evaluating for Secondary Causes of Osteoporosis 25(OH)D Creatinine Estradiol Serum protein electrophoresis

Alkaline phosphatase Phosphate Free testosterone

Calcium, serum Thyroid-stimulating hormone PTH (PTH intact)

PTH = parathyroid hormone.

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Assess patient risk using screening recommendations (Table 3) and risk assessment tools (Table 4)

NO

History of fragility fracture

DXA Recommended?

YES

Periodically reassess screening recommendations and risk calculations

T-score 0 to -1

T-score -2.5 or lessa

T-score -1 to -2.5a

FRAX Score

Assess risk factors annually Repeat dXA in 5 years Recommend calcium + vitamin D Recommend exercise and fall prevention counseling

Patient would benefit from fracture prevention mediationb

Hip fracture risk less than 3% or major fracture less than 20%

Hip fracture risk greater than 3% or major fracture greater than 20%

Alternative First-Line Therapy

Third-Line Therapy

Teriparatide/ Abaloparatide

SERM

Estrogen

First-Line Therapy

Denosumab

Bisphosphonate therapy c

Romosozumab Review Z-score for secondary causes of bone density loss. Calcium + vitamin D, exercise, and fall prevention counselling. c Alendronate, risedronate, and zoledronic acid. For very high-risk patients, zoledronic acid is preferred. DXA = dual-energy absorptiometry; NS = not significant vs. placebo; SERM = selective estrogen receptor modifier. a

b

Figure 1. Osteoporosis evaluation and treatment algorithm.*,**

*Denosumab may be considered an alternative first-line therapy in patients with contraindications to therapy with bisphosphonates (i.e., renal dysfunction or declining renal function). **Treatment decisions may be guided by categorizing patients as having high risk/no prior fractures or very high risk/prior fractures. Indicators of very high fracture risk in patients with low bone density include advanced age, frailty, glucocorticoid use, very low T-scores, and increased fall risk.

2020 guideline updates: Camacho PM, Petak SM, Binkley N, et al. Postmenopausal osteoporosis guidelines. Endocr Pract 2020;26:1-46; Shoback D, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J Clin Endocrinol Metab 2020;105:587-94.

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Patient Cases 2. M.J. is a 61-year-old white woman (height 65 inches, weight 68 kg) who consults with her pharmacist about how best to preserve her bone density and prevent a fracture. The patient’s medical history is significant for a maternal hip fracture (mother was age 71). Her 10-year risk of a major osteoporotic fracture (FRAX score) is estimated at 19% and, for the hip, 6.3%. From these results, which is the best course of action for the pharmacist to take?

A. Recommend that the patient contact her primary care provider to request a DEXA scan. B. Recommend that the patient contact her primary care provider to request a DEXA scan and start calcium plus vitamin D supplementation. C. Recommend that the patient contact her primary care provider to request a DEXA scan, start calcium plus vitamin D supplementation, and start taking a bisphosphonate. D. Recommend that the patient NOT have a DEXA scan and that she begin calcium plus vitamin D supplementation and start taking a bisphosphonate.

3. O.T. is a 65-year-old woman given a diagnosis of osteopenia after a scheduled DEXA scan. Her other medical conditions include type 2 diabetes, irritable bowel syndrome, gastroesophageal reflux disease, and migraine headaches. Her medications include metformin, pantoprazole, amitriptyline, and sumatriptan. She regularly participates in aqua aerobics and walking and uses laundry detergent bottles to strengthen her upper body. Her dietary calcium intake is limited to 1 glass of milk (8 oz each) per day. She has not yet started calcium, but she would like to add it to her medications and daily supplements. Which OTC calcium regimen is best to recommend for her? A. B. C. D.

Calcium carbonate 600 mg/vitamin D 500 international units 1 tablet twice daily with food. Calcium carbonate 600 mg/vitamin D 500 international units 2 tablets twice daily with food. Calcium citrate 315 mg/vitamin D 500 international units 1 tablet twice daily. Calcium citrate 315 mg/vitamin D 250 international units 2 tablets twice daily.

4. E.U. is a 58-year-old woman with a medical history significant for primary progressive multiple sclerosis with severe limitation, for which she spends most of her time in bed or lying on a couch. She tries to ambulate but cannot do so without a walker and/or assistance. Her DEXA scan reveals osteoporosis of the lumbar spine, and she now requires treatment. She has no history of fracture. Her provider deems her disease in the “high-risk” category. She already takes 1200 mg of calcium carbonate daily (600 mg twice daily) and 800 units of vitamin D (400 units twice daily). Which is best for E.U. to prevent vertebral fracture? A. B. C. D.

Zoledronic acid 5-mg infusion once yearly. Risedronate 150-mg tablet once monthly. Raloxifene 60-mg tablet once daily. Romosozumab 210 mg once monthly.

Table 6. Nonpharmacologic Interventionsa Dietary Changes

Adequate intake of calciumcontaining foods Adequate intake of vitamin D and exposure to sunlight

Physical Activity

Aerobic exercise Low impact Weight bearing Muscle strengthening Balance training

Other Interventions

Fall assessments Timed Up and Go (TUG) test Vision correction Medication review Fall prevention counseling Smoking cessation

See Table 2.

a

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C. Pharmacologic Interventions (Domain 1, Task 2, Knowledge 5 and Task 3, Knowledge 7) 1. Calcium supplementation: Available formulations (be aware of whether calcium supplement labels list calcium content as elemental or compound) a. Calcium carbonate (40% elemental) 500- to 600-mg tablets available b. Calcium citrate (21% elemental) 200- to 315-mg tablets available Table 7. Calcium STEPS Analysis

Safety

Tolerability Efficacy

Preference (Pearls) Simplicity

May increase risk of MI Nephrolithiasis risk slightly increased with calcium carbonate Hypercalcemia in patients with later-stage CKD Constipation GI discomfort, flatulence

Improves and/or sustains BMD With or without vitamin D, evidence that calcium supplementation reduces fracture risk is not robust; some isolated studies show benefit, but systematic reviews and meta-analyses do not agree whether the impact is significant Calcium citrate preferred in the following instances: Chronic gastric acid-suppressive therapy Should be used (at a minimum) in patients receiving chronic systemic corticosteroid therapy Should be administered with an appropriate dose of vitamin D Various formulations available to meet the needs of patients: Tablets (varying sizes) Chewable tablets Soft chews and “gummy” formulations Liquid

BMD = bone mineral density; CKD = chronic kidney disease; MI = myocardial infarction; STEPS = Safety, Tolerability, Efficacy, Preference (Pearls), Simplicity.

D. Vitamin D: Available formulations a. Vitamin D2 (ergocalciferol) – Available as prescription b. Vitamin D3 (cholecalciferol) – Available as over-the-counter (OTC) Table 8. Vitamin D STEPS

Safety

Tolerability Efficacy

Annual dosing alternatives (500,000 units) may cause higher rates of falls and fractures in older patients Toxicity concerns – Excessive vitamin D supplementation may increase the risk of hypercalcemia, hypercalciuria, and kidney stones Hypercalcemia Constipation

Increases BMD and calcium absorption May reduce risk of falls in older adults with low serum vitamin D concentrations

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Table 8. Vitamin D STEPS (continued)

Preference (Pearls)

Simplicity

Unclear whether vitamin D without calcium improves BMD or fracture prevention In older adult patients with low vitamin D concentrations, daily administration of vitamin D may be associated with a reduced fall risk (800 units/day) Institute of Medicine recommends a 25(OH)D concentration > 20 ng/mL NOF, International Osteoporosis Foundation, American Geriatrics Society suggest a minimum 25(OH)D concentration of 30 ng/mL AACE/ACE recommends that adults who are vitamin D insufficient or deficient (serum 25(OH)D 20–29 or < 20 ng/mL, respectively) be treated with 50,000 international units of vitamin D2 or vitamin D3 once a week or 5000 international units of vitamin D2 or vitamin D3 daily for 8–12 wk to achieve a 25(OH)D blood concentration > 30 ng/mL. Then maintenance therapy of vitamin D3 1000–2000 international units daily Other recommendations for vitamin D deficiency: For serum 25(OH)D 20–30 ng/mL: Treat with 600–800 units of vitamin D2 once daily or 1000– 2000 units once daily; may consider a repeat serum 25(OH)D concentration in 12 wk to determine whether the target has been achieved Co-formulated with calcium supplements (200–400 units per dose) Administered daily as 400- to 1000-unit tablets/capsules Option for quarterly dosing (100,000 units every 3 mo) is available

1. Bisphosphonates: Available agents a. Alendronate (Fosamax; Fosamax Plus D; Binosto [effervescent]) b. Ibandronate (Boniva) c. Risedronate (Actonel, Atelvia [delayed release]) d. Zoledronic acid (Reclast) Table 9. Bisphosphonates STEPS

Safety

Tolerability

Major concerns, but of low prevalence (risk increases with longer duration of use): Osteonecrosis of the jaw (medication-related osteonecrosis of the jaw [MRONJ]) Subtrochanteric fracture Major concerns, proven NOT to be of risk: Esophageal cancer Atrial fibrillation Cautious use in patients with impaired renal function (CrCl < 30 mL/min for risedronate and ibandronate or < 35 mL/min for alendronate and zoledronic acid) or low serum calcium concentration In patients with hypocalcemia, resolve low calcium values before starting therapy

Abdominal pain, cramping Acute-phase reaction (zoledronic acid and ibandronate infusions) Arthralgias Dyspepsia Cautious use in patients with severe esophageal reflux disease, Barrett esophagus, or esophageal strictures Scleritis and/or uveitis (rare)

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Table 9. Bisphosphonates STEPS (continued)

Efficacy

Preference (Pearls)

Simplicity

All bisphosphonates have evidence to support use for preventing vertebral fractures Alendronate, risedronate, and zoledronic acid have prevented non-vertebral and hip fractures Ibandronate only effective for vertebral fractures Used in patients taking chronic systemic corticosteroids to prevent BMD loss and subsequent fracture (see RA section, Figure 2, for assistance when deciding to use a bisphosphonate for corticosteroidinduced BMD loss)

Most oral doses should be taken with 6–8 oz of water at least 30–60 min before food, drink, or other medications (risedronate delayed release should be taken with 4 oz of water right after breakfast) Patients should remain upright for at least 30 min after being administered an oral dose (60 min with ibandronate) (Domain 1, Task 6, Knowledge 5) If a patient cannot tolerate one bisphosphonate, discontinue the agent until the adverse effect resolves, and offer the patient the option to try another available bisphosphonate For IV therapy with zoledronic acid, ensure patient is counseled on adequate hydration before and after infusion. Severe dehydration before or after treatment may increase the risk of acute renal impairment/ renal failure; diuretic therapy increases this risk Questionable risk-benefit profile beyond 5 yr; may warrant reevaluation and possible discontinuance of therapy (see Table 10)

Once-daily, once-weekly, and once-monthly tablets; quarterly and yearly infusions Alendronate: Prevention (5 mg/day or 35 mg/week) and treatment (10 mg daily or 70 mg weekly) Risedronate: Prevention and treatment (5 mg daily, 35 mg weekly, or 150 mg monthly) Ibandronate: Prevention (150 mg monthly) and treatment (150 mg monthly OR 3 mg IV every 3 mo) Zoledronic acid: Prevention (5 mg IV every 2 yr) and treatment (5 mg IV every year) All dosage forms and intervals are equally effective (except for ibandronate), so consider the patient’s prescription drug coverage (or lack of) when choosing a medication or patient preference

CrCl = creatinine clearance; IV = intravenous(ly).

Table 10. AACE 2020 Recommendations for Bisphosphonate Discontinuance and Holidays Fracture Risk

High

Very High

Recommendation

Consider a drug holiday after 5 yr of oral and 3 yr of IV bisphosphonate therapy

Consider a drug holiday after 6 yr of IV zoledronate. During the holiday, an anabolic agent or a weaker antiresorptive such as raloxifene can be used

Indicators of very high fracture risk in patients with low BMD include advanced age, frailty, glucocorticoids, very low T scores, or increased fall risk. Information from: Camacho PM, Petak SM, Binkley N, et al. Postmenopausal osteoporosis guidelines. Endocr Pract 2020;26:1-46.

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2. RANKL antagonist – Denosumab (Prolia) Table 11. RANKL Antagonist STEPS

Safety

Tolerability Efficacy Preference (Pearls)

Simplicity

Cellulitis was the most common serious adverse event in clinical trials Osteonecrosis of the jaw (rare) Infections Injection site reactions Eczema Flatulence

Decreased incidence of vertebral, non-vertebral, and hip fractures in patients with osteoporosis Increases BMD in the hip and lumbar spine Similar efficacy to the bisphosphonates, but with much less frequent dosing

Recommended for patients at risk of an osteoporotic fracture and unable to tolerate a bisphosphonate and as an alternative initial treatment (i.e., kidney dysfunction) Clinically, the risk of infections associated with denosumab is low. Data analyses suggest that the rate of hospitalized infections among patients with RA receiving denosumab with biologics for RA was not increased compared with patients who received zoledronic acid (Arthritis Rheumatol 2015;67:1456-64) Must be administered by a health professional, either in a physician’s office practice or by a pharmacist Effects on bone remodeling reverse after 6 mo if denosumab is not taken on schedule; therefore, a drug holiday is not recommended. Treatment with denosumab not recommended if ongoing or long-term continuation is not feasible Subcutaneous injection every 6 mo

3. Estrogen replacement therapy – For further detail, see the Obstetrics and Gynecology chapter. Table 12. Estrogen Replacement STEPS

Safety

Estrogen was previously a therapy of choice but is now only recommended as prophylactic therapy in appropriate candidates According to information from the WHI trial, the risk of adverse events with hormone replacement therapy exceeds the fracture prevention benefits Hormone replacement therapy is more likely to be associated with the following: Coronary heart disease (estrogen/progesterone only) Stroke Invasive breast cancer (estrogen/progesterone only) Venous thromboembolic event

Tolerability Breast discomfort GI symptoms Headache disorders Vaginal bleeding Venous thromboembolism Efficacy

Reduced risk of vertebral fractures Reduced risk of non-vertebral fractures

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Table 12. Estrogen Replacement STEPS (continued)

Preference (Pearls) Simplicity

WHI trial results showed the benefit of fracture prevention to be similar to or less than the patient’s risk of heart disease, stroke, venous embolism, and breast cancer Acts in conjunction with a bisphosphonate to increase BMD more than either agent alone Once-daily oral dosing Transdermal patch is approved for the prevention of postmenopausal osteoporosis

WHI = Women’s Health Initiative (trial).

4. Estrogen receptor agonist/antagonist: Available agents: Raloxifene (Evista) Table 13. Estrogen Receptor Agonist/Antagonist STEPS

Safety

Tolerability

Efficacy Preference (Pearls) Simplicity

Increased risk of fatal stroke in women with a history of coronary heart disease Increased risk of venous thromboembolism Arthralgias Hot flashes/flushes Peripheral edema Sweating

Increased BMD Reduced incidence of vertebral fractures, but not non-vertebral fractures

Rates of preventing clinical vertebral fractures are similar to rates of venous thromboembolisms Consider use for primary prevention in women with low BMD and a 5-year risk of developing invasive breast cancer > 3% (Ann Intern Med 2013;158:604) Fixed-dose, once-daily dosing

5. Parathyroid hormone: Available agent: Teriparatide (parathyroid hormone 1–34) (Forteo), abaloparatide (Tymlos) Table 14. PTH STEPS

Safety

Tolerability

Efficacy

Avoid use in patients with the following: Alkaline phosphatase elevation (unexplained) Open epiphyses Paget disease Prior skeletal radiation Associated with osteosarcoma (in rats) after about 24 mo of therapy (3–60 times the human dose); therefore, therapy duration in humans is limited to 2 yr Influenza-like symptoms Hypercalcemia Injection site pain and/or rash Orthostatic hypotension Urolithiasis

Increases vertebral and total hip BMD Decreased incidence of new or worsening vertebral and non-vertebral fractures Prevents BMD loss and vertebral fractures in patients receiving chronic systemic corticosteroid therapy (reserved for second- or third-line options or in patients with severe osteoporosis/high risk of fracture)

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Table 14. PTH STEPS (continued)

Preference (Pearls)

Simplicity

Diminished efficacy if used concurrently with a bisphosphonate After discontinuing or completing therapy, antiresorptive therapy must be initiated to preserve BMD benefits Adherence may be a concern in some patients because the daily subcutaneous injection and pen needles may prove challenging for patients with dexterity issues Dropout and discontinuance rates in clinical studies are almost double those for alendronate Once-daily injection Both available as multidose prefilled autoinjector pens Teriparatide pen has 28 doses (requires refrigeration) Abaloparatide pen has 30 doses (refrigerate before first dose; then store at room temperature for up to 30 days

6. Calcitonin (Miacalcin, Fortical) Table 15. Calcitonin STEPS

Safety

Anaphylactoid and anaphylaxis reactions associated with injection

Efficacy

Reduced incidence of recurrent vertebral fractures Beneficial effects on BMD in patients with steroid-induced disease

Tolerability

Preference (Pearls)

Simplicity

Injection GI symptoms Injection site reaction Flushing

Nasal spray Rhinitis Nasal congestion Mucosal irritation

Inferior to alendronate for preventing BMD loss May help relieve bone pain associated with fractures but is not an indication to choose as the primary treatment FDA (2013) stated that the lack of effectiveness, combined with the increased risk of cancer (oral calcitonin), raises concerns about the overall usefulness of calcitonin Nasal administration in only ONE nostril per day, alternating nostrils each day

FDA = U.S. Food and Drug Administration.

7. Sclerostin inhibitor: Available agent: Romosozumab (Evenity) Table 16. Romosozumab STEPS

Safety

Tolerability

Boxed warning: May increase the risk of MI, stroke, and CV death and should not be initiated in patients who have had an MI or stroke within the previous year. Consider risk-benefit of therapy in patients with other CV risk factors Hypocalcemia Osteonecrosis of the jaw (undefined prevalence) Arthralgias Headache Injection site reactions Hypersensitivity reactions CV disorders

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Table 16. Romosozumab STEPS (continued)

Efficacy

Preference (Pearls)

Simplicity

Decreased incidence of vertebral and non-vertebral fractures in patients with osteoporosis Increases BMD in the hip and lumbar spine

Not currently considered initial therapy for most patients with osteoporosis Possible candidates include patients with multiple fragility fractures, those at high risk of fracture who cannot tolerate any other osteoporosis therapies, or those for whom other osteoporosis therapies fail (fracture with loss of BMD despite adherence to therapy) Because the anabolic effect of romosozumab wanes after 12 monthly doses of therapy, treatment is limited to 12 monthly doses Patients treated initially with an anabolic agent are typically treated with an antiresorptive agent (preferably a bisphosphonate) after discontinuation to preserve the gains in BMD achieved with the anabolic agent Once-monthly injections administered by a health care provider Available as a 105-mg prefilled syringe (total dose of 210 mg once monthly requires 2 injections)

E. Follow-Up 1. DEXA a. Reassess yearly; however, some payers only provide coverage every 2 years if the patient is not on therapy. Do not consider treatment failure if initial, solitary evaluation reveals net bone loss. b. In patients who discontinue drug therapy, consider rechecking DEXA annually. c. In patients NOT receiving drug therapy, may recheck DEXA findings every 5 years unless the patient has developed risk factors for osteoporotic fracture 2. Medication adherence a. Review adherence at least every 6 months. b. As many as one-half of patients being treated with a bisphosphonate will self-discontinue therapy within the first 6 months, so pharmacists should continually assess for medication adherence. Table 17. Drugs and Doses Reference Table Medication Name

Calcium + vitamin D

Brand Name

Dosing

Several OTC formulations

500 mg of elemental calcium + vitamin D 400 international units twice daily

Alendronate

Fosamax; Binosto

Risedronate

Actonel; Atelvia

Treatment: 10 mg orally daily or 70 mg orally weekly Prevention: 5 mg orally daily or 35 mg orally weekly

Ibandronate

Boniva

Zoledronic acid

Reclast

Bisphosphonates

RANKL Inhibitor

Denosumab

Prolia

Treatment and prevention: 5 mg orally daily, 35 mg orally weekly, 150 mg orally monthly

Treatment: 150 mg orally monthly, 3 mg IV every 3 mo Prevention: 150 mg orally monthly

Treatment: 5 mg IV infusion yearly; Prevention: 5 mg IV infusion every 2 yr 60 mg subcutaneously every 6 mo

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Table 17. Drugs and Doses Reference Table (continued) Medication Name

Brand Name

Estrogen Receptor Agonist – Antagonist

Dosing

Raloxifene

Evista

60 mg by mouth once daily

Teriparatide

Forteo

20 mcg subcutaneously once daily

Recombinant PTH Abaloparatide Calcitonin

Calcitonin

Tymlos Miacalcin

100 units intramuscularly every other day 200 units sprayed into one nostril each day

Evenity

105 mg each subcutaneously (as two consecutive injections) for a total dose of 210 mg once monthly; treatment duration: 12 mo

Sclerostin Inhibitor Romosozumab

80 mcg subcutaneously once daily

OTC = over-the-counter.

II.  RHEUMATOID ARTHRITIS A. Clinical Guidelines (Domain 1; Tasks 3, 6, 7; Knowledge 2/1/2) 1. 2021 ACR guideline for RA treatment (Arthritis Rheumatol 2021;73:1108-23) 2. European League Against Rheumatism (EULAR) 2019 recommendations for managing RA with synthetic and biologic disease-modifying drugs 2019 (Ann Rheum Dis 2020;79:685-99) 3. 2010 RA classification criteria: an ACR/EULAR collaborative initiative B. Patient Symptom Presentation 1. Diffuse pain (myalgias, arthralgias, arthritis) 2. Variable time to symptom onset 3. Morning joint stiffness (gelling) lasting more than 1 hour; stiffness worse with rest 4. Affected joints are swollen and inflamed. a. Large joints: Shoulders, elbows, hips, knees, ankles b. Small joints: Wrists and hands/fingers (proximal interphalangeal and metacarpo(tarso)phalangeal joints; distal interphalangeal joints generally spared in RA) C. Other Contributing Factors 1. Family history of other inflammatory disorders such as the following: a. Autoimmune thyroid disease b. Multiple sclerosis c. Myasthenia gravis d. RA e. Systemic lupus erythematosus (SLE) 2. Smoking is associated with increased disease activity.

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D. Evaluation and Diagnosis: 2010 ACR/EULAR Classification Criteria for RA 1. Screen patients who have at least one joint with clinical synovitis not otherwise explained by another disease (e.g., SLE, gout, psoriatic arthritis [PsA]). 2. Although this tool (Table 18) is not intended to be diagnostic, a score of at least 6 of 10 points classifies patients as having definite RA. (Note: Use the highest score from each category.) Table 18. 2010 ACR/EULAR Classification Criteria for RA Classification Criteria

Joint involvement > 10 joints, including at least 1 small joint 4–10 small joints 1–3 small joints 2–10 large joints 1 large joint

Serology Positive RF or positive ACPA test results > 3 times the upper limit of normal Positive RF or positive ACPA test results up to 3 times the upper limit of normal Negative RF and ACPA test results

Acute-phase reactants Abnormal CRP or ESR test results Normal CRP and ESR test results

Duration of symptoms At least 6 wk < 6 wk

Total points

Scoring (points) 5 3 2 1 0 3 2 0 1 0 1 0

ACPA = anti–citrullinated protein antibody; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor.

3. Laboratory and radiographic testing in RA a. Rheumatoid factor (RF) is detectable in 60%–70% of patients and may be present in other autoimmune diseases. b. Anti–citrullinated protein antibodies (ACPAs) have similar sensitivity to RF (50%–85%) but are more specific (90%–95%) and are present earlier in the disease. c. Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are nonspecific markers for inflammation; elevated concentrations may not be associated with only RA disease activity (i.e., illness or stressful event).

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Table 19. Testing to Consider for Diagnosis and Treatment Decisions in RA Diagnosing RA

Laboratory ACPA CBC with differential CRP ESR Liver function tests RFa Radiographic: Radiography, ultrasonography, or MRI of affected joints

ACR-Suggested Baseline Evaluation

Laboratory CBC Creatinine CRP ESR Liver function tests Metabolic (Chem) panel Stool guaiac Synovial fluid (to rule out other diseases) Urinalysis Radiographic: Radiography, ultrasonography, or MRI of affected joints

ACR Recommendations for Initiating or Titrating Pharmacotherapy

Laboratory CBC Creatinine Hepatitis B and Cb (synthetic and biologic DMARDs) Liver function tests Retinal examinationc (hydroxychloroquine) TB screeningd (bDMARDs)

May repeat at 6–12 mo if the initial value is low or negative.

a

b

If patient has a high-risk history.

Every 5 yr for low-risk patients and annually for high-risk patients.

c

d

Screen regardless of history of BCG vaccination.

ACPA = anti–citrullinated protein antibody; BCG = bacillus Calmette-Guérin; bDMARD = biologic disease-modifying antirheumatic drug; CBC = complete blood cell count; DMARD = disease-modifying antirheumatic drug; MRI = magnetic resonance imaging; TB = tuberculosis.

Table 20. Disease Prognosis

Factors of poor prognosis

Disease activity during first 3–6 mo of treatment

Functional limitations Positive RF or ACPA test results Radiographic evidence of bony erosions Extra-articular disease (Felty syndrome, RA lung disease, RA vasculitis, rheumatoid nodules, secondary Sjögren syndrome)

Lower disease activity (tender or swollen joints) for up to 6 mo increases the likelihood of 12-mo disease remission Higher disease activity (tender or swollen joints) in first 3 mo increases likelihood of presence of symptoms at 12 mo NOTE: Disease activity may be defined with one of several scoring tools, including: PAS, RAPID3, CDAI, DAS, and/or SDAI

CDAI = Clinical Disease Activity Index; DAS = Disease Activity Score; PAS = Patient Activity Scale; RAPID3 = Routine Assessment of Patient Index Data 3; SDAI = Simple Disease Activity Index.

E. Before Initiating Pharmacologic Therapy 1. Address the entire scope of patient needs with respect to RA. a. Discuss potential functional limitations and strategies to overcome and/or compensate. b. Involve other health professionals to care for and educate the patient. i. Physical therapy ii. Occupational therapy iii. Social workers and counseling/cognitive services 2. Educate the patient regarding physical conditioning. a. Discuss balancing exercise to prevent atrophy of joints with rest to prevent disease flare. b. Energy conservation

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c. Joint protection d. Range-of-motion exercises e. Strengthening exercises 3. Tuberculosis screening (see Figure 3) 4. Immunizations Table 21. Vaccinations to Consider in Patients Receiving RA Immunosuppressive Therapy (Domain 1, Task 5 Knowledge 6; Domain 5, Task 2, Knowledge 2)

Vaccination

Before Starting DMARDs

During DMARD Therapy

Administer to all patients receiving biologic DMARDs, tofacitinib, MTX, leflunomide, and/or sulfasalazine before PPSV23 or at least 1 yr after administering PPSV23

Yes

Yes

Recommendations

Influenza vaccine (inactivated)

Administer annually to all patients

PPSV23

Administer to all patients receiving biologic DMARDs, tofacitinib, MTX, leflunomide, and/or sulfasalazine at least 8 wk after administering PCV13

Yes

Yes

Administer to all patients with risk factors and receiving biologic DMARDs, tofacitinib, MTX, and/or leflunomide

Yes

Yes

Administer to all patients who meet the CDC recommendations

Administer to all patients who meet the CDC recommendations

Yes

Yes

Diphtheria, tetanus, and acellular pertussis (Tdap)

Administer to all patients who meet the CDC recommendations

Yes Yes

COVID-19

Please see most updated recommendations for COVID-19 guidance here: https://www.rheumatology.org/announcements

PCV13a

Hepatitis B vaccine series

Human papillomavirus Live vaccines

Herpes zoster

Yes

Yes

Yes/Nob Yes

Currently, there is no recommendation regarding inactivated herpes zoster – Patients with RA were excluded from clinical trials but are not listed as contraindication in the prescribing information. There is theoretical concern of disease flare, given it is an adjuvanted vaccine; however, this is not supported by any evidence

PCV13 is not included in the ACR 2012 update, but the CDC/ACIP recommendations for iatrogenic immunosuppression apply.

a

Yes: Patients who are actively being treated with DMARD monotherapy or combination therapy. No: Patients who are actively being treated with an anti-TNF or non-TNF biologic agent or tofacitinib.

b

ACIP = Advisory Committee on Immunization Practices; CDC = Centers for Disease Control and Prevention; MTX = methotrexate; PCV13 = pneumococcal vaccine (13-valent conjugate); PPSV23 = pneumococcal vaccine (23-valent polysaccharide); TNF = tumor necrosis factor.

F. Terminology for Common Medications in Rheumatology 1. Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids (prednisone and methylprednisolone) 2. Conventional disease-modifying antirheumatic drugs (cDMARDs) a. Methotrexate b. Leflunomide c. Sulfasalazine d. Hydroxychloroquine e. Mycophenolate mofetil ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 309

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f. Azathioprine g. Cyclophosphamide 3. Biologic DMARDs (bDMARDs) a. Tumor necrosis factor (TNF) inhibitor b. Interleukin (IL)-17 inhibitor c. IL-12/23 inhibitor d. T-cell co-stimulation modulator e. B-cell modulator 4. Targeted synthetics (tsDMARDs) a. Apremilast b. Tofacitinib c. Baricitinib d. Upadacitinib G. Guideline Recommendations (Domain 1; Tasks 2, 6, 7; Knowledge 2/1/2) 1. American College of Rheumatology (2021 update) H. Supportive Care Medications 1. NSAIDs: Systemic and/or topical Table 22. Oral NSAID STEPS

Safety

All NSAIDs carry the risk of causing changes in renal function Patients at greater risk of GI toxicity include the following: Older adults Patients with a history of GI bleed Patients concurrently using anticoagulants, antiplatelet drugs, and/or systemic corticosteroids Choice between nonselective NSAIDs and COX-2 inhibitors depends on risk factors for GI adverse effects Patients with a history of symptomatic or complicated upper GI bleeding: • > 1 yr ago: Use COX-2 inhibitor or nonselective NSAID with a PPI • Within 1 yr ago: Use COX-2 inhibitor with a PPI Consider adding a PPI to reduce the risk of gastropathy in any patient receiving chronic oral NSAID therapy In patients at risk of or with existing CV disease, NSAIDs may increase the risk of a fatal or nonfatal event Avoid NSAIDs in patients at high CV risk • Increased blood pressure or exacerbation of heart failure • Chronic NSAID therapy increases the risk of CV events • Increased CV risk with all NSAIDs used chronically (except low-dose aspirin); naproxen may be the least harmful NSAID; however, the most recent study, the PRECISION trial, showed no differences in CV outcomes between celecoxib, naproxen, and ibuprofen, though limitations to this trial exist • Overall relative risk of CV events is small; however, risk-benefit consideration is important (medication guides are required by the FDA) • NSAID use is contraindicated immediately before and after coronary artery bypass grafting surgery

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Table 22. Oral NSAID STEPS (continued)

Tolerability Efficacy Preference (Pearls)

Simplicity

Dyspepsia Prolonged bleeding Dermatologic reactions

Available NSAIDs are equally effective, but responses to agents will vary NSAIDs will reduce joint pain and swelling to some degree but will not modify the destruction or progression of RA

Celecoxib has fewer GI adverse events than other NSAIDs; however, it is no more effective at reducing pain and inflammation Adding misoprostol to an NSAID will decrease the risk of GI ulceration Adding a PPI to an NSAID will decrease nonulcerative symptoms If a patient does not respond to NSAID therapy (after an appropriate 14- to 28-day trial), providers should consider trying other NSAIDs before concluding therapeutic failure Widely available prescription and OTC agents Once-daily formulations allow continuous analgesia As-needed use for RA flares

*See OA section for more information on topical NSAIDs.

2. Corticosteroids: Oral or intra-articular injections Table 23. Corticosteroid STEPS

Safety

Tolerability

Efficacy

Preference (Pearls) Simplicity

Increased risk of osteoporosis and fracture Increased risk of infection (dose- and duration-dependent) Risk of symptoms of a psychiatric disturbance with increasing doses of corticosteroids < 40 mg of prednisone per day (1%–2% incidence) 40 mg of prednisone per day (5% incidence) 80 mg of prednisone per day (20% incidence) Cataracts Dyslipidemia (high dose) Glaucoma Hirsutism Hyperglycemia

Hypertension (high dose) Hypothalamic-pituitary-adrenal axis suppression Osteoporosis Pancreatitis (high dose) Weight gain

Short-term (weeks), low-dose (< 10 mg of prednisone daily) corticosteroids are effective for symptoms flare Early initiation of corticosteroids and continuance at a low dose reduce joint destruction and increase likelihood of clinical remission Higher corticosteroid doses may be warranted to treat symptoms of severe or advanced disease (e.g., presence of vasculitis) Intra-articular injections may be beneficial, but limit injections in joint to no more often than every 3–4 mo Initiate calcium and vitamin D supplementation in all patients taking corticosteroid therapy See Figure 2 for recommendations for using bisphosphonates in patients receiving chronic corticosteroid therapy Once-daily dosing should be administered in the morning to minimize insomnia

Once-daily fixed dose appears effective for symptom control and possibly slowing disease progression

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Figure 2. Risk assessment and treatment for patients at risk of glucocorticoid-induced osteoporosis. PE = prednisone equivalents.

Adapted from: Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatology guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheumatol 2017;69:1521-37.

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I. ACR 2021 Guideline Recommendations (Fraenkel 2021) 1. Recommendations for patients with symptomatic early RA: a. Regardless of disease activity level, use a treat-to-target strategy instead of a nontargeted approach. b. Low disease activity plus disease-modifying antirheumatic disease (DMARD) naive: i. Hydroxychloroquine is conditionally recommended over other conventional DMARDs (csDMARDs). ii. Sulfasalazine is conditionally recommended over methotrexate. c. Moderate or high activity plus DMARD naive: i. Strong recommendations: (a) Methotrexate over hydroxychloroquine or sulfasalazine (b) Methotrexate monotherapy over biologic DMARD (bDMARD) or targeted synthetic DMARD (tsDMARD) monotherapy (c) Methotrexate monotherapy over methotrexate plus a non–tumor necrosis factor (TNF) inhibitor bDMARD or tsDMARD ii. Conditional recommendations: (a) Methotrexate over leflunomide (b) Methotrexate monotherapy over dual or triple csDMARD therapy (c) Methotrexate monotherapy over methotrexate plus a TNF inhibitor d. Initiation of a csDMARD without short-term (less than 3 months) glucocorticoids is conditionally recommended over initiation of a csDMARD with short-term glucocorticoids. e. Initiation of a csDMARD without longer-term (3 months or more) glucocorticoids is strongly recommended over initiation of a csDMARD with longer-term glucocorticoids. 2. Recommendations for methotrexate administration: a. Oral methotrexate is conditionally recommended over subcutaneous methotrexate for patients starting methotrexate. b. Initiation/titration of methotrexate to a weekly dose of at least 15 mg within 4–6 weeks is conditionally recommended over initiation/titration to a weekly dose of less than 15 mg. c. A split dose of oral methotrexate over 24 hours or weekly subcutaneous injections, and/or an increased dose of folic/folinic acid, is conditionally recommended over changing to an alternative DMARD for patients not tolerating oral weekly methotrexate. d. Changing to subcutaneous methotrexate is conditionally recommended over adding or changing to an alternative DMARD for patients taking oral methotrexate who are not at target. 3. Patients taking maximally tolerated doses of methotrexate who are not at target: a. Adding a bDMARD or tsDMARD is conditionally recommended over triple therapy (i.e., adding sulfasalazine and hydroxychloroquine). 4. Patients not at target while taking a bDMARD or tsDMARD: a. Changing to a bDMARD or tsDMARD of a different class is conditionally recommended over changing to a bDMARD or tsDMARD belonging to the same class. 5. Adding or changing to DMARDs is conditionally recommended over continuing glucocorticoids for patients taking glucocorticoids to remain at target. 6. Adding or changing to DMARDs (with or without intra-articular glucocorticoids) is conditionally recommended over the use of intra-articular glucocorticoids alone for patients taking DMARDs who are not at target. 7. Recommendations for tapering/discontinuing DMARDs: a. Continuation of all DMARDs at their current dose is conditionally recommended over dose reduction of a DMARD. b. Dose reduction is conditionally recommended over gradual discontinuation of a DMARD. c. Gradual discontinuation is conditionally recommended over abrupt discontinuation of a DMARD.

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d. Gradual discontinuation of sulfasalazine is conditionally recommended over gradual discontinuation of hydroxychloroquine for patients taking triple therapy who wish to discontinue a DMARD. e. Gradual discontinuation of methotrexate is conditionally recommended over gradual discontinuation of the bDMARD or tsDMARD for patients taking methotrexate plus a bDMARD or tsDMARD who wish to discontinue a DMARD. Patient Case 5. K.W. is a 37-year-old female executive (height 64 inches, weight 70 kg [155 lb]) with RA (diagnosed 3 months ago), type 2 diabetes, and hypertension who smokes cigarettes. Her basic metabolic profile and complete blood cell count (CBC) are all within normal limits. Her RF is about 4 times the upper limit of normal; she has elevated anticyclic citrullinated peptide antibody values and ESR (high disease activity). Her radiographs reveal evidence of bony erosions. During the 2 months before her diagnosis, she had severe functional limitation, sometimes missing work because she could not prepare herself in a timely fashion. She is married and has two children with no plans for additional children. According to the ACR recommendations, which medication regimen is best for K.W.? A. B. C. D.

Hydroxychloroquine 400 mg once daily and folic acid 1 mg daily. Methotrexate 10 mg once weekly titrated to a target dose of 20–25 mg once weekly and folic acid 1 mg daily. Methotrexate 10 mg once weekly, folic acid 1 mg daily, and infliximab 3 mg/kg every 8 weeks. Methotrexate 10 mg once weekly, folic acid 1 mg daily, and anakinra 100 mg daily.

J. Conventional DMARDs 1. Methotrexate Table 24. MTX STEPS

Safety

Tolerability

Contraindicated in pregnancy and breastfeeding; prescribing information states that pregnancy should be avoided for at least 3 mo for men and at least one ovulatory cycle for women after discontinuing MTX; updated EULAR recommendations include expert consensus that states holding 1–3 mo before pregnancy Low doses used in RA may only slightly diminish ability to generate an immune response Increased incidence of the following: Any malignancy Lung cancer Melanoma Non-Hodgkin lymphoma Clinically relevant drug interactions: Avoid low-dose MTX in combination with sulfamethoxazole and trimethoprim because of increased serum concentrations of MTX; penicillin derivatives are generally safe in combination with low-dose MTX Avoid in patients with the following: CrCl < 30 mL/min Platelet count < 50,000/mm3 WBC < 3 x 103 cells/mm3 Liver transaminase concentrations > 2 times the upper limit of normal Concurrent use of NSAIDs in patients receiving low-dose MTX for RA is safe and clinically acceptable; use of NSAIDs with high-dose MTX should be avoided Abdominal cramping Anorexia Bone marrow suppression Hypersensitivity pneumonitis

Increased aminotransferases Infections Nausea Stomatitis

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Table 24. MTX STEPS (continued)

Efficacy

Preference (Pearls)

Simplicity

Intense treatment strategy and dose may increase chance of disease remission but also increase the likelihood of having an adverse event or discontinuing therapy Proposed benefit of decreased risk of CV mortality

Considered first choice for therapy in both ACR and EULAR recommendations Folic acid should be given with MTX; folic acid supplement decreases adverse events (1 mg daily or 5–10 mg weekly) Emerging evidence that coadministration of omega-3 fatty acids with triple DMARD therapy (MTX, sulfasalazine, and hydroxychloroquine) significantly reduces disease progression Administration errors are common, and patients should be counseled on once-weekly administration; oral formulations available as 2.5-mg tablets, which requires several tablets taken on the same day (once weekly) Consider changing to subcutaneous MTX in patients with an inadequate response to oral therapy (secondary to increased bioavailability of the injectable formulation) and/or unable to use bDMARDs because of cost or other factors Dosed as one oral dose or one subcutaneous injection weekly (5–25 mg)

WBC = white blood cell count.

2. Leflunomide (Arava) Table 25. Leflunomide STEPS

Safety

Stevens-Johnson syndrome and toxic epidermal necrolysis May decrease defenses against malignancy Pregnancy category X; women who wish to become pregnant or men who wish to father children should discontinue leflunomide use and use cholestyramine or activated charcoal to achieve plasma (leflunomide) active metabolite concentrations < 0.02 mg/L Patients with preexisting liver disease or aspartate aminotransferase/alanine aminotransferase values > 2 times the upper limit of normal should not receive leflunomide Caution use in patients with interstitial lung disease

Tolerability Alopecia Debilitating diarrhea Peripheral neuropathy (with long-term use)

Efficacy

Preference (Pearls) Simplicity

Rash Severe hepatotoxicity

Available evidence shows leflunomide is similar to MTX therapy May be added to MTX therapy to further improve symptoms, but at risk of hepatic toxicity

An alternative for patients unable to tolerate or who do not respond to MTX therapy Enterohepatic recycling contributes to the long half-life, which requires activated charcoal or cholestyramine to reduce plasma concentrations; consider avoiding therapy in women of childbearing age 100 mg by mouth daily for 3 days (loading dose) and then 20 mg by mouth once daily; some experts omit loading dose because of the risk of toxicities; however, this may result in delayed onset of action Dosage may be reduced (10 mg daily) for patients unable to tolerate full dose Loading dose can be omitted for patients at high risk of hepatic or hematologic toxicities

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3. Sulfasalazine (Azulfidine) Table 26. Sulfasalazine STEPS

Safety

“Probably” safe for use in pregnancy; has not shown abnormal/adverse fetal outcomes Duplicate therapy with oral mesalamine Avoid use in patients with the following: Platelet count < 50,000/mm3 Liver transaminase concentrations > 2 times the upper limit of normal Acute hepatitis B/C Chronic hepatitis B, not receiving therapy Chronic hepatitis B, Child-Pugh class C Chronic hepatitis C, Child-Pugh class B or C

Tolerability

GI effects (may be lessened with enteric-coated tablets); consider titrating dose every 2–4 wk to improve GI tolerability A lupus-like syndrome has been reported in patients taking sulfasalazine

Efficacy

Available data analyses suggest that sulfasalazine modifies rheumatic disease activity, but data analyses are less supportive of its effects on radiologic progression

Preference (Pearls)

May be an alternative for women who are (or planning to become) pregnant

Simplicity

Two- or three-times-daily dosing May require 2–4 tablets per dose

4. Other considerations: Routine monitoring of CBC, hepatic transaminases, and serum creatinine when starting or adjusting DMARD therapy (methotrexate, leflunomide, sulfasalazine) a. Every 2–4 weeks for the first 3 months b. Every 8–12 weeks until month 6 c. Every 12 weeks thereafter 5. Additional agents to consider: If low disease activity and no poor prognostic factors: Hydroxychloroquine (see Table 58) Patient Case 6. T.D. is a 28-year-old female graduate student meeting with a rheumatologist regarding worsening RA symptoms. She currently takes methotrexate 20 mg by mouth weekly, folic acid 1 mg by mouth daily, and naproxen 500 mg by mouth twice daily as needed for pain. Her symptoms have been worse during the past 3 months, and she has been using naproxen around-the-clock for the past 30 days. Which is best to help T.D. control her symptoms? A. B. C. D.

Recommend that she change methotrexate to hydroxychloroquine 200 mg once daily. Increase methotrexate to 30 mg weekly. Continue methotrexate and add adalimumab 40 mg subcutaneously every other week. Replace methotrexate with infliximab 3 mg/kg intravenously every 8 weeks.

K. Biologic DMARDs 1. TNF inhibitors a. Adalimumab (Humira) b. Certolizumab pegol (Cimzia) c. Etanercept (Enbrel)

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d. Golimumab (Simponi and Simponi Aria) e. Infliximab (Remicade) f. Biosimilars* i. Infliximab-dyyb (Inflectra) ii. Infliximab-abda (Renflexis) iii. Infliximab-qbtx (Ixifi) iv. Adalimumab-atto (Amjevita) v. Adalimumab-adbm (Cyltezo) vi. Adalimumab-adaz (Hyrimoz) vii. Adalimumab-bwwd (Hadlima) viii. Etanercept-szzs (Erelzi) ix. Etanercept-ykro (Eticovo) * For more information on biosimilars: https://www.fda.gov/drugs/therapeutic-biologics-applicationsbla/biosimilars Table 27. TNF Inhibitors STEPS

Safety

Tolerability

Efficacy

Preference (Pearls)

Increased risk of serious bacterial and/or fungal infections Associated with reactivation of TB May increase risk of malignancy, including melanoma, leukemia, and lymphoma; emerging data support lack of association with solid tumors and recurrence of solid tumors Linked with new or worsening heart failure and possibly death in patients with heart failure Rare cases of new-onset or exacerbation of CNS demyelinating disorders have occurred; avoid use in patients with conditions such as multiple sclerosis or strong family history of demyelinating diseases Headache Fatigue during initiation of therapy Injection site reactions Upper respiratory tract infection Infusion reactions (infliximab)

First-line choice for bDMARDs because they improve physical function and delay radiographic changes Superior to cDMARDs with respect to radiographic outcomes Combination with MTX yields better outcomes than TNF inhibitors alone Should not be used in combination with other bDMARDs

ACR generally recommends bDMARDs after insufficient response to synthetic DMARDs EULAR recommends bDMARDs after insufficient response to MTX or other synthetic DMARDs All patients receiving bDMARDs should be tested (and treated) for TB before starting therapy (see Figure 3 for TB screening recommendations) Frequent laboratory monitoring is not required; however, some experts suggest monitoring liver function tests every 3–6 mo because rare cases of hepatotoxicity have been reported Treatment is expensive for patients without insurance or suboptimal coverage Infliximab in combination with MTX may decrease the risk of antidrug antibody development Adalimumab, infliximab, and certolizumab pegol are preferred for patients with overlapping inflammatory bowel disease Certolizumab pegol and etanercept are preferred for patients who require therapy during preconception, pregnancy, and breastfeeding

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Table 27. TNF Inhibitors STEPS (continued)

Simplicity

Doses may be given subcutaneously weekly (etanercept), every other week (adalimumab), or every 4 wk (golimumab); golimumab IV infusion is given every 8 wk Certolizumab is dosed subcutaneously every other week when initiating therapy and may be extended to every 4 wk for maintenance therapy Infliximab is dosed IV every 8 wk after completing induction therapy at 0, 2, and 6 wk; interval may be decreased to every 4 wk, if necessary; weight-based dosing allows for flexible dosing

cDMARD = conventional disease-modifying antirheumatic drug.

2. T-cell inhibitor – Abatacept (Orencia) Table 28. Abatacept STEPS

Safety

Tolerability Efficacy Preference (Pearls) Simplicity

In patients with COPD, abatacept has been linked with more adverse pulmonary effects Increased risk of developing serious infections Acute infusion reactions Upper respiratory tract infections

Should not be used in combination with other bDMARDs Improves RA symptoms but should not be introduced until failure of at least one TNF inhibitor Combination with MTX causes higher remission rates than MTX monotherapy

ACR recommendations suggest abatacept as an option for patients with moderate to severe disease who have not achieved remission with a nonbiologic DMARD ACR recommendations suggest abatacept is preferred to TNFi in patients with a history of serious infections IV regimen: After initial infusion, administer again at 2 wk and then at 4 wk; then begin administering every 4 wk Subcutaneous regimen: Initial IV infusion; then subcutaneous injection within 24 hours; and then weekly thereafter

TNFi = tumor necrosis factor alpha inhibitor.

3. Anti-CD20 – Rituximab (Rituxan) a. Biosimilars i. Rituximab-pvvr (Ruxience) ii. Rituximab-abbs (Truxima) Table 29. Rituximab STEPS

Safety

Although reported, patients treated with rituximab for RA have a much lower risk of the following adverse events than those treated for oncologic conditions: Acute renal failure Cardiac arrhythmias Linked to fatal infusion-related adverse reactions Mucocutaneous reactions Progressive multifocal leukoencephalopathy Infections (including opportunistic) Tumor lysis syndrome

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Table 29. Rituximab STEPS (continued)

Tolerability Arthralgias Infusion reactions Upper respiratory tract infections Hematologic effects may include lymphopenia, neutropenia, leukopenia, thrombocytopenia, and anemia Hepatitis B reactivation Hypogammaglobulinemia Hyperphosphatemia Hypertension Hyperuricemia Efficacy

Preference (Pearls)

Simplicity

Has efficacy as monotherapy or as add-on therapy to MTX Should not be used in combination with other bDMARDs

Avoid use in patients who have not had an adequate trial with a TNF inhibitor All patients receiving bDMARDs should be tested (and treated) for TB before starting therapy (see Figure 3 for TB screening recommendations) Patients should be screened for hepatitis B and C before therapy Rituximab may be beneficial in patients with overlap autoimmune diseases such a interstitial lung disease, Sjögren syndrome, myositis, multiple sclerosis, or SLE Premedicate with acetaminophen, antihistamine, and corticosteroid before infusion A two-dose therapeutic course (separated by 14 days) every 24 wk (frequency may be reduced to as short as every 16 wk, depending on clinical response)

SLE = systemic lupus erythematosus.

4. IL-6 antagonist a. Tocilizumab (Actemra) b. Sarilumab (Kevzara) Table 30. IL-6 Inhibitor STEPS

Safety

Tolerability

Efficacy

Serious bacterial, fungal, and viral infections reported with use All patients should receive monitoring for TB before and after starting tocilizumab therapy Increased risk of GI perforation Risk of hepatoxicity Avoid use in patients with the following: Absolute neutrophil count < 2000/mm3 Platelet count < 100,000/mm3 Aminotransferase concentrations > 1.5 times the upper limit of normal

Dyslipidemias reported Hypersensitivity reactions starting with the second to fourth infusion/injection Neutropenia or thrombocytopenia Transaminase elevations Upper respiratory tract infections

Effective treatment option for patients not responding, or with inadequate response, to MTX therapy Used in combination with MTX therapy; can be used as monotherapy; should not be combined with other biologics

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Table 30. IL-6 Inhibitor STEPS (continued)

Preference (Pearls) Simplicity

FDA approved for patients with an inadequate response to ≥ 1 TNF inhibitors Tocilizumab: IV infusion every 4 wk or subcutaneous injection given once weekly or every other week Sarilumab: Subcutaneous injection given every other week

L. Targeted Synthetic DMARD – Janus Kinase (JAK) Inhibitors 1. Tofacitinib (Xeljanz) 2. Baricitinib (Olumiant) 3. Upadacitinib (Rinvoq) Table 31. JAK Inhibitors STEPS

Safety

Tolerability Efficacy Preference (Pearls)

Simplicity

Bone marrow suppression GI perforation in those with a history or at risk Hepatotoxicity Malignancy TB reactivation Thrombosis (increased incidence with higher than approved dose for RA with tofacitinib [i.e., 10 mg twice daily]) Caution in kidney disease Increased risk of infection Diarrhea

Headache Upper respiratory tract infections

Reduces symptoms of RA May be used as monotherapy or in combination with cDMARDs for RA

Tofacitinib included in 2015 ACR update as an option for patients with established disease (> 6 mo) with continued disease activity despite treatment with MTX and/or a TNF inhibitor or non-TNF biologic agent EULAR recommends using tofacitinib after other biologic treatments fail to control the disease Tofacitinib requires dose adjustment for drug interactions (strong and moderate CYP3A4 inhibitors, strong CYP3A4 inducers, and potent CYP2C19 inhibitors) Dose reduction for moderate to severe renal impairment Oral therapy, dosed once or twice daily Price (per month) is similar to that for most bDMARDs

CYP = cytochrome P450.

M. Other Considerations with bDMARDs 1. Tuberculosis

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Figure 3. 2012 ACR recommendations for tuberculosis screening in patients using biologic DMARD therapy.

Reprinted with permission from: Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of diseasemodifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 2012;64:625-39.

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2. bDMARDs and targeted synthetic DMARDs are quite expensive. Medication assistance programs (www. needymeds.com) are available for those who qualify on the basis of financial need. The financial impact of biosimilars on the U.S. market has not yet been seen; however, predictions show a potential for cost savings. Many factors may play a role in diminishing the cost savings, such as provider awareness/education, litigation by pharmaceutical manufacturers, and influences of insurers and managed care. (Domain 2, Task 6, Knowledge 2) 3. Many pharmacy insurance providers require authorization paperwork before paying for bDMARD therapy. (Domain 2, Task 6, Knowledge 3; Domain 4, Task 6, Knowledge 6) a. Step therapy: Documentation of unsuccessful treatment with one or several available cDMARDs b. Prior authorization: Documentation of symptom severity or contraindications requiring advancement of therapy beyond recommended first-line agents c. Authorization is usually temporary (12 months) and requires reevaluation to continue coverage. d. Specialty pharmacies may ship medications to the patient’s physician’s office or directly to the patient. All subcutaneous options are self-administered. e. Pharmacies (specialty or otherwise) may wait for full payment by insurance before releasing the medication to patients, thereby delaying therapy or making administration scheduling difficult. Patient Case 7. D.K. is a 37-year-old woman with RA for the past 8 years. She is currently treated with methotrexate 25 mg orally once weekly and etanercept 50 mg subcutaneously once weekly, but she returns to the rheumatology office today with worsening RA symptoms (classified as moderate to severe disease). She previously tried infliximab; however, she developed an infusion-related reaction to treatment and was subsequently changed to etanercept. Her concerns were the same 6 months ago, but she was given a course of oral corticosteroids in the hope that they would cause her symptoms to remit. However, her symptoms are still present and worsening. Which is the best next step to help control the patient’s RA and symptoms? A. B. C. D.

Initiate another course of prednisone, but increase the dose to 20 mg daily and continue indefinitely. Add another anti-TNF agent to the patient’s regimen, such as adalimumab. Discontinue etanercept, and initiate abatacept therapy for the patient. Continue etanercept, and initiate abatacept therapy for the patient.

4. Patient resources (Domain 5, Task 2, Knowledge 5) a. Patient handouts from American Family Physician b. Online information from the Arthritis Foundation (www.arthritis.org) c. Online information from the ACR (https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Patientand-Caregiver-Resources) Table 32. Drugs and Doses Reference Table Medication Name cDMARDs

MTX

Brand Name

Leflunomide

Arava

Hydroxychloroquine

Plaquenil

Sulfasalazine

Azulfidine

Dosing 5–25 mg by mouth once weekly 10–20 mg by mouth once daily

1–3 g by mouth in two divided doses daily

200–400 mg by mouth once daily or in two divided doses. Limit max dose to 5 mg/kg daily because of risk of retinal toxicity

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Table 32. Drugs and Doses Reference Table (continued) Medication Name

Brand Name

bDMARDs

Tumor Necrosis Factor (alpha) Inhibitor

Adalimumab

Humira

Certolizumab

Cimzia

Golimumab

Simponi (SC) Simponi Aria (IV)

Etanercept

Dosing

40 mg subcutaneously every other week; may increase to 40 mg once weekly without combination therapy with MTX

Loading dose of 400 mg subcutaneously at weeks 0, 2, and 4; then maintenance dose 200 mg subcutaneously every other week (or 400 mg every 4 wk) 2 mg/kg IV at weeks 0 and 4; then every 8 wk thereafter 50 mg subcutaneously once monthly

Enbrel

50 mg subcutaneously once weekly

Orencia

Initial weight-based infusion, then IV at weeks 2 and 4, and then every 4 wk thereafter 125 mg subcutaneously within 24 hr of infusion, and then 125 mg subcutaneously every week thereafter (loading dose can be omitted)

Rituxan

1000 mg IV at days 1 and 15, and then repeated every 24 wk

Tocilizumab

Actemra

Sarilumab

Kevzara

4–8 mg/kg IV every 4 wk (maximum dose 800 mg) 162 mg subcutaneously once weekly or every other week (depending on clinical response)

Remicade

Infliximab T-cell Inhibitor

Abatacept

Anti-CD20

Rituximab

IL-6 Inhibitor

Targeted Synthetic DMARDs Tofacitinib

Xeljanz

Baricitinib

Olumiant

Upadacitinib

Rinvoq

3 mg/kg IV at weeks 0, 2, and 6; then 3–10 mg/kg every 4–8 wk thereafter

200 mg subcutaneously every 2 wk JAK Inhibitor

IR: 5 mg by mouth twice daily XR: 11 mg by mouth once daily 2 mg by mouth once daily

15 mg by mouth once daily

IR = immediate release; XR = extended release.

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III.  PSORIATIC ARTHRITIS A. Clinical Guidelines (Domain 1; Tasks 3, 6, 7; Knowledge 2/1/2) 1. 2018 ACR/National Psoriasis Foundation (NPF) guideline for PsA treatment 2. 2015 EULAR 3. 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 4. 2008 American Academy of Dermatology guidelines on managing psoriasis and PsA B. Clinical Presentation 1. Subtypes a. Arthritis mutilans – Progressive disease with “telescoping digits” b. Distal interphalangeal disease (DIP arthritis) – Classic symptoms presentation c. Oligoarticular – Asymmetric arthritis, typically with dactylitis (sausage digits) d. Polyarticular – Symmetric arthritis e. Spondyloarthropathy – Symptoms predominantly in vertebrae, hip, and shoulder 2. History and physical findings a. Spondylitis – Inflammation of the joints of the backbone b. Neck pain – Inflammation in the neck c. Thoracic inflammation – Inflammation between the neck and the abdomen d. Axial symptoms – Involve the part of the skeleton that consists of the bones of the head and trunk e. Sacroiliitis – Inflammation of the sacroiliac joint f. Psoriasis – Inflammatory skin changes involving flaking, thick, white, silvery, or red patches of skin; typically presents 10–15 years before joint-related symptoms g. Onycholysis – Involves pits or detachment of the nail from the nail bed (onycholysis) h. Dactylitis – Inflammation of fingers or toes i. Enthesitis – Inflammation of the sites where tendons or ligaments insert into the bone (enthesis) j. Uveitis – Inflammation of the middle layer of tissue in the eye wall (uvea) C. Risk Factors 1. Presence of psoriasis, specifically at sites such as the scalp, nails, and/or gluteus and perineum 2. Environmental exposures – Trauma (Koebner effect) or infectious origin 3. Genetic predisposition – First-degree relative with disease increases risk 4. Obesity – Negative predictor of achieving and maintaining minimal disease activity in patients with PsA (modifiable risk factor) D. Disease Complications 1. Rarely as severe as RA and not usually as debilitating (still painful and debilitating) 2. May result in premature cardiovascular (CV) damage or pulmonary fibrosis E. Diagnostic Evaluation (Domain 1, Task 2, Knowledge 1) 1. CASPAR (Classification Criteria for Psoriatic Arthritis) criteria are both highly sensitive and specific for the diagnosis of PsA. 2. Requires a score of at least 3 (of possible 6) points plus established articular inflammation a. Current (2 points) or personal/family history of (1 point) psoriasis b. Dactylitis (1 point) c. Juxta-articular new bone formation (1 point) d. Negative RF finding (1 point) e. Nail dystrophy (1 point)

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3. Negative prognostic indicators a. More than five actively inflamed joints b. Increased acute-phase reactants (CRP, ESR) c. Evidence of progressive radiographic changes d. Previous treatment with glucocorticoids e. Functional decline (or loss thereof) f. Deteriorated quality of life F. Treatment Recommendations Table 33. GRAPPA Treatment Guidelines for PsA Presenting Symptoms

Initial Treatment Recommendations

Peripheral arthritis

NSAID, intra-articular corticosteroids, csDMARD, bDMARD

Skin and nail disease

Topical agents, PUVA/UVB, csDMARD, bDMARD

Axial disease

NSAID, physical therapy, bDMARD

Dactylitis

NSAID, bDMARD

Enthesitis

NSAID, bDMARD

bDMARD = biologic disease-modifying anti-rheumatic drug (TNF inhibitor); csDMARD = conventional disease-modifying anti-rheumatic drug (MTX, leflunomide, sulfasalazine); PUVA = psoralen ultraviolet A; UVB = ultraviolet B.

1. Treatment is based on agents for psoriasis and type of arthritis. 2. Initial therapy is determined by level of severity (mild, moderate, or severe), joints involved (peripheral vs. axial), and skin involvement. 3. Systemic glucocorticoids may be used for inflammatory arthritis but may exacerbate skin manifestations (i.e., psoriasis). Table 34. AAD Recommendations for Classification and Treatment of PsAa Classification

Mild

Moderate Severe

Impact on Quality of Life

Therapy Choice(s)

Minimal

Affects daily tasks of living and physical/mental functions Lack of response to NSAID

Cannot perform major daily tasks without pain or dysfunction Large impact on physical/mental functions Lack of response to either DMARD or TNF blockers as monotherapy

NSAID

cDMARD Anti-TNF

DMARD + anti-TNF or other biologic therapy

See RA section for information about the safety, tolerability, and simplicity of the medications listed in the following text to treat PsA.

a

AAD = American Academy of Dermatology.

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Moderate to severe disease

Clinical diagnosis of active PsA

Mild disease

Predominant enthesitis or axial disease?

Initiate cDMARD • Methotrexate • Leflunomide or sulfasalazine (if methotrexate is contraindicated

Start NSAID therapy ± topical agent

NO

YES

Factors of poor prognostic factors persist after adequate cDMARD trial (i.e., five or more actively inflamed joints, elevated acute phase reactants, radiographic damage that is progressing, previous use of glucocorticoids, loss of function, and diminished quality of life) YES

NO

TNFi + cDMARD • Adalimumab • Certolizumab pegol • Etanercept • Golmumab • Infliximab

Add a second cDMARD • Methotrexate • Leflunomide • Sulfasalazine Note: For refractory skin disease, may add cyclosporine

Change to a different TNFi ± cDMARD • Adalimumab • Certolizumab pegol • Etanercept • Golimumab • Infliximab

Change to a different boilogic therapy ± cDMARD • Abatacept • Apremilast • Secukinumab • Ustekinumab

Figure 4. General approach to managing psoriatic arthritis.a

a For specific drug selection, consider domain of disease and primary symptoms. For each step, if patients achieve their target within 3–6 mo, continue the therapy. If not, proceed to the next step. Consider symptomatic relief with NSAIDs, COX-2 inhibitors, and/or local glucocorticoid injections.

PsA = psoriatic arthritis.

Information from: Gossec L, Smolen JS, Gaujoux-Viala C, et al. European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. Ann Rheum Dis 2012;71:4-12; and Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol 2011;65:137-74.

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Table 35. 2018 ACR/National Psoriasis Foundation Guideline for PsA Treatment Classification

Therapy Choice(s)

Treatment-naive active Start TNFi PsA Start OSMsa Start MTX

Start IL-17i Active PsA despite OSM or MTX monotherapy

Change to a TNFi Change to IL-17i Change to IL-12/23i

Still active PsA on TNFi + MTX

Change to a different class monotherapy

Still active PsA on TNFi monotherapy

Alternative Choice

If severe psoriasis or TNFi contraindicated: IL-17i or IL-12/23i

If severe PsA or psoriasis, concomitant IBD, or prefers less frequent drug administration: IL-17i OR IL-12/23i (i.e., ustekinumab) If less active disease: NSAIDs

If patient has concomitant IBD or less frequent administration: IL-12/23i Still active despite additional therapy: Change to a new class (if TNFi. then ± MTX)

Change to a different TNFi Consider adding MTX Change to IL-17i Change to IL-12/23i

Change to a different agent within the same class

OSMs include MTX, sulfasalazine, cyclosporine, leflunomide, and apremilast.

a

IBD = inflammatory bowel disease; OSM = oral small molecule.

Patient Case 8. T.M. is a 42-year-old man with a medical history significant for psoriasis and PsA. His current medications include topical betamethasone/calcipotriene and diclofenac extended release 150 mg daily. His psoriatic arthritis symptoms, including peripheral joint swelling and pain in his right hand and both feet with new-onset axial symptoms, have worsened during the past 12 months, but he has been reluctant to use anything more than an NSAID. A recent imaging study reveals sacroiliitis. He has extreme debilitation more days than not and sometimes requires assistance with tasks such as dressing and simple cleaning. If he chooses to intensify his therapy, which is the best approach? A. B. C. D.

Prednisone 10 mg once daily for 6 weeks. Methotrexate 10 mg once weekly. Golimumab 50 mg once monthly. Methotrexate 10 mg once weekly plus golimumab 50 mg once monthly.

4. NSAIDs Table 36. Efficacy and Preference/Pearls for NSAIDs in PsA

Efficacy

Preference (Pearls)

Monotherapy with NSAID is as effective as combination therapy with dual-NSAID or non-NSAID analgesic + NSAID for pain associated with PsA NSAIDs may worsen dermatologic symptoms/skin lesions in some patients

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5. cDMARDs Table 37. Efficacy and Preference/Pearls for Synthetic DMARDs in PsA

Efficacy

Preference (Pearls)

MTX, leflunomide, and sulfasalazine all appear to reduce dermatologic and peripheral arthritic symptoms; lack data for axial disease symptoms

May be used as first-line therapy in patients with mild to moderate peripheral PsA and/or an insufficient response to NSAID therapy. In general, not used in patients with severe disease and/or axial symptoms

6. Apremilast (Otezla) Table 38. Apremilast STEPS

Safety

Depression and suicidal ideations

Efficacy

As monotherapy, improved patients’ arthritic symptoms and quality of life

Tolerability Preference (Pearls)

Simplicity

Unintentional weight loss Nausea (dose related) Diarrhea

Dose reduction required in patients with CrCl < 30 mL/min Dose titration required to help patients with GI tolerance In clinical research, improvements over placebo were noted when using both the ACR20 and the ACR50 response criteria Can be used in combination with biologics, considered an immunomodulator, not immunosuppressive Oral medication dosed once (renally impaired) or twice daily; starter dose pack available for slow titration

7. bDMARDs Table 39. Efficacy and Preference/Pearls for bDMARDs in PsA

Efficacy

Preference (Pearls)

All agents (TNF inhibitors, T-cell inhibitor, and IL-12/IL-23 inhibitor) reduce the symptoms and slow PsA disease progression, including axial disease

Consider for first-line therapy in patients with moderate to severe symptoms and functional limitations with PsA May consider use in combination with a synthetic DMARD for severe or refractory cases of PsA See STEPS tables in RA section for additional information

8. IL inhibitors a. Secukinumab (IL-17A; Cosentyx) b. Ustekinumab (IL-12 and IL-23; Stelara) c. Ixekizumab (IL-17; Taltz) d. Guselkumab (IL-23; Tremfya)

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Table 40. IL Inhibitor STEPS

Safety

Tolerability Efficacy

Preference (Pearls)

Simplicity

Risk of severe infection such as sepsis, TB, or opportunistic infections; risk of candidiasis more common with IL-17 inhibitors Hypersensitivity reactions Malignancy (Rare) neurotoxicity (with ustekinumab) Headache Fatigue Arthralgia Injection site reactions

Has efficacy in patients with PsA

Provide all necessary immunizations before initiating therapy If necessary, may administer inactivated vaccines during therapy, but avoid all live vaccines May be used in combination with MTX. In clinical research, improvements vs. placebo are noted in the ACR20 and ACR50 response criteria For patients with concomitant IBD, ustekinumab recommended as an alternative to TNFi Infection rates appear clinically lower than with TNFi All given as self-administered subcutaneous injections

9. JAK-associated inhibitor – tofacitinib (Xeljanz) – See Table 31. 10. Surgery may be necessary for patients whose condition does not respond sufficiently to pharmacotherapy or who have progressive loss of joint function. 11. Psoralen ultraviolet A/ultraviolet B therapy may help patients with both (extensive) skin and articular disease. G. Patient Information – Few resources are dedicated specifically to PsA because most originate from “arthritis” advocacy and information groups. (Domain 5, Task 2, Knowledge 5) 1. Arthritis Foundation (www.arthritistoday.org) 2. American College of Rheumatology (www.rheumatology.org) 3. Mayo Clinic (www.mayoclinic.com) Table 41. Drugs and Doses Reference Table Medication Name cDMARD

MTX

Leflunomide

Sulfasalazine

Brand Name

Otrexup; Rasuvo; 5–25 mg by mouth or subcutaneously once weekly RediTrex; Trexall; Xatmep Arava

Azulfidine

Phosphodiesterase-4 Inhibitor

Apremilast

Dosing

Otezla

10–20 mg by mouth once daily

2–3 g by mouth once or twice daily 10 mg once daily on DAY 1 10 mg twice daily on DAY 2 10 mg in the morning and 20 mg in the evening on DAY 3 20 mg in the morning and 20 mg in the evening on DAY 4 20 mg in the morning and 30 mg in the evening on DAY 5 30 mg twice daily thereafter

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Table 41. Drugs and Doses Reference Table (continued) Medication Name

Brand Name

Dosing

Adalimumab

Humira

40 mg subcutaneously every other week

Etanercept

Enbrel

50 mg subcutaneously once weekly

TNF Inhibitor

Golimumab

Simponi Aria and Simponi

Infliximab

Remicade

T-cell Inhibitor

Abatacept

Orencia

Phosphodiesterase-4 Inhibitor

Apremilast

2 mg/kg IV at weeks 0 and 4; then every 8 wk thereafter 50 mg subcutaneously once monthly 5 mg/kg IV at weeks 0, 2, and 6; then every 8 wk thereafter Initial weight-based infusion, and then IV at weeks 2 and 4; then every 4 wk thereafter 125 mg subcutaneously within 24 hr of infusion; then 125 mg subcutaneously every week thereafter

Otezla

10 mg once daily on DAY 1 10 mg twice daily on DAY 2 10 mg in the morning and 20 mg in the evening on DAY 3 20 mg in the morning and 20 mg in the evening on DAY 4 20 mg in the morning and 30 mg in the evening on DAY 5 30 mg twice daily thereafter

Ustekinumab

Stelara

Secukinumab

Cosentyx

45 mg (or 90 mg if > 100 kg) subcutaneously at weeks 0 and 4; then every 12 wk thereafter

Ixekizumab

Taltz

IL Inhibitors

Guselkumab

Tremfya

Janus Kinase Inhibitor

Tofacitinib

Xeljanz

150 mg subcutaneously once weekly for five doses; then 150–300 mg every 4 wk thereafter 160 mg subcutaneously once, followed by 80 mg every 4 wk 100 mg at weeks 0, 4, and then every 8 weeks thereafter

Use in combination with nonbiologic DMARDs: IR: 5 mg orally twice daily XR: 11 mg orally

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IV.  OSTEOARTHRITIS A. Treatment Guidelines: 1. ACR 2019 recommendations for nonpharmacologic and pharmacologic therapies in OA of the hand, hip, and knee (Arthritis Care Res (Hoboken) 2020;72:149-62) 2. Michigan Quality Improvement Consortium 2015 3. National Institute for Health and Care Excellence Table 42. Disease Characteristics Osteoarthritis (OA)

Rheumatoid Arthritis (RA)

Disease process

Breakdown of cartilage (not autoimmune), localized

Autoimmune (immune system attacks joint), systemic disease

Host factors

Genetic, trauma, biomechanical, metabolic, older age

Genetic, sex, smoking status, environmental exposure

None or mild, local inflammation

Chronic local and systemic inflammation

None specific, mild leukocytosis in synovial fluid

Elevated ESR, RF may present, leukocytosis in synovial fluid

Joints affected

Symmetrical, Symmetrical, small asymmetrical large joints joints Neck, spine, knees, Hands, wrists, and feet shoulders

Presence of inflammation Morning stiffness

No (stiffness lasting < 30 min)

Laboratory

Yes (lasting > 60 min)

Psoriatic Arthritis (PsA)

Gout

Autoimmune (immune Breakdown of cartilage system attacks joint), (not autoimmune), systemic disease localized uric acid crystal deposits Genetic, sex, smoking status, environmental exposure

Sex (men > women)

Asymmetrical, large and small joints; extraarticular (e.g., uveitis, tendonitis)

Asymmetrical, large and small joints

Yes (lasting > 60 min)

If during/after recent attack

Elevated ESR, leukocytosis in synovial fluid

Elevated uric acid and ESR

Chronic local and Local inflammation systemic inflammation

B. Risk factors for developing disease are not always risk factors for clinical progression (e.g., a high bone density may be a risk factor for developing OA, but a low bone density increases the chance of clinical progression). Table 43. Factors Associated with Developing OA

Biomechanical

Constitutional Genetic

Joint injury Occupational/recreational use Joint laxity

Reduced muscle strength Joint malignancy

Aging Obesity

40%–60% of hand, knee, and hip OA is inherited through unknown genes

Female sex High bone density

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Table 44. Clinical Findings in OA by Joint Back (chronic low back pain)

Knee

Patient concerns

Low back pain for > 3 mo

Physical findings

Pain with straight leg raise examination (30–70 degrees)

Imaging

Radiography is not routinely Radiography findings may be recommended for nonspecific normal and are only adjunct back pain to diagnosis Consider MRI or CT for Neither CT nor MRI is patients only if they are indicated candidates for surgery

Laboratory evaluation

Only in the presence of “red flags”a

Activity related Instability or buckling Morning stiffness < 30 min Recurrent pain Bony enlargement Crepitus Limited range of motion

ESR (< 40 mm/hr) RF < 0-20 u/ml Synovial fluid aspiration unremarkable

Hand (metacarpophalangeal)

Thumb or radial hand pain Difficulty with manual dexterity Gelling with inactivity < 10 min Morning stiffness < 30 min Localized tenderness Limited range of motion

Radiography (for staging)

Aspirate evaluation if suspected infection

a Red flags: Age at onset > 50, pain unrelenting at night or unrelated to activity, widespread symptoms, progressive motor or sensory deficit, unexplained weight loss, fevers/ chills/infection, significant trauma, indications of nerve root problem, history of cancer, HIV, steroids, osteoporosis, or substance abuse.

CT = computed tomography.

C. Nonpharmacologic Interventions 1. Education about expectations for therapy, importance of nonpharmacologic management strategies, and cognitive behavioral therapy (chronic low back pain) 2. Weight loss (at least 5%) 3. Low-impact exercise 4. Physical therapy 5. Support braces, orthotics, and assistive devices also have mixed results and are not strongly recommended by the American Academy of Orthopedic Surgeons (AAOS). 6. Nonpharmacologic interventions are the only therapies shown to reduce the progression of OA.

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Patient Case 9. T.W. is a 67-year-old man with severe degenerative joint disease of his right knee. His medical history is significant for coronary artery disease (myocardial infarction 6 years earlier), heart failure (ejection fraction 30%), hypertension, erectile dysfunction, and gastroesophageal reflux disease. He takes lovastatin 40 mg daily, fosinopril 20 mg daily, carvedilol 12.5 mg twice daily, aspirin 81 mg daily, calcium carbonate chewable tablets as needed (about three times weekly), and sildenafil 25 mg as needed. His knee pain causes significant physical limitations, and he is embarrassed to use an electronic cart when he shops at grocery and department stores. He would like to be more active but has difficulty even with the activities of daily living. Given this information, which is the best initial choice for this patient’s knee OA? A. B. C. D.

Take acetaminophen 650 mg two tablets every 6 hours as needed for pain. Take ibuprofen 400 mg one tablet every 6 hours as needed for pain. Take naproxen 500 mg one tablet every 12 hours as needed for pain. Apply diclofenac 1% gel to affected knee up to four times daily.

Table 45. Pharmacologic Interventions Class/Agent

Acetaminophen

Topical applications

Comments

Recommended as the first-line pharmacologic agent (as needed or scheduled) for pain associated with (mild) OA (Exception: Acetaminophen is not recommended by the ACR for hand OA) Maximal dose of 4 g daily is still acceptable, though much more likely to have transaminase elevations with higher doses Most research finds acetaminophen more effective than placebo for OA pain, but only minimally effective overall and less effective than NSAIDs Topical NSAIDs have proven short-term efficacy, but information is insufficient to comment on long-term use (> 12 wk), and they are markedly more expensive than oral NSAIDs Topical NSAIDs are recommended over oral NSAIDs for patients > 75 Consider for patients with a history of CV disease and those who should not use systemic NSAIDs May not be useful for hip OA, given the mass of tissue between skin and joint Capsaicin should reduce pain in about 2 wk

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Table 45. Pharmacologic Interventions (continued) Class/Agent

Comments

NSAIDs

Controlled opioid analgesics

Glucosamine and chondroitin

Low-dose corticosteroids

Naproxen, ibuprofen as needed or scheduled NSAIDs are more effective than acetaminophen at reducing pain, but their adverse event profile is less favorable No single NSAID is preferred to another, though the ACR does not recommend ibuprofen for patients using aspirin for CV disease prevention because of FDA documentation that ibuprofen interferes with aspirin activity Current data analyses suggest that CV risk is not equal among all NSAIDs; however, evidence may be insufficient to definitively say that the risk of any one NSAID is higher or lower than that of any other NSAID The selective COX-2 inhibitor agent celecoxib may also be considered an alternative to nonselective NSAIDs; efficacy profile is the same as that for traditional NSAIDs, but with fewer reports of adverse GI events, and COX-2 agents do not affect platelet function; however, celecoxib may not be safer than nonselective NSAIDs past 6 mo of use with respect to adverse GI events For patients with a history of GI ulceration, a COX-2 inhibitor or an NSAID with a PPI is recommended as primary therapy For patients with a GI bleed in the past 12 mo, ACR recommends a COX-2 inhibitor with a PPI Opioid analgesics may be useful but should not be used routinely to treat pain associated with OA Patients may respond to therapy, but limit use to patients with severe pain that is inadequately controlled with previously mentioned therapies Likelihood of adverse event similar to that of NSAIDs NOT routinely recommended for OA because risk and severity of adverse events outweigh benefit potential Delayed onset of effects, cannot be used for immediate pain relief Glucosamine (with or without chondroitin) has questionable benefits from clinical trials Research is usually small and of variable quality, resulting in highly heterogeneous conclusions in meta-analyses and systematic reviews Chondroitin has shown benefit for knee OA in studies with high heterogeneity but appears to lose efficacy when paired with glucosamine NOT routinely recommended by ACR

May help with short-term pain reduction and increased mobility for patients with moderate to severe OA of the knee Oral corticosteroids are not recommended by ACR

COX-2 = cyclooxygenase-2.

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D. Tramadol (Con Zip, Rybix, Ryzolt, Ultram, Ultram ER [extended release]) Table 46. Tramadol STEPS

Safety

Tolerability

Efficacy

Preference (Pearls) Simplicity

Avoid use (Rybix, Ultram, Ultram ER) when opioids are not indicated, including acute intoxication with alcohol, hypnotics, opioids, or psychotropic drugs Avoid use (Con Zip, Ryzolt) in patients with severe/acute asthma, hypercapnia, or severe respiratory depression in the absence of resuscitative equipment Contraindicated within 14 days of monoamine oxidase inhibitor therapy Seizures: As monotherapy or with greater risk when combined with other agents that lower the seizure threshold Limit IR dose to 50 mg every 12 hr in patients with cirrhosis Avoid XR formulations in severe hepatic impairment (Child-Pugh class C) Cautious use in patients with mild to moderate renal impairment, and avoid ER formulations in severe renal impairment (CrCl < 30 mL/min) Risk of serotonin syndrome in patients concurrently using agents that act on the serotonin system, particularly at high doses CNS depression Constipation Dizziness Dyspepsia Flushing

Provides a small degree of pain relief

Headache Nausea Postural hypotension Pruritus Somnolence

Consider as an alternative in patients who do not receive adequate pain relief from acetaminophen and cannot tolerate it or for whom NSAID therapy is contraindicated May administer dose as needed up to four times daily (maximum 100 mg per dose) Classified by the DEA as schedule IV

CNS = central nervous system; DEA = Drug Enforcement Agency; ER = extended release.

E. Other Interventions 1. Intra-articular corticosteroids may provide short-term pain relief (less than 4 weeks), but benefit usually diminishes beyond that time. a. Joint injections should not be done more often than every 3 months because of the risk of worsened or accelerated joint tissue degradation. b. OA symptoms requiring regular corticosteroid injections (three or four a year) should be considered for surgical intervention. 2. Intra-articular hyaluronic acid may be as effective as intra-articular corticosteroids for some patients, but with benefits for up to 6 months. a. No benefits over corticosteroids until 4 weeks after injections b. Much more costly alternative to intra-articular corticosteroids c. More frequent injections because many regimens require weekly injections for 3–5 consecutive weeks F. Surgery 1. Total arthroplasty (joint replacement) 2. Arthroscopic debridement (surgical removal of “debris” within the joint) 3. Arthroscopic lavage (flushing the joint internally with water)

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G. Alternative Treatments (Domain 1, Task 3, Knowledge 3) 1. S-adenosylmethionine may reduce NSAID need and improve functional limitations in patients with OA. 2. Avocado/soybean unsaponifiables appear to help reduce pain in patients with OA, but few trials with questionable supportive bias 3. Devil’s claw and willow bark have been associated with OA pain reduction. 4. Tai chi may improve strength and balance, but not falls, in patients with OA of the knee. 5. Acupuncture does not provide reliable pain relief. Acupuncture is reserved for patients with moderate to severe disease who are not candidates for or who refuse surgery. H. Patient Resources 1. Patient handouts from American Family Physician 2. Online information from the Arthritis Foundation

V.  FIBROMYALGIA A. Clinical Guidelines 1. 2016 EULAR evidence-based recommendations for managing fibromyalgia syndrome 2. 2010 ACR preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity B. Patient Presentation and Symptoms 1. Patients will have the following: a. Physical symptoms (weakness, fatigue, decrements in physical function, morning stiffness, heat or cold disturbances, swelling in extremities) b. Psychological symptoms (mood disturbances) c. Cognitive problems (difficulty concentrating, diminished mental clarity, memory problems) d. Photophobia, phonophobia, and/or osmophobia Patient Case 10. M.F. is a 32-year-old woman presenting to her primary care physician’s office with fatigue, “pain all over,” and headaches for the past 4 weeks. She has a history of major depression but has successfully been treated with regular counseling. She has a dull, aching pain most days in her shoulders and upper arms (bilateral), hips (bilateral), neck, and lower back. She says that she has fatigue daily (cannot play with children), difficulty sleeping 2 or 3 nights per week, and chronic headaches. She heard from a friend that she has all the symptoms of fibromyalgia, and she would like to be treated for it. Which is the best response for the physician to provide to the patient? A. B. C. D.

Her symptoms do not meet the fibromyalgia diagnosis criteria. Her fibromyalgia would benefit most from tai chi. Her fibromyalgia requires drug therapy. Her fibromyalgia will require treatment with a two-drug regimen.

2. Diagnostic tools a. Widespread pain index (WPI): Award 1 point for each location a patient has had pain in the past 7 days.

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Table 47. Locations included in the widespread pain index (WPI) score Shoulder girdle, left Upper leg, left Lower leg, left Abdomen

Shoulder girdle, right

Upper arm, left

Upper arm, right

Lower arm, left

Jaw, left

Hip (buttock, trochanter), right

Lower arm, right

Lower leg, right

Hip (buttock, trochanter), left Lower back

Neck

Upper leg, right

Upper back

Jaw, right

Chest

b. Symptom severity scale (SSS): Award 0–3 points for each level of severity of fatigue, waking unrefreshed, cognitive symptoms, and somatic symptoms. i. 0 = No problem/symptoms ii. 1 = Slight or mild problems/few symptoms iii. 2 = Moderate or considerable problems/moderate number of symptoms iv. 3 = Severe, pervasive, life-disturbing problems/great deal of symptoms c. ACR updated the criteria for diagnosis in 2010 to include the following: i. Symptoms for more than 3 months PLUS (a) WPI of 7 or higher and SSS of 5 or higher OR (b) WPI of 3–6 and SSS of 9 or higher ii. Absence of other disorders that could cause the same symptoms C. Professional Treatment Recommendations 1. Educate patients about pain management and self-treatment (good sleep hygiene, regular physical activity, stress management). 2. Cognitive behavioral therapy will help reduce pain, improve function, and enhance self-efficacy. 3. Exercise programs should be of moderate intensity. a. High-intensity exercise will make fibromyalgia symptoms worse. b. Exercise recommendations state the patient should exercise two or three times per week to a target of 60%–75% of his or her age-adjusted maximum heart rate (210 minus patient age). c. Patients should stretch before exercise to the point of mild resistance to reduce exercise-induced pain and injury. 4. Nonconventional treatment strategies may complement conventional management, but evidence is not yet sufficiently robust to recommend as alternative strategies. a. Acupuncture b. Biofeedback c. Chiropractic manipulation d. Heated pool treatments (with or without exercise) e. Hypnosis f. Osteopathic manipulation g. Therapeutic massage 5. Pharmacologic treatment strategy a. Tricyclic antidepressants, particularly amitriptyline, are the first-line treatment for reducing pain and symptoms associated with fibromyalgia. b. If patient has a contraindication to, cannot tolerate, or does not respond to therapy with a tricyclic antidepressant (at target dose), consider therapy with an alternative agent. c. Additional classes with efficacy (vs. placebo) include the following: i. α2δ ligands (gabapentin, pregabalin) ii. Dopamine D3 receptor agonists (pramipexole)

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iii. Selective serotonin reuptake inhibitors (fluoxetine, paroxetine) iv. Serotonin and norepinephrine dual reuptake inhibitors (duloxetine, milnacipran) v. Nonopioid mu-receptor antagonist (tramadol) 6. Tricyclic antidepressants a. Amitriptyline b. Cyclobenzaprine c. Nortriptyline Table 48. Tricyclic Antidepressant STEPS

Safety

The FDA warns that antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder Orthostatic hypotension Use with caution in patients with a history of CV disease, diabetes, hepatic impairment, mania/ hypomania, renal impairment, seizure disorders, or thyroid dysfunction Patients should discontinue tricyclic antidepressants before general elective surgery that requires anesthesia

Tolerability Anticholinergic effects Anorexia Dizziness Hypertension/hypotension Insomnia Numbness Efficacy

Paresthesia Syncope Tachycardia Urticaria Weight gain

Tricyclic antidepressants, particularly amitriptyline, are first line for improving fibromyalgia symptoms Have been proven to decrease symptoms of pain, fatigue, sleep, and depressed mood

Preference (Pearls)

Target dose of amitriptyline or cyclobenzaprine is 10–40 mg (cyclobenzaprine) or 50 mg (amitriptyline) in the evening before sleep Likelihood of having pain relief is about the same as the likelihood of having an adverse event

Simplicity

Once-daily dosing in the evening, before sleep, to decrease adverse event severity

Patient Case 11. S.E. is a 39-year-old woman with a medical history significant for minor depressive disorder. She presents to a medication management clinic after starting amitriptyline therapy for fibromyalgia. She increased the dose to 50 mg during the past 4 weeks but with no significant change in her symptoms. However, she does report that her negative feelings have lessened and her sleep is much improved, but the pain and discomfort associated with her fibromyalgia remain. She asks for a new medication to help control her symptoms. Which medication would be best to replace amitriptyline? A. B. C. D.

Gabapentin titrated to 800 mg three times daily. Pregabalin 75 mg twice daily. Duloxetine 30 mg once daily titrated to 60 mg once daily. Tramadol 50 mg every 6 hours as needed for pain.

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7. Selective serotonin reuptake inhibitors a. Fluoxetine b. Paroxetine Table 49. Selective Serotonin Reuptake Inhibitor STEPSa

Safety

Tolerability

Efficacy Preference (Pearls) Simplicity

The FDA warns that antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder Allergic skin reactions May increase bleeding risk when used in conjunction with antiplatelet or anticoagulation therapy Use with caution in patients with a history of CV disease, diabetes, mania/hypomania, hepatic effects, renal impairment, and/or seizure disorders Anticholinergic effects Diarrhea Dizziness Dyspepsia

Headaches Insomnia Nausea Sexual dysfunction

Evidence supports use in fibromyalgia, but strength of recommendation is not as strong as with tricyclic antidepressants A selective serotonin reuptake inhibitor + a tricyclic antidepressant is better than either class alone Fluoxetine and paroxetine are the most-studied agents to affect patients with fibromyalgia symptoms Small clinical trial with citalopram vs. placebo did not show significantly reduced symptoms Once-daily dosing

See Psychiatric Disorders chapter for more detail.

a

8. Serotonin and norepinephrine dual reuptake inhibitors a. Duloxetine b. Milnacipran Table 50. Serotonin and Norepinephrine Dual Reuptake Inhibitor STEPS

Safety

The FDA warns that antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder Increased risk of bleeding when used with antiplatelet or anticoagulation therapy Severe skin reactions have been reported with duloxetine Blood pressure and heart rate may be increased with milnacipran (because of increased selectivity for norepinephrine compared with serotonin)

Tolerability Anticholinergic effects Dizziness Headache Hyperhidrosis Insomnia

Nausea (dose related) Hot flashes (milnacipran) Sexual dysfunction

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Table 50. Serotonin and Norepinephrine Dual Reuptake Inhibitor STEPS (continued)

Efficacy

Preference (Pearls) Simplicity

Agents equally improve pain, sleep, depressed mood, and quality of life in patients with fibromyalgia Duloxetine up to 60 mg daily is effective for fibromyalgia syndrome NOTE: 120 mg does not have benefit beyond 60 mg, but increases likelihood of adverse events Milnacipran’s target dose is 50 mg twice daily (start with 12.5 mg twice daily and titrate every 7 days to target dose) Class efficacy is equal to that of pregabalin, but assumed from indirect comparisons of all three agents Data analyses on venlafaxine’s efficacy in fibromyalgia are limited and conflicting; use in combination with pregabalin may be considered by some clinicians Both duloxetine and milnacipran are FDA approved for fibromyalgia syndrome Duloxetine requires slow titration because of significant dose-related nausea Duloxetine requires dose adjustments when CrCl < 30 mL/min Agents are dosed once or twice daily and have a relatively quick onset of effect

9. α2δ ligand a. Gabapentin b. Pregabalin Table 51. α2δ Ligand STEPS

Safety

Safety concerns are relatively rare, but still present: Angioedema Visual field disturbances have been reported Use with caution in patients with cardiac disease, particularly heart failure, because of the risk of edema

Tolerability Dizziness Edema (peripheral) Efficacy

Preference (Pearls)

Simplicity

Somnolence Weight gain

Both gabapentin and pregabalin improve pain, sleep, fatigue, and quality of life Poor tolerability reported in clinical trials Consider lowest effective dose, may require up to: Gabapentin 2400 mg total daily Pregabalin 300–450 mg total daily Dosage adjustments are required in patients with renal impairment Pregabalin is registered as a schedule V substance (euphoria)

Pregabalin is dosed twice daily Titration schedule for gabapentin can be lengthy and requires thrice-daily dosing

10. Nonopioid mu-receptor antagonist (tramadol; see STEPS analysis and Osteoarthritis section) 11. Dopamine D3 receptor agonists (pramipexole): One small clinical trial (60 patients) reported at least 50% improvement in symptoms in significantly more patients using pramipexole titrated to 4.5 mg daily than placebo. 12. Memantine caused a 2-point pain scale reduction versus placebo in patients not actively receiving other medications for fibromyalgia (dose titrated to 20 mg/day). D. Patient Information 1. Medications are effective for symptom relief, but all professional organizations advocate education and cognitive behavioral therapy as the root of all treatments. 2. Most clinical trials evaluate and report symptom improvement but not complete symptom resolution.

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3. Patient information resources available online: a. Arthritis Foundation offers a variety of resources, including a self-help course, books, and educational videos (www.arthritis.org/conditions-treatments/disease-center/fibromyalgia-fms/). b. Exercise videos are available for purchase ($30 per video) through the Fibromyalgia Information Foundation (www.myalgia.com). Table 52. Drugs and Doses Reference Table Medication Name

Brand Name

Dosing

Amitriptyline

Elavil

25–100 mg once daily at bedtime

Cyclobenzaprine

Flexeril

5–10 mg by mouth three times daily

Nortriptyline Fluoxetine

Paroxetine

Pamelor

25–100 mg once daily at bedtime

Prozac

20–80 mg by mouth once daily

Paxil

Duloxetine

20–60 mg by mouth once daily

Cymbalta

Milnacipran

60 mg by mouth once daily

Savella

Gabapentin

50 mg by mouth twice daily

Neurontin

Pregabalin

300–1200 mg by mouth three times daily

Lyrica

75–150 mg twice daily

VI.  SYSTEMIC LUPUS ERYTHEMATOSUS A. Clinical Guidelines 1. 2019 EULAR recommendations on managing SLE 2. 2009 EULAR recommendation on monitoring patients with SLE in clinical practice and in observational studies 3. 2012 European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association. Joint European League Against Rheumatism and European Renal AssociationEuropean Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the treatment of adult and pediatric lupus nephritis 4. 2012 ACR recommendations for lupus nephritis Table 53. Definitions/Stages of SLE

Active SLE

Patient has signs/symptoms and tests that are attributed to inflammation and are reversible (target organ damage) with therapy

Mild SLE

Uncontrolled SLE

Complete response Remission

Patient’s condition is clinically stable without progressing organ damage or toxicity Patient’s signs/symptoms of SLE continue despite pharmacologic treatment Clinical remission with pharmacologic treatment

Patient does not have signs/symptoms of SLE and is not receiving treatment

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Table 54. Organ Systems Involved and Potential Complications Organ System

Potential Complications

CV

Hypertension, dyslipidemia, endocarditis, pericardial effusion, valvular disease

GI tract

Mesenteric vasculitis, pancreatitis

CNS

Cognitive disorders, neuropsychiatric disorders, depression, seizures

Hematologic/oncologic Joints

Kidneys Lungs

Hemolytic anemia, neutropenia, thrombosis, thrombocytopenia, thrombotic thrombocytopenic purpura, non-Hodgkin lymphoma Arthritis

Renal disease (lupus nephropathy or lupus nephritis)

Pulmonary hypertension, pneumonitis, pulmonary embolus, interstitial fibrosis

B. Risk Factors for Disease 1. Family history of SLE or other autoimmune disorders 2. Sex and ethnicity a. Women at greater risk than men b. Whites at greater risk than African Americans, Asians, and Hispanics 3. Exposure to silica, mercury, and/or pesticides 4. Drug-induced disease a. Captopril b. Chlorpromazine c. Hydralazine d. Isoniazid e. Methyldopa f. Procainamide g. Quinidine h. TNFα inhibitors i. Sulfasalazine j. Statins k. Proton pump inhibitors (PPIs) l. Estrogens and oral contraceptives (not causative, but may provoke and worsen flares in patients with lupus) C. Clinical Presentation: There are several clinical findings during a patient’s history and physical examination, but some are more common than others. 1. Arthritis 2. Malar rash (“butterfly” rash) 3. Active nephropathy 4. Neurologic changes 5. Fever 6. Raynaud phenomenon 7. Serositis 8. Thrombocytopenia 9. Thrombosis

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D. Diagnosis 1. ACR criteria for classification require four positive (of possible 11) findings. 2. Findings may be present sequentially or at the same time. Table 55. Eleven Criteria to Evaluate for the Diagnosis of SLE

Malar (butterfly) rash

Discoid lupus

Oral or nasopharyngeal ulcers

Photosensitivity

Serositis

Persistent proteinuria or casts

Immunologic abnormalities

a

Nonorganic seizures or psychosis

Positive ANA test result without drug-induced causes

Nonerosive arthritis

Hematologic changesb

a Immunologic abnormalities: anti-DNA, anti-SmAb, or one of the following (abnormal immunoglobulin [Ig]G or IgM cardiolipin antibodies, positive lupus anticoagulant, or confirmed false positive for > 6 mo for syphilis).

Hematologic changes: hemolytic anemia with reticulocytosis or WBC < 4 x 103 cells mm3 at least twice, absolute lymphocyte count < 1.5 x 103/mm3 at least twice, or platelet count < 100,000/mm3 without thrombocytopenia-inducing medications.

b

ANA = antinuclear antibody.

Table 56. Diagnostic Testing for SLE

Antinuclear antibody

Anti-La antibody

Anti-phospholipid

Anti–double-stranded DNA antibody

Anti-RNP antibody C3, C4

Anti-Ro antibody

Anti-Sm antibody

RNP = ribonucleic protein.

Table 57. Other Pretreatment and “Routine” Testing for SLE Baseline

Validated symptoms survey Routine every 6–12 mo

Complete blood cell count

Albumin, serum

Creatinine/microalbumin ratio

Quality-of-life assessment

Ophthalmologic examinationa

ESR

CRP

Creatinine, serum

Urinalysis

See antimalarial drugs for more specific recommendations.

a

E. Drug Treatment Strategies (EULAR recommendations) 1. Antimalarial drugs are first-line therapy for all patients with newly diagnosed SLE and/or without major organ involvement, unless otherwise contraindicated. 2. Systemic corticosteroids may be used to prevent flares and clinical relapse. 3. Steroids can be used in addition to antimalarial agents to control symptoms and prevent seromarker elevation. 4. NSAIDs may be used briefly, but patients need to be aware of GI, CV, and/or renal complications. 5. Immunosuppressive agents (methotrexate, azathioprine, mycophenolate cyclophosphamide, belimumab, rituximab) are reserved for patients who: a. Cannot achieve disease control with antimalarial drugs and corticosteroids

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b. Have International Society Nephrology/Renal Pathology Society (ISN/RPS) class III (focal lupus nephritis), class IV (diffuse lupus nephritis), class 5 (membranous lupus nephritis), class 6 (advanced sclerosing lupus nephritis) i. High-dose methylprednisolone for 3 days, followed by a maintenance dose for up to 6 months, PLUS ii. Immunosuppressive therapy for up to 6 months Patient Case 12. D.B. is a 29-year-old woman with a medical history significant for SLE and lupus nephritis. Her current treatment is hydroxychloroquine 200 mg once daily, but she continues to have complications because of the disease, including persistent proteinuria and serositis. To control her symptoms, which intervention would be best? A. B. C. D.

Increase the hydroxychloroquine dose to achieve a serum concentration greater than 1000 ng/mL. Add prednisone 40 mg daily for the next 6 months. Add omega-3 fatty acids (eicosapentaenoic acid 1.8 g and docosahexaenoic acid 1.2 g) per day. Add azathioprine 2 mg/kg/day.

6. Antimalarial agents a. Chloroquine b. Hydroxychloroquine Table 58. Antimalarial Agents STEPS

Safety

Tolerability

Efficacy

Risk of adverse drug reactions is higher for chloroquine; minimal risk for hydroxychloroquine for all safety issues listed in the text that follows Cardiomyopathy with long-term hydroxychloroquine use (rare) May cause the following: Agranulocytosis, aplastic anemia, and/or thrombocytopenia Exfoliative dermatitis, Stevens-Johnson syndrome Myopathy and muscle weakness Exacerbation of porphyria and/or psoriasis Loss of visual acuity and macular pigment changes (risk is highest with hydroxychloroquine doses > 6.5 mg/kg of lean body weight) Updated guidelines recommend maximum dose of 5 mg/kg of hydroxychloroquine to reduce risk of ocular toxicity Use with caution in patients with hepatic disease or receiving concurrent hepatotoxic agents, G6PD deficiency (chloroquine only), or renal insufficiency (no dosing recommendations provided) Abdominal cramping Alopecia Diarrhea Emotional changes

Nightmares Psychosis Tinnitus Urticaria

Reduces disease activity in most patients and reduces the average dose of corticosteroids needed to control symptoms Associated with a reduced mortality, irreversible organ damage, and progression to active disease

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Table 58. Antimalarial Agents STEPS (continued)

Preference (Pearls)

Recommended as first-line treatment by both EULAR (SLE without major organ involvement) and ACR (mild SLE) Hydroxychloroquine is preferred to chloroquine because of safety Dosing to achieve serum hydroxychloroquine concentration > 1000 ng/mL does not reduce the likelihood of disease flare American Academy of Ophthalmology recommends that patients have funduscopic and visual field examination within the first year of starting hydroxychloroquine; ophthalmologic screening recommendations are based on risk of drug-related disease (see Table 59)

Simplicity

May be dosed either once or twice daily, depending on tolerability or patient preference

G6PD = glucose-6-phosphate dehydrogenase.

Table 59. Ophthalmologic Screening Recommendations for Patients Treated with Antimalarial Agents Risk Category

Lesser

Major

Recommendations

Baseline evaluation as part of regular examination during the first 5 yr Reevaluate if drug dose is increased or if there are changes in patient weight or renal/hepatic function

Baseline evaluation and sooner than 5 yr if a risk factor is present Annually thereafter

Criteria

Absence of a major risk (see the following row) Older age Liver disease Genetic abnormalities (CYP polymorphisms or abnormal ABCA4 gene)

Dose > 5 mg/kg for hydroxychloroquine or 2.3 mg/kg for chloroquine Treatment for > 5 yr Renal disease Concurrent use of tamoxifen Current retinal or macular disease

7. Corticosteroids (see RA section for full STEPS analysis) a. Corticosteroids will delay the onset and prevent relapse or flares of SLE. b. May be dosed daily for patients with stable disease or as needed for flares c. Doses of 20 mg or higher (prednisone equivalent) may be necessary for patients with progressive endorgan damage caused by lupus. 8. Immunosuppressive therapy (azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil, cyclosporine, voclosporin, and anifrolumab) a. Agent of choice for patients when unable to prevent disease progression or induce remission with antimalarial drugs b. Recommended for patients with organ involvement (neuropsychiatric lupus, lupus nephritis, cutaneous lupus) c. Consider for use in patients who are unable to reduce their corticosteroid dose (to less than 10 mg of prednisone equivalent per day). d. Appears that azathioprine and cyclosporine are equal with respect to efficacy and safety in patients with SLE e. Both methotrexate and mycophenolate mofetil will decrease steroid requirements for patients treated with higher-than-acceptable corticosteroid doses.

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f. Rituximab, belimumab, or epratuzumab (investigational), added to standard therapy, has had benefits in patients with treatment-refractory disease. Newly approved therapies include voclosporin for lupus nephritis and anifrolumab for moderate to severe SLE. Place in therapy for both agents is evolving. F. Nonpharmacologic Interventions 1. Lifestyle modifications include smoking cessation, weight control, and exercise (when applicable). a. Omega-3 fatty acid intake (1.2 g of docosahexaenoic acid and 1.8 g of eicosapentaenoic acid each day) reduced scores on validated SLE symptom surveys. b. CV training programs may improve SLE symptom score surveys. c. Cognitive behavioral therapy and counseling may reduce fatigue and improve patient-reported mental health. 2. Recommend that patients regularly use sunscreen in all outdoor exposure. 3. Do not use live vaccines in patients taking more than 20 mg of corticosteroids (prednisone equivalents) each day. G. Patient Information – Several online resources and professional groups provide patient information. 1. American College of Rheumatology (www.rheumatology.org) 2. Lupus Foundation of America (www.lupus.org) 3. National Institute of Arthritis and Musculoskeletal and Skin Diseases (www.niams.nih.gov) Table 60. Drugs and Doses Reference Table Medication Name

Hydroxychloroquine MTX

Brand Name

Plaquenil

Azathioprine

Imuran

Cyclophosphamide

Cytoxan

Mycophenolate mofetil

CellCept

Rituximab

Rituxan

Belimumab

Benlysta

Voclosporin

Lupkynis

Anifrolumab

Saphnelo

Dosing

200–400 mg by mouth once daily (avoid doses > 5 mg/kg/day) 10–25 mg by mouth once weekly 50–100 mg by mouth once daily

250 mg to 3 g by mouth in divided doses

500 mg IV once every 2 wk for six doses OR 500–1000 mg/m2 IV once every month for six doses OR 500–1000 mg/m2 IV every month for 6 mo; then every 3 mo for a total of at least 2.5 yr

375 mg/m2 IV once weekly for four doses OR 500–1000 mg IV on days 0 and 15 10 mg/kg IV every 2 wk for three doses; then 10 mg/kg every 4 wk OR 200 mg subcutaneously once weekly 23.7 mg twice daily in combination with corticosteroids and mycophenolate. Dose adjustments determined by eGFR after initiation of therapy 300 mg IV every 4 wk

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VII.  GOUT AND HYPERURICEMIA A. Professional Treatment Recommendations and Guidelines 1. 2020 ACR guidelines for the management of gout (Arthritis Rheumatol 2020;72:879-95) 2. Management of acute gout: a clinical practice guideline from the American College of Physicians (2017) 3. 2006 EULAR evidence-based recommendations for the diagnosis and management of gout Table 61. Characteristics of Gout Type

Acute gout (gouty arthritis)

Chronic tophaceous gout

Characteristics

Severe pain and swelling with erythema First event is usually monoarticular (commonly first metatarsophalangeal joint) and presents to patient overnight or in the early morning Subsequent attacks may involve more joints such as the ankle, finger(s), foot, knee, and/or wrist May resemble cellulitis Persistent pain and swelling, accompanied by joint stiffness Polyarticular involvement Soft tissue mass composed of monosodium urate crystals and forming in areas of lowest body temperature (fingers, hands, toes, feet, ears) Frequent recurrent attacks Persistently elevated serum uric acid concentrations

Table 62. Risk Factors for Developing Gout and Hyperuricemia (uric acid, serum concentration > 6.8 mg/dL) Conditions

Alcoholism CV disease Diabetes mellitus Dyslipidemia Hypothyroidism Lead exposure Metabolic syndrome Organ transplantation Renal disease Myeloproliferative disorders Genetic disorders

Lifestyle

Obesity Increased animal purine intake Consuming high-fructose foods and drinks Alcohol (beers, liquors more than wines)

Medications

Thiazide diuretics Low- to moderate-dose aspirin Ethambutol Nicotinic acid Vitamin B12 Cyclosporine Levodopa Pyrazinamide Cytotoxic agents Ethanol

B. Gout Complications 1. Uric acid nephrolithiasis 2. Acute uric acid nephropathy 3. CKD secondary to urate crystal deposition C. Treatment Options for Acute Attacks 1. Nonpharmacologic a. Rest and elevate the affected joint(s). b. Ice packs

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Figure 5. Management of acute gouty attack.

Reprinted with permission from: Khanna D, Khanna PP, Fitzgerald J, et al. 2012 American College of Rheumatology guidelines for the management of gout, part 2: therapy and anti-inflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res 2012;64:1447-61.

2. Pharmacologic a. NSAIDs i. Safety and tolerability discussed previously in this chapter in the RA section ii. All NSAIDs appear equally effective. iii. Recommended as a first-line option for managing a gouty attack iv. May be recommended for use with colchicine for acute attacks v. Treatment should continue until symptoms subside (1–2 weeks).

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Patient Case 13. M.K. is a 46-year-old man with a medical history significant for chest pain with exertion, dyslipidemia, impaired fasting glucose, hypertension, obesity, and gout (one episode, 5 months ago). His current medications include simvastatin 40 mg daily, nicotinic acid (extended release) 1000 mg at bedtime, lisinopril 40 mg daily, amlodipine 5 mg daily, and aspirin 81 mg daily. He presents to his primary care practitioner’s office with symptoms consistent with gout in his left first metatarsophalangeal joint and left ankle, starting this morning. The metatarsophalangeal joint is swollen, inflamed, erythematous, and sensitive to light touch. Which is the best approach for M.K.’s therapy? A. B. C. D.

Colchicine 1.2 mg for first dose and then 0.6 mg 1 hour after and daily until symptoms resolve. Colchicine 1.2 mg for first dose and then 0.6 mg 1 hour after; also, initiate allopurinol 300 mg once daily. Colchicine 1.2 mg for first dose and then 0.6 mg every hour thereafter as tolerated. Colchicine 1.2 mg for first dose and then 0.6 mg every hour thereafter as tolerated; also, initiate allopurinol 300 mg once daily. b. Colchicine

Table 63. Colchicine STEPS

Safety

Tolerability Efficacy

Preference (Pearls) Simplicity

Doses > 4 mg may cause multiple organ failure and death Maximum daily dose 1.8 mg/day Dose adjustment not necessary when CrCl > 30 mL/min When CrCl < 30 mL/min: Do not use more than one acute treatment course every 2 wk Do not use > 0.3 mg daily for prophylaxis initially Metabolized by the CYP3A4 enzyme (elevated plasma colchicine concentrations can lead to fatal toxicity); dose adjustments for strong and moderate inhibitors and P-glycoprotein inhibitors Risk of adverse hematologic events includes myelosuppression, leukopenia, thrombocytopenia, and pancytopenia GI discomfort Diarrhea

Updated dosing strategy decreases the likelihood of adverse events without affecting efficacy Slower to work than NSAIDs for pain relief, but still at least a 50% reduction in pain at 24 hr

2 tablets/capsules (0.6 mg each x 2 = 1.2 mg) within 12 hr of onset and 1 (0.6 mg) tablet 60 min later c. Corticosteroids i. Safety and tolerability discussed previously in this chapter in the RA section ii. Excellent option for patients with acute gout and renal insufficiency iii. Prednisone is as efficacious as NSAIDs for reducing pain and discomfort. iv. Recommended dose of prednisone 0.5 mg/kg for 5–10 days with or without steroid taper v. Intra-articular corticosteroids are especially effective with large joint involvement. vi. Intra-articular formulations are superior to oral NSAIDs at 72 hours, but equal at 1 week. d. Anakinra – Off-label when conventional therapy is ineffective, contraindicated, or not tolerated. Subcutaneous: 100 mg once daily. Most patients received therapy for 3 days.

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Table 64. Anakinra STEPS

Safety

Tolerability Efficacy

Preference (Pearls) Simplicity

Increased risk of neutropenia when combined with TNF inhibitors High doses are associated with an increased risk of serious infection Diarrhea Influenza-like reaction Injection site reactions

Effective for decreasing RA symptoms, but not as effective as TNF inhibitors

Do not administer live vaccines to patients receiving anakinra Not included in the ACR recommendations or EULAR treatment recommendations because of limited data and, when available, show lesser clinical efficacy Once-daily subcutaneous injection

D. Prevention Options for Recurrent Attacks 1. Nonpharmacologic a. Adequate hydration (2 L or more of water daily) b. Discontinue diuretic therapy whenever possible. c. Moderate, low-impact exercise d. Restrict dietary animal and yeast purine intake and alcohol (especially beer). e. Avoid highly refined carbohydrates and sugars. f. Weight reduction 2. Consideration and expectations of prevention a. Consider preventive therapy in individuals with more than one acute gouty arthritis attack per year. b. Therapy goal is a serum uric acid concentration less than 5 mg/dL (with tophi) or 6 mg/dL (without tophi). c. Patients should be counseled and aware that flares may increase briefly at initiation of urate-lowering therapy (ULT). d. 2020 ACR guidelines suggest that prophylactic therapy can be initiated during an acute gouty attack if anti-inflammatory management has been started. e. 2017 American College of Physicians guidelines recommend continuing anti-inflammatory treatment for at least 8 weeks after an acute attack while initiating prophylactic treatment with allopurinol or febuxostat. 2020 ACR guidelines recommend anti-inflammatory treatment for 3–6 months while initiating ULT. f. Evaluate serum uric acid concentrations every 3 months for the first year after an attack and then annually thereafter. g. May try to discontinue agents at any time, but most patients will have at least one gouty attack (90%) during the next 10 years 3. Xanthine oxidase inhibitors a. Allopurinol (Zyloprim) b. Febuxostat (Uloric)

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Table 65. Allopurinol STEPS

Safety

Tolerability Efficacy Preference (Pearls)

Simplicity

Allopurinol hypersensitivity syndrome, which can include exfoliative dermatitis, StevensJohnson syndrome Severe cutaneous adverse reactions (SCARs) Drug reaction with eosinophilia and systemic symptoms (DRESS)

Hepatotoxicity Mucositis Renal insufficiency Thiazides decrease excretion of allopurinol Allopurinol decreases metabolism of thiopurines (azathioprine)

Elevated transaminases or alkaline phosphatase values Transient rash

Prevents recurrent gouty arthritis attacks and reduces uric acid concentrations Reduces tophi in patients with tophaceous gout

First-line agent for preventing recurrent gout and hyperuricemia Evaluate renal function for possible dose adjustments Do not discontinue therapy during an acute attack if the patient’s condition is already managed with allopurinol Start at 100 mg daily and titrate by 50–100 mg daily every 2 weeks (maximum 800 mg daily) to achieve a uric acid concentrations < 5–6 mg/dL ACR guidelines state that in patients with stage 4 CKD or worse, allopurinol therapy can be initiated at 50 mg/day, increasing the dose every 2–5 wk to achieve desired uric acid concentrations; doses > 300 mg/day are allowed but with appropriate patient education and monitoring for toxicity 2020 ACR guidelines suggest HLA-B*5801 testing for at-risk populations for allopurinol hypersensitivity syndrome (patients of Korean descent with CKD stage 3 or worse, Han Chinese descent, or Thai descent) Daily dosing OR may be divided, depending tolerability or patient preference Relatively inexpensive (< $20 a month)

Table 66. Febuxostat STEPS

Safety

Tolerability

Efficacy

Contraindicated in patients using azathioprine, mercaptopurine, or theophylline (Canada only); dose adjustments in U.S. labeling Higher incidence of CV events than in patients using allopurinol, though no causal relationship has been proven. Boxed warning added in 2018 for CV death Hepatotoxicity Arthralgias Nausea Rash Increased liver function tests

Approved to treat hyperuricemia in patients with gout Greater efficacy for reducing uric acid concentration, but no more efficacious for preventing gout flares than allopurinol (maximum dose of allopurinol in clinical trials was 300 mg

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Table 66. Febuxostat STEPS (continued)

Preference (Pearls)

Should be used as second-line ULT in patients who have an absolute contraindication to allopurinol or whose allopurinol therapy has failed Used to reduce tophi in patients with tophaceous gout Updated safety warnings for CV risks; patients with established CV disease had a higher rate of CV death when treated with febuxostat than did patients treated with allopurinol in a CV outcomes study. Febuxostat should only be used in patients who have an inadequate response to a maximally titrated dose of allopurinol, patients who are intolerant of allopurinol, or when treatment with allopurinol is contraindicated. Consider risk-benefit when prescribing or continuing febuxostat

Simplicity

Daily dosing Considerably more expensive than allopurinol (about $150–$200 per month)

ULT = urate-lowering therapy.

4. Uricosuric agent – Probenecid Table 67. Probenecid STEPS

Safety

Avoid use in patients with uric acid kidney stones May worsen existing blood dyscrasias Many drug interactions and may increase the serum concentration of target agents

Tolerability

Dyspepsia Reflux esophagitis

Efficacy

Increases urate excretion and decreases serum uric acid concentrations Efficacy may be diminished when coadministered with salicylates

Preference (Pearls)

Ineffective in patients with even mild renal insufficiency Start with low doses to reduce the likelihood of precipitating another gouty attack

Simplicity

Co-formulated with colchicine May cost $35–$100 per month (depending on daily dose and frequency)

5. Other medications a. Colchicine i. For prophylaxis of gout induced by ULT ii. Not for use as monotherapy to prevent gouty attacks iii. Give during the first 6 months of ULT. Patient Case 14. Y.W. is a 58-year-old man with a medical history significant for hypertension, type 2 diabetes, dyslipidemia, and obesity. His medications include glimepiride 2 mg daily, hydrochlorothiazide 12.5 mg daily, bisoprolol 5 mg daily, and simvastatin/ezetimibe 20/10 mg at night. During a routine laboratory evaluation, his primary care provider finds his serum uric acid concentration to be 7.3 mg/dL. Which is the most appropriate strategy to decrease the patient’s serum uric acid concentration? A. B. C. D.

Therapy is not indicated because the patient has not yet had a gouty attack. Initiate allopurinol 100 mg daily and titrate to achieve a serum uric acid concentration less than 6 mg/dL. Initiate febuxostat 40 mg daily and titrate to achieve a serum uric acid concentration less than 6 mg/dL. Initiate probenecid 500 mg twice daily and titrate to achieve a serum uric acid concentration less than 6 mg/dL.

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b. Pegloticase (Krystexxa) Table 68. Pegloticase STEPS

Safety

Tolerability

Efficacy

Preference (Pearls)

Simplicity

Contraindicated in patients with G6PD deficiency FDA black box warning regarding anaphylaxis and infusion reactions; patients should be closely monitored for at least 2 hr after infusion, though delayed reactions have been reported Risk of infusion reaction is increased when the patient’s uric acid concentration is > 6 mg/dL; consider discontinuing therapy if uric acid concentration is > 6 mg/dL, especially if it is above this limit on two consecutive occasions, because this indicates the development of antidrug antibody formation Acute gout flare within the first 3 mo of therapy Heart failure exacerbations have been reported in clinical trials (associated with fluid required for infusion) Increased risk of anaphylaxis in patients who are restarting therapy after discontinuing it for > 4 wk Bruising Chest pain Constipation Dyspnea

Erythema Nausea Pruritus Urticaria

Decreased uric acid concentrations and number of gout flares in clinical trials

Administer by IV infusion over no less than 120 min Elimination half-life is about 14 days Recommended for patients with severe gout refractory to or intolerant of conventional ULTs Begin gout flare prophylaxis (NSAIDs or colchicine) 1 wk before infusion and continue for at least 6 mo Usefulness is limited because of high rates of antidrug antibody development and risk of subsequent infusion reaction 120-min infusion (8 mg) every 2 wk

6. Patient information a. Information from National Institute of Arthritis and Musculoskeletal and Skin Diseases (www.niams. nih.gov/Health_Info/Gout/default.asp) b. Gout and Uric Acid Education Society i. Website for information and social networking ii. http://gouteducation.org/ Table 69. Drugs and Doses Reference Table Medication Name

Anakinra

Colchicine

Brand Name

Kineret

Colcrys/Mitigare

Dosing

100 mg subcutaneously once daily for 3 days

0.6 mg once or twice daily (for prophylaxis)

Allopurinol

Zyloprim

Febuxostat

Uloric

40–80 mg by mouth each day

Pegloticase

Krystexxa

8 mg IV every 2 wk

Probenecid

Starting doses: 200–300 mg by mouth each day Dose range: 50 mg every other day to 800 mg daily

250–500 mg by mouth twice daily Combination product available with colchicine 0.5 mg/500 mg

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Key Takeaways/Practice Points • All postmenopausal women older than 50 with risk factors (low BMI, previous low-trauma fracture, high-risk medication use, height loss) should undergo osteoporosis screening, and treatment should be considered in patients with osteoporosis or osteopenia with a FRAX score greater than 3% for hip fracture or greater than 20% for major fracture. • DMARDs should be initiated as soon as a diagnosis of RA is made, with methotrexate as the preferred first-line option unless contraindicated. • Low-dose corticosteroids may be used for symptomatic relief in various rheumatic diseases such as RA, PsA, and SLE; however, the lowest effective dose for the shortest duration should be used to decrease the risk of glucocorticoid-induced adverse events such as osteoporosis, infection, diabetes, and cushingoid syndrome. • Screening for infections (including tuberculosis and hepatitis C and B) should be done before initiating treatment with biologics. • Treatment options for OA include acetaminophen, systemic or topical NSAIDs, tramadol, or intra-articular injections, with choice of therapy often requiring a “trial-and-error” approach with careful consideration of adverse events associated with therapies. • Choice of therapy for fibromyalgia and gout often depends on comorbidities.

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Psoriatic Arthritis 1. DynaMed [Internet database]. Ipswich, MA: EBSCO Publishing. Available at www.www.dynamed.com. Accessed December 3, 2019. 2. Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis 2016;75:499-510. 3. Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis, section 2: psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol 2008;58:851-64. 4. Jones G, Crotty M, Brooks P. Interventions for psoriatic arthritis. Cochrane Database Syst Rev 2000;3:CD000212. 5. Mease P, Goffe BS. Diagnosis and treatment of psoriatic arthritis. J Am Acad Dermatol 2005;52:1-19. 6. Mease PJ, Gladman DD, Keystone EC. Alefacept in combination with methotrexate for the treatment of psoriatic arthritis: results of a randomized, doubleblind, placebo-controlled study. Arthritis Rheum 2006;54:1638-45.

Nijsten T, Wakkee M. Complexity of the association between psoriasis and comorbidities. J Invest Dermatol 2009;129:1601-3. Ramiro S, Radner H, van der Heijde D, et al. Combination therapy for pain management in inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis). Cochrane Database Syst Rev 2011;10:CD008886. Ravindran V, Scott DL, Choy EH. A systematic review and meta-analysis of efficacy and toxicity of disease modifying anti-rheumatic drugs and biological agents for psoriatic arthritis. Ann Rheum Dis 2008;67:855-9. Ritchlin CT, Kavanaugh A, Gladman DD, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis 2009;68:1387-94. Singh JA, Guyatt G, Ogdie A, et al. Special Article: 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis. Arthritis Care Res (Hoboken) 2019;71:2-29. Soriano ER, McHugh NJ. Therapies for peripheral joint disease in psoriatic arthritis: a systematic review. J Rheumatol 2006;33:1422-30. Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 2006;54:2665-73.

Osteoarthritis 1. Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. Choosing nonopioid analgesics for osteoarthritis: clinician summary guide. J Pain Palliat Care Pharmacother 2009;23:433-57. 2. Bannuru RR, Natov NS, Obadan IE, et al. Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis. Arthritis Rheum 2009;61:1704-11. 3. DynaMed [Internet database]. Ipswich, MA: EBSCO Publishing. Available at www.www.dynamed.com. Accessed December 3, 2019. 4. Fransen M, McConnell S, Bell M. Exercise for osteoarthritis of the hip or knee. Cochrane Database Syst Rev 2003;3:CD004286. 5. Heyneman CA, Lawless-Liday C, Wall GC. Oral versus topical NSAIDs in rheumatic diseases: a comparison. Drugs 2000;60:555-74.

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10. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain and fibromyalgia. Cochrane Database Syst Rev 2014;1:CD007115. 11. Macfarlane GJ, Kronisch C, Dean LE, et al. EULAR revised recommendations for the management of fibromyalgia. Ann Rheum Dis 2017;76:318-28. 12. Meyer BB, Lemley KJ. Utilizing exercise to affect the symptomatology of fibromyalgia: a pilot study. Med Sci Sports Exerc 2000;32:1691-7. 13. Moore RA, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012;12:CD008242. 14. Moore RA, Wiffen PJ, Derry S. Gabapentin for chronic neuropathic pain and fibromyalgia is adults. Cochrane Database Syst Rev 2014;4:CD007938. 15. Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken) 2010;62:600-10. 16. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160-72.

Hochberg MC, AltmanRD, AprilKT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res 2012;64:465-74. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2020;72:149-62. Nuesch E, Rutjes AW, Husni E, et al. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database Syst Rev 2009;4:CD003115. Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005;2:CD002946.

Fibromyalgia 1. Chakrabarty S, Zoorob R. Fibromyalgia. Am Fam Physician 2007;76:247-54. 2. DynaMed [Internet database]. Ipswich, MA: EBSCO Publishing. Available at www.www.dynamed.com. Accessed December 3, 2019. 3. Goldberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA 2004;292:2388-95. 4. Hauser W, Bernardy K, Uceyler N, et al. Treatment of fibromyalgia syndrome with antidepressants: a metaanalysis. JAMA 2009;301:198-209. 5. Hauser W, Bernardy K, Uceyler N, et al. Treatment of fibromyalgia syndrome with gabapentin and pregabalin – a meta-analysis of randomized controlled trials. Pain 2009;145:69-81. 6. Hauser W, Urrutia G, Tort S, et al. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome. Cochrane Database Syst Rev 2013;1:CD010292. 7. Holman AJ, Myers RR. A randomized, doubleblind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum 2005;52:2495-505. 8. Li YH, Wang FY, Feng CQ, et al. Massage therapy for fibromyalgia: a systematic review and metaanalysis of randomized controlled trials. PLoS One 2014;9:e89304. 9. Lump MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy or chronic pain. Cochrane Database Syst Rev 2009;4:CD007115.

Systemic Lupus Erythematosus 1. No authors listed. Guidelines for referral and management of systemic lupus erythematosus in adults: American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum 1999;42:1785-96. 2. Bertsias G, Ioannidis JP, Boletis J, et al. EULAR recommendations for the management of systemic lupus erythematosus: report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis 2008;67:195-205. 3. Bertsias GK, Tektonidou M, Amoura Z, et al.; European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association. Joint European League Against Rheumatism and European Renal AssociationEuropean Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012;71:1771-82. 4. Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late

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disease activity in systemic lupus erythematosus. Ann Rheum Dis 2008;67:841-8.

manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003;82:299-308. Costedoat-Chalumeau N, Galicier L, Aumaître O, et al. Hydroxychloroquine in systemic lupus erythematosus: results of a French multicentre controlled trial (PLUS Study). Ann Rheum Dis 2013;72:1786-92. DynaMed [Internet database]. Ipswich, MA: EBSCO Publishing. Available at www.www.dynamed.com. Accessed December 3, 2019. Griffiths B, Emery P, Ryan V, et al. The BILAG multi-centre open randomized controlled trial comparing ciclosporin vs azathioprine in patients with severe SLE. Rheumatology (Oxford) 2010;49:723-32. Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res 2012;64:797-808. Haq I, Isenberg DA. How does one assess and monitor patients with systemic lupus erythematosus in daily clinical practice? Best Pract Res Clin Rheumatol 2002;16:181-94. Madhok R, Wu O. Systemic lupus erythematosus. Am Fam Physician 2007;76:1351-3. Marmor MF, Carr RE, Easterbrook M, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. Ophthalmology 2002;109:1377-82. Mosca M, Tani C, Aringer M, et al. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis 2010;69:1269-74. Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008;358:929-39. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010;69:20-8. Wallace DJ, Kalunian K, Petri MA, et al. Efficacy and safety of epratuzumab in patients with moderate/ severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, doubleblind, placebo-controlled, multicentre study. Ann Rheum Dis 2014;73:183-90. Wright SA, O’Prey FM, McHenry MT, et al. A randomised interventional trial of omega-3-polyunsaturated fatty acids on endothelial function and

Gout and Hyperuricemia 1. DynaMed [Internet database]. Ipswich, MA: EBSCO Publishing. Available at www.www.dynamed.com. Accessed December 3, 2019. 2. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Rheumatol 2020;72:879-95. 3. Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician 1999;59:925-34. 4. Khanna D, Fitzgerald J, Khanna PP, et al. 2012 American College of Rheumatology guidelines for the management of gout, part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res 2012;64:1431-46. 5. Khanna D, Khanna PP, Fitzgerald J, et al. 2012 American College of Rheumatology guidelines for the management of gout, part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res 2012;64:1447-61. 6. Qaseem A, Harris RP, Forciea MA. Management of acute and recurrent gout: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2017;166:58-68. 7. Sivera F, Andrés M, Carmona L, et al. Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative. Ann Rheum Dis 2014:328-35. 8. Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum 2010;62:1060-8. 9. University of Texas at Austin School of Nursing, Family Nurse Practitioner Program. Management of Chronic Gout in Adults. Austin, TX: University of Texas at Austin, School of Nursing, 2012. Available at www.guideline.gov/content. aspx?id=37278. Accessed May 27, 2017. 10. Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum 1977;20:895-900. 11. Wilson JF. Gout. Ann Intern Med 2010;152:ITC2-1.

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12. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout, part II: management: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65:1312-24.

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ANSWERS AND EXPLANATIONS TO PATIENT CASES 1. Answer: C Many medications contribute to BMD loss by either accelerating bone resorption or inhibiting osteogenesis. For this patient, levothyroxine most significantly affected her BMD by speeding up the bone resorption process (Answer C is correct; Answers A, B, and D are incorrect). Excessive thyroid hormone supplementation or drug-induced hyperthyroidism places patients at risk of OA and fracture. Practitioners should be cognizant of TSH and free thyroid hormone concentrations, treating patients to a euthyroid state and a TSH concentration of around 2.0–3.0 mIU/L. This suggestion does not apply to patients who require maximal thyroid hormone suppression (i.e., have a history of thyroid cancer).

and patients do not have to adhere to strict post-dosing restrictions when using it. Risedronate is appropriate if the patient can remain upright for 30–60 minutes, but this may be too physically demanding for the patient. Romosozumab is reserved for patients as a later line option would be a poor choice for the patient. Raloxifene has a high incidence of venous thromboembolism and, in conjunction with the patient’s limited mobility, might increase her risk of a venous thromboembolism (Answer A is correct; Answers B-D are incorrect) 5. Answer: B The 2015 update to the ACR recommendations for managing RA advocate DMARD monotherapy, particularly methotrexate, for all patients regardless of their disease severity and time since symptom onset. For this patient, Answer B is correct. She may combine TNF inhibitors with methotrexate, but this would be only after she cannot achieve disease remission with methotrexate alone. Hydroxychloroquine alone is not a preferred DMARD monotherapy, and combining anakinra with methotrexate would be inappropriate; anakinra is not included in the guidelines as an appropriate biologic option because of its lack of efficacy in patients with RA (Answer B is correct; Answers A, C and D are incorrect).

2. Answer: B The patient in question has not yet had a DEXA scan or received a T-score for her lumbar spine or femoral neck. Therefore, antiresorptive therapy is unwarranted until the results are available. She should begin treatment with calcium and vitamin D to preserve BMD. If the DEXA scan reveals osteopenia (T-score between -1.0 and -2.5), bisphosphonate therapy should be initiated because the patient’s risk of hip fracture in the next 10 years is greater than 3% (Answer B is correct; Answers A, C and D are incorrect) 3. Answer: D Because the patient has an extensive history of GI disease and receives chronic therapy with a PPI, she will most likely benefit from treatment with a calcium citrate supplement. Calcium carbonate salts, when administered with an acid-suppressing agent, yield less calcium availability than a calcium citrate formulation. However, when converting from a calcium carbonate tablet to a calcium citrate tablet, the “serving size” is usually doubled, and the patient requires 2 tablets of calcium citrate to equal the elemental calcium in 1 calcium carbonate tablet (Answer D is correct; Answers A–C are incorrect) The maintenance therapy of vitamin D3 is 1000-2000 IU daily.

6. Answer: C Although the maximal studied dose of methotrexate for patients with RA can be up to 30 mg weekly, the maximal recommended dose is 25 mg weekly. If a patient reaches the 25-mg dose by mouth without sufficient clinical effect, a prescriber should reconsider the effectiveness of the current therapeutic approach. Hydroxychloroquine is not recommended as monotherapy in a patient who has not responded adequately to methotrexate. Both adalimumab and infliximab are TNF inhibitors, but only adalimumab can be used as monotherapy (between the two agents). Infliximab should always be given in combination with methotrexate (Answer C is correct; Answers A, B and D are incorrect).

4. Answer: A This patient’s inability to be mobile (and possibly upright) drastically limits her medication choices for the primary prevention of an osteoporotic fracture. Zoledronic acid seems to be the most appropriate agent because data analyses support its ability to maintain vertebral bone density,

7. Answer: C The patient should discontinue etanercept and begin therapy with abatacept. The ACR recommends abatacept for patients without an adequate rheumatologic response to methotrexate and an anti-TNF agent, which would be appropriate for this patient, especially given that she has

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alternative agents such as duloxetine, fluoxetine, or gabapentin (Answer A is correct; Answers B-D are incorrect).

tried two anti-TNF agents. Increasing and continuing prednisone may help alleviate pain, but long-term treatment with corticosteroids is not warranted for everyone, and efforts should focus on the best way to maximally suppress bone deformation. Adding another anti-TNF agent or combining abatacept with an anti-TNF agent is also not recommended due to additive risk of infection (Answer C is correct; Answers A, B and D are incorrect).

11. Answer: C This patient may benefit most from a trial of duloxetine 60 mg once daily. She has minor depressive disorder and states that some of her symptoms (sad feelings and sleep issues) have improved with the tricyclic antidepressant but that the main reason for the medication (her pain) was unaffected. When patients do not respond to first-line treatment, alternative agents should be used. The α2δ ligands (gabapentin and pregabalin) are acceptable, but her beneficial response for non-pain symptoms with the antidepressant would warrant a trial of another agent with antidepressant properties. In addition, tramadol is recommended only for patients with fibromyalgia when all other alternative agents have been tried and have failed (Answer C is correct; Answers A, B and D are incorrect).

8. Answer: D The patient presents with severe PsA with axial symptoms and requires treatment with a combination biologic and synthetic DMARD – in this case, golimumab and methotrexate. Although using either agent alone may help alleviate the symptoms, the extreme severity of the patient’s symptoms requires an aggressive treatment approach that can eventually be decreased once his symptoms are lessened with combination therapy. Systemic corticosteroids are not recommended in patients with PsA. This is an insufficient dose of burst therapy, and systemic corticosteroids should not be used as chronic maintenance therapy for controlling PsA symptoms (Answer D is correct; Answers A–C are incorrect).

12. Answer: D In this patient’s situation, adding azathioprine will offer more benefit than the other listed options. In patients with SLE and evidence of lupus-related organ damage, adding an immunologic agent is warranted when the patient lacks a sufficient response to an antimalarial agent such as hydroxychloroquine. The practice of treating patients to a serum hydroxychloroquine concentration of greater than 1000 mg/mL has not proven beneficial. In addition, using systemic corticosteroid doses greater than 10 mg daily for extended periods is not recommended. Introducing an immunologic agent is meant to control symptoms and limit the amount of systemic corticosteroid use in a patient. Although fish oil reduces disease severity scores for those with SLE, the presence of target-organ damage requires more aggressive treatment (Answer D is correct; Answers A–C are incorrect).

9. Answer: D The man in this case has moderate to severe OA of the knee that causes considerable limitations in the activities of daily living. Given his history of a myocardial infarction, ibuprofen is discouraged by the ACR for pain control because of its potential interaction to decrease the cardioprotective efficacy of aspirin. Although naproxen is recommended over ibuprofen, the patient’s heart failure could be made worse with scheduled use. The acetaminophen dose exceeds 4 g daily. The topical NSAID is appropriate for this person because of its low likelihood of adverse events and interactions with other medications and diseases (Answer D is correct; Answers A–C are incorrect).

13. Answer: A Because this patient is having an acute gouty attack, allopurinol is inappropriate. Allopurinol should be initiated at a starting dose (100 mg), but the time separating the acute attack and the prophylaxis remains unanswered (immediate vs. 1–2 weeks later). Older data analyses suggest that starting ULT during an acute attack will prolong the attack because uric acid is mobilized out of the joint space too quickly; however, newer evidence suggests this is not true, but the evidence is very limited. Therefore, many clinicians still choose to wait until the acute attack is resolved before initiating ULT. For colchicine, the maximum daily dose is

10. Answer: A Although the patient’s physical symptoms meet the criteria for diagnosing fibromyalgia (WPI score 8 and SSS estimated to be greater than 5), she has had these symptoms for only the past 4 weeks. According to the ACR, the patient must have had symptoms for at least 3 months and elevated WPI and SSS scores. If these symptoms continue, the patient will qualify for a diagnosis of fibromyalgia, and she should be treated with a tricyclic antidepressant such as amitriptyline. If she does not have sufficient pain relief or if she has adverse events, she may try one of the

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1.8 mg because of safety concerns and lack of efficacy with higher doses. The “as-tolerated” instructions for Answers C and D would place the patient at risk of overdosing and could cause the patient to have GI adverse effects and even life-threatening hematologic effects (Answer D is correct; Answers A–C are incorrect). 14. Answer: A The patient should not be treated for hyperuricemia. Patients are candidates for ULT if they have two or more attacks per year, presence of tophi, stage 2 CKD or worse, or a history of urolithiasis. One to 2 weeks after the first attack, patients may begin uric acid–lowering therapy, and they should be treated until a serum uric acid concentration of less than 6 mg/dL is attained. Until their first attack, treatment with a xanthine oxidase inhibitor or uricosuric agent is not indicated (Answer A is correct; Answers B-D are incorrect).

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ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS 1. Answer: D According to her DEXA scan results, the patient would traditionally be classified as having osteopenia in her lumbar spine. In many cases, this would require her to be treated only with calcium and vitamin D supplementation. However, because her 10-year risk of a hip fracture is greater than 3% with the FRAX tool, the NOF would consider this patient to have osteoporosis and recommend that she receive antiresorptive therapy. Of the choices, alendronate is the only agent to have antiresorptive properties, and of the two doses, 70 mg once weekly is recommended (Answer D is correct; Answers A–C are incorrect). Alendronate 35 mg once weekly is considered a prevention dose for bisphosphonates.

supplementation is warranted (Answer C is correct; Answers A, B and D are incorrect). 4. Answer: D Patients with RA receiving bDMARDs should not be administered live vaccines such as oral typhoid. The intramuscular typhoid vaccination is an inactivated vaccine and is therefore safe to administer in patients receiving bDMARDs. It is unnecessary to hold biologics before vaccination with an inactivated vaccine (Answer D is correct; Answers A–C are incorrect). 5. Answer: A For this patient, the ACR 2015 treatment recommendations encourage providers to use methotrexate as a first-line agent for patients presenting within the first 3 months of diagnosis. Although leflunomide may be an option, it is recommended as an add-on to methotrexate if monotherapy insufficiently controls the patient’s symptoms. A TNF inhibitor such as adalimumab could also be an option and would have been an option for this patient using the 2012 guideline update, but it has been moved to second line, after failure of methotrexate, for the 2015 iteration (Answer A is correct; Answers B-D are incorrect). The JAK inhibitor tofacitinib is recommended for disease-naive patients (less than 6 months) whose second-line measures fail or for disease-experienced patients (more than 6 months) in whom at least a TNF inhibitor fails.

2. Answer: D The patient should restart therapy but change to a nonbisphosphonate antiresorptive agent. Using an agent for osteoporosis for this patient is important because of her history of osteoporosis with fracture. Continuing a bisphosphonate is an option, but the likelihood of a serious adverse event (MRONJ [medication-related osteonecrosis of the jaw], atypical femur fracture) increases with duration of bisphosphonate use. Reducing the dose would not be appropriate for secondary fracture prevention. Although raloxifene is efficacious for secondary fracture prevention, its usefulness is more for preventing breast cancer in women at high risk, and it is not cost-effective to use routinely for fracture prevention. Denosumab is the best option for this patient because it will maintain the same efficacy as a bisphosphonate for fracture prevention (Answer D is correct; Answers A–C are incorrect). Unfortunately, we do not yet know whether the risk of serious adverse events is increased with the duration of sequenced medication use (i.e., bisphosphonate to RANKL inhibitor). An anabolic agent should be reserved for future use, more severe disease, lack of response, and/or contraindication to antiresorptive therapies.

6. Answer: A According to the ACR and GRAPPA, patients with minimal to no functional limitations from PsA should be treated only with NSAIDs or other analgesics. When the symptoms progress to moderate severity and affect the patient’s activities of daily living, or when the symptoms do not respond to simple analgesics, providers should consider adding either a DMARD (e.g., sulfasalazine) or a biologic agent (e.g., etanercept). Combination DMARD and biologic agent should be reserved for patients with severe disease or for those whose condition does not respond to either agent alone (Answer A is correct; Answers B-D are incorrect).

3. Answer: C According to the latest edition of the ACR’s guidelines for managing glucocorticoid-induced osteoporosis, bisphosphonates should be used for patients older than 40 with moderate fracture risk (according to Z-score) if they are using 7.5 mg or more of prednisone daily for more than 6 months. Because the patient meets these criteria, risedronate 150 mg monthly plus calcium and vitamin D

7. Answer: B For this patient, the next best choice for pain relief is topical diclofenac 1% gel. The ACR 2012 guidelines do not recommend the routine use of opiate analgesia for OA pain. In addition, given her history of ischemic heart disease, she

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stage 4 CKD or worse, allopurinol therapy can be initiated at 50 mg/day, increasing the dose every 2–5 weeks to achieve the desired uric acid concentrations; doses greater than 300 mg/day are allowed but with appropriate patient education and monitoring for toxicity (Answer B is correct; Answers A, C and D are incorrect)

should avoid using meloxicam or oral diclofenac because of an FDA report regarding NSAID use and risk of CV events. Although diclofenac gel is an NSAID, its topical application limits the amount of systemic absorption and possibly systemic adverse events (Answer B is correct; Answers A, C and D are incorrect). Patients who use topical NSAIDs are at a higher risk of dermatologic reactions than those who use systemic NSAIDs. 8. Answer: B Even though the patient has used hydroxychloroquine for less than 5 years, her current daily dose is greater than 5 mg/kg/day, placing her in a higher-risk category for hydroxychloroquine-related ocular complications. People in the major risk category should have a baseline, followed by annual, funduscopic examination. (Answer B is correct; Answers A, C and D are incorrect) 9. Answer: C The patient would best begin treatment with pregabalin 75 mg twice daily. Although all the medications listed are appropriate for treating fibromyalgia syndrome, several issues need to be considered. Nortriptyline and duloxetine would create a significant drug-drug interaction with transdermal selegiline because it inhibits both monoamine oxidase A and monoamine oxidase B (nonselective), most likely resulting in hypertensive crisis and/or serotonin syndrome. However, this is not true for oral selegiline. Oral selegiline at a dose of 5 mg twice daily maintains specificity to inhibit monoamine oxidase B, which is primarily responsible for monoamine oxidase activity in platelets and the brain. Because of this selectivity, when used at approved doses, oral selegiline and other serotonergics pose no increased risk of serotonin syndrome. The gabapentin dose is too low for the patient and would most likely not have a clinically significant change in her symptoms. The target dose for gabapentin for fibromyalgia is 1800– 2400 mg daily (divided three times). (Answer C is correct; Answers A, B and D are incorrect) 10. Answer: B The patient has CKD, thereby limiting the choice of medications and doses that can be used to prevent recurrent gouty attacks. The patient is a candidate for gout prevention and treatment of hyperuricemia. The number of attacks per year does not factor in when initiating therapy. Colchicine does not affect tophi formation. Xanthine oxidase inhibitors (allopurinol first line) are the drug of choice for patients with tophi. The ACR guidelines state that in patients with

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 365

Diabetes Mellitus Diana Isaacs, Pharm.D., FCCP, FADCES, BCPS, BCACP, CDCES, BC-ADM Cleveland Clinic Diabetes Center Cleveland, Ohio

Diabetes Mellitus

Diabetes Mellitus Diana Isaacs, Pharm.D., FCCP, FADCES, BCPS, BCACP, CDCES, BC-ADM Cleveland Clinic Diabetes Center Cleveland, Ohio

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Diabetes Mellitus

Learning Objectives 1. Identify differences between prediabetes, type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM), including differences in diagnostic criteria and clinical presentation. 2. Describe the pathophysiology of T1DM and T2DM. 3. Compare agents used in the treatment of diabetes mellitus (DM), including their mechanisms of action, adverse effects, contraindications, advantages, and disadvantages. 4. Select appropriate insulin regimens for patients on the basis of desired onset, peak, and duration of insulin effects. 5. Individualize a comprehensive glycemic treatment and monitoring plan for patients with prediabetes, DM, and gestational DM. 6. Discuss appropriate blood pressure and lipid management for patients with DM. 7. Discuss the acute and chronic complications associated with DM and the strategies used to prevent them or slow their progression.

Abbreviations in This Chapter

FBG Fasting blood glucose FDA U.S. Food and Drug Administration FPG Fasting plasma glucose FXR Farnesoid X receptor GDM Gestational diabetes mellitus GI Gastrointestinal GLP-1 Glucagon-like peptide 1 GLP-1 RA Glucagon-like peptide 1 receptor agonist HDL High-density lipoprotein cholesterol HTN Hypertension LDL Low-density lipoprotein cholesterol MACE Major adverse cardiovascular events NNT Number needed to treat NPH Neutral protamine Hagedorn OGTT Oral glucose tolerance test PCOS Polycystic ovary syndrome PCSK9 Proprotein convertase subtilisin–kexin type 9 serine protease PCV13 Pneumococcal conjugate vaccine 13 PPSV23 Pneumococcal polysaccharide vaccine SGLT2 Sodium-glucose cotransporter-2 T1DM Type 1 diabetes mellitus T2DM Type 2 diabetes mellitus TG Triglycerides UKPDS United Kingdom Prospective Diabetes Study

AACE

American Association of Clinical Endocrinology ACE American College of Endocrinology ACEI Angiotensin-converting enzyme inhibitor ACOG American Congress of Obstetricians and Gynecologists ADA American Diabetes Association ADCES Association of Diabetes Care & Education Specialists ASCVD Atherosclerotic cardiovascular disease ARB Angiotensin receptor blocker BG Blood glucose BMI Body mass index CDCES Certified Diabetes Care and Education Specialist CGM Continuous glucose monitoring CKD Chronic kidney disease CV Cardiovascular CVD Cardiovascular disease CVOT Cardiovascular Outcome Trial DCCT Diabetes Control and Complications Trial DHP-CCB Dihdyropyridine-calcium channel blocker DKA Diabetic ketoacidosis DM Diabetes mellitus DPP-4 Dipeptidyl peptidase-4 DSMES Diabetes self-management education and support eGFR Estimated glomerular filtration rate

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Domain 3: Translation of Evidence into Practice Task 1: Respond to requests for information from patients and health care professionals using evidencebased literature.

Board of Pharmacy Specialties Ambulatory Care Pharmacy Certification Domains Covered in This Chapter Domain 1: Patient-Centered Care: Ambulatory Care Pharmacotherapy Task 1: Obtain accurate and pertinent patient information, including history and physical assessment(s), to ensure the appropriate selection of therapeutic options. Task 2: Interpret patient history, laboratory, physical assessment, and other clinical information to determine if and when modifications to medication therapy are warranted. Task 3: Assess pertinent information to identify medication and non-medication–related problems to achieve specific therapeutic goals that maximize patient outcomes and response to therapy. Task 4: Assess the benefit and risks of medication and non-medication therapy for patients, considering concomitant disease states, other medications, and other patient-specific characteristics. Task 5: Create a therapeutic plan for prevention, wellness, and self-care to optimize patient outcomes. Task 6: Manage medication and disease-state therapy, including initiation, administration, modification, or discontinuation of therapy to optimize patient outcomes. Task 7: Develop patient-specific monitoring and follow-up plans to assess response to both medication and non-medication therapy, and modify to optimize patient outcomes. Domain 2: Patient-Centered Care: Collaboration and Patient Advocacy Task 1: Conduct interviews to obtain information relevant to the patient’s care. Task 2: Assess the patient’s willingness, selfmonitoring knowledge, understanding, skills, and ability to participate actively in the patient’s own care through strong patient–provider relationships to optimize care. Task 3: Implement a plan to overcome patient-specific barriers to care. Task 4: Provide education to patients on wellness, prevention, monitoring, and outcomes of medicationand disease-related issues.

Baseline Knowledge Statements Readers of this chapter are presumed to be familiar with the following: • Treatment goals for glucose, blood pressure, and lipids based on the most updated national clinical guidelines for type 2 diabetes mellitus (T2DM) • Pharmacotherapeutic options (both insulin and noninsulin) to treat T2DM, including the mechanism of action, dosing, potential adverse effects, warnings and precautions, contraindications, and monitoring guidelines • Potential complications of uncontrolled diabetes (neurologic, cardiovascular, and renal) Additional Readings The following resources have additional background information on the topics included in this chapter: • American Diabetes Association Standards of Medical Care in Diabetes - 2022. • American Association of Clinical Endocrinologists and American College of Endocrinology. Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan—2015. • American Association of Clinical Endocrinologists (AACE) Comprehensive Type 2 Diabetes Treatment Algorithm 2020. • 2020 Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients with Type 2 Diabetes. Link: https://care. diabetesjournals.org/content/44/Supplement_1 • 2021 AACE Advanced Diabetes Technology Guideline. Link: https://marlin-prod. literatumonline.com/pb-assets/Health%20Advance/ journals/eprac/EPRAC180.pdf

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Self-Assessment Questions Answers and explanations to these questions can be found at the end of the chapter.

3. Which option most appropriately lists the insulins in order from fastest acting to the longest acting? A. Degludec (Tresiba), glargine (Lantus), regular insulin, aspart (NovoLog) B. Lispro (Humalog), regular insulin, neutral protamine Hagedorn (NPH), degludec (Tresiba) C. Glargine (Lantus), detemir (Levemir), regular insulin, glulisine (Apidra) D. Regular insulin, NPH, glulisine (Apidra), glargine (Lantus)

1. P.A. is a 55-year-old woman with a history of type 2 diabetes mellitus (T2DM), hypertension (HTN), hyperlipidemia, and chronic urinary tract infections. She has tolerated metformin well but has noticed an increase in hemoglobin A1C values during the past 6–9 months. A review of blood glucose (BG) readings reveals a record of fasting blood glucose (FBG) values at 140–190 mg/dL and premeal BG values at 180–260 mg/dL. In addition, today’s laboratory values include the following: A1C 8.4%; aspartate aminotransferase (AST) 28 U/L; alanine aminotransferase (ALT) 35 U/L; serum creatinine concentration 1.4 mg/dL, and estimated glomerular filtration rate (eGFR) 52 mL/ minute/1.73 m2. The patient has a current body mass index (BMI) of 31 kg/m2, and she is concerned about weight gain with changes in her regimen. Which is the most appropriate therapeutic change for this patient?

4. G.D. is a 76-year-old woman who lives alone. She was given a diagnosis of T2DM 2 years ago. Yesterday her A1C reading was 8.5%, and her most recent eGFR value was 28 mL/minute/1.73 m2. She has a history of osteoporosis and had a hip fracture 3 years ago; she still often uses a walker for stability. Her family is concerned about hypoglycemia in anticipation of her starting DM medication. Which medication is best for this patient? A. B. C. D.

A. Discontinue metformin (Glucophage) because of poor renal function and start basal/bolus insulin. B. Add glargine (Lantus) insulin 10 units subcutaneously at bedtime to her current regimen. C. Add liraglutide 0.6 mg subcutaneously every day, with a goal of titrating to a dose of 1.8 mg every day, to her current regimen. D. Add empagliflozin 10 mg in the morning, with a goal of titrating to a dose of 25 mg, to her current regimen.

Glipizide Metformin Pioglitazone Alogliptin

5. E.C. is a 38-year-old patient with no history of HTN but a 2-year history of T2DM. Results of the previous two urine analyses have shown results with urine albumin/creatinine ratio values greater than 30 mg/dL. Which intervention is best to slow the progression of this patient’s diabetic nephropathy? A. Low-sodium diet B. Angiotensin-converting enzyme inhibitor (ACEI) C. Dihydropyridine calcium channel blocker (DHP-CCB) D. Aspirin

2. Which is the best recommendation for preventive measures and screening assessments for patients with diabetes mellitus (DM).

A. Annual: fasting lipid panel, influenza vaccine, dilated eye examination, A1C assessment B. Each visit: blood pressure assessment, urinary albumin, comprehensive foot examination C. Annual: urinary albumin, comprehensive foot examination, dilated eye examination, influenza vaccine D. Each visit: fasting lipid panel, blood pressure assessment, urinary albumin, A1C assessment

6. Which statement is the most accurate regarding the use of antiplatelet therapy in patients with DM?

A. Aspirin 325 mg once daily should be used as a secondary-prevention strategy in patients with DM and atherosclerotic cardiovascular (CV) disease. B. Dual antiplatelet therapy is recommended for patients with DM with a 10-year CV risk of greater than 10%.

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C. Aspirin 75–162 mg once daily should be used for primary prevention in patients older than 65 years with a history of renal disease. D. Aspirin 75–162 mg once daily may be considered as a primary prevention strategy in patients with DM who are at increased CV risk, after a discussion with the patient on the benefits versus increased risk of bleeding. 7. Which activity best differentiates the mechanisms of action of semaglutide compared with linagliptin?

A. Semaglutide causes a glucose-dependent increase in insulin secretion. B. Semaglutide causes a glucose-dependent decrease in glucagon secretion. C. Semaglutide increases satiety. D. Semaglutide reduces the extent of postmeal carbohydrate absorption.

8. J.C. is a 62-year-old man with a BMI of 32.5 kg/m2 who was given a diagnosis of T2DM about 5 years ago and is concerned about weight gain. He has taken oral antihyperglycemic agents since the time of diagnosis. J.C. was prescribed insulin protamine/lispro (Humalog 75/25) 40 units twice daily 5 months ago because of an increased A1C of 9.4%. Since starting therapy with Humalog 75/25, his A1C has decreased to 7.2%. However, J.C. notes that he has hypoglycemic episodes midmorning most days of the week. His BG logs show FBG values in the near-normal range. Which is the most appropriate adjustment to this patient’s therapy? A. Decrease the morning dose of Humalog 75/25 to 30 units, and keep the evening dose at 40 units. B. Increase the amount of carbohydrates eaten during breakfast. C. Stop Humalog 75/25 and start 48 units of insulin glargine daily and 6-7-7 units of insulin aspart at meals. D. Stop Humalog 75/25 and start 60 units of insulin glargine daily and 8 units of insulin aspart at meals.

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I.  GUIDELINES A. American Diabetes Association (ADA). Standards of medical care in diabetes—2022 Diabetes Care 2022;45:S1-S255 B. Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2020;43:487-93. C. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2020 executive summary. Endocr Pract 2020;26:107-39. D. Grundy SM, Stone NJ, Bailey AL, et al. 2018 ACC/AHA/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e286-350. E. Powers MA, Bardsley JK, Cypress M, et al. Diabetes self-management education and support in adults with type 2 diabetes: a consensus report of the American Diabetes Association, the Association of Diabetes Care & Education Specialists, the Academy of Nutrition and Dietetics, the American Academy of Family Physicians, the American Academy of PAs, the American Association of Nurse Practitioners, and the American Pharmacists Association. Diabetes Care 2020;43:1636-49. F. Schwartz SS, Epstein S, Corkey BE, et al. The time is right for a new classification system for diabetes: rationale and implications of the beta cell-centric classification schema. Diabetes Care 2016;39:179-86. G. Whelton P, Carey P, Aronow WS, et al. 2017 ACC/AHA guideline for prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2018;71:e127-248. H. Das SR, Everett BM, Birtcher KK, et al. 2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2020;76:1117-45. I. Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care 2019;42:731-54. J. Dickinson JK, Guzman SJ, Maryniuk MD, et al. The use of language in diabetes care and education. Diabetes Care 2017;40:1790-9. K. Grunberger G, Sherr J, Allende M, et al. American Association of Clinical Endocrinology clinical practice guideline: the use of advanced technology in the management of persons with diabetes mellitus. Endocr Pract 2021;27:505-37.

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II.  HELPFUL WEBSITES A. www.cdc.gov/diabetes/ (Centers for Disease Control and Prevention [CDC]–Diabetes Public Health Resource) B. www.diabetes.org (American Diabetes Association) C. www.aace.com (American Association of Clinical Endocrinology) D. www.niddk.nih.gov/ (National Institute of Diabetes and Digestive and Kidney Diseases) E. www.diabeteseducator.org (Association of Diabetes Care & Education Specialists [ADCES]) F. www.cdc.gov/diabetes (Centers for Disease Control and Prevention) G. www.easd.org (European Association for the Study of Diabetes) H. www.idf.org (International Diabetes Federation) I. www.diabetes.ca (Canadian Diabetes Association) J. www.diabetesincontrol.com (Diabetes in Control) K. www.jdrf.org (formerly the Juvenile Diabetes Research Foundation) L. www.diatribe.org (Diatribe) M. www.diabeteswise.org (Diabetes Wise)

III.  CLASSIFICATION (Domain 1) A. Type 1 DM (T1DM; formerly, insulin-dependent, juvenile onset): 5%–10% of all diabetes cases 1. Results from the absolute insulin deficiency typically caused by autoimmune beta-cell destruction 2. Immune-mediated and/or idiopathic etiology 3. T1DM progresses in three distinct stages a. Stage 1: autoimmune, normoglycemic, presymptomatic b. Stage 2: autoimmune, dysglycemic, presymptomatic c. Stage 3: hyperglycemic, symptomatic B. T2DM (formerly, non–insulin-dependent, adult onset): 90%–95% of all diabetes cases 1. Insulin resistance with progressive insulin deficiency associated with genetics, metabolic stress, and inflammation 2. Adults may be asymptomatic for years (50% present with diabetes-related complications at time of diagnosis) 3. Increasing diagnosis in adolescents and children

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C. Risk Factors for T2DM 1. A1C 5.7% or more, impaired fasting glucose, or impaired glucose tolerance 2. First-degree relative with T2DM 3. Overweight or obese: Body mass index (BMI) 25 kg/m2 or greater or 23 kg/m2 or greater for Asian Americans 4. High-risk ethnicity: African American, Asian American, Native American, Latino, Pacific Islander 5. Physical inactivity 6. History of gestational diabetes mellitus (GDM) 7. History of prediabetes 8. Hypertension (HTN) 140/90 mm Hg or more, or therapy for HTN 9. Triglycerides (TG) concentration (greater than 250 mg/dL) 10. High-density lipoprotein cholesterol (HDL) concentration (less than 35 mg/dL) 11. History of polycystic ovary syndrome (PCOS) 12. History of cardiovascular disease (CVD) 13. Conditions associated with insulin resistance: acanthosis nigricans D. GDM: Diabetes diagnosed during the second or third trimester of pregnancy; represents about 7% of all pregnancies, resulting in more than 200,000 cases annually 1. Women should undergo blood glucose (BG) testing at the first prenatal visit if they are known to have risk factor(s) (e.g., physical inactivity, first-degree relative with diabetes, high-risk race or ethnic group)— otherwise, at 24–28 weeks’ gestation if there is no history of diabetes. 2. For women with a history of GDM, American Diabetes Association recommends a life-long screening for the development of diabetes or prediabetes every 3 years. E. Other Classification Factors 1. Drug induced: pentamidine, corticosteroids, nicotinic acid, interferon alfa, diazoxide, thiazide diuretics, beta blockers, atypical antipsychotics, protease inhibitors 2. Endocrinopathies: acromegaly, Cushing syndrome, pheochromocytoma 3. Genetic defects of beta-cell function or insulin function: maturity-onset diabetes of the young, Donohue syndrome, Rabson-Mendenhall syndrome 4. Pancreatic exocrine disease: pancreatitis, trauma, infection, cystic fibrosis, hemochromatosis

IV.  DIAGNOSIS (Domain 1) A. Glycemic Values Confirm Diagnosis: Testing options include fasting plasma glucose (FPG), 2-hour plasma glucose during oral glucose tolerance test (OGTT), and A1C 1. Diagnosis can be obtained by two abnormal results for the same sample (i.e., FPG and A1C) or in two separate samples. a. If two different tests are available for an individual and the results are discordant, the test with the result that is above the diagnostic cut point should be repeated, and the diagnosis should be based on the confirmed test. b. However, if patient is symptomatic the diagnosis can be made without a second diagnostic test. c. The same diagnostic test can be used to diagnose prediabetes. 2. FPG test: Concentration 126 mg/dL or greater (no caloric intake for at least 8 hours) (prediabetes: FPG 100–125 mg/dL)

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3. OGTT test a. 75-g OGTT, 2-hour glucose concentration 200 mg/dL or greater (prediabetes: OGTT result of 140–199 mg/dL) b. Fewer false negatives than FPG test but more expensive and more difficult to perform 4. Symptoms associated with hyperglycemia, such as polyuria, polydipsia, polyphagia with or without weight loss, and/or blurred vision with a random plasma glucose reading of 200 mg/dL or greater 5. A1C test a. 6.5% or greater (prediabetes: A1C 5.7%–6.4%) b. National Health and Nutrition Examination Survey data analyses show that, assuming the universal screening of the undiagnosed individual, the A1C cutoff point of 6.5% or greater identifies one-third fewer cases of undiagnosed diabetes than a fasting blood glucose (FBG) cutoff point of 126 mg/dL or greater; however, the wider application of a more convenient test (A1C) can increase the number of diagnoses made. c. Point-of-care A1C assays are not tested for proficiency; therefore, they are not recommended for diagnosing. B. Diagnosis of GDM 1. Screen between weeks 24 and 28 of gestation if the patient has no diabetes risk factors. 2. Screen at first prenatal visit for a patient with even one diabetes risk factor, and, if finding is normal, repeat between weeks 24 and 28. 3. One-step strategy a. Screen with a 75-g 2-hour OGTT using the diagnostic cut points listed in Table 1. b. Measurements convey an odds ratio of an adverse maternal, fetal, or neonatal outcome of at least 1.7 compared with glucose values lower than the cut points in Table 1. c. One abnormal BG result makes the diagnosis. Table 1. Gestational DM: OGTT One-Step Diagnostic Cut Points Measurement Time

75-g Glucose Load, mg/dL

1 hr

180

Fasting 2 hr

92

153

DM = diabetes mellitus; OGTT = oral glucose tolerance test.

4. Two-step strategy a. Screen with a 50-g non-FBG load test with plasma measurement at 1 hour, at 24–28 weeks in women with no previous diagnosis of overt diabetes. b. If the plasma glucose concentration 1 hour after the load is 140 mg/dL or greater, continue to a 100-g OGTT using the diagnostic cut points listed in Table 2. c. Diagnosis is made if at least two of the four measures (fasting, 1 hour, 2 hours, and 3 hours after the OGTT) are met or exceeded.

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Table 2. Gestational DM: OGTT Two-Step Diagnostic Cut Points 100-g Glucose Load, mg/dL

Measurement Time

Carpenter/Coustan Method

NDDG Method

1 hr

180

190

3 hr

140

145

Fasting 2 hr

95

105

155

165

DM = diabetes mellitus; NDDG = National Diabetes Data Group; OGTT = oral glucose tolerance test.

5. Women with a history of GDM should be screened for diabetes 4–12 weeks postpartum using OGTT and clinically appropriate nonpregnancy criteria (and lifelong screening, at least every 3 years). Patient Case 1. A 50-year-old Hispanic woman with a medical history of GDM and obesity presents to the clinic for her annual physical examination. Her family history is significant for T2DM, affecting her parents, both sets of grandparents, and several aunts and uncles. Today her FPG concentration is 160 mg/dL. She describes no diabetes-related symptoms. Which best conveys how this patient should be medically managed? A. B. C. D.

Rescreen in 3 years. Order an OGTT before she leaves the clinic. Obtain an A1C in clinic today. Diagnose T2DM, and initiate lifestyle changes.

6. If prediabetes is confirmed at a 3-year postpartum follow-up, appropriate interventions include lifestyle modifications and/or metformin.

V.  SCREENING (Domain 1) A. T1DM 1. Screen only symptomatic patients. 2. Screening for monitoring purposes can be considered if the patient has a first-degree relative with T1DM (blood test for islet cell antibodies, insulin antibodies, and/or glutamic acid decarboxylase antibodies). 3. Research trial screening in T1DM may result in a clinical intervention if 2 or more autoantibodies are discovered during the screening process. B. T2DM 1. Test all adults age 35 years and older every 3 years 2. Consider testing earlier if overweight or obese (BMI 25 kg/m2or greater) with one or more of the risk factors for T2DM as stated in Section III: Classification. C. GDM: Section IV: Diagnosis describes screening in GDM.

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VI.  PREDIABETES (Domain 1) A. Diagnosis: described in Section IV: Diagnosis. B. Interventions for Preventing Progression to Diabetes 1. Sustained weight loss of 7% is optimal. 2. Physical activity should be increased to at least 150 minutes/week of moderate activity. 3. Medications a. Metformin may be considered in those at high risk of diabetes (A1C continues to increase regardless of lifestyle modifications, HTN, low HDL concentration, elevated TG concentration, or history of diabetes in a first-degree relative), especially those who have obesity, are younger than 60 years, or have a history of GDM. b. α-glucosidase inhibitors, orlistat, thiazolidinediones, and glucagon-like peptide 1 receptor agonist (GLP1 RA) also delay the onset of T2DM, although there are no drugs approved by the U.S. Food and Drug Administration (FDA) for the prevention of diabetes. 4. Annual monitoring is recommended. 5. Lifestyle modifications may include technology-assisted tools such as mobile apps for food and activity tracking.

VII.  DIABETES PATHOPHYSIOLOGY (Domain 1) A. T1DM: autoimmune process; destruction of insulin-secreting beta cells B. T2DM 1. Overview of defects a. Insulin resistance b. Relative insulin deficiency c. Increased hepatic glucose production d. Increased gastric emptying rate e. Neuroendocrine dysfunction i. Decreased amylin secretion ii. Impaired incretin effect 2. Many cellular defects occur in T2DM—the “Egregious Eleven” (Diabetes Care 2016;39:179-86) follow: a. Beta cell: insulin deficiency (relative or absolute) b. Muscle: insulin resistance c. Liver: increased glucose production d. Fat cell (adipocytes): accelerated lipolysis e. Incretin effect: deficient f. Colon/gut microbiome: decreased GLP-1 production g. Stomach/small intestine: increased glucose absorption h. α cell: hyperglucagonemia i. Kidney: increased glucose reabsorption j. Brain: neurotransmitter dysfunction k. Immune system: dysregulation/systemic inflammation

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3. Take-home points a. T2DM is a multi-pathophysiologic, progressive disease. b. Many drugs will be required to correct several pathophysiologic defects; this goal is best accomplished with combination therapy. c. Treatment should be based on the reversal of known pathogenic abnormalities (not just on reducing A1C values). d. Therapy must be initiated early to prevent or slow the progressive nature of the disease.

VIII.  TREATMENT GOALS (Domain 1) A. Comprehensive Diabetes Medical Evaluation: use and prioritize components of this evaluation to optimize patient outcomes B. Eliminate Symptoms, such as polyuria, polydipsia, polyphagia, and fatigue C. Prevent Acute Complications, such as hypoglycemia and diabetic ketoacidosis (DKA)/hyperglycemic hyperosmolar state D. Prevent Chronic Complications, such as microvascular and macrovascular E. Attain Glycemic Goals 1. Patient-specific 2. In most cases, A1C of less than 7% (defined by American Diabetes Association [ADA]) or 6.5% (American College of Endocrinology [ACE]/American Association of Clinical Endocrinology [AACE]) 3. Less stringent goal of A1C is less than 7.5%–8% a. Severe hypoglycemia b. Limited life expectancy c. Advanced complications (e.g., moderate to severe renal dysfunction) d. Extensive comorbid conditions e. Uncontrolled DM despite appropriate management, including self-management and medication 4. Consider A1C goal less than 8.5% a. Older adults with diabetes and very complex/poor health i. Long-term care of end-stage chronic illness ii. Moderate to severe cognitive impairment iii. Dependency on others for two or more activities of daily living 5. More stringent goal of A1C less than 6%–6.5% a. Short disease duration b. Long life expectancy c. No significant CVD d. Managed with lifestyle changes with or without metformin or other medications that are not expected to cause hypoglycemia 6. Preprandial BG concentration: 80–130 mg/dL (ADA); less than 110 mg/dL (ACE/AACE); less than 95 mg/dL for patients with GDM (American Congress of Obstetricians and Gynecologists [ACOG]) 7. Postprandial BG concentration (1–2 hours after initiation of meal): less than 180 mg/dL (ADA); 2 hours after initiation of meal less than 140 mg/dL (ACE/AACE); 1 hour less than 140 mg/dL, 2 hours less than 120 mg/ dL for patients with GDM (ACOG) ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 380

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8. Monitor A1C every 3 months until individualized A1C goal is attained; then can decrease monitoring to twice a year 9. Time in range a. Greater than 70% time in range of 70–180 mg/dL is recommended for most people with T1DM or T2DM with less than 4% time spent below range (glucose less than 70 mg/dL). b. Greater than 50% time in range at 70–180 mg/dL is recommended for those at higher risk of hypoglycemia and less than 1% time spent below range (glucose less than 70 mg/dL). c. Greater than 70% time in range of 63–140 mg/dL is recommended in pregnancy with preexisting T1DM with less than 4% time spent below 63 mg/dL.

IX.  TREATMENT (Domain 3) A. Nonpharmacologic Treatment 1. Weight management a. Weight reduction in individuals with obesity will reduce all CVD risk factors associated with T2DM and will improve hyperglycemia. b. Weight loss i. Measure height and weight and calculate BMI at least annually. ii. Greater than 5% weight loss is recommended in those who have overweight or obesity. iii. Benefits in control of diabetes and CV risk factors are often greater from even more weight loss. 2. Medical nutrition therapy a. Associated with the following A1C reductions: i. T1DM: 1.0–1.9% ii. T2DM: 0.3–2.0% b. Requires an individualistic approach with regard to macronutrient distribution (i.e., protein, fat, carbohydrates) c. Identify total energy intake to achieve body weight goals. d. Macronutrient distribution: no specific percentage required, and a variety of eating patterns can be considered i. Reducing overall carbohydrate intake has the most evidence for improved glycemia. e. Avoid both sugar-sweetened and nonnutritive-sweetened beverages, and increase water consumption. f. Ample intake of dietary fiber (14 g/1000 calories), ideally 50 g or greater per day to provide additional A1C reduction g. Alcohol limitation: 1 drink daily for women; 2 drinks daily for men h. Blood pressure attainment: reduction in sodium intake to 1500–2300 mg/day 3. Diabetes self-management education and support (DSMES) a. All people with diabetes should participate in DSMES and receive the support needed to facilitate the knowledge, decision-making, and skills mastery necessary for diabetes self-care. b. Reduces emergency department visits, hospital admissions, hypoglycemia, and all-cause mortality c. Lowers A1C 4. Physical activity a. Adults with diabetes should be advised to engage in moderate-intensity aerobic physical activity for at least 150 minutes/week (50%–70% of maximum heart rate), spread over at least 3 days/week with no more than 2 consecutive days without exercise. b. Reduce sedentary time, particularly by breaking up extended amounts of time spent sitting

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c. For long-term maintenance of major weight loss, more exercise (7 hours of moderate or vigorous aerobic physical activity per week) may be helpful. d. In absence of contraindications, adults with T2DM should be encouraged to perform resistance training at least twice per week. 5. Metabolic surgery a. Consider if BMI is 30.0 kg/m2 or greater (27.5 kg/m2 or greater for Asian Americans). b. Recommended if BMI is 40 kg/m2 or greater (37.5 kg/m2 or greater for Asian Americans) c. AACE recommends bariatric surgery for patients with a BMI of 35 kg/m2 or greater with comorbidities. B. Approach to Pharmacologic Management of T2DM 1. Treatment initiation based on patient-specific factors a. Unless contraindicated, initiate metformin as monotherapy, or consider the following: b. Consider dual therapy (metformin plus another agent) if A1C is more than 1.5% above individualized glycemic target. c. Consider insulin therapy if: i. BG concentrations greater than 300 mg/dL ii. A1C greater than 10% iii. Symptoms of hyperglycemia (polyuria, polydipsia) or evidence of catabolism (weight loss) 2. Treatment progression, if A1C goals are unmet after treatment initiation a. If no risk of atherosclerotic cardiovascular disease (ASCVD) and if A1C targets are not attained with 3 months of monotherapy i. Add a second antihyperglycemic agent. ii. If A1C targets are not met with 3 months of dual therapy, step up therapy with an additional antihyperglycemic agent. iii. Each medication addition should be made with careful consideration of drug- and patient-specific factors. b. If ASCVD risk, recommend one of the following as a second antihyperglycemic agent in addition to metformin plus lifestyle modifications independent of A1C on the basis of patient-specific factors: i. Glucagon-like peptide-1 (GLP-1) agonist with proven CVD benefit (dulaglutide, semaglutide, liraglutide) ii. Sodium-glucose cotransporter-2 (SGLT2) inhibitor with proven CVD benefit (canagliflozin, dapagliflozin, empagliflozin) iii. If A1C targets not met with 3 months of dual therapy, step up therapy with an additional antihyperglycemic agent. c. If heart failure or chronic kidney disease (CKD) is predominant, recommend an SGLT2 inhibitor with evidence of reducing heart failure and/or CKD progression if estimated glomerular filtration rate (eGFR) is adequate independent of A1C. i. Heart failure: Canagliflozin, dapagliflozin, empagliflozin, ertugliflozin ii. CKD: Canagliflozin, dapagliflozin, empagliflozin d. Compelling need to minimize hypoglycemia i. Dipeptidyl peptidase-4 (DPP4) inhibitor ii. GLP-1 RA iii. SGLT2 inhibitor iv. Thiazolidinedione e. Compelling need to minimize weight gain or promote weight loss i. GLP-1 RA ii. SGLT2 inhibitor

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f. Cost is a major issue i. Sulfonylurea ii. Thiazolidinedione iii. Lowest cost insulin 3. Include lifestyle modifications at each phase in therapy, including referral to a diabetes care and education specialist for DSMES.

Figure 1. Combination injectable therapy for type 2 diabetes.

ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CVD = cardiovascular disease; CVOTs = cardiovascular outcomes trials; DPP-4i = dipeptidyl peptidase 4 inhibitor; eGFR = estimated glomerular filtration rate; GLP-1 RA = glucagon-like peptide1 receptor agonist; HF = heart failure; SGLT2i = sodiumglucose contransporter 2 inhibitor; SU = sulfonylurea; T2D = type 2 diabetes; TZD = thiazolidinedione.

Used with permission from American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022 [position statement]. Diabetes Care 2022:45(Supplement_1):S125–S143.

C. Pharmacologic Treatment for T1DM 1. Insulin (basal-bolus regimen) 2. Amylin analogues (pramlintide) 3. Other agents used for T2DM (i.e., metformin) are sometimes used off-label such as if BMI is greater than 25 kg/m2.

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D. Pharmacologic Treatment for GDM 1. Insulin is preferred. 2. Glyburide 3. Metformin E. Pharmacologic Treatment for T2DM 1. Biguanides 2. GLP-1 RA 3. SGLT2 inhibitors 4. Sulfonylureas 5. Meglitinides 6. Thiazolidinediones 7. DPP-4 inhibitors 8. α-glucosidase inhibitors 9. Bile acid sequestrant 10. Dopamine agonist 11. Amylin analog 12. Insulin (basal, bolus, mixed) F. Biguanides: Metformin (Glucophage, Riomet, Glucophage XR, Glumetza, Fortamet) 1. Mechanism of action a. Primarily inhibits hepatic glucose production b. Secondarily, some improvement in peripheral insulin resistance by increasing peripheral glucose uptake and use c. Can decrease intestinal absorption of glucose (small intestine) 2. Efficacy a. Optimal first-line drug unless contraindicated b. A1C reduction of 1%–2% c. Primarily reduces FPG values d. Secondary failure rate of 5%–10% per year 3. Dose a. 500 mg once or twice daily with food to start (decrease gastrointestinal [GI] adverse effects); increase dose by 500 mg/day at weekly intervals b. Maximum dose: 2550 mg/day c. Clinical maximum effective dose: 2000 mg/day d. Dosing adjustments for renal function i. All patients should have an eGFR measured before starting metformin ii. Contraindicated in patients with eGFR less than 30 mL/minute/1.73 m2 iii. Not recommended to start in patients with eGFR of 30–45 mL/minute/1.73 m2 (a) If eGFR is 30–45 mL/minute/1.73 m2 while taking metformin, the risk versus benefit of continuing metformin should be assessed. (b) Using one-half the maximum dose and monitoring renal function every 3 months can also be considered. iv. Obtain an eGFR annually in all patients, and more often for patients at increased risk of developing renal impairment (i.e., 65 or older)

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4. Adverse effects a. Common: nausea, vomiting, diarrhea (especially early) b. Uncommon: macrocytic anemia (caused by vitamin B12 deficiency); lactic acidosis (uncommon but life threatening) 5. Monitoring: A1C values, renal function, hemoglobin, hematocrit, vitamin B12 concentration 6. Contraindications a. Renal disease or renal dysfunction suggested by eGFR less than 30 mL/minute/1.73 m2; creatinine cutoffs no longer suggested b. Known hypersensitivity to metformin hydrochloride c. Acute or chronic metabolic acidosis, including DKA, with or without coma d. Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin; therefore, in patients with an eGFR of 30–60 mL/minute/1.73 m2 for whom any such study is planned, metformin should be discontinued temporarily before or at the time of the procedure, withheld for 48 hours after the procedure, and reinitiated only after renal function has been reevaluated and found to be normal. 7. Advantages a. Improved microvascular and macrovascular outcomes (United Kingdom Prospective Diabetes Study [UKPDS]) b. No hypoglycemia as monotherapy c. Weight neutral or loss d. High initial response rate e. Positive lipid effects f. Inexpensive g. Can induce ovulation in women with PCOS 8. Disadvantages a. GI adverse effects are common. i. These adverse effects occur early, especially if dose is not slowly titrated or if the patient does not take immediate-release formulation with food. ii. Consider an extended-release formulation if patient cannot tolerate immediate release. b. Dependence on renal function c. Vitamin B12 deficiency, requires periodic monitoring 9. Recommended for pre-diabetes: BMI of 35 kg/m2 or greater, age 60 years or older, history of GDM, increasing A1C despite lifestyle modifications G. GLP-1 RAs 1. Mechanism of action: synthetic analogs of human GLP-1 with resultant supraphysiologic (pharmacologic) incretin values, causing the following: a. Glucose-dependent increase in insulin secretion b. Glucose-dependent inhibition of glucagon secretion c. Reduced gastric emptying d. Increased satiety 2. Efficacy a. A1C reduction of 0.5%–1.5% with short-acting agonist b. A1C reduction of 0.8%–1.8% with long-acting agonist c. Primarily a postprandial glucose reduction short-acting agonist d. Mixed postprandial BG and FPG reduction with long-acting agonist

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 385

Diabetes Mellitus

3. Dose a. Exenatide (Byetta) i. Indications: Adults with T2DM for glycemic control ii. 5 mcg subcutaneously twice daily 1–60 minutes before meals iii. Inject into thigh, abdomen, or upper arm. iv. Increase to 10 mcg before breakfast and dinner after 4 weeks as tolerated. v. Not recommended when creatinine clearance (CrCl) is less than 30 mL/minute b. Liraglutide (Victoza) i. Indications: (a) FDA approved in ages 10 years and older for glycemic control (b) To reduce risk of major adverse CV events (CV death, nonfatal myocardial infarction, or nonfatal stroke) in adults with T2DM and established CVD ii. 0.6 mg subcutaneously once daily independent of meals or time of day (treatment initiation not intended for glycemic control). After 1 week, increase the dose to 1.2 mg daily. iii. Inject into thigh, abdomen, or upper arm. iv. If additional glycemic control is required, increase the dose to 1.8 mg daily after at least 1 week of treatment with the 1.2-mg daily dose. v. A 3.0-mg formulation (Saxenda) is also available that is FDA approved for weight management independent of a diabetes diagnosis. vi. No dosage adjustment for renal impairment, limited data for end-stage renal disease c. Lixisenatide (Adlyxin) i. Indications: Adults with T2DM for glycemic control ii. Initiate at 10 mcg subcutaneously once daily for 14 days within 1 hour before the first meal of the day. iii. Inject into the thigh, abdomen, or upper arm. iv. On Day 15, increase dosage to 20 mcg once daily. v. Use caution if eGFR is less than 30 mL/minute/1.73 m2; avoid if eGFR is less than 15 mL/minute/1.73 m 2. d. Exenatide extended release (Bydureon) i. Indications: Ages 10 years and older for glycemic control ii. 2 mg subcutaneously once weekly independent of meals or time of day iii. Inject into thigh, abdomen, or upper arm. iv. Not recommended when CrCl is less than 30 mL/minute e. Dulaglutide (Trulicity) i. Indications: (a) Adults with T2DM for glycemic control (b) To reduce the risk of MACE in adults with T2DM who have established CVD or multiple CV risk factors ii. 0.75 mg subcutaneously once weekly independent of meals or time of day iii. Inject into thigh, abdomen, or upper arm. iv. If additional glycemic control is needed, increase the dose at 4-week intervals to 1.5 mg, 3.0 mg, and 4.5 mg, respectively. The max dose is 4.5 mg weekly. f. Semaglutide (Ozempic) i. Indications: (a) Adults with T2DM for glycemic control (b) To reduce risk of MACE in adults with T2DM and establishd CVD ii. 0.25 mg subcutaneously independent of mealtimes once weekly for 4 weeks (treatment initiation not intended for glycemic control), then increase to 0.5 mg weekly for 4 weeks

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4.

5.

6.

7.

iii. A 2.4 mg dose is available for weight management independent of diabetes diagnosis. (Wegovy) iv. If BG remains above target, may increase to max dose 1 mg weekly g. Oral semaglutide (Rybelsus) i. Indications: Adults with T2DM for glycemic control ii. 3 mg by mouth for first 30 days (treatment initiation not intended for glycemic control); then increase to 7 mg by mouth daily iii. If BG remains above target, may increase to max dose of 14 mg daily after 30 days on the 7-mg dose iv. Must take 30 minutes before eating with up to 4 oz of water v. Take separately from all other medications. vi. Must keep in original blister pack before use Adverse effects a. Nausea b. Vomiting c. Diarrhea d. Headache e. Injection-site nodule (exenatide extended release) f. Rare: pancreatitis, renal dysfunction g. Risk of retinopathy Contraindications a. Gastroparesis b. For twice-daily and weekly exenatide only: eGFR less than 30 mL/minute/1.73 m2 c. For liraglutide, weekly exenatide, semaglutide, and dulaglutide only: i. Personal or family history of medullary thyroid carcinoma ii. Patients with multiple endocrine neoplasia syndrome type 2 Advantages a. Weight loss b. Convenient dosing c. Beta cell-sparing effect d. No hypoglycemia as monotherapy e. ASCVD benefits (liraglutide, dulaglutide, semaglutide) f. ASCVD neutral (exenatide LAR, lixisenatide) g. Pediatric indication approved in ages over 10 years (liraglutide, exenatide ER) Disadvantages a. Increased risk of adverse effects in renal insufficiency b. Acute risk of pancreatitis c. Black box warning: thyroid C cell tumors associated with liraglutide, dulaglutide, semaglutide, and exenatide extended release d. High cost

H. SGLT-2 Inhibitors 1. Mechanism of action: SGLT-2 is responsible for most of the reabsorption of filtered glucose from the tubular lumen. SGLT-2 inhibition decreases reabsorption of filtered glucose, lowers renal glucose threshold, and increases urinary excretion of glucose. 2. Efficacy a. A1C reduction of 0.8%–1.2% b. Mixed effect: lowers both postprandial and fasting hyperglycemia c. Limited glucose lowering efficacy when eGFR is less than 45

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3. Dose a. Canagliflozin (Invokana) i. Indications: (a) Type 2 diabetes as adjunct to diet and exercise to improve glycemic control (b) To reduce risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) in adults with T2DM and established CVD (c) To reduce risk of end-stage kidney disease, doubling of serum creatinine, CV death, and hospitalization for heart failure in adults with T2DM and diabetic nephropathy with albuminuria greater than 300 mg/day ii. 100–300 mg before the first meal of the day if eGFR 60 mL/minute/1.73 m2 or greater iii. 100 mg daily if eGFR 30 to less than 60 mL/minute/1.73 m2 iv. Initiation not recommended when eGFR is less than 30; however, patients with albuminuria greater than 300 mg/day may continue 100 mg once daily to reduce the risk of end-stage kidney disease, doubling of serum creatinine, CV death and hospitalization for heart failure. v. Not recommended with end-stage renal disease or hemodialysis b. Dapagliflozin (Farxiga) i. Indications: (a) T2DM as adjunct to diet and exercise to improve glycemic control (b) To reduce risk of hospitalization for heart failure in adults with T2DM and established CVD or with multiple CVD risk factors (c) To reduce risk of CV death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction (d) To reduce the risk of sustained eGFR decline, end-stage kidney disease, CV death, hospitalization for heart failure in adults with CKD at risk of progression ii. 5–10 mg before the first meal of the day for glycemic control, 10 mg for all other indications iii. Not recommended to be initiated with eGFR less than 25 mL/minutes/1.73 m2; however, patients may continue 10 mg orally once daily to reduce the risk of eGFR decline, end-stage kidney disease, CV death, and hospitalization for heart failure iv. Contraindicated with dialysis c. Empagliflozin (Jardiance) i. Indications: (a) T2DM as adjunct to diet and exercise to improve glycemic control (b) To reduce risk of CV death in adults with T2DM and established CVD (c) To reduce risk of CV death plus hospitalization for heart failure in adults with HF and reduced ejection fraction ii. 10–25 mg before the first meal of the day iii. Not recommended to be initiated if eGFR less than 30 mL/minute/1.73 m2 iv. Contraindicated in dialysis d. Ertugliflozin (Steglatro) i. Indication: T2DM as adjunct to diet and exercise to improve glycemic control ii. 5–15 mg before the first meal of the day if eGFR 60 or greater; iii. Initiation not recommended in patients with eGFR less than 45 mL/minute/1.73 m2 iv. Contraindicated in patients with eGFR less than 30 mL/minute/1.73 m2 4. Adverse effects a. Hypotension b. Hyperkalemia c. Genital mycotic infections d. Urinary tract infections, including urosepsis

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 388

Diabetes Mellitus

e. Increased urination/volume depletion f. DKA including euglycemic DKA 5. Advantages a. Specific mechanism of action b. No hypoglycemia with monotherapy c. Weight loss d. Blood pressure lowering e. ASCVD benefits i. Canagliflozin – reduces risk of 3-point major adverse cardiovascular events (MACE), hazard ratio (HR) 0.86 (0.75–0.97) (CANVAS). ii. Dapagliflozin – did not reduce 3-point MACE, but did decrease CV death and hospitalization for heart failure, HR 0.83 (0.73–0.95) (DECLARE-TIMI 58) iii. Empagliflozin – reduces risk of cardiovascular death, HR 0.62 (0.49–0.77) and 3-point MACE, HR 0.86 (0.74–0.99) (EMPA-REG). iv. Ertugliflozin is noninferior to placebo with respect to MACE (VERTIS-CV). f. Renal benefits i. Canagliflozin – reduced composite end point (end-stage renal disease, doubling of SCr, renal death, or CV death), HR 0.70 (0.59–0.82), number needed to treat (NNT) 23 (CREDENCE). ii. Dapagliflozin – reduced composite end point (decrease in eGFR of 50%, end-stage renal disease, or death from renal or CV causes), HR 0.61 (0.51–0.72), NNT 19 (DAPA-CKD) iii. Empagliflozin – reduced risk of incident or worsening nephropathy (composite of progression to urinary albumin excretion greater than 300 mg/day, doubling of SCr, end-stage renal disease, or death from end-stage renal disease) by 39% (EMPA-REG) iv. Ertugliflozin – no renal benefits observed in the VERTIS-CV trial g. Heart failure benefits i. Canagliflozin – reduces hospitalization rates in heart failure HF 0.67 (0.52–0.87) CANVAS plus CANVAS-R ii. Dapagliflozin – reduces hospitalization rates and CV death in heart failure, HR 0.74 (0.65–0.85), NNT 21 (DAPA-HF) iii. Empagliflozin – reduces hospitalization rates and CV death in heart failure in those with reduced ejection fraction, HR 0.75 (0.65–0.86) (EMPEROR-Reduced). Empagliflozin reduced combined risk of CV death or hospitalization for heart failure in patients with heart failure and preserved ejection fraction with and without diabetes, HR 0.79 (0.69–0.90) (EMPERER-Preserved) iv. Ertugliflozin – reduces hospitalization rates in heart failure, HR 0.70 (0.54–0.90) (VERTIS-CV) 6. Disadvantages a. Adverse effects (mycotic infections) b. Potential for increased risk of lower limb amputations with canagliflozin; black box warning added in 2017 but removed in 2020; avoid in patients with peripheral vascular disease c. Decreased bone mineral density (canagliflozin); increased risk of factures d. Increased LDL e. Cost 7. Precautions/Contraindications a. Euglycemic DKA b. Orthostatic hypotension c. Less glucose lowering in renal impairment d. Temporarily discontinue SGLT2 inhibitors before any scheduled surgery to avoid potential risk of DKA.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 389

Diabetes Mellitus

I. Sulfonylureas 1. Mechanism of action: stimulates insulin secretion from the beta-cells by binding to the adenosine triphosphatedependent potassium channel receptors, which depolarizes the cell membrane and opens a calcium channel, resulting in an increase in intracellular calcium concentration causing insulin to be released, regardless of ambient glucose concentration. 2. Efficacy a. A1C reduction of 1%–2% b. Reduces postprandial BG greater than FBG (mixed effect) c. 50% of the maximum dose accounts for 80% of the drug efficacy d. A 5%–10% primary failure rate (defined as the disease does not respond to therapy); 5%–10% per year secondary failure rate (subsequent loss of response to therapy after an initial response) 3. Dose a. First-generation agents seldom used (chlorpropamide, tolazamide, tolbutamide) b. Second-generation agents i. Glipizide (Glucotrol, Glucotrol XL) (a) 2.5–40 mg/day (taken once [Glucotrol XL] or twice daily; 20 mg maximum clinical effective dose) (b) Sulfonylurea of choice in renal insufficiency (c) Initiate at 2.5 mg/day to reduce the risk of hypoglycemia. ii. Glimepiride (Amaryl) (a) 1–8 mg/day (once daily) (b) Initiate at 1 mg/day to reduce the risk of hypoglycemia. iii. Glyburide (DiaBeta, Glynase) (a) 1.25–20 mg/day (once or twice daily) (b) Avoid in renal insufficiency (c) Avoid in people over 65 years iv. Titrate dose weekly on the basis of BG response 4. Adverse effects a. Hypoglycemia b. Weight gain c. Less common: rash, photosensitivity, dyspepsia, nausea, headache 5. Precautions a. Severe liver or kidney disease (glipizide is the sulfonylurea of choice in renal insufficiency) b. Hypoglycemia unawareness 6. Contraindications a. Hypersensitivity b. DKA c. T1DM 7. Advantages a. Works quickly (within hours) b. High initial response rate c. Neutral for major adverse cardiovascular events: CAROLINA trial d. Inexpensive 8. Disadvantages a. Hypoglycemia, especially in older adults b. Weight gain c. Durability (efficacy) often wears off over time (e.g., 5–10 years)

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 390

Diabetes Mellitus

J. Meglitinide 1. Mechanism of action is similar to that of sulfonylureas by stimulating insulin secretion from the pancreas in a glucose-independent manner; however, meglitinide has a more rapid onset and shorter duration than sulfonylureas. 2. Efficacy a. A1C reduction of 0.5%–1% (greater with repaglinide than with nateglinide) as monotherapy or add-on therapy b. Reduces postprandial BG values 3. Dose a. Repaglinide (Prandin) i. Initiate at 0.5–1 mg at 1–15 minutes before meals. ii. Maximum daily dose 16 mg; 4 mg four times daily iii. Initiate at 0.5 mg if eGFR less than 30 mL/minute/1.73 m2. b. Nateglinide (Starlix) i. 60 or 120 mg before meals ii. Initiate at 60 mg if eGFR less than 30 mL/minute/1.73 m2. c. Mealtime (e.g., three times daily) dosing 4. Adverse effects a. Hypoglycemia (less than with sulfonylurea but greater if taken without a meal) b. Weight gain (less than with sulfonylurea) 5. Contraindications a. DKA b. Repaglinide use with gemfibrozil 6. Advantages a. Rapid onset of action b. Less hypoglycemia and weight gain than with sulfonylurea c. Targets postprandial glucose values 7. Disadvantages a. Hypoglycemia b. Weight gain c. Secondary failure d. Need for multiple dosing (can reduce adherence) K. Thiazolidinediones 1. Mechanism of action: peroxisome proliferator-activated receptor γ agonists; results in an increase in insulindependent glucose disposal (insulin sensitivity) in skeletal muscle and adipocytes (primarily) and a decrease in hepatic glucose production (secondarily) 2. Efficacy a. A1C reduction of 0.8%–1.5% b. Primarily targets FPG values (modest decrease in postprandial glucose) c. Delayed onset of action before glycemic effect is observed; maximum effect 8–12 weeks d. Increases HDL concentration (pioglitazone and rosiglitazone) and lowers TG concentration (pioglitazone) 3. Dose a. Pioglitazone (Actos): 15–45 mg once daily b. Rosiglitazone (Avandia): 1–2 mg/day, up to 8 mg/day (twice-daily dosing is more effective) i. U.S. FDA restricted access program on September 23, 2010, created restrictions as part of an FDA Risk Evaluation and Mitigation Strategy. ii. Restrictions were based on data from meta-analyses that suggest an elevated risk of myocardial infarction in patients treated with rosiglitazone. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 391

Diabetes Mellitus

4.

5.

6.

7.

iii. In 2013, FDA removed prescribing and dispensing restrictions because reevaluation of rosiglitazone data showed no statistically significant increase in myocardial infarction with rosiglitazone compared with metformin and sulfonylureas. iv. In 2015, FDA removed the Risk Evaluation and Mitigation Strategy for all products containing rosiglitazone. v. In practice, rosiglitazone is rarely used because it is only available as a brand name (more expensive), and its negative reputation from previous FDA restrictions. Adverse effects a. Weight gain b. Fluid retention, which is usually seen with use of concomitant insulin, nonsteroidal anti-inflammatory agents, glucocorticoids, or dihydropyridine calcium channel blockers (DHP-CCBs) c. Heart failure exacerbation d. “Atypical” (hands and feet) bone fractures (pioglitazone) in postmenopausal women; proximal bone fractures (women more often than men) e. Rare hepatotoxicity f. Concerns of potential cause of bladder cancer (pioglitazone) g. Rare macular edema Contraindications and precautions a. Precautions i. Alanine aminotransferase concentration greater than 2.5-fold, the upper limit of normal (unless nonalcoholic steatohepatitis) ii. History of or risk factors for bladder cancer (pioglitazone) iii. Class I and II heart failure b. Contraindications i. Hypersensitivity ii. Class III and IV heart failure Advantages a. No hypoglycemia as monotherapy b. Favorable metabolic effects for pioglitazone (e.g., increased HDL, decreased TG, and decreased plasminogen activator inhibitor-1 values) c. Potential beta cell-sparing (maintain viability of beta cell function) effect d. Can induce ovulation in women with PCOS e. Macrovascular benefits (pioglitazone) in patients with prediabetes (N Engl J Med 2016;374:1321-31) f. Benefits in nonalcoholic steatohepatitis (NASH) – pioglitazone (Clin Gastroenterol Hepatol 2018;16:558. e2-566.e2) Disadvantages a. Delayed onset of action; maximum effect 8–12 weeks b. Black box warning: Heart failure with pioglitazone and rosiglitazone c. Increase in low-density lipoprotein cholesterol (LDL) with rosiglitazone d. Can use in renal insufficiency; but not recommended because of the risk of fluid retention e. Liver function test monitoring recommended before starting therapy and periodically thereafter f. Pioglitazone linked to bladder cancer g. Associated with bone fractures h. Weight gain

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 392

Diabetes Mellitus

L. DPP-4 Inhibitors 1. Mechanism of action: inhibits the enzyme DPP-4 from breaking down endogenous GLP-1, resulting in the following: a. Glucose-dependent increase in insulin secretion b. Glucose-dependent inhibition of glucagon secretion 2. Efficacy a. A1C reduction of 0.6%–0.8% b. Primarily reduces postprandial glucose 3. Dose a. Sitagliptin (Januvia) i. 100 mg once daily ii. Decreased dosage in renal insufficiency (a) 50 mg/day for eGFR 30–50 mL/minute/1.73 m2 (b) 25 mg/day for eGFR less than 30 mL/minute/1.73 m2 b. Saxagliptin (Onglyza) i. 5 mg once daily ii. Decreased dosage in renal insufficiency: 2.5 mg/day for eGFR 50 mL/minute/1.73 m2 or less c. Linagliptin (Tradjenta) i. 5 mg once daily ii. No dosage adjustment required in renal or hepatic insufficiency d. Alogliptin (Nesina) i. 25 mg once daily ii. Decreased dosage in renal insufficiency (a) 12.5 mg for eGFR 30–60 mL/minute/1.73 m2 (b) 6.25 mg for eGFR less than 30 mL/minute/1.73 m2 4. Adverse effects a. Placebo-like incidence of adverse effects (upper respiratory tract infection, headache, GI distress) 5. Advantages a. Used in renal insufficiency with appropriate dosing b. Weight neutral c. Placebo-like adverse effect profile d. Potential beta cell-sparing effect 6. Disadvantages a. Acute pancreatitis b. Joint pain c. Saxagliptin and alogliptin associated with potential risk of heart failure 7. Cautions a. History of pancreatitis; caution in patients with several risk factors for pancreatitis b. Increased risk of hospital admission for heart failure (saxagliptin and alogliptin)

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 393

Diabetes Mellitus

Patient Case 2. A 65-year-old woman with a medical history of osteopenia and T2DM that was diagnosed about 3 years ago is currently treated with vitamin D3 and metformin. The patient notes that her postprandial blood glucose values range from 180–240 mg/dL. She has a seafood allergy, no known drug allergies, and normal organ function. She states that she will never try insulin because she fears needles. Which medication should be added to the patient’s current therapy? A. B. C. D.

Sitagliptin Liraglutide Canagliflozin Pioglitazone

M. α-Glucosidase Inhibitors 1. Mechanism of action: inhibits the enzyme α-glucosidase, found along the brush border of the small intestine, which is responsible for the breakdown of complex carbohydrates into glucose, thus delaying and reducing postmeal carbohydrate absorption and postprandial BG values 2. Efficacy a. A1C reduction of 0.5%–1% b. Reduces postprandial BG values c. Mealtime (e.g., three times daily) dosing, which may reduce adherence 3. Dose a. Acarbose (Precose) i. Administer as 25 mg with first bite of meal. ii. Start once daily and then increase weekly to twice daily; then take three times daily with meals to decrease GI adverse effects. iii. Typical maintenance dose is 50–100 mg with meals; maximum daily dose for 60 kg or less is 50 mg three times daily; for greater than 60 kg, 100 mg three times daily iv. Avoid if eGFR is less than 30 mL/minute/1.73 m2. b. Miglitol (Glyset) i. Administer as 25 mg with first bite of meal. ii. Start once daily and then increase weekly to twice daily; then use three times daily with meals to decrease GI adverse effects. iii. Typical maintenance dose is 50 mg with meals; maximum daily dose is 100 mg three times daily. iv. Avoid if eGFR less than 25 mL/minute/1.73 m2. 4. Adverse effects a. Common: flatulence, abdominal discomfort, diarrhea; may occur in up to 80% of patients but may diminish after 4–8 weeks of therapy b. Rare: transient elevations in liver function tests 5. Contraindications a. Inflammatory bowel disease b. Intestinal obstruction c. Malabsorption d. DKA e. Cirrhosis f. Hypersensitivity to acarbose or miglitol

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 394

Diabetes Mellitus

6. Advantages a. No hypoglycemia as monotherapy i. Use only simple sugar (e.g., glucose tablets) or skim milk to treat hypoglycemia in patients receiving these in combination with a secretagogue or insulin. ii. Acarbose can delay the absorption time of sucrose (cane sugar). b. Weight-neutral 7. Disadvantages a. Modest efficacy b. Poorly tolerated GI adverse effects c. Need for slow titration d. Need for multiple dosing (e.g., three times daily) N. Bile Acid Sequestrant: Colesevelam (WelChol) 1. Mechanism of action a. Farnesoid X receptor (FXR) antagonist b. Bile acids activate the FXR, leading to increased expression of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme necessary for hepatic gluconeogenesis. c. Colesevelam inhibits bile acid reabsorption, thus preventing FXR activation and up-regulation of PEPCK, leading to decreased hepatic glucose production. 2. Efficacy a. A1C reduction of 0.4%–0.6% b. Primarily targets FPG reduction c. LDL reduction of 15%–18% 3. Dose a. 625-mg tablets; 3 tablets twice daily, or 6 tablets once daily with food b. Suspension 3.75 g per packet, 1 packet every day with largest meal 4. Adverse effects a. Constipation, dyspepsia b. Potential TG increase 5. Contraindications a. History of bowel obstruction b. TG concentration greater than 500 mg/dL c. History of hypertriglyceridemia-induced pancreatitis 6. Advantages a. No hypoglycemia as monotherapy b. LDL reduction of 15%–18% c. Can increase tolerability to metformin by 20% in patients with resistant diarrhea (Endocr Pract 2010;16:629-40) 7. Disadvantages a. Modest A1C efficacy b. High pill burden (full dose: 6 tablets) c. Taste of suspension in packets d. Can raise TG concentration e. Potential for drug interactions (levothyroxine, ezetimibe, phenytoin)

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 395

Diabetes Mellitus

O. Dopamine Receptor Agonist: Bromocriptine (Cycloset) 1. Mechanism of action: glucose-lowering mechanism is unknown, but it improves glucose and energy metabolism with no effect on plasma insulin concentration; acts to reset aberrant central neurometabolic control of peripheral metabolism toward normal in patients with diabetes, resulting in reduced insulin resistance; improves glucose and energy metabolism by activating central nervous system dopaminergic pathways responsible for metabolic control. 2. Efficacy a. A1C reduction of 0.4%–0.6% b. Modestly reduces FPG values; has even less effect on postprandial glucose 3. Dose: 0.8-mg tablet each morning (within 2 hours of waking) with food; titrate by 0.8 mg/week to a daily dose of 4.8 mg (6 tablets) each morning as tolerated 4. Adverse effects a. Nausea, vomiting b. Asthenia c. Constipation d. Dizziness e. Somnolence 5. Contraindications a. Hypersensitivity b. Lactation c. Syncopal migraines d. Uncontrolled HTN 6. Advantages a. Specific mechanism of action b. CV benefit (Cycloset safety trial) 7. Disadvantages a. Modest efficacy b. Adverse effects c. Cost P. Amylin Analog: Pramlintide (Symlin) 1. Mechanism of action: synthetic analog of human amylin that causes the following: a. Glucose-dependent inhibition of glucagon secretion b. Reduced rate of gastric emptying c. Increased satiety 2. Efficacy (indicated for patients receiving mealtime insulin) a. A1C reduction of 0.5%–0.7% b. Primarily lowers postprandial glucose values 3. Dose a. T1DM: initiate at 15 mcg subcutaneously with meals daily, and increase by 15 mcg per dose every 3–7 days as tolerated; maximum of 60 mcg with meals (mealtime insulin dose must be reduced by 50% on initiation of pramlintide) b. T2DM: initiate at 60 mcg subcutaneously with meals, and increase to 120 mcg with meals in 3–7 days as tolerated (mealtime insulin dose must be reduced by 50% on initiation of pramlintide). 4. Administration a. Inject in abdomen or thighs only. b. Avoid injecting into the arm, given variable absorption

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 396

Diabetes Mellitus

5. Adverse effects a. Nausea b. Vomiting c. Hypoglycemia with insulin (mealtime insulin dose must be reduced by 50% on initiation of pramlintide) 6. Contraindications a. Gastroparesis b. Hypoglycemia unawareness 7. Advantages a. Use is associated with weight loss b. Primarily targets postprandial BG values 8. Disadvantages a. Requires three additional injections per day and should only be prescribed in people using prandial insulin b. Can reduce the rate and extent of absorption of drugs that require rapid absorption (e.g., pain relievers, antibiotics, oral contraceptives); separate administration by at least 1 hour c. Adverse GI effects d. Significant risk of hypoglycemia with use of meal-time insulin; must reduce dose 50% e. Cost Patient Case 3. A patient with T2DM receiving basal insulin is interested in a drug that he heard would aid in his weight loss efforts in addition to lifestyle modifications. Which medication best fits this description? A. B. C. D.

Dulaglutide Glipizide Alogliptin Pioglitazone

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 397

Diabetes Mellitus

Q. Insulin 1. Comparison of human insulins is shown in Table 3 2. Individual insulins and their appropriate BG targets are shown in Table 4. Table 3. Comparison of Human Insulins Category

Insulin

Rapid-acting Ultra-rapid-acting Short-acting

Intermediate-acting Long-acting

a

Lispro insulin (U-100, U-200) (Humalog, Admelog) Aspart insulin (Novolog) Glulisine insulin (Apidra) Insulin aspart (Fiasp) Insulin lispro-aabc U-100, U-200 (Lyumjev) Inhaled insulin (Afrezza) Human regular (Humulin R, Novolin R) Human NPH (Humulin N, Novolin N)

Detemir insulin (Levemir) Insulin glargine (Lantus, Basaglar, Semglee) Insulin glargine U-300 (Toujeo) Insulin degludec (U-100, U-200) (Tresiba)

Onset of Action

5–15 min

Peak Duration of Effect, hr Action, hr 1–2

3–5

5 min

1–1.5

3–5

30–60 min

2–4

6–8

1–2 hr

3–4 hr 4–6 hr 2-4 hr 1.5 hr

6–12

Peakless

10–16 6–24 ~ 24 > 24 > 24

All insulins are U-100 unless otherwise specified.

a

NPH = neutral protamine Hagedorn (insulin).

Table 4. Individual Insulins and Their Appropriate Blood Glucose Targets Target Blood Glucose Fasting (prebreakfast)

Prelunch (postbreakfast) Predinner (postlunch) Bedtime (postdinner)

Target Insulin

Bedtime or predinner NPH, detemir, glargine, degludec

Prebreakfast regular, aspart, glulisine, lispro, inhaled insulin

Prebreakfast NPH, detemir, prelunch regular, aspart, glulisine, lispro, inhaled insulin Predinner regular, aspart, glulisine, lispro, inhaled insulin

NPH = neutral protamine Hagedorn.

3. Basal insulin: long-acting (detemir, glargine, degludec) and intermediate-acting insulin a. Decreases fasting glucose (hepatic glucose production) b. Requires consistent (constant) insulin doses c. Approximates 40%–50% of daily insulin needs in T1DM d. Equivalent doses i. Most once-daily basal insulins can be switched in a 1:1 ratio (i.e., 30 units of insulin glargine is equivalent to 30 units of insulin degludec). ii. Most twice-daily basal insulin regimens should be reduced by 20% when switching to once daily (i.e., 30 units twice daily of detemir would be 48 units of insulin glargine once daily). 4. Bolus insulin (regular, aspart, glulisine, lispro, inhaled insulin) a. Limits postprandial hyperglycemia b. Characterized by immediate insulin peak and onset of activity c. Around 50%–60% of daily insulin needs in T1DM split between meals d. Requires glucose monitoring and insulin dosing

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 398

Diabetes Mellitus

5. Concentrated insulin a. Advantage is that less volume of injection may improve absorption. b. Many formulations have pen options that hold more than the traditional 300 units/pen. c. Humulin R U-500 (500 units/mL) i. 5 times more concentrated than U-100 insulin products ii. Delayed onset, longer duration of action iii. Considered in patients with significant insulin resistance and total daily insulin doses greater than 200 units/day iv. Dosed two to four times daily before meals and snacks v. Has both basal and prandial properties vi. Use U-500 pen or dedicated U-500 syringe for dosing (dosed in 5-unit increments). d. Glargine U-300 i. Longer duration of action than glargine U-100 ii. 3 times as concentrated iii. Available in a pen up 80 units max dose (1-unit dose increments) or 160 units max dose (2-unit dose increments) iv. Not available as a vial e. Degludec U-200 i. Same duration of action as degludec U-100 ii. Available as a 160-unit max-dose pen (2-unit dose increments) iii. Not available as a vial f. Lispro and lispro-aabc U-200 i. Same duration of action as lispro and lispro-aabc U-100 ii. Available as a 60-unit max-dose insulin pen iii. Not available as a vial Patient Case 4. J.L. is a 48-year-old white woman with obesity and T2DM who is treated with metformin 1 g twice daily. She has a postprandial BG concentration higher than desired, and her most recent A1C is 7.5%. Which best represents how this patient’s diabetes regimen should be changed? A. B. C. D.

Increase the metformin dose to 850 mg three times daily. Substitute metformin with a sulfonylurea. Add a bedtime dose of NPH insulin. Add oral semaglutide.

6. Initial dosing of insulin a. T2DM: initiate insulin therapy (fix the fasting first); basal insulin i. Continue oral agent(s) or non-insulin injectables at same dosage. ii. Single daily basal insulin dose (glargine, detemir, degludec or NPH 0.1–0.2 unit/kg) or 10 units/day iii. Adjust dose according to individualized FBG concentration (treat to target) such as increasing by 2 units every 3 days until FBG is at target without hypoglycemia. iv. For hypoglycemia, determine cause; if no clear reason, lower dose by 10%–20% v. If basal dose greater than 0.5 units/kg/day and A1C or FBG above target, add prandial insulin b. T1DM: initiate multiple daily insulin injection therapy i. Calculate daily dose (0.5 unit of insulin per kilogram per day). ii. Give 50% as basal insulin; perform dose titration to FPG values. iii. Give 50% as bolus insulin; split into three mealtime doses. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 399

Diabetes Mellitus

iv. Example: 80-kg patient starting multiday injection therapy: 0.5 unit/kg equals 40 units of insulin/ day; half as basal, half as bolus, with the following: (a) Glargine or detemir or degludec 20 units every day (b) Aspart of glulisine or lispro 6 units prebreakfast (c) Aspart or glulisine, lispro 7 units prelunch (d) Aspart or glulisine, lispro 7 units predinner (e) Titrate insulin doses to BG values. v. Correctional insulin dosing is meant to correct for premeal glycemic excursions. (a) Rapid-acting insulin – “the rule of 1800” (1) 1800/current total daily insulin dose equals mg/dL change/1 unit (2) Example of 40 units/day: 1800/40 equals 45 mg/dL (insulin sensitivity) (b) Regular insulin – “the rule of 1500” (1) 1500/current total daily insulin dose equals mg/dL change/1 unit (2) Example of 50 units/day: 1500/50 equals 30 mg/dL (insulin sensitivity) vi. Establish an insulin/carbohydrate ratio (a) Insulin/carbohydrate ratio – “the rule of 500” – requires extensive patient education on counting carbohydrates and can be used to estimate the early use of rapid-acting insulins at mealtime to prospectively cover what is to be ingested. (b) 500/daily insulin dose equals insulin/carbohydrate ratio (c) Example of 50 units/day: 500/50 Insulin/carbohydrate ratio equals 1 unit for 10 g of carbohydrates Patient Case Questions 5–7 pertain to the following case. B.L. is a 40-year-old patient who received a diagnosis T1DM 28 years ago. His C-peptide concentration is undetectable, and he is treated with a basal/bolus insulin regimen of glargine and lispro insulins. His insulin requirements total 100 units of insulin per day. 5. Which value best approximates this patient’s insulin sensitivity? A. B. C. D.

15 mg/dL 16 mg/dL 17 mg/dL 18 mg/dL

6. Which best approximates this patient’s insulin/carbohydrate ratio? A. B. C. D.

3 4 5 6

7. B.L. has a predinner blood glucose reading today of 184 mg/dL (goal of 130 mg/dL), and he plans to eat 60 g of carbohydrates at dinner. Which best approximates this patient’s predinner lispro insulin dose? A. B. C. D.

15 units 16 units 17 units 18 units

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 400

Diabetes Mellitus

7. Mixed insulin a. Typically reserved for patients who will not or cannot be treated with dosing regimens that are more complex, and typically dosed before the morning and evening meals i. Humulin 70/30: 70% NPH, 30% regular ii. Humalog Mix 75/25: 75% lispro protamine, 25% lispro iii. Humalog Mix 50/50: 50% lispro protamine, 50% lispro iv. Novolin 70/30: 70% NPH, 30% regular v. NovoLog Mix 70/30: 70% aspart protamine, 30% aspart b. Premixed insulin/GLP-1 RA i. Dosing is based on the insulin dose with a corresponding increase in the GLP-1 RA dose. ii. Degludec/Liraglutide (a) Initial dose: 16 units (insulin degludec 16 units-liraglutide 0.58 mg) subcutaneously once a day (b) Titrate by 2 units every 3–4 days on the basis of BG monitoring results until the desired glucose targets are achieved. (c) Maintenance dose: 16–50 units subcutaneously once a day (d) Maximum daily dose: 50 units (50 dose steps: insulin degludec 50 units–liraglutide 1.8 mg (e) Can be dosed at any time of day with or without food iii. Glargine/Lixisenatide (a) Initial dose: 15 units (insulin glargine 15 units/lixisenatide 5 mcg) once daily if naive to basal insulin or taking less than 30 units of basal insulin/day or 30 units (insulin glargine 30 units/ lixisenatide 10 mcg) once daily if currently taking 30–60 units of basal insulin/day (1) Titrate in increments of 2–4 units weekly on the basis of BG monitoring until desired glucose targets are achieved. (b) Maintenance dose: 15–60 units per day (c) Maximum dose: insulin glargine 60 units/lixisenatide 20 mcg once a day (d) Administer within 1 hour of the first meal of the day. c. Advantages i. Injections less often ii. Short-term mealtime coverage with 1 injection iii. Lower cost through one co-pay instead of two d. Disadvantages i. Less dosing flexibility ii. Not as suitable as single-insulin formulations for adjusting daily doses to account for changes in activity levels and meal regimens 8. Insulin delivery devices a. Vial and syringe b. Disposable insulin pens c. Insulin pump i. Use one type of insulin (usually rapid acting), and some is delivered in the background as basal and bolus calculator used to calculate mealtime and correction doses. ii. Some insulin pumps can communicate with a continuous glucose monitor (CGM) to automate insulin delivery. iii. Can be an option for people with T1DM or T2DM taking several daily injections of insulin iv. Reports downloaded to view insulin delivery and glucose information (BG monitor or CGM) d. Patch pump i. The device allows a person to bolus in 2-unit increments, but no technology to calculate or record insulin doses

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 401

Diabetes Mellitus

e. Smart (connected) pens and pen caps i. Ability to record insulin doses ii. Use a bolus calculator to calculate insulin doses and keep track of active insulin time (amount of time insulin is still working in the body). iii. Reports downloaded to view insulin delivery and glucose information (BG monitor or CGM) iv. Nondisposable Patient Case 8. C.D. is a 19-year-old woman just given a diagnosis of T1DM. She weighs 80 kg and has normal renal function (serum creatinine is 0.6 mg/dL). She has a significant fear of hypoglycemia. Which choice represents the most appropriate empiric basal insulin and dose for this patient? A. B. C. D.

Glargine 10 units twice daily Glargine 20 units at bedtime Novolin 70/30 20 units twice daily NPH insulin 20 units twice daily

f. Knowledge of and competence in using insulin pens and pumps, GLP-1 and amylin analog devices, glucose-monitoring systems, site care, device storage, priming, the injection process, proper use of pens and syringes, needle length, site rotation, and proper device disposal are important for maximum patient benefit. g. For example, pen-type insulin delivery devices allow more accurate dosing, faster and easier setting of dose, and increased patient acceptance and adherence than insulin and syringe use, but can be more expensive. 9. The primary glycemic effects of these diabetes drugs are shown in Table 5. Table 5. Drugs and Their Primary Glycemic Effects Fasting Glucose

Bile acid sequestrant Long-acting insulin

Intermediate-acting insulin

Metformin

Mixed Glycemic Effects Long-acting GLP-1 RA

Postprandial Glucose

α-Glucosidase inhibitors

SGLT2 inhibitors

Bromocriptine

Thiazolidinediones

Meglitinides Pramlintide Once- or twice-daily dosed GLP-1 RA

Sulfonylurea

DPP-4 inhibitors Short-acting insulin Rapid-acting insulin Ultra-rapid-acting insulin

DPP-4 = dipeptidyl peptidase-4; NPH = neutral protamine Hagedorn; SGLT-2 = sodium--glucose transporter-2.

10. Considerations for initiation of drug therapy in T2DM a. Baseline A1C and BG values: If A1C is greater than 10% or BG measurements are 300 mg/dL or higher with symptoms of hyperglycemia, typically insulin is used as initial therapy. b. Organ function: Certain diabetes medications must be avoided or doses adjusted according to the individual patient’s renal and hepatic function.

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Diabetes Mellitus

c. In people with established ASCVD or indicators of high risk, established CKD, or heart failure, an SGLT2 inhibitor or a GLP-1 RA with proven CVD benefit is recommended independent of A1C. i. If patient is already receiving dual therapy or several glucose-lowering therapies and not an SGLT2 inhibitor or GLP-1 RA, consider changing to one of these agents with proven CV benefit. d. A GLP-1 RA is preferred to insulin, when possible. e. Other key considerations (need to minimize hypoglycemia, need for weight loss, reduce cost of medications) f. Contraindications to therapy: Always know when NOT to use a particular therapy (i.e., do not use thiazolidinediones in a person with heart failure). g. Duration of disease: reduced beta-cell function as disease progresses can limit the choice of some drugs (secretagogues). h. Glucose monitoring: a patient who starting insulin therapy must monitor BG concentration to maximize its potential (for dose adjustment) and to reduce the risk of hypoglycemia. i. Hypoglycemia unawareness i. Avoid secretagogue use or insulin therapy, if possible, for patients with hypoglycemia unawareness. ii. Frequent glucose monitoring is imperative for these patients; A1C targets will be higher for them (e.g., 8%). j. Baseline weight i. Weight gain exacerbates hyperglycemia, blood pressure, and lipid values ii. Encourage medications that are weight neutral or associated with weight loss, if possible (i.e., GLP-1 RAs, SGLT2 inhibitors). k. Route of administration: some patients prefer to avoid injectable therapy. l. Cost: high medication costs and/or medical insurance co-pays may discourage medication use for some patients; some drugs such as sulfonylureas and metformin are very inexpensive (e.g., $4/month). i. Some insulins such as Novolin N and novolin R can be purchased for $25 per vial. m. Follow-on biologics (i.e., Basaglar, Semglee, Admelog), generic insulins (insulin aspart, insulin lispro), and combination products may help reduce out-of-pocket cost. 11. Patient-centered A1C decision-making a. The ADA and European Association for the Study of Diabetes position statement supports this decisionmaking (Diabetes Care 2020;43:487-93). b. Elements of hyperglycemia decision-making should include diabetes duration, life expectancy, drug risks (especially hypoglycemia), comorbidities, presence or absence of vascular complications, patient attitude and expected treatment efforts, and resources/support system. 12. Key points a. Glycemic targets and glucose-lowering therapies must be individualized. b. Healthy eating, physical activity, and DSMES remain the foundation of any T2DM treatment program. c. Certain agents are now preferred because of their positive CVD outcomes. d. Combination therapy with an additional one or two oral or injectable agents is reasonable, with the aim of minimizing adverse effects, when possible. Ultimately, many patients will require insulin therapy alone or in combination with other agents to obtain glucose targets. e. All treatment decisions, when possible, should be made in conjunction with the patient, focusing on their preferences, needs, and values. f. Comprehensive CV risk reduction must be a primary focus of therapy.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 403

Diabetes Mellitus

X.  POINT-OF-CARE TESTING (Domain 1) A. Point-of-care testing can be used by clinicians to accomplish the following: 1. Screen for diabetes using glucose monitors and A1C tests 2. Adjust diabetes medication regimens such as by hemoglobinA1C tests 3. Identify and improve the care of patients with diabetes and hyperlipidemia (by a cholesterol test) 4. Screen for and treat diabetic nephropathy/CKD (by urine microalbumin determination) B. Diagnosis requires laboratory screening.

XI.  CONTINUOUS GLUCOSE MONITORING A. Measures interstitial glucose rather than capillary BG 1. Contains three components: sensor, transmitter, and display device (reader, receiver, or smartphone) B. Key differences between devices include wear time, required calibrations (fingerstick verification of readings), accuracy, and integration with insulin pump, smartphones, or connected smart pens. C. Real-time CGM devices measure glucose continuously and include real-time high, low, and predictive glucose alerts together with trend arrows indicating how quickly glucose is rising or falling. Must be near reader, receiver, or smartphone to avoid data gaps 1. Eversense: Implantable sensor through an in-office procedure; may be worn up for to 3 months with external transmitter that should be charged daily, calibrations required every 12 hours 2. G6: 10-day wear, no calibrations required, 3. Guardian Connect and Guardian 3: 7-day sensor wear, two to four calibrations required/day D. Intermittently scanned CGMs display glucose concentration and trend arrow when the sensor is scanned by a reader or smartphone. Some have the option for real-time alerts. 1. Freestyle Libre 14 day: 14-day sensor, no calibration required 2. Freestyle Libre 2: 14-day sensor, no calibration required, optional alerts 3. Must scan every 8 hours to avoid data gaps E. When used properly, real-time CGM and intermittently scanned CGM are useful to lower A1C and reduce hypoglycemia in people with diabetes taking insulin. F. When used as an adjunct to pre- and postprandial self-monitoring of blood glucose, CGM can help to achieve A1C targets in diabetes and pregnancy. G. Professional CGM is owned by the clinic and worn by the person with diabetes on a temporary basis (up to 14 days). 1. It can help identify and correct patterns of hyper- and hypoglycemia and improve A1C in people with diabetes not using insulin. 2. Professional CGM can be blinded (person does not see data in real time while wearing it) or unblinded (person sees glucose while wearing device).

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 404

Diabetes Mellitus

H. H. Professional CGM devices include: 1. G6 Pro: 10-day wear, blinded or unblinded 2. Libre Pro: 14-day wear, blinded only I. Evaluate the ambulatory glucose profile and standardized CGM metrics to make adjustments in therapy. J. Benefits seen in patients who often experience hypoglycemia, nocturnal hypoglycemia, and hypoglycemic unawareness

XII.  NEW DRUG TREATMENT REQUIREMENTS: (Domain 3) Approval of all new diabetes drugs is now contingent on proof of CV safety. New FDA regulations went into effect in 2008 in the wake of the rosiglitazone CV safety issues (as described in Section IX: Treatment). The regulations require the following: A. Approval of diabetes drugs only with the exclusion of a 30% relative increase in CV events compared with placebo or an active comparator, or of an 80% relative excess of events with a postmarketing study to evaluate the risk. If statistical noninferiority versus placebo or comparator is confirmed, testing for superiority is appropriate. B. Data on patients with advanced diabetes, older adult patients, and patients with some degree of renal impairment – groups typically excluded from pivotal trials – are included in the regulatory submission. C. At least 2 years of CV safety data, to include major adverse CV events as an end point with independent adjudication of events

XIII.  DIABETES COMPLICATIONS (Domain 1) A. Acute Complications 1. Hypoglycemia classification a. Level 1 – Hypoglycemia alert value: 70 mg/dL or less b. Level 2 – Clinically significant hypoglycemia: less than 54 mg/dL c. Level 3 – Severe hypoglycemia: hypoglycemia plus cognitive impairment and requiring assistance 2. Hypoglycemia: signs/symptoms of hypoglycemia a. BG concentration usually lower than normal (less than 70 mg/dL) b. Signs/symptoms: i. Tremor ii. Nervousness/anxiety iii. Diaphoresis iv. Tachycardia v. Hunger vi. Headache c. Provider/family member may notice that the patient has the following: i. Irritability ii. Confusion iii. Sleepiness ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 405

Diabetes Mellitus

d. Treatment i. If the patient is conscious, give 15 g of rapid-acting carbohydrates (e.g., four Life Savers or other hard candy to chew, 4 teaspoons of sugar, one-half cup of soda or juice, 1 cup of skim milk, or 3 or 4 glucose tablets). ii. Recheck BG concentration in 15 minutes, and repeat treatment if reading remains less than 70 mg/ dL or if patient remains symptomatic. iii. If BG is greater than 70 mg/dL and it is more than 1 hour until the next scheduled meal, give a longacting source of carbohydrates (e.g., half of a peanut butter sandwich). iv. If patient is unconscious, administer glucagon, place patient in position to avoid aspiration from potential vomiting, and call 911. v. If patient is still unconscious, a second dose may be given after 15 minutes. vi. Available glucagon formulations (a) Nasal glucagon (Baqsimi): Administer 4-mg dose intranasally. (b) Liquid stable glucagon (Gvoke or dasiglucagon): Available as prefilled syringe or auto-inject pen; inject subcutaneously (c) Glucagon emergency kit: Available as a dry power and liquid that must be reconstituted immediately before use. Inject subcutaneously or intramuscularly. vii. Look for causes; adjust insulin doses if repeated hypoglycemia. e. DKA i. Low-insulin, high-glucagon state primarily seen in patients with T1DM ii. DKA is a medical emergency. f. Hyperglycemic hyperosmolar state: occurs primarily in patients with T2DM and is a medical emergency g. Sick-day rules for patients receiving insulin i. Never stop insulin: continue basal insulin at normal dose, and cover hyperglycemia with quickacting insulin (discontinue scheduled “premeal” doses of quick-acting insulin if the patient is not eating, but use every 4–6 hours to keep BG concentration less than 250 mg/dL. ii. Hydration: 8–12 ounces of fluid (with calories) per hour (e.g., sports drink) iii. Self-monitoring of BG or CGM: check every 1–2 hours, and correct with rapid-acting insulin if glucose readings are greater than 250 mg/dL. iv. Check for ketones: check every 4 hours when BG concentration is greater than 250 mg/dL (T1DM). v. Ketones can be checked via urine or blood through a special meter vi. Call the provider or health care team as soon as possible if vomiting occurs with BG values greater than 500 mg/dL or if a moderate to large amount of urine ketones is present with a BG concentration greater than 250 mg/dL. B. Chronic Complications (Domain 3) 1. Microvascular a. Retinopathy is the leading cause of adult-onset blindness in the United States; a comprehensive eye examination by an ophthalmologist or optometrist should be performed annually. May consider evaluation every 1–2 years in patients with well-controlled diabetes who do not have retinopathy. b. Nephropathy: CKD can progress to end-stage renal disease and increase CV risk; nephropathy occurs in 20%–40% of patients with diabetes and represents the most common cause of end-stage renal disease in the United States. i. Measure albumin/creatinine ratio at least annually ii. Albuminuria: recommend treating persistent albuminuria with an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB); reducing albuminuria from concentrations of 300 mg/g or greater may improve renal and CV outcomes.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 406

Diabetes Mellitus

iii. Finerenone (Kerendia) is a nonsteroidal mineralcorticoid receptor antagonist FDA approved to reduce risk of sustained eGFR decline, end-stage kidney disease, CV death, nonfatal myocardial infarction, and hospitalization for heart failure in adult patients with CKD associated with T2DM. iv. Trials (a) Diabetes Control and Complications Trial (DCCT) (b) UKPDS (c) Action to Control CV Risk in Diabetes (ACCORD) (d) ACCORD Follow-on (ACCORDION) (e) Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (Fidelio-DKD) c. Neurologic i. Peripheral neuropathy (a) All patients should be screened for distal symmetric polyneuropathy at diagnosis and at least annually thereafter using a 10 g monofilament pressure sensation test and an additional assessment, such as pinprick sensation or tuning fork. (b) Pulses in the legs and feet should also be assessed. (c) Patients should be educated to visually inspect feet daily. ii. Autonomic neuropathies (a) Gastroparesis (b) Erectile dysfunction (c) Urinary retention (d) Diabetic diarrhea (e) CV autonomic neuropathy, such as orthostatic hypotension and resting tachycardia (f) Hypoglycemia unawareness 2. Macrovascular: DM is a coronary disease risk equivalent, and it is the seventh leading cause of death in the United States. a. Coronary artery disease b. Cerebrovascular disease c. Peripheral arterial disease i. Can lead to ulcers, Charcot joints, and amputation ii. Leading cause of nontraumatic lower limb amputations in the United States iii. All patients require daily foot inspections, assessment of foot pulses, and testing for loss of protective sensation. d. Trials i. Epidemiology of Diabetes Interventions and Complications (EDIC) – follow-up of DCCT ii. 10-year follow-up of UKPDS iii. Action to Control Cardiovascular Risk in Diabetes (ACCORD) iv. Action in Diabetes and Vascular Disease (ADVANCE) v. Veterans Affairs Diabetes Trial (VADT) vi. Cardiovascular Outcome Trials (CVOTs) (a) FDA in 2008 required CVOTs for all new T2DM agents. (b) Goal was to prevent newly approved agents for T2DM that increase CV risk from going to market (e.g., rosiglitazone) (c) CVOT results are summarized in Table 6.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 407

408

n=8246

Ertugliflozin

n=4744 (n=1983 with diabetes)

Dapagliflozin

n=17,160

Dapagliflozin

n=4401

Canagliflozin

n=10,142

Canagliflozin

n=3730

Empagliflozin

n=7020

Empagliflozin

SGLT2 Inhibitors

Drug/Size

Placebo

Placebo

Placebo

VERTIS-CV

HAPA-HF

DECLARETIMI 58

CREDENCE

CANVAS program

Placebo

Placebo

EMPERORReduced

EMPA-REG Outcomes

Trial

Placebo

Placebo

Comparator

Table 6. CV Benefits of Different Diabetes Agentsa

0.97 (0.85–1.11)b

0.74 (0.65– 0.85)b HHF + CV death only

0.93 (0.84–1.03)b

0.80 (0.67–0.95)

0.86 (0.75–0.97)b

0.75 (0.65– 0.86) HHF + CV death only

0.86 (0.74–0.99)b

Major Adverse CV Events

N

Y

N

Y

Y

Y

Y

Benefit Yes/No

0.70 (0.54–0.90)

0.70 (0.59–0.83)

0.73 (0.61–0.88)

0.78 (0.61–1.0)

0.67 (0.52–0.87)

0.69 (0.59–0.81)

0.65 (0.5–0.85)

Hospitalizations for Heart Failure

Y

Y

Y

N

Y

Y

Y

Benefit Yes/No

0.81 (0.63–1.04)

0.71 (0.44–1.16)

0.53 (0.43–0.66)

ESRD, doubling of SCr or death from renal of CV cause: 0.70 (0.59– 0.82)b

0.60 (0.47–0.77)

0.50 (0.32–0.77)

0.61 (0.53–0.70)

Renal Outcomes

N

N

Y

Y

Y

Y

Y

Benefit Yes/No

Diabetes Mellitus

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

409

n=6042

Linagliptin

n=6979

Linagliptin

n=14,671

Sitagliptin

n=5380

Alogliptin

n=16,492

Saxagliptin

DPP-4 Inhibitors

Drug/Size

Glimepiride

Placebo

Placebo

Placebo

Placebo

Comparator

CAROLINA

CARMELINA

TECOS

EXAMINE

SAVOR-TIMI

Trial

0.98 (0.84– 1.14)b

1.02 (0.89– 1.17)b

0.99 (0.89– 1.10), 4-point MACE

0.96 (UL ≤ 1.16)b

1.0 (0.89–1.12)b

Major Adverse CV Events

Table 6. CV Benefits of Different Diabetes Agentsa (continued)

N

N

N

N

N

Benefit Yes/No

1.21 (0.92–1.59)

0.90 (0.74–1.08)

1.0 (0.83–1.20)

1.19 (0.90–1.58)

1.27 (1.07–1.51)

Hospitalizations for Heart Failure

N

N

N

N

N, negative impact

Benefit Yes/No

N/A

Composite of ESRD, sustained > 40% decrease in eGFR, or renal death: 1.04 (0.89–1.22)

N/A

N/A

1.08 (0.88–1.32)

Renal Outcomes

N/A

N

N/A

N/A

N

Benefit Yes/No

Diabetes Mellitus

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Comparator

410

Placebo

Placebo

Placebo

Placebo

Placebo

Placebo

Placebo

REWIND

HARMONY

EXSCEL

PIONEER-6

SUSTAIN-6

LEADER

ELIXA

Trial

0.88 (0.79–0.99)b

0.78 (0.68–0.90)b

0.91 (0.83–1.0)b

0.78 (0.57–1.11)b

0.76 (0.62–0.92)b

0.87 (0.78–0.97)b

1.02 (0.89–1.17)b 4-point MACE

Y

Y

N

N

Y

Y

N

Benefit Yes/No

0.93 (0.77–1.12)

N/A

1.05 (0.74–1.50)

0.86 (0.48–1.55)

0.82 (0.47–1.44)

0.87 (0.73–1.05)

0.96 (0.75–1.23)

Hospitalizations for Heart Failure

N

N/A

N

N

N

N

N

Benefit Yes/No

0.85 (0.77–0.93)

N/A

N/A

N/A

0.64 (0.46–0.88)

0.78 (0.67–0.92)

N/A

Renal Outcomes

Primary outcome, renal outcomes refer to worsening nephropathy unless otherwise indicated.

ESRD = end-stage renal disease; GLP-1 = glucagon-like peptide-1; HHF = hospitalization for heart failure; MACE = major adverse CV events; N/A = not applicable; UL = upper limit.

c

Removed from market.

b

a

Outcomes are expressed as hazard ratios and confidence intervals. MACE refers to 3-point MACE (stroke, nonfatal myocardial infarction, and CV death) unless otherwise indicated.

n=9901

Dulaglutide

n=9463

Albiglutidec

n=14,752

Exenatide weekly

n=3183

Semaglutide oral

n=3297

Semaglutide

n=9340

Liraglutide

n=6068

Lixisenatide

GLP-1 Receptor Agonists

Drug/Size

Major Adverse CV Events

Table 6. CV Benefits of Different Diabetes Agentsa (continued)

Y

N/A

N/A

N/A

Y

Y

N/A

Benefit Yes/No

Diabetes Mellitus

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Diabetes Mellitus

e. Take-home point: Tighter glycemic control early after diagnosis can decrease macrovascular complications; however, aggressive A1C goal setting (less than 6%) in patients with long-standing diabetes and high preexisting CV risk without a history of tight glycemic control might not provide the same benefit and could increase mortality. f. Newer agents (SGLT2 inhibitors, GLP-1 RAs) have micro- and macrovascular benefits beyond A1C lowering.

XIV.  MONITORING: Prevention and Management of Diabetes Complications. (Domain 1) A. Goal: Attainment of appropriate A1C values with self-monitoring of BG concentration or CGM, together with appropriate and regular dental, eye, foot, kidney, nerve, and CV examinations, is the goal to reduce the risk of diabetes-related complications. B. Mind Your ABCs 1. As a. A1C b. Antiplatelet therapy (when indicated) 2. Bs a. Blood pressure control b. Self-monitoring of BG 3. Cs a. Cholesterol control: lipid-lowering agents b. Cessation of cigarette smoking C. Blood Pressure 1. Uncontrolled blood pressure is a risk factor for ASCVD and microvascular complications. 2. Blood pressure should be measured at every routine visit. 3. Home blood pressure monitoring is encouraged and may be associated with increased medication-taking behavior and reduced CV risk. 4. Goals a. Blood pressure targets should be individualized through a shared decision-making process that addresses cardiovascular risk, potential adverse effects of antihypertensive medications, and patient preferences. b. For patients at higher CVD risk (existing ASCVD or 10-year ASCVD risk ≥15%), a BP target of less than 130/80 mmHg may be appropriate, if it can be safely attained. c. For patients at lower risk for CVD (10-year ASCVD risk 30 kg/m2. Approved 2021 Seasonale: 84 active tablets to have menses every 3 mo Seasonique: 84 active tablets; then 10 mcg of estrogen for 7 days for menses every 3 mo and fewer estrogen withdrawal symptoms during menses Estrogen/ progestin

Oral

Daily for 21 days

1–3 mo

CDC efficacy category: effective (9% risk of pregnancy) Biphasic, triphasic, and quadriphasic

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 431

Obstetrics and Gynecology

Table 1. Hormonal Contraceptive Comparison (continued)

Product

Ethinyl estradiol and etonogestrel vaginal ring (NuvaRing)

Hormones

Estrogen/ progestin

Route

Vaginal

Administration (standard) 3 wk

Return of Ovulation (may take up to) Notes 6 wk

CDC efficacy category: effective (9% risk of pregnancy) Only one strength available Can safely be removed for up to 3 hr during intercourse; rinse product and then reinsert

Ethinyl estradiol and segesterone vaginal ring (Annovera)

Estrogen/ progestin

Vaginal

3 wk, remove for 1 wk and then reinsert

3–6 mo

Squeeze ring and insert into vagina while sitting, squatting, or standing with one leg up; if discomfort arises, push farther back into the vagina CDC efficacy category: effective (9% risk of pregnancy)

The same ring is used for 13 cycles (1 yr); wash the ring with mild soap and water, rinse with water, and pat dry after removal and before next insertion; store the ring in the case when removed Only one strength available Can be safely removed for up to 2 hr during intercourse Avoid oil-based vaginal products (including miconazole suppository) because of increased Annovera concentrations

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 432

Obstetrics and Gynecology

Table 1. Hormonal Contraceptive Comparison (continued)

Product

Ethinyl estradiol and norelgestromin patch (Xulane)

Hormones

Estrogen/ progestin

Route

Topical

Administration (standard)

Weekly for 3 wk

Return of Ovulation (may take up to) Notes 6 wk

CDC efficacy category: effective (9% risk of pregnancy) Only one strength available Higher cumulative estrogen exposure than most oral contraceptives (see disadvantages section for thromboembolism risk) Avoid if BMI ≥ 30 kg/m2 due to increased risk of thromboembolism and pregnancy

Ethinyl estradiol and levonorgestrel patch (Twirla)

Estrogen/ progestin

Topical

Weekly for 3 wk

3 mo

Apply to clean and dry area on body that will not be rubbed by tightfitting clothing (i.e., avoid waistband); rotate patch site; avoid cream/lotion/ powder at the patch site

CDC efficacy category: effective (9% risk of pregnancy) Approved in 2020

Package insert: contraindicated in patients with BMI ≥ 30 kg/m2 because of increased risks of thromboembolism and pregnancy Apply to clean and dry area on the abdomen, buttock, or upper torso (excluding breasts); rotate patch site; avoid powder/ oil/moisturizer/lotion at the patch site

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 433

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Table 1. Hormonal Contraceptive Comparison (continued)

Product

Progestin-only pills (various names)

Progestin-only pill, cycled (Slynd)

Hormones

Progestin

Progestin

Route Oral

Oral

Administration (standard)

Daily for 28 days

Daily for 24 days; then 4 placebo pills

Return of Ovulation (may take up to) Notes 1 mo

1 mo

CDC efficacy category: effective (9% risk of pregnancy) Must be taken within 3 hr of usual time or backup method of contraception needed for 48 hr Uses norethindrone CDC efficacy category: effective (9% risk of pregnancy) Approved 2019

Medroxyprogesterone Progestin acetate (DepoProvera, Depo SubQ Provera)

IM, SC

Every 13 ± 2 wk

Average 9 mo (up to 18 mo)

Contains drospirenone

CDC efficacy category: effective (6% risk of pregnancy) Risk of bone loss after 2 yr of continued use, reversible on discontinuation Weight gain (see medroxyprogesterone disadvantages section below)

Etonogestrel (Nexplanon)

Progestin

Intradermal

Every 3 yr

1 mo

Depo SubQ Provera is available for selfadministration

CDC efficacy category: most effective (0.05% risk of pregnancy) Radiocontrast dye added to Nexplanon to facilitate removal if unable to locate device

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 434

Obstetrics and Gynecology

Table 1. Hormonal Contraceptive Comparison (continued)

Product

LNG-IUD (Mirena)

Hormones

Progestin

Route

Intrauterine

Administration (standard) Every 6 yr (off-label may use 7 yr)c

Return of Ovulation (may take up to) Notes 1 mo

CDC efficacy category: most effective (0.2% risk of pregnancy) Studied in parous and nulliparous women

LNG-IUD (Skyla)

LNG-IUD (Liletta)

LNG-IUD (Kyleena)

Progestin

Progestin

Progestin

Intrauterine

Intrauterine

Intrauterine

Every 3 yr

Every 6 yr

Every 5 yr

1 mo

1 mo

1 mo

Noninferior to copper IUD as emergency contraception (N Engl J Med 2021;384:335-44)

CDC efficacy category: most effective (0.2% risk of pregnancy) Smaller than Mirena and intended for use in nulliparous women, although the FDA does not comment on use in parous or nulliparous women CDC efficacy category: most effective (0.2% risk of pregnancy)

Studied in both parous and nulliparous women CDC efficacy category: most effective (0.2% risk of pregnancy)

Studied in both parous and nulliparous women Monophasic: Constant dose of estrogen and progestin throughout the active pills.

a

b

Multiphasic: Varying estrogen and progestin concentrations throughout the active pills. Each time the hormone(s) level(s) change, the pill color changes.

Rowe P, Farley T, Peregoudov A. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated uterine device: a 7-year randomized comparative study with the TCu380A. Contraception 2016;93:498-506. c

FDA = U.S. Food and Drug Administration; IM = intramuscular(ly); LNG-IUD = levonorgestrel intrauterine device; SC = subcutaneous(ly).

B. Extended-Interval Dosing (i.e., stacking packs) 1. Monophasic oral contraceptives a. Take 3 weeks of active pills from pack 1. b. Throw out placebo tablets from pack 1. Start active pills from pack 2 immediately. c. Extends cycle by 3 weeks d. Can use several packs in a row to extend cycle. Each additional pack will extend the cycle by 3 additional weeks. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 435

Obstetrics and Gynecology

2. Multiphasic oral contraceptives a. Option 1 (to extend cycle by 5–11 days, depending on brand of contraceptive) i. Take 3 weeks of active pills from pack 1. ii. Throw out the placebo tablets from pack 1. Start highest-progestin-concentration active pills in pack (usually 7 [range 5–11] tablets, depending on brand). iii. Use of each additional pack extends the cycle by 1 week. b. Option 2 (to extend cycle by several weeks) (Table 2) Table 2. Using Several Packs of Multiphasic Contraceptives (example of two packs; two packs below would extend the cycle by 3 additional wk) Steps

Directions

1

Take level 1 tablets (e.g., week 1: Low-estrogen, low-progestin tablets) of pack 1

3

Take level 2 tablets (e.g., week 2: High-estrogen, low-progestin tablets) of pack 1

2 4 5 6

Take level 1 tablets of pack 2; repeat with number of packs using to extend cycle Take level 2 tablets of pack 2; repeat with number of packs using to extend cycle

Take level 3 tablets (e.g., week 3: High-estrogen, high-progestin tablets) of pack 1 Take level 3 tablets of pack 2; repeat with number of packs using to extend cycle

3. Ethinyl estradiol and etonogestrel vaginal ring (NuvaRing) a. Insert vaginal ring for 3 weeks; then remove. b. Immediately insert a new ring for 3 weeks. c. May use several rings in a row to extend cycle 4. Ethinyl estradiol and norelgestromin patch (Xulane) a. Apply patch for 1 week and remove. b. Immediately place on a new patch for 1 week. c. May use several patches in a row to extend cycle C. Advantages/Disadvantages of Products (Domain 1; Tasks 1, 2, 3) 1. Estrogen/progestin products a. Advantages i. High efficacy if taken as instructed. CDC efficacy category: effective (9% risk of pregnancy) ii. Improved menstrual symptoms; decreased amount of blood loss and length of menses (decreases by 40%–50% according to ACOG bulletin No. 110). (a) Decreased risk of iron-deficiency anemia (b) Decreased premenstrual symptoms (c) Improved menstrual disorders (amenorrhea, heavy menstrual bleeding, premenstrual dysphoric disorder [PMDD], and dysfunctional uterine bleeding). See the Menstrual Disorder section. (d) Decreased mittelschmerz (pain associated with ovulation) iii. Decreased risk of ectopic pregnancies iv. Safe throughout reproductive years v. Readily reversible on discontinuation (average 3 months) vi. Cycle manipulation vii. Decreased incidence and severity of pelvic inflammatory disease (PID); decreased menstrual blood loss, which may act as a medium for bacterial growth viii. Decreased risk of ovarian and endometrial cancer ix. Decreased risk of functional ovarian cysts

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Obstetrics and Gynecology

x. Decreased risk of fibrocystic breast disease xi. Helpful for patients with polycystic ovarian syndrome (PCOS) (a) Decreased stimulation of androgen production in the ovaries (b) Decreases free testosterone by increasing sex hormone–binding globulin xii. May decrease acne by increasing sex hormone–binding globulin levels (decreases free testosterone) xiii. Decreased risk of endometriosis xiv. Decreased risk of uterine fibroids xv. Patch and ring products do not require daily administration. b. Disadvantages i. No protection against sexually transmitted infections ii. Pills require timely daily administration. iii. Increased blood pressure (a) Increased angiotensinogen (b) Sodium and water retention iv. Increased risk of stroke and myocardial infarction (a) Mainly with 50-mcg ethinyl estradiol products and concomitant risk factors (b) Smokers older than 35 v. Increased risk of thromboembolic disorders; FDA Risk Estimate per 10,000 patient-years: (a) Nonuser 1–5 (b) Estrogen/progestin 3–9. Highest risk with drospirenone-containing products, Xulane, and 50 mcg of ethinyl estradiol products (c) Pregnancy 5–20 (d) Postpartum 12 weeks 40–65 (e) U.S. Food and Drug Administration (FDA) warning 2012. Available at www.fda.gov/Drugs/ DrugSafety/ucm299305.htm vi. Increased risk of glucose intolerance vii. Increased risk of chlamydial infections (a) Associated with cervical ectopy (cervical surface becomes covered with mucus-secreting cells that normally line the cervical canal), increasing the risk of chlamydial infections (b) PID infection rate is not increased. viii. Increased risk of gallbladder disease ix. May decrease milk production during lactation 2. Progestin-only products a. Advantages of progestin-only pills (POPs) i. Used for patients with contraindications to estrogen products (e.g., older than 35 and who smoke, history of thromboembolism) ii. Good for patients with intolerable adverse events to estrogen products iii. Less risk of myocardial infarction and stroke in patients older than 35 iv. Compatible with breastfeeding; progestin has no effect on milk production, whereas estrogen decreases milk production b. Disadvantages of progestin-only pills i. Irregular menses and increased risk of breakthrough bleeding and spotting ii. Increased risk of ectopic pregnancy iii. Increased need for adherence and consistent administration time (norethindrone POP: use backup method of contraception for 48 hours if dose is taken 3 or more hours late; drospirenone POP: backup needed after 24 hours) iv. Increased risk of ovulation because of lower progestin dose (inhibits 50% of the time ACOG bulletin No. 110)

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Obstetrics and Gynecology

c. Advantages of depot medroxyprogesterone acetate i. Same advantages as POPs ii. Less user variance/error with less frequent administration iii. Scant to light menstrual bleeding with continued use; this characteristic makes it advantageous in the treatment of endometriosis iv. Decreased risk of anemia secondary to decreased menstrual bleeding v. Decreased menstrual cramps and mittelschmerz pain vi. Decreased risk of endometrial and ovarian cancer vii. Decreased risk of PID viii. No drug interactions d. Disadvantages of depot medroxyprogesterone acetate i. Delayed onset of returned fertility (see Table 1) ii. Menstrual irregularities with first several injections iii. Increased risk of bone loss (a) Bone loss is greatest in the early years of use but later resembles normal age-related loss (b) May not be fully reversible upon discontinuation iv. Decreases high-density lipoproteins v. Weight gain (year 1: 2.45 kg [5.4 lb]; year 2: 3.68 kg [8.1 lb]; year 4: 6.27 kg [13.8 lb]; year 6: 7.5 kg [16.5 lb]) e. Advantages of progestin-only intrauterine device (IUD) i. Same advantages as POPs ii. Less user variance/error with less frequent administration iii. LNG-IUD (Liletta, Mirena) can be left in place for up to 6 years; LNG-IUD (Kyleena) can be left in place for up to 5 years; LNG-IUD (Skyla) can be left in place for up to 3 years. Mirena has data to support use up to 7 years (off-label). iv. Amenorrhea (a) Mirena: 20% at 1 year (b) Skyla: 6% at 1 year f. Disadvantages of progestin-only IUD i. Must check monthly for strings ii. Cautions: Increased risk of PID; do not initiate if active chlamydia, gonorrhea, or purulent cervicitis infection iii. Heavy menstrual bleeding and cramping after placement may occur in the first week after insertion but should resolve by 3–6 months after insertion.

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D. Adverse Events: Adjusting Products (Domain 1, Task 4) Patient Case 2. A 21-year-old woman has been taking contraceptive X for the past 8 months. She calls today because she had been experiencing breakthrough bleeding for 2 days, and then her menses began 4–5 days later. She states it is bothersome to have so much bleeding in the past two cycles. Her medical history includes dysmenorrhea. Product

Estrogen Activity

Progestin Activity

Androgen Activity

A

++

+++

++

+

++

++

X

++

B

+++

D

++

C

++

++

++

++

+

++

Which contraceptive product is the best recommendation? A. B. C. D.

A. B. C. D.

Table 3. Signs/Symptoms of Hormone Excesses and Deficiencies Estrogen Excess

Nausea Dizziness Edema Bloating Cyclic weight gain, vision changes, headaches Chloasma Uterine cramping, heavy menstrual bleeding Irritability Depression Poor contact lens fit Headaches during active pill regimen Hypertension Breast tenderness Increased breast size Thrombophlebitis Stroke Myocardial infarction Decreased lactation

Progestin Excess

Moodiness Noncyclic weight gain, increased appetite Fatigue Depression Increased libido Alopecia Decreased menstrual bleeding length Insulin resistance Headaches between pill packs Vaginal candidiasis Hypertension Breast tenderness Leg vein dilation Decreased breast size

Androgen Excess

Increased appetite Noncyclic weight gain Increased libido Oily skin Hirsutism Acne Pruritus Edema

Estrogen Deficiency Progestin Deficiency

Irritability Nervousness Vasomotor symptoms Early- to mid-cycle (pill days 1–9) breakthrough bleeding/spotting Decreased libido Dry vaginal mucosa Atrophic vaginitis Dyspareunia Decreased or absent menstrual flow

Weight loss Heavy menstrual bleeding Late-cycle (pill days 10–21) breakthrough bleeding/ spotting Delayed onset of menstrual bleeding Dysmenorrhea, heavy menstrual bleeding

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1. Identify whether an adverse event is related to hormone deficiency/excess; need to rule out that the adverse event is related to incorrect use or timing of administration (i.e., nausea with morning dose) 2. Select a product with more or less activity than the hormone abnormality thought to be causing the adverse event. 3. If you choose a replacement product with higher endometrial activity, you can change products at any time in the pack. If the new product has less endometrial activity, wait until the next cycle before changing. 4. Use Dickey’s Managing Contraceptive Pill Patients reference tables (requires purchase of the reference). E. Contraindications (Domain 1; Tasks 2, 3) Table 4. Contraindications to Hormonal Contraceptives (U.S. Medical Eligibility Criteria 2016 update) Contraindications to the Various Hormonal Contraceptives and Copper IUD

Definitions: 3 = Condition for which the theoretical or proven risks usually outweigh the advantages of using the method 4 = Condition that represents an unacceptable health risk if the contraceptive method is used

Breast cancer -Disease free for > 5 yr -Current breast cancer

Estrogen/ Progestin

Progestin Only

LNG-IUD

3 4

3 4

3 4

4

3

3/4 3/4

3 3

Cerebrovascular -Stroke

Diabetes mellitus -Diagnosed > 20 yr ago -Diabetes with end-organ damage

Gallbladder -Symptomatic gallstones without cholecystectomy -Hormone-related gallstones

3 3

Heart disease -Ischemic heart disease -Complicated valvular heart disease -Several risk factors (older age, tobacco, low HDL, high LDL, diabetes, high TG) Hypertension -Controlled blood pressure -SBP 140–160 mm Hg or DBP 90–99 mm Hg -SBP > 160 mm Hg or DBP > 100 mm Hg -Hypertension + vascular disease Inflammatory bowel diseasea -Moderate disease or increased risk of VTE

4 4 3/4

3 3 (DMPA)

3 3 4 4

3 (DMPA) 3 (DMPA)

3

3

Liver -Severe cirrhosis -Tumors (hepatocellular adenoma or malignant) -Acute or flare viral hepatitis

4 4 4

3 3

3 3 3

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Copper IUD

Obstetrics and Gynecology

Table 4. Contraindications to Hormonal Contraceptives (U.S. Medical Eligibility Criteria 2016 update) (continued) Contraindications to the Various Hormonal Contraceptives and Copper IUD

Definitions: 3 = Condition for which the theoretical or proven risks usually outweigh the advantages of using the method 4 = Condition that represents an unacceptable health risk if the contraceptive method is used Estrogen/ Progestin

Migraines -With aurab

Copper IUD

4 4

4 4

4c 4c 4c/3

4c 4c 4c/3

4 3 4

Postpartum -< 21 days -21–42 days with risk factors for thromboembolism -Postpartum sepsis -Immediate post-septic abortion

4 3

Rheumatoid arthritis -Receiving immunosuppressive therapy

DMPA 3d

Sexually transmitted infections -Current pelvic inflammatory disease -Purulent cervicitis, chlamydia, gonorrhea -Pelvic tuberculosis

Systemic lupus erythematosus -Positive or unknown antiphospholipid antibodies -Severe thrombocytopenia

LNG-IUD

4

Peripartum cardiomyopathy -Class I or II < 6 mo ≥ 6 mo -Class III or IV

Surgery -Major with prolonged immobility -Gastric bypass (malabsorptive)

Progestin Only

4 3 (oral) 4

Thromboembolism -History of DVT/PE with ≥ 1 risk factorse -History of DVT/PE without risk factorse -DVT/PE during anticoagulation therapy -Known thrombogenic mutations -Superficial venous thrombosis (acute or history)

3 (oral) 3 3c

3

3c

4 3 4 4 3

Tobacco use -< 15 cigarettes/day and ≥ 35 years of age -≥ 15 cigarettes/day and ≥ 35 years of age

3 4

Transplantation -Complicatedf

4

3c

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3c

Obstetrics and Gynecology

Table 4. Contraindications to Hormonal Contraceptives (U.S. Medical Eligibility Criteria 2016 update) (continued) Contraindications to the Various Hormonal Contraceptives and Copper IUD

Definitions: 3 = Condition for which the theoretical or proven risks usually outweigh the advantages of using the method 4 = Condition that represents an unacceptable health risk if the contraceptive method is used Estrogen/ Progestin

Genitourinary -Unexplained vaginal bleeding -Gestational trophoblastic disease with hCG persistently elevated -Endometrial/cervical cancer awaiting treatment -Ovarian cancer -Uterine fibroids with torsion -Distorted uterine cavity Additional Product Contraindications -Contraindication: Wilson disease -Contraindication: BMI > 30 kg/m2

Progestin Only

LNG-IUD

Copper IUD

3 (DMPA)

4c

4c

4 4c 3c 4 4

4 4c 3c 4 4 ✓

✓g

Increased risk of VTE (active or extensive disease, surgery, immobilization, corticosteroid use, vitamin deficiencies, fluid depletion).

a

Classification depends on accurate diagnosis of those severe headaches that are migraines and aura (neurologic symptom). Any new or marked changes in headaches should be evaluated. The concern is risk of stroke associated with 50 mcg of EE contraceptives. See Headache 2017;57:184-93 for more discussion. However, MEC still lists as a level 4.

b

Initiation of product.

c

Only if taking steroids long term or patient has other risk factors for bone fracture.

d

Risk factors include age 35 yr who smoke, previous thromboembolism, thrombophilia, major surgery with prolonged immobility, active cancer (metastatic, on therapy, or within 6 mo after clinical remission). e

Complicated transplantation: graft failure, rejection, cardiac allograft vasculopathy.

f

Transdermal patch

g

BMI = body mass index; DBP = diastolic blood pressure; DMPA = depot medroxyprogesterone acetate; DVT = deep venous thrombosis; EE = ethynil estradiol; hCG = human chorionic gonadotropin; HDL = high-density lipoprotein cholesterol; LDL = low-density lipoprotein cholesterol; PE = pulmonary embolism; SBP = systolic blood pressure; TG = triglycerides; VTE = venous thromboembolism.

F. Drug Interactions (Domain 1, Tasks 2, 3) – According to the Centers for Disease Control and Prevention (CDC) medical eligibility criteria, many of the previously thought drug interactions are not significant enough to avoid concomitant use with hormonal contraceptives (broad-spectrum antibiotics, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, and St. John’s wort) and have received a 1 (no restriction) or 2 (advantages generally outweigh theoretical or proven risks) rating.

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Estrogen/Progestin Vaginal Ring

Estrogen/ Progestin Patch

443

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Other 2 Medications Efavirenz St. John’s wort Nelfinavir Ritonavir-boosted atazanavir/darunavir/ fosemprenavir/saquinavir/tipranavir

2e

3 Avoid

2e

3 Avoid

3

3

3

2e

Drospirenone

3

3

POP

Lamotrigine concentrations are significantly reduced when used as monotherapy with estrogen/progestin contraceptives.

DMPA

2e

Implantable Progestin

LNG IUD

Two, according to the Medical Eligibility Criteria, but the package insert notes that efficacy may be decreased and states to avoid concomitant use.

AUC = area under the curve; EC = emergency contraception; POP = progestin-only pill; SPRM = selective progesterone receptor modulator.

e

Two, according to the Medical Eligibility Criteria, but noted as might reduce effectiveness.

d

c

Note: Antibiotics: The American College of Obstetricians and Gynecologists states that penicillin, ampicillin, doxycycline, fluconazole, miconazole, metronidazole, fluoroquinolones, and tetracycline do not interact with hormone concentrations. The American Medical Association and the Centers for Disease Control and Prevention Medical Eligibility Criteria for hormonal contraceptives state that rifampin is the only major interacting antiinfective but that patients should be notified of low potential interactions with other anti-infectives.

b

a

2d

2d

SPRM

Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2006;61:246-55. Topiramate induces enzymes at doses ³ 200 mg daily.

Drospirenone

3 Avoid

3

3

3 3

3

3

Increased Potassium ACEI ARB Renin inhibitors Potassium-sparing diuretics Aldosterone antagonists NSAID/COX-2 (especially long-term use) Heparin

Antiretroviral therapy Fosamprenavir Glecaprevir/Pibrentasvir

Anti-infectives (see note following table) Rifampin, Rifabutinc

Anticonvulsants (Enzyme inducing) Barbiturates Phenytoin Carbamazepine Felbamate Oxcarbazepine Primidone Topiramatea Vigabatrin Anticonvulsants (other) Lamotrigineb

Definitions: 2 = A condition for which advantages outweigh the theortical or proven risks of using the method 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method

Interacting Agent

Estrogen/ Progestin Oral

Table 5. Drug Interactions with Hormonal Contraceptives (U.S. Medical Eligibility Criteria 2016 update)

Obstetrics and Gynecology

Obstetrics and Gynecology

G. Product Initiation (Domain 1, Tasks 1–5) 1. Interview the patient. a. Preferences (e.g., personal, religious), plans for future pregnancy (if/when), desired frequency of menses (monthly vs. less frequent) b. History with previous products c. Purpose of product (e.g., contraceptive, sexually transmitted infection protection, cycle control, treatment of menstrual-related disorder) d. Adherence e. Partner’s (or partners’) support for various methods f. Cost/insurance coverage 2. Review patient-specific factors to aid with initiation. a. Can use adverse event table to help with initiation. For example, if patient has heavy menses, choose a product with moderate to high progestin activity. b. No need to perform any laboratory tests or examinations before initiation of products, except baseline blood pressure for estrogen/progestin products. Consider baseline weight and body mass index (BMI) to monitor changes. c. Obesity i. Potential for decreased efficacy with oral estrogen/progestin contraceptives when used in patients with obesity with a BMI greater than 30, but data mixed ii. One study found that a traditional pill pack did not provide steady-state levonorgestrel concentrations until cycle day 12 (Contraception 2014;90:550-6). iii. Estrogen/progestin users with obesity have an increased risk of thromboembolism compared with users with a normal BMI (Thromb Haemost 2003;89:493-8; Br J Haematol 2007;139:289-96). iv. Options to provide higher efficacy (a) Copper IUD and LNG-IUD: Maintain efficacy and have minimal weight gain (b) Estrogen/progestin pills: Continuous pill use, 24 active pill packs, can use higher-dose products but may still cause a delay in achieving steady state (Contraception 2014;90:550-6; Obstet Gynecol 2011;117:33-40) (c) Estrogen-progestin vaginal ring: Limited data, but no change in efficacy noted (d) DMPA: May cause excessive weight gain d. Contraindications e. Drug interactions H. Education (Domain 1, Tasks 5, 6) 1. Purpose 2. Proper use a. Initiation if reasonably certain the patient is not pregnant (patient has to meet one criterion of the following [i–v]): products can be initiated on the first day of menses, first Sunday after menses, or day prescribed (quick jump-start) (from CDC U.S. Practice Recommendations, 2016). i. 7 or fewer days from onset of menses, spontaneous abortion, or elective abortion ii. No intercourse since onset of latest menses iii. Has been correctly and consistently using current form of contraception iv. Is within 4 weeks postpartum v. Is currently breastfeeding at least 85% of time, is still experiencing amenorrhea, and is fewer than 6 months postpartum (a) Can initiate if uncertain about pregnancy status: Benefits of initiating a contraceptive likely outweigh any potential risk, except with IUD. If a product is started (except IUD), consider checking a pregnancy test result in 2–4 weeks to confirm pregnancy status.

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(b) Take at any time of the day, but bedtime administration may help with nausea. (c) Patient to select administration time for ease/convenience to improve adherence. (d) Backup method of contraception or abstinence with initiation if more than 5–7 days after onset of menses (1) 5 days: estrogen/progestin products, implant, POPs (2) 7 days: LNG-IUD, injectable b. Encourage taking consistently. Pill users should be encouraged to take around the same time. i. Set up a routine. ii. Use reminders (phone, calendar, medication alert apps) for daily, weekly, and monthly products. c. Demonstrate correct use for the patient and/or feel the device placement. Demonstration devices are often available from the manufacturer (e.g., patches, rings, IUDs, implants). 3. Potential adverse drug reactions a. Common i. Breakthrough bleeding, spotting, nausea, breast tenderness, weight gain (cyclic verus noncyclic), fluid retention, dizziness, sexual adverse drug events, mood changes ii. Symptoms may improve after three cycles, so generally wait until after three cycles before changing. b. Serious: Warrant emergency department visit i. A: Abdominal pain ii. C: Chest pain (severe), cough, shortness of breath iii. H: Headache (severe), dizziness, weakness, or numbness; speech problems iv. E: Eye problems (vision loss or blurring) v. S: Severe leg pain (calf or thigh) 4. Missed doses (Domain 1, Tasks 2-5) Table 6. U.S. Medical Eligibility Criteria Recommendations After Late or Missed Combined Oral Contraceptives Late or Missed Pills

Time in Cycle Management

1 pill late (< 24 hr)

Anytime

≥ 2 pills missed (≥ 48 hr)

Weeks 1–2

1 pill missed (24–48 hr)

Week 3

-Take late/missed pill as soon as possible -Continue remaining pills as scheduled -No backup is needed -EC is not usually needed but can be considered (except ulipristal) if pills were missed earlier in the cycle or last week of the previous cycle

-Take the most recent missed pill as soon as possible; discard other missed pills -Continue remaining pills as scheduled -Use backup method or avoid sexual intercourse until hormone pills have been taken for 7 consecutive days -EC should be considered (except ulipristal) if hormone pills were missed during the first week and unprotected sexual intercourse occurred in the previous 5 days -EC may also be considered at other appropriate times As above, plus: -Omit the hormone-free interval by finishing the hormone pills and start a new pack the next day -If unable to start a new pack, use a backup method or avoid sexual intercourse until hormone pills from the new pack have been taken for 7 consecutive days

Information from: Centers for Disease Control and Prevention (CDC). Update to CDC’s U.S. medical eligibility criteria for contraceptive use, 2016: revised recommendations for the use of contraceptive methods during the postpartum period. MMWR 2016;65:1-104; Natazia [package insert]. Whippany, NJ: Bayer 2017.

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5. Use of backup methods a. Length of time to use backup methods i. All products except for norethindrone POPs and Natazia: 7 days ii. Natazia: 9 days (according to the package insert) iii. Norethindrone POP initiation: 48 hours b. Situations when backup method is needed i. Product initiation if initiating after cycle days 5–7 or unknown cycle day ii. With drug interactions that decrease efficacy: During interacting drug and for 7–9 days afterward iii. If severe diarrhea and/or vomiting (a) Lasts for more than 48 hours for oral estrogen/progestin contraceptives (b) Occurs within 3 hours of taking a norethindrone POP (c) Lasts more than 1 day for drospirenone POP (package insert) iv. If a norethindrone POP dose is more than 3 hours late, use backup method for 48 hours. v. With missed doses (as stated previously) 6. Follow-up appointments a. Any time patient wants to discuss adverse events or alternative choices or needs refills b. At routine visits: Review satisfaction, adverse events, concerns, and changes in health status. Review drug interactions, check blood pressure (if using/wanting an estrogen containing product) and contraindications for changes in health status. Change as appropriate. I. Permanent Contraception: Surgery (tubal ligation, total abdominal hysterectomy with or without bilateral salpingo-oophorectomy) J. Emergency Contraception (EC) (Domain 1, Tasks 1–5) 1. Product dosing Table 7. EC Options Class

Progestin only

Selective progestin receptor modulator

Dose

Levonorgestrel 1.5 mg for one (many; dose example: Plan B One-Step)

Ulipristal (Ella) 30 mg × 1 dose

Yuzpe method

IUD

Drug

Estrogenprogestin (ethinyl estradiol plus levonorgestrel or norgestrel) Copper IUD

Initiate Within…

72 h per FDA; studies support 120 hr but may have decreased efficacy 120 hr

One dose q12hr × 72 hr 2 doses (number of tablets per dose varies depending on product used; see note) IUD

120 hr

MOA

Notes

Before ovulation -Prevent/delay ovulation

No age or dispensing restrictions May be less effective with BMI > 25 kg/m2

Prevent implantation

Serves as regular contraceptive afterward

Prescription only After ovulation -Limited to no May be less effective effects with BMI > 35 kg/m2 -May prevent implantation Uses current OC if patient receives at least If embryo 100 mcg of ethinyl implanted, estradiol and 500 mcg EC will not of levonorgestrel per interrupt dosea

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Table 7. EC Options (continued) Class

Drug

Levonorgestrel Levonorgestrel IUD IUD (Mirena)

Dose

IUD

Initiate Within…

120 hr

MOA

Notes

One trial found it noninferior to the copper IUD. Failure rate was 1/317 for levonorgestrel IUD and 0/321 for copper IUD ( N Engl J Med 2021;384:335-44)

ACOG recommends using this website for products and doses for the Yuzpe method: https://ec.princeton.edu/questions/dose.html#dose.

a

MOA = mechanism of action; OC = oral contraceptive; OTC = over the counter; q = every.

Patient Case 3. A 17-year-old patient is crying in the examination room, saying she does not know what to do. She tells you that she had chlamydia a few months ago and was shocked, so she did not have sex again until a few days ago with her new boyfriend. Because she did not want to have chlamydia again, they used male and female condoms, but both broke. She is afraid she has chlamydia again because of vaginal discharge and fears getting pregnant. She wants to know whether her tests are back and what she can use for EC. Her laboratory tests just resulted in the electronic medical system and were positive for chlamydia and trichomoniasis. Her medical history includes chlamydia (4 months ago) and acne. After discussing it with you, her provider plans to prescribe doxycycline 100 mg twice daily for 7 days and metronidazole 500 mg twice daily for 7 days today. Her current medications include OTC adapalene at bedtime. Which is the best recommendation? A. B. C. D.

Recommend Plan B One-Step (levonorgestrel 1.5 mg) every 12 hours for two doses. Recommend a levonorgestrel IUD today. Recommend ulipristal 30 mg for one dose. Refuse EC because it has been too long since unprotected intercourse.

2. Contraindication: Pregnancy. (If a woman takes while pregnant, no harm to pregnancy or fetus is expected. ACOG bulletin No. 152) 3. Education a. Purpose b. Proper use c. Patient still needs a regular form of contraception for future intercourse. 4. Potential adverse events (Yuzpe method > progestin only > selective progestin receptor modulator) a. Nausea (50% > 13%–23% > 12%) for up to 2 days, bloating, menstrual cramps, headache b. Give an antiemetic (e.g., metoclopramide 10 mg, meclizine 50 mg, or other antiemetic) 1 hour before Yuzpe method or other methods if there is concern about nausea. Meclizine is available over the counter in 25-mg tablets. c. IUD: Abdominal cramping, heavy bleeding, spotting, and breakthrough bleeding 5. Menstrual changes a. Start date and amount of blood loss during menses vary after progestin-only pill EC. b. If taken before ovulation, early onset of menses (3–7 days) is common. c. If taken post-ovulation, normal to late onset of menses is common. d. Breakthrough bleeding and spotting can occur.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 447

Obstetrics and Gynecology

e. Ulipristal extends cycle by a mean of 2.5 days. f. ACOG recommends taking a pregnancy test if menses is more than 1 week late. 6. Restarting regular contraceptives a. Barrier method immediately b. Yuzpe and levonorgestrel: hormonal contraception the day after Yuzpe or levonorgestrel. c. Ulipristal: wait 5 days 7. Pharmacist-provided contraceptive services access (https://www.birthcontrolpharmacies.com/) K. Nonhormonal Contraception Options (independent study) (Domain 1; Tasks 1–5) Table 8. Comparison of Nonhormonal Contraceptives Failure Rate Sexually in Typical Use/ Transmitted Perfect Use, Infection Respectively Protection

Product

Male latex condoms

18%/2%

Yes

Male polyurethane condoms

18%/2%

Yesa

18%/2%

Male lamb cecum condoms

Minimum Time Before Efficacy

Single

Avoid oil-based lubricants

Immediate

Single

Can use water- or oil-based lubricants

Yesa

Immediate

Single

Avoid oil-based lubricants

18%/2%

No

Immediate

Single

Can use water- or oil-based lubricants

Female nitrile (FC2 formulation) condoms

21%/5%

Yes

Immediate

Single

Spermicidal foam/gel (nonoxynol-9)

28%/18%

No

Immediate

Single

Can insert up to 2 hr before intercourse Do not use in combination with male condoms Use lubricant if squeaking occurs

Spermicidal film (nonoxynol-9)

28%/18%

No

15 min

Single

28%/18%

No

10–15 min

Single

Male polyisoprene condoms

Spermicidal suppository (nonoxynol-9)

Immediate

Use for Single or Several Acts of Intercourse Notes

Can use if condom breaks Check dosing for individual products Re-dose after 60 min Re-dose after 3 hr

Re-dose after 60 min

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Table 8. Comparison of Nonhormonal Contraceptives (continued)

Product

Spermicidal gel (lactic acid, citric acid, potassium bitartrate)

Contraceptive sponge

Failure Rate Sexually in Typical Use/ Transmitted Perfect Use, Infection Respectively Protection

Minimum Time Before Efficacy

Use for Single or Several Acts of Intercourse Notes

13.7%/6.7% over seven cycles

No

24%/20% (parous)

No

Immediate

Several

16%/6%

No

No

Immediate

Several

2%/0.5%

No

See notes

–

Immediate

Single

12%/9% (nulliparous)

IUD (copper) Diaphragm

Lactational amenorrhea

0.8%/0.6%

Immediate

Several

Approved 2020 Re-dose after 60 min Compatible with all condoms Avoid using with vaginal rings or in patients with a history of recurrent urinary tract infections or urinary tract abnormalities

Do not use if structural abnormalities, history of toxic shock syndrome, during menses, or < 6 wk postpartum Can insert up to 24 hr before intercourse Leave in place for 6 hr after intercourse (max 30 hr) Check for strings monthly

Use with spermicidal gel Reapply gel with each act Leave in place for 6 hr Need to be remeasured after miscarriage/abortion, postpartum, a 6.8-kg (15 lb) weight change, after lactation

All criteria must be met for adequate pregnancy prevention Amenorrhea Fully or almost fully breastfeeding < 6 mo postpartum Can provide effects for 6 mo but generally need backup method after 6 wk postpartum

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Table 8. Comparison of Nonhormonal Contraceptives (continued) Failure Rate Sexually in Typical Use/ Transmitted Perfect Use, Infection Respectively Protection

Product

Calendar method

Minimum Time Before Efficacy

13%/5%

No

N/A

No

See notes

–

Standard days method

12%/5%

No

See notes

–

2-day method

14%/4%

No

See notes

–

Cervical mucus method

22%/3%

No

See notes

–

Basal body temperature

See notes

Use for Single or Several Acts of Intercourse Notes –

To calculate time that is unsafe for intercourse (fertile time): First fertile day: Average cycle length (days) – 18 Last fertile day: Average cycle length (days) – 11 Unsafe during these days of the cycle

Check temperature daily before any movement An increase of 0.4°F notes ovulation; safe time is 3 days after this day to menses

Menses cycles need to occur every 26–32 days. Do not use if two or more cycles within a year are outside this length Use backup contraception or avoid intercourse on cycle days 8–19

Monitor vaginal secretions twice daily. If any secretions present yesterday or today, the patient is fertile Check cervical mucus daily for amount and characteristics Unsafe from detection of cervical mucus until 3 days after peak mucus Peak mucus is clear, increased production and elasticity Postovulation mucus thickens, may be white, low elasticity

FDA labeling restricts use to latex sensitive-allergy.

a

max = maximum; N/A = not applicable.

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Obstetrics and Gynecology

II.  MENSTRUAL DISORDERS Patient Case 4. A 42-year-old woman was referred to the office by her local pharmacist because her heavy bleeding was not improving with ibuprofen. She says that her menstrual cycles have always been heavy but that now, they seem excessive and are coming every 2.5–3 weeks. She admits feeling tired and having shortness of breath with longer walks. She admits craving corn starch and eating a jar over 3 days. She states that she would be willing to use a contraceptive. Her blood pressure today was 130/72 mm Hg. Her BMI is 29 kg/m2. Her laboratory test results today show hemoglobin 9 g/dL, hematocrit 28%, mean corpuscular volume 77 fL/red cell, red cell distribution width 14%, platelet count 180,000/mm3, percent iron saturation 2%, and ferritin 5 ng/mL. Her comprehensive metabolic panel and thyroid stimulating hormone concentrations were normal. Her hCG was negative. Her medical history is significant for dysmenorrhea, DVT (occurred when 20 years old), and uterine fibroids. Her current medication is ibuprofen 600 mg every 6 hours as needed for pain (uses during each menses). Which is the best recommendation? A. B. C. D.

LNG-IUD (Liletta). Estrogen/progestin pill (Portia). Estrogen-progestin vaginal ring (NuvaRing). Tranexamic acid (Lysteda).

A. Amenorrhea (Domain 1; Tasks 2–5) 1. Definitions (Obstet Gynecol 2015;126:e143-6) a. Primary: absence of menarche by 15 years of age with the presence of secondary development or absence of menarche by 13 years of age in the absence of secondary development b. Secondary: absence of menses for 6 months if cycles were previously irregular or three cycles if cycles were previously regular c. Symptoms include menses cessation. Other symptoms vary depending on potential cause. 2. Treatment a. Always rule out pregnancy. b. Ensure adequate calcium (1000 mg) and vitamin D (400 units) daily. c. Correct underlying etiology. i. Functional hypothalamic amenorrhea (includes anorexia or excessive exercise) (J Clin Endocrinol Metab 2017;102:1413-39.) (a) Decrease exercise and encourage weight gain. In secondary amenorrhea, one study found that weight gain of 2 kg or more above the weight when menses stopped is needed to resolve amenorrhea (Arch Pediatr Adolesc Med 1997;151:16-21). Guidelines recommend an adequate trial of nonpharmacologic therapy as first line. (b) Psychological therapy such as cognitive behavioral therapy (c) Transdermal estradiol with cyclic progestin to help prevent bone loss. Oral contraceptives (or ethinyl estradiol) do not protect against bone loss and should not be used solely for bone health and restarting menses. (d) Avoid using bisphosphonates, denosumab, testosterone, and leptin to increase bone mineral density. Rarely, recombinant parathyroid hormone can be considered if patients experience delayed fracture healing and very low bone mineral density. (e) If the patient is sexually active, contraceptives (either hormonal or non-hormonal) are needed because ovulation can occur before the return of menses. If estrogen/progestin products are used, the guidelines recommend educating patients that spontaneous menses return may be masked and continued bone loss can occur, especially if the patient has an energy deficiency while using estrogen/progestin contraceptives. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 451

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ii. Secondary treatment (a) Estrogen-progestin contraceptives (b) Conjugated equine estrogens 0.625–1.25 mg/day on cycle days 1–25 (c) Estradiol patch 50 mcg/day iii. Hyperprolactinemia (a) Cabergoline 0.25 mg twice weekly; then titrated as needed: Has higher efficacy and improved tolerability than bromocriptine (N Engl J Med 1994;331:904-9) (b) Bromocriptine 2.5 mg three times daily iv. PCOS (see lecture for more details) (a) Desires pregnancy (1) Letrozole if attempting pregnancy (see infertility) (2) Clomiphene (3) Metformin (with or without clomiphene) (b) Does not desire pregnancy (1) Estrogen-progestin contraceptives (2) Progestin only contraceptives (LNG-IUD, DMPA) (3) Metformin v. Unknown secondary (a) Medroxyprogesterone acetate 5–10 mg every day on cycle days 14–25 (95% efficacy to induce menses) (b) Micronized progesterone 400 mg/day for 7–10 days (90% efficacy to induce menses) (c) Vaginal progesterone gel 1.125 g of 4% gel every other day × 6 doses. Increase to 8% if no response (d) Norethindrone 5 mg daily for 7–10 days (e) Estrogen/progestin therapy (estrogen/progestin contraception, transdermal estrogen-cyclic progestin, oral estrogen-cyclic progestin) vi. Other (a) Procedures/surgery may be needed for structural abnormalities. (b) Genetic testing may be required for further evaluation and guiding therapy. B. Anovulatory Bleeding/Dysfunctional Uterine Bleeding (Domain 1; Tasks 2-5) 1. Definition: Menstrual bleeding that occurs because of disorganized menstrual system from irregular or absences of ovulation a. Without ovulation, progesterone is not produced, and the endometrium continues to thicken without regulation. Eventually, the thickened endometrium irregularly sloughs off, causing irregular and sometimes heavy bleeding. b. Adolescent anovulatory bleeding is normal for up to 5 years because of an immature hypothalamuspituitary-ovarian axis. 2. Treatment a. Ensure intake of at least 1000 mg of elemental calcium and 400 units of vitamin D. b. Estrogen/progestin contraceptives c. Progestin-only contraceptives, including LNG-IUD d. Treat any underlying etiologies (PCOS, hyperprolactinemia). e. Dilation and curettage C. Dysmenorrhea (Domain 1; Tasks 2-5) 1. Definition: Cramping and pelvic pain just before and/or during menses a. Primary: Normal pelvic anatomy b. Secondary: Pelvic abnormalities ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 452

Obstetrics and Gynecology

2. Treatment a. Nonpharmacologic recommendations i. Ensure intake of at least 1000 mg of elemental calcium and 400 IU of vitamin D. ii. Sleep iii. Apply heat (hot baths, heating pads, heating patches). iv. Exercise v. Low-fat vegetarian diet vi. Smoking cessation b. Nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors started 1–2 days before menses and continue scheduled dosing for 48–72 hours after the onset of menses i. Naproxen 220–550 mg twice daily for 1–2 days before menses; then 275 mg every 6–12 hours ii. Ibuprofen 200–800 mg three times daily iii. Diclofenac 50 mg three times daily iv. Celecoxib 400 mg initially; then 200 mg twice daily c. Estrogen/progestin contraceptives i. Prefer levonorgestrel or norgestrel products ii. Prefer extended-interval dosing d. Levonorgestrel IUD e. Medroxyprogesterone acetate (Depo-Provera) D. Heavy Menstrual Bleeding (previously termed menorrhagia) (Domain 1; Tasks 2-5) 1. Definition: Menstrual blood loss of at least 80 mL per cycle or menses that lasts greater than 7 days 2. Treatment a. Contraception desired i. LNG-IUD. Most effective treatment and reduces blood loss by 79%–97% ii. Estrogen/progestin contraceptive. Natazia is FDA approved for this, but any can be used. Reduces blood loss by 40%–50% iii. Surgery b. Contraception not desired i. NSAIDs during menses. Reduces blood loss by 10%–51%. More effective than placebo but less effective than tranexamic acid, danazol, and LNG-IUD (Cochrane Database Syst Rev 2013;1:CD000400) ii. Progesterone (norethindrone acetate or medroxyprogesterone acetate) for 21 days starting on cycle day 5. Reduces blood loss by 37%–87% iii. Tranexamic acid 1.3 g three times daily during menses (maximum 5 days). May increase risk of thrombosis. Reduces blood loss by 34%–60% iv. Elagolix with add-back estrogen has been effective for heavy menstrual bleeding in patients with uterine fibroids (N Engl J Med 2020;382:328-40). v. Ulipristal 5–10 mg daily for 3 months (for uterine fibroids and adenoymyosis) vi. Surgery (endometrial ablation, hysterectomy) E. Premenstrual Syndrome and Premenstrual Dysphoric Disorder (Domain 1; Tasks 2-5) 1. Definition a. Premenstrual syndrome: Physical symptoms with mild mood disorder that resolves with the onset of menses. Please see the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). b. Premenstrual dysphoric disorder: Severe mood disorder that occurs during the luteal phase of the menstrual cycle and that interferes with work or social life. Please see the DSM-V for full criteria (American Psychiatric Association 2013).

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2. Treatments a. Nonpharmacologic i. Well-balanced diet that includes complex carbohydrates and that is low in fat and low in caffeine, refined sugar, and sodium ii. Exercise iii. Support groups and counseling b. Nutritional supplements i. Vitamin B6 50–100 mg/day (meta-analysis supports use for PMS and PMDD; Arch Womens Ment Health 2013;16:279-91) ii. Calcium elemental 600 mg twice daily (Can Pharm J 2009;142:228-33) c. Antidepressants daily during at least the luteal phase or continuously i. Citalopram 10–30 mg ii. Escitalopram 10–20 mg iii. Fluoxetine 10–20 mg iv. Fluvoxamine 50 mg v. Paroxetine 10–30 mg vi. Sertraline 25–150 mg vii. Venlafaxine 50–200 mg/day viii. Clomipramine 25–75 mg/day d. Estrogen/progestin contraceptives. Ethinyl estradiol 20 mcg and levonorgestrel 90 mcg reduced symptoms by 30–59%. Consider continuous use or stacking packs for longer cycles. FDA-approved product for improving premenstrual symptoms in women with PMDD: Ethinyl estradiol 20 mcg plus drospirenone 3 mg product e. Leuprolide 3.75 mg intramuscularly every 3 months. Limited to 3–12 months administration F. Resources (Domain 1, Task 5)) 1. American College of Obstetricians and Gynecologists a. Patient education b. Practice bulletins 2. Association of Reproductive Health Professionals a. Patient education b. Continuing education Patient Case 5. A 38-year-old woman and her partner have been unsuccessful in achieving a pregnancy after 10 months including three cycles of letrozole (including this month). Her menses started 3 days ago. Her medical history is significant for WHO class 2 infertility, PCOS, asthma, and anxiety. Initial evaluation of fertility revealed no additional significant findings in either partner. Her current medications include a prenatal vitamin, albuterol 2 puffs every 6 hours as needed for asthma, fluticasone 44 mcg 2 puffs twice daily, and buspirone 15 mg twice daily. Her laboratory test results were within normal limits. She has an allergy to latex. Which is the best initial therapy for her infertility? A. B. C. D.

Add metformin. Change to follitropin-alfa. Change to clomiphene. Add progesterone for 10 days.

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III.  INFERTILITY A. Evaluation (Domain 1, Tasks 1, 2) 1. Infertility is a challenge for the couple, not just the woman; abnormalities occur in 40%–50% of male partners. 2. Evaluation begins after 12 months except as follows (Fertil Steril 2020;3:533-5). a. Begin after 6 months if the woman is 35–40 years of age. b. Begin without delay if the woman is i. Older than 40 ii. Has any medical history, sexual or reproductive history, or physical findings that suggest the possibility of impaired reproductive function c. If using cryopreserved donor sperm, consider evaluation and therapy before 12 months if the woman is younger than 35 and before 6 months if the woman is older than 35. 3. Evaluation should include both partners to determine the correct type of infertility. B. Types of Infertility (Domain 1, Task 2) 1. Tubal a. Endometriosis: Endometrial tissue outside uterus that increases risk of blockage and scar tissue b. Scar or blockage after PID: Infection of the upper reproductive tract caused by sexually transmitted infections c. Treatment: Surgical and IVF 2. Ovulatory (defined as a history of oligomenorrhea or amenorrhea; luteal phase progesterone concentrations less than 3 ng/mL) a. WHO class 1 – hypogonadotropic hypogonadal anovulation (includes functional hypothalamic amenorrhea) b. WHO class 2 – normogonadotropic normoestrogenic anovulation (includes PCOS) c. WHO class 3 – hypergonadotropic hypoestrogenic (includes primary gonadal failure/ovarian failure, premature ovarian insufficiency, gonadal dysgenesis) d. Hyperprolactinemic anovulation e. Treatment: Lifestyle modifications, medications, and IVF 3. Uterine a. Polyps b. Fibroids c. Congenital/structural abnormalities such as synechiae (uterine adhesions) and müllerian anomalies d. Diethylstilbestrol exposure e. Treatment: Surgical and IVF 4. Cervical factor infertility a. Inadequate/abnormal or abnormal mucus b. Treatment: IUI 5. Unexplained – Treatment: Medications, IUI, and IVF 6. Male infertility (Chapter 26: Male infertility. In: Speroff’s Clinical Gynecologic Endocrinology and Infertility, 9th ed.) a. Idiopathic (40%–50%) b. Primary gonadal disorders (30%–40%) i. Genetic disorders ii. Cryptorchidism iii. Varicoceles iv. Infection (tuberculosis, leprosy, viral orchitis, HIV) v. Radiation

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vi. Environmental gonadotoxins (heat, smoking, metals, organic solvents, pesticides, heavy marijuana use, alcohol, cocaine) vii. Medications (radiation, alkylating agents, antiandrogens, ketoconazole, cimetidine, anabolic steroids) viii. Chronic illness (chronic kidney disease, cirrhosis, cancer, sickle cell disease, amyloidosis, vasculitis, celiac disease) c. Disorders of sperm transport (10%–-20%) i. Dysfunction/obstruction of epididymis ii. Congenital bilateral absence of the vas deferens iii. Infection (gonorrhea, chlamydia) iv. Vasectomy v. Genetic disorders vi. Ejaculatory disorders (retrograde, spinal cord disease, sympathectomy, or autonomic disease) d. Hypothalamus-pituitary disorders (1%–2%) i. Idiopathic ii. Genetic disorders iii. Tumors iv. Hyperprolactinemia v. Medications (gonadotropin-releasing hormone [GnRH] analog, androgens, glucocorticoids, opiates) vi. Critical injury (e.g., head trauma) or infection (e.g., meningitis) vii. Chronic illness/malnutrition (e.g., diabetes) viii. Obesity e. Seek evaluation and treatment with reproductive endocrinologist or specialist for male infertility. C. Nonpharmacologic Treatment (Domain 1, Tasks 3, 4) 1. Avoid medications, products, and activities known to interfere with fertility (e.g., nicotine, alcohol, illicit drugs; Table 9, 10). 2. Achieve a BMI of less than 27 kg/m2 but avoid excessive dieting or overstrenuous exercise. 3. Eat a well-balanced diet. 4. Decrease stress. 5. Take a multivitamin with at least 0.4 mg of folic acid (preferably 1 mg). 6. Avoid water-based lubricants. If a lubricant is needed, use hydroxyethylcellulose-based products. 7. Have intercourse every 1–2 days in the 6 days before expected ovulation, as desired. 8. Test for ovulation. D. Medications Known to Decrease Fertility (Domain 1; Tasks 2, 3) Table 9. Medications Known to Increase Prolactin Values

Chlorpromazine

Medroxyprogesterone acetate Reserpine

Cimetidine

Estrogen

Tricyclic antidepressants

Verapamil

Methyldopa

Phenothiazines

Table 10. Medications and Substances Known to Decrease Sperm Activity

Allopurinol Colchicine

Anabolic/androgenic steroids

Nitrofurantoin

Caffeine

Spironolactone

Calcium channel blockers

Sulfasalazine

Haloperidol Pimozide

Chemotherapeutic agents Tetracycline

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 456

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E. Pharmacologic Treatment (Domain 1; Tasks 3, 4)) 1. Role of hormones a. Follicle-stimulating hormone (FSH): Matures egg (initial) (exogenous FSH: stimulates granulosa cell proliferation and follicular growth and aids in estradiol production) b. Luteinizing hormone (LH): Final egg maturation (stimulates theca cells to produce androgens that are aromatized to estrogen in the granulosa cells, promotes larger follicle development) and stimulates ovulation c. Human chorionic gonadotropin i. Structurally similar to LH ii. Mimics LH to trigger ovulation d. Progesterone i. Induces menses when used for short courses ii. Provides luteal support to help thicken endometrium to support a pregnancy 2. Definitions a. Ovulation induction: Goal is produce a single follicle. b. Ovarian stimulation: Goal is to stimulate development of multiple follicles as part of assistive reproductive technology (including IVF). i. The FDA has rules and requires outcome reporting. ii. Depending on patient-specific factors such as age, providers may start immediately with IVF rather than trying ovulation induction. iii. The three parts of IVF are ovarian stimulation (involves pharmacotherapy), embryo creation, and embryo transfer (involves pharmacotherapy). (a) Ovarian stimulation: GnRH agonist or antagonist to suppress the natural hypothalamuspituitary-ovarian axis. This prevents unpredictable follicle recruitment and ovulation. Class used can depend on whether using the long or short protocol. (b) Ovarian stimulation part 2: Gonadotropin therapy (FSH/LH or FSH plus human chorionic gonadotropin [hCG]). This provides controlled follicle recruitment with optimally timed ovulation/egg retrieval. iv. Adjunctive therapies (a) Estrogen: May be used to help prepare uterine lining before embryo transfer (b) Progesterone: Provides luteal support to decrease early pregnancy loss (c) Other therapies that may be used to improve clinical pregnancy rates: dexamethasone, vitamin D, testosterone, omega-3 fatty acids, sildenafil 3. Medication treatment by female infertility type a. Ovulatory WHO type 1 i. Ovulation induction: step 1 (a) Nonpharmacologic and behavioral therapy to improve diet, optimize exercise, improve energy balance and weight gain (b) Unlikely to respond to oral agents (clomiphene, letrozole) ii. Ovulation induction: step 2 (a) Gonadotropin therapy (FSH/LH, FSH plus hCG) and progesterone iii. IVF b. Ovulatory WHO type 2 i. Ovulation induction: step 1 (a) Letrozole (b) Alternative: clomiphene (c) Metformin can be added to help with insulin resistance. ii. Ovulation induction: step 2 (see above) iii. IVF ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 457

Obstetrics and Gynecology

c. Ovulatory WHO type 3 i. IVF ii. Donor eggs and embryo transfer d. Ovulatory as the result of hyperprolactinemia i. Cabergoline ii. Bromocriptine e. Unexplained infertility i. Ovulation induction (American Society of Reproductive Medicine [ASRM] recommends up to three or four cycles) (a) Clomiphene plus IUI (b) Alternative: letrozole plus IUI (c) ASRM recommends against using gonadotropin therapies. ii. If failed ovulation induction, immediately start IVF to improve success rate (ovarian stimulation therapy used) 4. Assistive reproductive technologies a. IUI b. IVF and embryo transfer

Figure 1. Hypothalamus-pituitary-ovary axis.

FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = leutinizing hormone.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 458

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Table 11. Comparison of Medications for Infertility (independent study) Step

Drug

Adverse Events

Ovulation induction level 1 (ovulatory dysfunction and unexplained infertility)

Clomiphene 80%–85% of patients will ovulate; 40%–50% of patients will become pregnant in 6 mo

Multiple gestation about 6% Vasomotor symptoms, abdominal pain, bloating, breast tenderness, vaginal dryness, moodiness (10%) Thickened cervical mucus Visual disturbances (2%) Discontinue if patient experiences: Weight gain Increased mittelschmerz Abdominal symptoms (discomfort, distention, bloating, abnormal uterine bleeding) (6%)

Ovulation induction level 1 (ovulatory dysfunction and unexplained infertility)

Letrozole 44%–90% of patients with PCOS will ovulate; 9.7%–40% of patients with PCOS will become pregnant

Vasomotor symptoms, headache, breast tenderness, fatigue, dizziness (> 10%) Multiple gestation (about 2%–3%)

Adjunct in patients with PCOS

Metformin

Abdominal symptoms (nausea, diarrhea) Often continued through first trimester of pregnancy because it can decrease risk of spontaneous abortion

Miscellaneous

25–50 mg/day for 5 days and started on cycle day 3, 4, or 5; increase by 25–50 mg/day per cycle to maximum 150 mg/ day until ovulation occurs Basal body temperature monitoring not recommended Monitor for ovulation with ovulation kit. Sometimes blood concentrations or ultrasonography is used If no pregnancy within three or four cycles, consider alternative therapy Need normal liver function test results and estrogen values before therapy initiation Use for > 12 mo increases risk of ovarian cancer Ovulation typically occurs on cycle days 14–19 Unexplained infertility: first line when combined with IUI

Letrozole 2.5–5 mg/day for 5 days started on cycle day 3, 4, or 5 Anastrozole 1 mg/day for 5 days started on cycle day 3, 4, or 5 Higher efficacy than clomiphene in treatment-naive patients with PCOSa Effective in clomiphene-resistant patients Limited data for safety in pregnancy after exposure, but potential for increased spontaneous abortions PCOS: preferred therapy Unexplained infertility: alternative therapy when combined with IUI 500 mg orally daily with meals titrated to 850–1000 mg PO BID with meals More effective than placebo in patients with PCOS but less effective than letrozole and clomiphene Combination with clomiphene and letrozole increased ovulation and clinical pregnancy rates but did not improve live birth rates Used to help with insulin resistance

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 459

Obstetrics and Gynecology

Table 11. Comparison of Medications for Infertility (independent study) (continued) Step

Drug

Adverse Events

Ovulation induction Gonadotropins level 2 (ovulatory (FSH + LH, FSH dysfunction, only) clomiphene failure, Human menopausal assistive technologies) gonadotropins (contain FSH and LH; menotropin) Recombinant products (contain FSH; follitropin alfa, follitropin beta)

Hyperstimulation Multiple gestation (11%–44%) Febrile reaction (10%–15%) Abdominal pain, nausea, vomiting, diarrhea (10%–12%) Injection site reaction Dry skin, rash, alopecia, hives

hCG (human and Ovulation induction recombinant level 2 (used in chorionic combination with FSH gonadotropin) products)

Hyperstimulation (3%) Enlargement or rupture of preexisting ovarian cysts Headache Irritability Aggressive behavior Restlessness, fatigue Depression Edema (especially with long periods in patients with epilepsy, migraines, asthma, or cardiac or renal disease) Injection site reactions (10%–13%)

Ovulation induction level 3 (failure of gonadotropin)

GnRH

Hyperstimulation Multiple gestation (8%–12%) Pump-related issues Injection site reactions

Miscellaneous

Ovulation induction: Initial dose of 37.5–75 international units/day but often started on the low side to decrease risk of multifetal gestation. If no follicles > 10 mm after 7 days, dose can be increased in small increments Ovarian stimulation: short and long protocols used Recombinant products are administered SC, whereas human products are administered IM Not recommended for women with WHO 3 ovulatory infertility (ovarian failure, FSH > 30 mIU/mL) because of lack of response Avoid if first degree of ovarian failure (FSH > 30 mIU/mL) Requires ultrasound monitoring for follicular development Requires luteal support Men: Decreased spermatogenesis from primary or secondary pituitary dysfunction 5000–10,000 international units or 250 mcg (recombinant) 3–4 days after clomiphene or if follicle is 16–18 mm on ultrasonography Recombinant products are administered SC, whereas human products are administered IM Requires ultrasound monitoring Luteal support needed

Pulsatile release by pump customized

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 460

Obstetrics and Gynecology

Table 11. Comparison of Medications for Infertility (independent study) (continued) Step

Drug

Ovulation induction level 3 (suppress female hypothalamuspituitary-ovarian axis, assistive technologies)

GnRH agonist Nafarelin Leuprolide

Ovulation induction level 3 (suppress female hypothalamuspituitary-ovarian axis, assistive technologies)

GnRH antagonist Ganirelix Cetrorelix

Luteal support and/or induce menses

Progesterone

Hyperprolactinemia

Adjunct

Adverse Events

Miscellaneous

Ovarian cysts (15%) Multiple gestation (8%) Bone loss Vaginal bleeding Pelvic pain Breast tenderness Estrogen deficiency

Given in long or short protocol Expense limits use Requires patient to use FSH/LH or FSH + hCG products; then progesterone support

Visual disturbances D/C product: Abdominal pain, cramps Bloating Headache Breast pain, enlargement Fatigue Nausea Constipation Mood swings, depression, nervousness Cervical mucus

If a pregnancy occurs, it is usually continued 10–12 wk Induce menses: administer for 6–14 days. One study found higher pregnancy rates if progesterone was not used to induce menses Products: Vaginal suppositories or insert: BID-TID Crinone gel: QD-BID Micronized progesterone 200-mg capsules inserted vaginally BID-TID; this product may contain peanut oil Sometimes added to ovulation induction level 1 therapy; required in levels 2 and 3

Ovarian hyperstimulation (2.4%–3.5%) Nausea, abdominal pain (4.8%) Fetal death (3.7%) Headache (3%) Vaginal bleeding (1.8%) Injection site reactions

Given in long or short protocol Axis returns to baseline 1–2 mo after discontinuation Requires patient to use FSH/LH or FSH + hCG products; then progesterone support

Bromocriptine Cabergoline

Nausea, vomiting, constipation (49%) Headache (19%) Dizziness (17%) Orthostatic hypotension (6%)

Sildenafil

Headache Flushing Blurry vision Nausea Dyspepsia Vaginal irritation

Bromocriptine 1.25 mg at bedtime for 1 wk and titrate Cabergoline 0.25 mg twice weekly and titrate Slow titration to decrease adverse events Administer at bedtime with food Barrier contraception often used until normal ovulation pattern established

Used to enhance endometrial thickness to improve implantation and decrease risk of spontaneous abortion 25–100 mg/day inserted vaginally or 25 mg orally up to three times daily for up to 11 days

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Table 11. Comparison of Medications for Infertility (independent study) (continued) Step

Adjunct

Drug

Dexamethasone

Adverse Events

Increased urination Headache Nausea Fatigue

Miscellaneous

Used in in vitro fertilization before and during implantation to improve implantation rates Sometimes used in combination with clomiphene for patients with PCOS 0.5–4mg at bedtime

Franik S, Kremer JAM, Nelen WLDM, et al. Aromatase inhibitors for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev 2014;2:CD010287.

a

BID = twice daily; D/C = discontinue; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LFT = liver function test; LH = luteinizing hormone; PCOS = polycystic ovarian syndrome; PO = oral(ly); QD = every day; TID = three times daily.

5. Risks associated with treatment a. Multiple gestation i. Ovulation induction: ASRM recommends cycle cancellation to reduce the risk of multifetal gestation (a) More than two follicles of 16 mm or greater develop (b) Three or more follicles of 10 mm or greater develop b. Ovarian hyperstimulation syndrome i. Risk with high-dose gonadotropins or GnRH agents ii. Exact mechanism unknown iii. Cabergoline can be used as prevention. iv. Symptoms begin 3–10 days after ovulation or hCG injection. (a) Weight gain greater than 1.4 kg (3 lb) in 2 days (b) Sudden onset of abdominal swelling, abdominal pain (c) Continued nausea, vomiting (d) Difficulty breathing (e) Decreased urination (f) Difficulty tolerating fluids (g) Other symptoms such as facial numbness, weakness, lower-extremity edema, or redness v. Discontinue current cycle. Restart next cycle with lower doses and/or slower titration. F. Education (Domain 1, Task 5) 1. Proper use of ovulation detection a. Urine LH kits. Easy to use. i. Patients need to check daily (usually afternoons/evenings) starting 2–3 days before the LH surge is expected. ii. Stop checking once a positive test occurs. iii. Ovulation usually occurs 14–26 hours (within 48 hours) after detection. iv. Check after completing clomiphene/aromatase inhibitors. b. Basal body temperature monitoring (oral, vaginal) i. Less accurate with clomiphene ii. Some devices are expensive iii. Optimal fertility timing of intercourse (every other day) starting 7 days before earliest increase in temperature c. Serum progesterone i. Concentrations greater than 3 ng/mL ii. Needs to be checked on cycle days 22–25

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d. Ultrasound monitoring i. Expensive but accurate ii. Used with ovulation induction levels 2 and 3 e. Considerations when selecting methods: Accuracy, cost, ease of use, interactions with conditions and medications 2. Medications: Purpose, proper use, and potential adverse events and risks 3. When to notify physician for symptoms of ovarian hyperstimulation syndrome (see above) 4. Support groups (RESOLVE: The National Infertility Association) and counseling

IV.  ENDOMETRIOSIS (INDEPENDENT STUDY) A. Definition: Endometrial Tissue Found Outside the Uterus; Associated with Pain, Scarring, and Infertility B. Treatment (Domain 1; Tasks 3, 4) 1. Asymptomatic patients: No treatment, and monitor for pain 2. Symptomatic a. Nonsteroidal anti-inflammatory drugs i. Role: Decrease pain ii. Agents (a) Ibuprofen 400 mg every 4–6 hours (b) Naproxen 250 mg every 4–6 hours iii. Cost: Low b. Estrogen-progestin contraceptives i. Role: Decrease pain, decrease menstrual flow, decrease endometrial implants. Can use contraceptives continuously to suppress menses ii. Cost: Low c. Progestins i. Role: Decrease pain, decrease menstrual flow, and induce atrophy of endometrial implants ii. Agents (a) Depot medroxyprogesterone acetate 150 mg intramuscularly or 104 mg subcutaneously every 12 weeks (b) Levonorgestrel 20 mcg/day IUD iii. Cost: Low d. Gonadotropin-releasing hormone agonist (in combination with add-back therapy) i. Role: Decrease pain, suppress menses, and induce atrophy of endometrial implants ii. Agents (a) Leuprolide 11.25 mg intramuscularly every 3 months (b) Goserelin 3.6 mg subcutaneously every month (c) Nafarelin 200 mcg one spray intranasally twice daily (d) Triptorelin 3.75 mg intramuscularly every 3 months (e) Elagolix 150 mg orally once daily for a maximum of 24 months. Endometriosis with dyspareunia: 200 mg orally twice daily for a maximum of 6 months iii. Adverse events: Estrogen deficiency effects such as vasomotor symptoms, vaginal dryness, bone loss

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iv. Add-back estrogen therapy should be initiated with the product to decrease the risk of bone loss and improve tolerability. (a) Norethindrone 5 mg is FDA approved as add-back therapy (available with leuprolide as Lupaneta Pack). (b) Oral conjugated equine estrogen 0.625 mg and norethindrone 5 mg daily (c) Transdermal estradiol 25 mcg twice weekly plus oral medroxyprogesterone 2.5 mg daily v. Ensure adequate calcium (1000 mg) and vitamin D (400 international units) intake. vi. Efficacy is not decreased with add-back therapy and can be initiated with the GnRH agonist. vii. Cost: High e. Danazol 600–800 mg/day in divided doses i. Role: Decrease pain and induce endometrial atrophy ii. Adverse events (a) Androgenic effects such as acne, weight gain, increase in low-density lipoprotein cholesterol (b) Estrogen deficiency effects such as vasomotor symptoms, breast reduction, vaginal dryness, bone loss iii. Cost: Moderate f. Aromatase inhibitors (in combination with progestin only contraceptive, estrogen/progestin contraceptive, or GnRH agonist) i. Role: decreasing estrogen levels by inhibiting the conversion of adrenal androgens to estrogen ii. Agents (a) Anastrazole 1 mg daily (b) Letrozole 2.5 mg daily iii. Adverse events: Estrogen deficiency effects, such as vasomotor symptoms, breast reduction, vaginal dryness, bone loss iv. Combination therapy (a) Estrogen-progestin contraceptives (b) Progestin contraceptives (c) GnRH agonist v. Cost: low to moderate g. Surgery 3. Efficacy a. Continuous dosed improved pain control compared with 28-day cycles and placebo at 6, 12, 18, and 24 months b. Similar efficacy between estrogen-progestin contraceptives, progestin contraceptives, progestin-releasing IUDs, GnRH agonists, and danazol for pain 4. Other: Ensure adequate calcium and vitamin D intake to help maintain bone health. C. Resources (Domain 1, Task 5) 1. Endometriosis.org (www.endometriosis.org/) a. Patient information b. Listing for support groups c. Clinical trial information 2. Endometriosis Association (www.endometriosisassn.org/) a. Patient information b. Listing for support groups c. Clinical trial information

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V.  PREGNANCY AND LACTATION (Domain 1, Tasks 1-5) A. Diagnosis of Pregnancy (independent study) (Domain 1, Tasks 1, 2) 1. Confirmed by the presence of hCG in the serum or urine 2. Human chorionic gonadotropin a. Concentration doubles every 2–3 days and peaks at 8–12 weeks. b. Composed of α and β subunits c. The α subunit has cross-reactivity with LH, thyroid-stimulating hormone, and FSH and may produce false-positive results. d. The β subunit is specific to hCG; used in newer pregnancy tests 3. Home pregnancy tests a. Ninety-seven percent accurate, but 25% false negative b. Ectopic pregnancies may increase the risk of false-negative tests. c. According to FDA minimum sensitivity requirements, devices may take up to 11 days after conception to detect pregnancy. B. Nutrition 1. Folic acid a. At least 0.4 mg of folic acid started 30 days before conception and continued through 12 weeks’ gestation to decrease the risk of neural tube defects. Neural tube forms by 6 weeks’ gestation (ACOG 2017, USPSTF). b. 4 mg for women with a personal history or history of a partner or child with a neural tube defect starting 3 months before conception (ACOG). American Academy of Neurologists recommends at least 0.4 mg daily of folic acid for patients using antiseizure medications. Some providers may still use 4 mg daily. 2. Iron: Requires 27 mg daily during the second and third trimesters for maternal and fetal erythropoiesis 3. Calcium: Requires at least 1000 mg daily for women 18 and older to help with maternal and fetal bone health C. Patient Interactions (Domain 1; Tasks 2–5) 1. Establish trust. a. Do not impose your values on the patient with drug and disease treatment during pregnancy. i. May seek treatment with other medications, herbal products, or illicit drugs ii. May never take prescribed therapy because patient believes all medications are harmful b. Actively listen to the patient. c. Teratogenicity (72% idiopathic, 25% genetic, and 3% medications) 2. Evaluate medication risk. a. Medications i. Evaluate risks with specific percentage, prevalence, etc. ii. Evaluate the background risk (risk of the same abnormality in the general population) with specific percentage, prevalence, etc. iii. Stage of development. Compare the critical time of development for that risk with patient’s current gestational age iv. Dosage-related risks b. Untreated disease i. Risks of abnormal pregnancy outcomes ii. Risks of malformations c. Decide on risks of the medication versus risk of the untreated disease. 3. Educate. a. Purpose b. Proper use ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 465

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c. Potential adverse events i. Maternal ii. Fetal d. Potential risks of untreated conditions i. Incorporate specific information when possible. ii. Timing (risk time for adverse event and current gestational week) iii. Present risk in understandable terms (percentage, prevalence). D. Principles of Medication Use in Pregnancy (Domain 1, Tasks 2, 3) 1. Factors influencing teratogenicity a. Stage at the time of exposure b. Maternal and fetal genotypes c. Dose and duration of exposure d. Specificity of the agent e. Other simultaneous exposures (other drugs or environmental agents) 2. Possible complications of medication exposure a. No effect b. Premature or delayed labor c. Spontaneous abortion d. Malformations—Major or minor e. Altered fetal growth f. Functional deficit g. Carcinogenesis h. Mutagenesis 3. Mechanisms of substance transfer a. Simple diffusion (most drugs) i. Molecular weight (MW) (low > high). (a) Low is defined as less than 500–600 Da (b) Although monoclonal antibodies have high molecular weight, these medications generally cross during the second half of pregnancy. ii. Lipid solubility (lipophilic > hydrophilic) iii. Ionization (nonionized > ionized) iv. Protein binding (free > low > high) v. Maternal and fetal blood flow (high > low) vi. Placental diffusion distance (thin > thick) vii. Placental villi exchange area (large > small) viii. Efflux proteins (no activity > high activity) b. Facilitated diffusion (glucose) c. Active transport (some vitamins, amino acids) d. Pinocytosis (immune antibodies) e. Breaks between cells (erythrocytes) 4. Physiologic changes affecting medication use in pregnancy

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Table 12. Effects of Physiologic Changes During Pregnancy on Medications Physiologic Change

Metabolic Placental

Volume

↑ Drug metabolism ↓ Metabolism

↑ Renal blood flow

↑↑ GFR and drug elimination ↓ Maternal concentrations

↓ Motility and intestinal blood flow

↑ Drug absorption

↑ Blood volume ↓ Albumin ↑ Body fat

Gastrointestinal

Potential Therapeutic Effects

↑ Hepatic metabolism ↓ Hepatic metabolism

Thinning of fetal-maternal barrier

Renal

Pharmacokinetic Effects

↑ Distribution

↓ Drug concentrations ↑ Drug concentrations

↑ Fetal concentrations and ↓ Maternal concentrations

↑ Distribution ↓ Protein binding ↑ Distribution of lipophilic medications

↓ Concentration ↑ Free drug ↓ Concentration of lipophilic medications ↑ Concentration

GFR = glomerular filtration rate.

5. FDA pregnancy categories for medication use in pregnancy (Table 13) a. Old system has many faults and should not be the only piece of information used to determine safety. b. New system approved by FDA and effective for all products approved after June 30, 2015 Table 13. New and Old FDA Pregnancy Categories OLD System (before June 30, 2015)

NEW System (after June 30, 2015)

Category

Category

A

B

C

D X

Description

-Adequate, well-controlled studies of pregnant women have not shown an increased risk of fetal abnormalities

Pregnancy

-Animal = risk; human = no controlled studies -Studies of women or animals are unavailable

Lactation

-Animal = no risk; human = no controlled studies -Animal = risk; human = controlled studies have no risk

-Known risk; benefit of medicine greater than risk

-Known risk; risk greater than benefit

Women and men with fertility potential

Description

-Required to provide registry and contact information if available -Risk summary -Clinical considerations +Dose adjustments during pregnancy and the postpartum period +Maternal adverse reactions +Fetal/neonatal adverse reactions +Labor or delivery -Human and animal data -Risk summary -Clinical considerations +Minimizing exposure +Monitoring adverse effects -Pregnancy testing -Contraception -Infertility

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E. Acute Conditions (Domain 1, Tasks 1–5) 1. Nausea and vomiting a. Clinicians can use the Pregnancy-Unique Quantification of Emesis and Nause scoring index to assess severity as mild, moderate, or severe (ACOG Obstet Gynecol 2018;131:e15-30). b. Nonpharmacologic i. Light snack 15–20 minutes before getting out of bed ii. Small, dry, more frequent meals iii. Prevent stomach from completely emptying. iv. Avoid spicy or fatty foods and strong odors. v. High protein and high carbohydrate vi. Ginger (ACOG recommends a 250-mg capsule four times daily) vii. Cold foods tolerated better than hot foods viii. Acupressure wrist bands ix. ACOG suggests to consider changing from a prenatal vitamin to a folic acid supplement only. c. Pharmacologic i. First-line options (ACOG) (select one of these options): (a) Vitamin B6 10–25 mg with or without doxylamine 25 mg ½ tablet three or four times per day (b) Vitamin B6 and Doxylamine delayed release (Diclegis) 10/10 mg (prescription only): Start 2 tablets at bedtime on days 1 and 2. If uncontrolled, add 1 tablet in the morning. If uncontrolled on day 4, add 1 tablet mid-afternoon. (c) Vitamin B6 and Doxylamine extended release (Bonjesta) 20/20 mg (prescription only): Start with 1 tablet at bedtime; can increase to 1 tablet twice daily on day 2 if needed ii. If uncontrolled, add on any of the following (ACOG) (select one of these options): (a) Dimenhydrinate 25–50 mg every 4–6 hours (max 200 mg/day if also taking doxylamine) (b) Diphenhydramine 25–50 mg orally every 4–6 hours (c) Prochlorperazine (available oral, rectal) 25 mg rectally every 12 hours (d) Promethazine (available orally, rectally, and intravenously) 12.5–25 mg orally or rectally every 4–6 hours (e) Adverse effects, especially sedation, may limit use. iii. If condition uncontrolled and patient not dehydrated, add on any of the following (ACOG) (select one of these options): (a) Metoclopramide 5–10 mg orally or intramuscularly every 6–8 hours (boxed warning for tardive dyskinesia; not recommended to use beyond 12 weeks) (b) Ondansetron 4 mg every 8 hours. ACOG recommends that ondansetron is not used as a first line agent before 10 weeks. If used before 10 weeks, patients should be educated about the data and individual use based on risks and benefits. (Use in the first 10 weeks has been associated with an increased risk of cardiovascular defects and oral clefts.) (c) Trimethobenzamide 200 mg intramuscularly every 6–8 hours (available orally and intramuscularly) (d) Promethazine orally, rectally, or intramuscularly 12.5–25 mg every 4–6 hours iv. If dehydrated, add intravenous fluids (ACOG) (a) If still uncontrolled, add any of the following: (1) Dimenhydrinate intravenously 50 mg in 50 mL of saline over 20 minutes every 4 -6 hours (2) Metoclopramide intravenously 5 -10 mg every 8 hours (3) Ondansetron intravenously 8 mg over 15 minutes every 12 hours (4) Promethazine intravenously 12.5 -25 mg every 4 -6 hours

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2.

3.

4.

5.

(b) If still uncontrolled, add any the following: (1) Chlorpromazine 25 -50 mg intravenously or intramuscularly every 4 -6 hours or 10 -25 mg orally every 4 -6 hours (2) Methylprednisolone 16 mg every 8 hours orally or intravenously for 3 days. Taper over 2 weeks to the lowest effective dose. If beneficial, limit total duration of use to 6 weeks. Gastroesophageal reflux disease a. Nonpharmacologic i. Smaller, more frequent meals ii. Avoid caffeine. iii. Avoid foods and liquids (other than water) for at least 3 hours before bedtime. iv. Elevate head of bed. v. Avoid foods and beverages that can trigger symptoms (e.g., tomato products, chocolate, spicy foods, peppermint, acidic items such as orange juice). b. Pharmacologic i. Antacids ii. Histamine-2 antagonists iii. Metoclopramide iv. Proton pump inhibitors v. Sucralfate vi. Avoid: sodium bicarbonate Constipation a. Nonpharmacologic i. Add bulky, high-fiber foods to diet. ii. Increase fluid intake. iii. Moderate exercise iv. Sitz baths for hemorrhoids b. Pharmacologic i. Fiber bulk-forming laxatives ii. Polyethylene glycol iii. Docusate sodium iv. Senna (long-term use: limit to 3 days/week) v. Bisacodyl (long-term use: limit to 3 days/week) vi. Lactulose vii. Avoid: castor oil and mineral oil Diarrhea a. Nonpharmacologic i. Maintain hydration. ii. Correct electrolyte abnormalities. b. Pharmacologic i. Fiber bulk-forming agents ii. Loperamide iii. Avoid: diphenoxylate plus atropine, paregoric Pain a. Acetaminophen b. Acetaminophen plus narcotics c. Avoid: NSAIDs (especially after 20 (FDA 2020) weeks), aspirin, NSAIDs plus narcotics

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6. Headaches a. Headaches in pregnancy can indicate a more serious underlying condition, including preeclampsia, stroke, postdural puncture, cerebral angiopathy, and cerebral venous thrombosis. Warning signs include increased blood pressure, altered mental status or confusion, fever, seizure, and abnormal findings on the neurologic examination (ACOG). b. Nonpharmacologic i. Relaxation therapy ii. Cognitive behavioral therapy iii. Biofeedback c. Pharmacologic for migraines i. Acetaminophen ii. Antiemetics (promethazine, prochlorperazine, metoclopramide are commonly used; may use with acetaminophen) iii. Serotonin-1b/1d receptor agonist (i.e., triptans; sumatriptan may be preferred) iv. Less preferred to use acetaminophen plus caffeine plus butalbital or acetaminophen plus narcotic agents because of the risk of overuse, rebound headaches, and chronic migraines v. Avoid: NSAIDs (especially after 20 weeks), aspirin, NSAIDs plus narcotics, aspirin plus caffeine plus butalbital, ergotamine, dihydroergotamine d. Tension headache i. Acetaminophen ii. Antiemetics (may use with acetaminophen) e. Migraine prophylaxis i. Riboflavin ii. Magnesium supplements (Obstet Gynecol 2019;134:211) 7. Smoking cessation a. Nonpharmacologic (see smoking cessation lecture) b. Nicotine replacement therapy c. Bupropion (Cochrane review found bupropion did not improve cessation rates during pregnancy. Cochrane Database Syst Rev 2020;3:CD010078.) d. Varenicline (limited data) 8. Preterm labor/delivery (before 37 weeks’ gestation) a. Prophylaxis if patient has a history of preterm labor/delivery i. Progesterone started at 16–24 weeks’ continued through 36 weeks’ gestation (a) 17-Hydroxyprogesterone acetate 250 mg intramuscularly or 275mg subcutaneously every week. However, 2019 PROLONG study found no difference between patients using 17-hydroxyprogesterone and placebo (Am J Perinatol 2020;37:127-36). ACOG and Society of Maternal Fetal medicine recognize population difference between PROLONG and previous Meis et al study (NEJM 2003;348;2379-85). ACOG and the Society of Maternal Fetal Medicine recognize population differences between the PROLONG and previous Meis et al trial (NEJM 2003;348:2379-85), and recommend shared decision making on whether to use 17-hydroxyprogesterone in pregnancy. (b) Vaginal progesterone suppository 100 mg every day (c) Micronized oral capsule 200 mg intravaginally every day ii. Surgical procedure (cerclage) iii. Inflatable pessary iv. Modified bed rest v. Hydration

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b. Abortive treatment (tocolysis) i. Not used before 24 weeks or after 34 weeks ii. Used for 48 hours to prolong pregnancy to allow for antenatal corticosteroids or transfer to another hospital iii. Treatment (a) Nifedipine immediate release 30 mg once, then 10–20 mg every 4–6 hours. Sometimes continued as needed for contractions (b) Indomethacin 50–100 mg once, then 25–50 mg every 6 hours or ketorolac 60 mg intramuscularly once, then 30 mg intramuscularly every 6 hours. Not recommended after 31–32 weeks (c) Terbutaline 0.25 mg subcutaneously every 20–30 minutes until tocolysis, then every 3–4 hours. Not recommended for use longer than 48 hours (boxed warning). c. Fetal neuroprotection: Magnesium sulfate 6 g intravenously over 20 minutes, then 2 g per hour infusion to decrease the risk of cerebral palsy d. Prelabor rupture of membranes i. If the patient is less than 34 weeks 0 days’ gestation, start intravenous ampicillin and erythromycin, followed by oral amoxicillin and erythromycin for 7 days. If erythromycin is unavailable or not tolerated, use azithromycin. ii. Do not use amoxicillin/clavulanic acid because of increased risk of necrotizing enterocolitis. e. Prevention of hyaline membrane disease i. Betamethasone 12 mg intramuscularly every 24 hours × 2 doses ii. Dexamethasone 6 mg intramuscularly every 12 hours × 4 doses iii. No other steroids cross the placenta for effects F. Chronic Conditions (Domain 1, Tasks 1–5) 1. Balance risks of uncontrolled disease with medication risk. 2. Hypertension Table 14. Hypertension in Pregnancya

Type

Definition (2 Blood Pressure Readings at Least 4 Hr Apart)

Fetal Risks

Gestational or pregnancy induced

> 140/90 mm Hg Usually after 20 wk

Cesarean delivery, mortality

Chronic

> 140/90 mm Hg Preexisting or onset < 20 wk gestation

IUFD, IUGR, PTD, malformations (cardiac, hypospadia, esophageal atresia), cesarean delivery

Maternal Risks

Preeclampsia, thrombocytopenia, liver dysfunction, long term risk of cardiovascular disease

Death, stroke, MI Pulmonary edema, renal insufficiency and failure, placental abruption, postpartum hemorrhage, GDM

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Table 14. Hypertension in Pregnancya (continued)

Type

Definition (2 Blood Pressure Readings at Least 4 Hr Apart)

Preeclampsia > 140/90 mm Hg plus one of the following: At least 300 mg of proteinuria in 24 hr, Protein/creatinine ratio of 0.3 mg/dL or more, or urine dipstick reading of 2+ (only if other quantitative methods not available)

Fetal Risks

Platelets < 100,000/mm3

Eclampsia

LFTs 2 × ULN New development of renal dysfunction (SCr > 1.1 mg/dL or doubling of previous SCr value) Pulmonary edema New-onset headache unresponsive to medication and not accounted for by alternative diagnoses or visual symptoms Usually after 20 wk Preeclampsia + seizures

Maternal Risks

Headache, visual disturbance, posterior reversible encephalopathy (PRES), stroke, oliguria, upper quadrant pain, LFT, HELLP, long-term risk cardiovascular disease

Above plus oligohydramnios, placental abruption

Death, hypoxia, trauma, aspiration, neurologic changes

a ACOG recognizes that gestational hypertension and preeclampsia may be diagnosed before 20 wk in some cases and that chronic hypertension may be diagnosed after 20 wk in some cases (ACOG Obstet Gynecol 2019;133:e26-50).

GDM = gestational diabetes mellitus; HELLP syndrome = hemolysis, elevated liver enzymes, low platelets; IUFD = intrauterine fetal demise; IUGR = intrauterine growth restriction; MI = myocardial infarction; PTD = preterm delivery; SCr = serum creatinine; ULN = upper limit of normal.

a. Prevention of preeclampsia (in women with increased risk) i. Aspirin 81–162 mg daily starting at week 12–16 preferred but up to 28 weeks (U.S. Preventive Services Task Force [USPSTF] 2021 and ACOG 2020) in women with one high or two moderate risk factors (a) High-risk factors: History of preeclampsia especially if accompanied by an adverse outcome, multifetal gestation, chronic hypertension, preexisting diabetes, renal disease, autoimmune disease (systemic lupus erythematous, the antiphospholipid syndrome) (b) Moderate-risk factors: Nulliparity, obesity (BMI greater than 30 kg/m2), socioeconomic demographics (African American race, low socioeconomic status), at least 35 years old, personal history of large birth weight or small for gestational age, pregnancy with adverse outcomes, or greater than 10 years between pregnancies ii. Calcium 500 mg twice daily for patients with low calcium intake. ACOG notes this is not the case in the United States or other developed countries. b. Initiate therapy. i. Goal blood pressure between 120–160/80–110 mm Hg (ACOG Obstet Gynecol 2019;133:e26-50). ii. In general, initiate treatment when greater than 160/110 mm Hg but tighter control may be appropriate for comorbidities or underlying impaired renal function (ACOG Obstet Gynecol 2019;133:e26-50).

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c. Treatment i. First line: nifedipine and labetalol ii. First-second line: methyldopa: most studied but limited use because not potent and high potential for adverse events (somnolence, depression) iii. Second line: hydralazine iv. Second-third line: hydrochlorothiazide v. Avoid: angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, minoxidil, aliskiren, atenolol 3. Diabetes Table 15. Risks of Uncontrolled Diabetes During Pregnancy

Background pregnancy rate Risk time

Uncontrolled DM

Any MCM 1%–5%

Cardiac

0.8%

Neural Tube Defects 0.2%

—

0–12 wk

0–5 wk

18.4%

8.5%

1%

Macrosomia

Other

10% • Central nervous system SD 0.5%–0.7% abnormalities Second/third • Intrauterine fetal demise • Respiratory distress trimester • Intrauterine growth restriction 12%–35% • Polyhydramnios SD 5%–7% • Progression of retinopathy

DM = diabetes mellitus; MCM = major congenital malformation; SD = shoulder dystocia.

a. Definitions: gestational diabetes i. Routine screening at 24–28 weeks using the two-step method or the one-step method ii. Screening during first trimester if overweight and obesity with BMI greater than 25 kg/m2 or greater than 23 kg/m2 if Asian American and one additional risk factor (physical inactivity, first-degree relative with diabetes, high-risk race or ethnicity, prior infant weighing 4 kg [9 lb] or more, previous gestational diabetes, chronic hypertension, high-density lipoprotein cholesterol less than 35 mg/ dL or triglycerides greater than 250 mg/dL, PCOS, previous A1C 5.7 or greater, impaired glucose intolerance, or other clinical conditions associated with insulin resistance such as pre-pregnancy BMI greater than 40 kg/m2, acanthosis nigricans, or history of cardiovascular disease) iii. One-step method (a) 75-g glucose tolerance test after 8-hour fast (b) Diagnosed if one reading is as follows: fasting blood glucose (BG) 92 mg/dL or greater; BG 180 mg/dL or greater at 1 hour; 153 mg/dL or greater at 2 hours iv. Two-step method (option from the American Diabetes Association; ACOG option (a) Glucose challenge (50 g) abnormal if BG 130 mg/dL or greater at 1 hour (b) Then, glucose tolerance test (100 g). Diagnosed if any two readings are as follows: fasting BG 95 mg/dL or greater; BG 180 mg/dL or greater at 1 hour, 155 mg/dL or greater at 2 hours; 140 mg/dL or greater at 3 hours b. Treatment i. First line: Insulin (increased requirement with increased gestational age) (a) Neutral protamine Hagedorn, glargine, or detemir (b) Aspart/lispro preferred to regular insulin

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ii. Alternative to insulin (if patient cannot afford or safely administer): Metformin. Not associated with malformations, and when continued in the first trimester can decrease the risk of spontaneous abortions. Not very potent during pregnancy (26%–46% of patients required insulin). May increase the risk of obesity in exposed children. MiTy trial found decrease in glucose, daily insulin requirements, birth weight, and adiposity in infants when patients with pregestational diabetes used insulin plus metformin compared with insulin alone (Lancet Diabetes Endocrinol 2020;8:834-44). iii. Glyburide. Not associated with malformations and not detected in cord blood samples likely because of high placental efflux protein activity (Obstet Gynecol 2018;131:e49-64. Not first choice because it has not shown similar outcomes to insulin). iv. Avoid other therapies because they have limited/no data in pregnancy and can reach the fetus. Patient Case 6. A patient is 18 weeks pregnant and here for her prenatal visit. You discover that she has not been taking lamotrigine because of a fear of birth defects. Her last seizure was 6 months ago. Which is best for educating the patient on the risk of birth defects?

A. Risk is low because she is past the stage when cleft palate/lip develops. B. Risk is low because intrauterine growth restriction is similar to uncontrolled epilepsy. C. Risk is high because lamotrigine is associated with the development of cardiac abnormalities during second trimester. D. Risk is high because neurodevelopmental delays are associated with exposure to lamotrigine during the second and third trimesters. 4. Epilepsy a. Risks of uncontrolled epilepsy i. Maternal: Anemia, hypertension, urinary tract infections, nausea/vomiting, vaginal bleeding, death ii. Pregnancy: Preterm labor (smokers), placental abruption or detachment, premature rupture of membranes iii. Fetal: Intrauterine fetal demise, tonic-clonic, focal with loss of consciousness, significant fetal heart rate decelerations, decreased intelligence quotient with five seizures during gestation b. Educate the patients about the risks of uncontrolled epilepsy and potential risks of the medications

Table 16. Preventive Recommendations for Patients Taking Seizure Medications During Pregnancy

Preconception care

Decrease risk of complications Therapy

If > 2–4 years since last seizure, consider trial off for 6 mo (Continuum 2016;22:204-26). If < 2 yr, continue therapy -Optimize medications by trying monotherapy, if possible, and changing to a less teratogenic medication, if possible; consider referral to neurologist -Start folic acid supplementation -Check concentration to establish a baseline concentration, when controlled Folic acid at least 0.4 mg; Preferred to start 3 mo before conception (ACOG) Adequate calcium and vitamin D intake

Continue therapy; monotherapy preferred Avoid phenobarbital, phenytoin, and valproic acid in women of childbearing age, if possible Consider referral to neurologist

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475

Limited to no data

Other agents

1%–2%

0.2%–1%

0–5 wk

0.2%

Neural Tube Defects

0.2%, no risk

0.23%

1.5%

0.4%

1.2%

0–9 wk

0.14%

Cleft Palate/ Lip

0.7%–0.9%

0.7%–0.9%

1.1%

1.2%

0–12 wk

0.5%–0.8%

Cardiac

No

Yes

No

No

No

Second to third trimester

Neurodevelopmental Delays

Possible

> 4%

b

4%

6.5%

11%

Any

0%

↓ Birth weight ↓ Concentrations

↓ Concentrations

↓ Concentrations, ↓ birth weight, hypospadia

↓ Birth weight, preterm delivery

IUGR, hernia, hypospadia

Possible ↓ concentrations,

↓ Concentrations, monitor free levels

Anticonvulsant Syndromeb Other

Fetal anticonvulsant syndrome: craniofacial abnormalities (drug specific), growth restriction, limb defects, cardiac lesions, hernias, and distal digital and nail hypoplasia.

Some medications have a dose threshold where doses above the threshold are associated with the risk. See pregnancy-specific references for more details.

a

2%

2.8%–3.2%

Lamotrigine

Levetiracetam

3.2%, higher risk

Gabapentin, pregabalin 7.1%–9%

6.2%–17.1%

Valproic acid

Topiramate

2.2%–4.5%

6.5%

3.67%–4.7%

—

1%–5%

Carbamazepine, oxcarbazepine

Phenobarbital, primidone

Phenytoin

Risk time

General pregnancy risk

Major Malformations

Table 17. Risks Associated with Epilepsy Medications During Pregnancya

Obstetrics and Gynecology

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5. Thyroid disorders a. Hyperthyroidism Table 18. Hyperthyroidism in Pregnancy Maternal Risk

Fetal Risk

Untreated hyperthyroidism (0.2%)

Heart failure, preeclampsia, preterm delivery

Propylthiouracil preferred first trimester

Usual adverse drug events (see thyroid lecture)

Methimazole

Stillbirth, imperforate anus, anencephaly, cleft lip, ↑ thyroidism, craniosynostosis, hydrops, advanced bone age Fetal hypothyroidism, goiter

Aplasia cutis, fetal hypothyroidism, goiter Rare: esophageal atresia, transesophageal fistula

b. Hypothyroidism Table 19. Hypothyroidism in Pregnancy Untreated hypothyroidism Levothyroxine Desiccated thyroid Liotrix

Maternal Risk

Hypertension, preeclampsia, preterm delivery, placental abruption

Not associated with harm and effective Usually requires 30% higher dosage

Fetal Risk

Spontaneous abortion, heart failure, low birth weight, cretinism, low IQ

Avoid: both products have a higher risk of thyrotoxicosis Desiccated: Malodorous

6. Asthma Table 20. Risks of Asthma in Pregnancy Uncontrolled asthma

Maternal Risks

Antepartum/postpartum hemorrhage, cesarean delivery, hypertension, preeclampsia, PTD, premature rupture of membranes

Fetal Risks

IUGR, low birth weight, fetal hypoxia, perinatal death

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Table 21. Safety of Asthma Medications in Pregnancy Medication

Fetal Risks

Albuterol

Minimal

Low systemic absorption

Salmeterol Formoterol

Minimal

No to low dose absorbed systemically Do not use as monotherapy

Cromolyn

Minimal

Beclomethasone Budesonide Flunisolide Fluticasone Mometasone Triamcinolone

Minimal

Do not need to change products if previously well controlled with an alternative inhaled corticosteroid As-needed inhaled corticosteroid/long-acting β-agonist therapy has not been studied in obstetric patients

Montelukast Zafirlukast Zileuton

Minimal data Minimal data Low birth weight, skeletal

Theophylline

Tachycardia, hypertension

Prednisone

Montelukast has more data than others

1%–4% of dose absorbed systemically

Therapeutic serum concentration: 5–12 µg/mL

Oral clefts (0–9 wk) Diabetes Preferred steroid mellitus

Omalizumab

Limited data

Benralizumab Mepolizumab Reslizumab

Limited or no data

Tiotropium

No data

Dupilumab

Notes

Does not appear to increase risk for malformation (J Allergy Clin Immunol. Epub May 27, 2019.)

No data

Around 33% absorbed systemically with the soft-mist inhaler

7. Coagulation disorders Table 22. Treatment of Coagulation Disorders in Pregnancy Place in Therapy

First line Preferred ≥ 36 wk or near delivery

Medication

Heparin

Fetal Risks

Notes

None to PG/fetus First line Preferred < 36 wk

LMWH

Readily reversed with protamine Heparin prophylaxis dosing by trimester: 1st: 5000–7500 units BID 2nd: 7500–10,000 units BID 3rd: 10,000 units BID Heparin therapeutic dosing: 10,000 units BID or 250 units/kg BID and adjust according to concentrations Less risk of heparin-induced thrombocytopenia, bone loss Daily BID dosing Anti-Xa monitoring 4 hr post-dose for at least therapeutic dosing

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Table 22. Treatment of Coagulation Disorders in Pregnancy (continued) Place in Therapy

Medication

Fetal Risks

Avoid Alternative for second/ third trimester

Warfarin

Warfarin syndrome Ophthalmic abnormalities, mental retardation

Alternatives

Lepirudin Bivalirudin Others

Limited data

Avoid

Direct oral anticoagulants

Notes

Warfarin risk of malformations is significantly increased with doses > 5 mg. Patients with mechanical valves may remain on warfarin for some or all of the pregnancy. Shared decision-making is recommended (Circulation 2021;143:e72-227) Use if patient unable to use heparin/LMWH

Limited to No data Potential to cross the placenta

LMWH = low-molecular-weight heparin; PG = pregnancy.

G. Pregnancy Termination (Domain 1; Task 3) 1. Ectopic pregnancy: Methotrexate 2. Intrauterine a. Misoprostol b. Mifepristone H. Lactation (Domain 1, Tasks 1–4) 1. Rule of thumb: Hale TW. Lactational pharmacology. In: Walker M, ed. Core Curriculum for Lactation Consultant Practice. Sudbury, MA: Jones & Bartlett, 2002:356-91. a. In general, less than 1% of the maternal dose will reach the infant. b. The American Academy of Pediatrics considers most medications safe for use in lactation, except for radioactive compounds; however, still check LactMed or other reference for safety (Pediatrics 2013;132:e796-809). c. Watch for exceptions to the rule. 2. Things to consider when determining medication use in lactation a. Evaluate mother’s need to use the medication. i. Can treatment be delayed? ii. Is the treatment effective for the condition? b. Safety to the infant i. Relative infant dose is calculated by dividing the infant dose in the milk (mg/kg/day) by the maternal dose (mg/kg/day). ii. If the relevant infant dose is less than 10%, it is generally safe. iii. Infant age (a) Medications cross easiest in the first 0–14 days postpartum. (b) Ability to metabolize medications: Adverse events tend to be higher when the infant is younger than 2 months or if the infant has certain medical conditions. (c) Oral absorption rate c. Effects on milk production 3. Medication management during breastfeeding a. Acute, short-term drug therapy: If drug is contraindicated during lactation, keep pumping breast milk and discard until drug therapy is complete. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 478

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b. Chronic medical condition treated with drug therapy i. Has the infant been exposed throughout pregnancy? If so, less likely to have problems during lactation ii. Is breastfeeding safe with this chronic condition? iii. Evaluate risk-benefit. 4. Minimizing effects of drug therapy on breastfeeding a. Minimize sustained-release preparations or drugs with long half-life values. b. Schedule doses immediately after feeding or before a long sleep period. Difficult to do with newborns because they eat about every 2 hours c. If there are several similar, equally effective medications from which to choose, choose the agent with the lowest concentration in breast milk and the least effect on the infant. d. Always consider—Can the medication be given to neonates? Table 23. Potential Effects of Drugs on Lactation Drugs That ↑ ­ Milk Production

Amoxapine Antipsychotics (more likely with first generation) Cimetidine Methyldopa Metoclopramide

Drugs That ↓ Milk Production

Androgens Bromocriptine Estrogens Ergot alkaloids Levodopa Monoamine oxidase inhibitors Nicotine Pyridoxine Sympathomimetics Dopamingerics Diuretics Alcohol Anticholinergics

Medications to Avoid During Lactation

Bromocriptine Cabergoline Cyclosporine Cyclophosphamide Doxorubicin Ergotamine Lithium Methotrexate Nicotine Retinoids Iodine Illicit drugs

5. Relactation a. Nonpharmacologic therapy i. Education with lactation specialist to review technique for proper latching, positioning, length of feeding ii. Adequate nutrition/fluid intake and rest overall. Try eating or drinking enjoyable foods during lactation. iii. Increased nipple stimulation by nursing or pumping (pump after nursing) iv. Relaxation techniques, including deep breathing, gentle massage, listening to favorite music, and decreased stress v. Massage and warm the breast during feeding. vi. Increase feeding/pumping time, decrease intervals between feeding/pumping. Look at a photograph of the baby or the baby’s items while pumping. b. Medications i. Minimal efficacy and safety data ii. Proposed: Fenugreek, metoclopramide, blessed thistle, domperidone 6. Mastitis a. Infection of the milk ducts b. Symptoms: Pain, tenderness, redness, warmness of the breast, fever, and flulike symptoms

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c. Etiology: Clogged milk ducts, cracked nipples or other breaks in the skin, breast engorgement d. Nonpharmacologic i. Keep breastfeeding, and start each feeding on the infected breast. ii. Use a warm compress. iii. Wear a bra. e. Treatment: Cephalosporins (cephalexin) or penicillinase-resistant penicillins (dicloxacillin, cloxacillin, oxacillin) for 10–14 days I. Resources (Domain 1, Task 5) 1. Drugs in Pregnancy and Lactation (Briggs 2017), TERIS database, and Reprotox database 2. Medications & Mothers’ Milk (Hale 2019) 3. Committee on Drugs of the American Academy of Pediatrics (Pediatrics 2001;108:776-89) 4. LactMed (http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT) 5. Organization of Teratology Information Specialists also known as MotherToBaby (www.mothertobaby.org) a. Patient information handouts b. Local teratology information services c. Toll-free patient counselors available d. Members have access to e-mail list. e. Provider information 6. Textbooks a. Creasy and Resnik’s Maternal-Fetal Medicine: Principles and Practice b. Olds’ Maternal-Newborn Nursing & Women’s Health Across the Lifespan c. Diseases, Complications, and Drug Therapy in Obstetrics: A Guide for Clinicians d. Core Curriculum for Lactation Consultant Practice Patient Cases 7. A 44-year-old woman is experiencing vasomotor symptoms that disrupt her ability to complete work activities and get a good night’s sleep. Her medical history is significant for hyperlipidemia and total abdominal hysterectomy with bilateral salpingo-oophorectomy (2 months ago). Laboratory values include total cholesterol 198 mg/ dL, triglycerides 225 mg/dL, and high-density lipoprotein cholesterol 44 mg/dL. Which product is most appropriate for this patient? A. B. C. D.

Estinyl tablet (ethinyl estradiol) 0.02 mg/day. Vivelle patch (17β-estradiol) 0.025 mg/day twice weekly. Prempro tablet (conjugated equine estrogens plus medroxyprogesterone) 0.45 mg/1.5 mg/day. Estratest tablet (esterified estrogens plus testosterone) 0.625 mg/1.25 mg/day.

8. A 66-year-old woman is experiencing vaginal dryness and painful intercourse. She states her symptoms are bothersome but not horrible. She would like therapy to help relieve the symptoms. Her medical history includes hyperlipidemia, hypertension, low bone mass, and coronary artery disease (myocardial infarction 3 years ago). Her allergies include adhesives (reaction is rash). Which is the best recommendation? A. B. C. D.

Estrogel (17β-estradiol gel) 0.75 mg daily. Venlafaxine XR (extended release) 37.5 mg daily. Ospemifene 60 mg daily. Lubricating gel three times daily.

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VI.  MENOPAUSAL SYMPTOMS A. Estrogen and Estrogen plus Progestogen (Domain 1; Tasks 2–4) 1. Overview a. Postmenopausal hormones are not contraceptives. These products contain around one-fifth dose of a contraceptive. If contraception is needed and appropriate for perimenopausal patients, use the hormonal contraceptive to relieve symptoms and provide contraception. b. Progestogen terminology i. Progestogen = include both natural and synthetic products ii. Progesterone = natural products iii. Progestin = synthetic products 2. Indications a. Moderate to severe symptoms associated with menopause b. Moderate to severe genitourinary syndrome of menopause c. Prevention of postmenopausal osteoporosis 3. Benefits a. Vasomotor symptoms: Systemic estrogens are the most effective treatment to decrease frequency and severity, but they can require 2–6 weeks to achieve effects. b. Genitourinary symptoms: Estrogens administered by any route is the most effective treatment. i. Genitourinary atrophy ii. Vaginal dryness iii. Dyspareunia iv. Increased risk of urinary tract infections. Only local estrogen has shown decreased risk in a randomized controlled trial. c. Osteoporosis prevention d. Quality of life e. Mood stability f. Fatigue g. Insomnia 4. Perimenopausal patients a. Still at risk of pregnancy if having unprotected intercourse b. Consider low-dose estrogen-progestin–containing contraceptives (20–25 mcg of ethinyl estradiol) i. Improves symptoms ii. Prevents pregnancy iii. Remember to review for contraindications (see contraception section) 5. Risks a. Cardiovascular risk i. Estrogen-progestin primary prevention: no overall increase in cardiovascular events or death, but hazard ratio (HR) 1.29 (95% confidence interval [CI], 1.02–1.63) with absolute risk of 7 per 10,000 person-years (Women’s Health Initiative [WHI] trial; JAMA 2002;288:321-33). ii. Estrogen-progestin secondary prevention: increased risk of myocardial infarction during first year of use (HR 1.52 [95% CI, 1.01–2.29]), but no overall difference for 6.8 years (HR 0.99 [95% CI, 0.80–1.22]) (Heart and Estrogen/Progestin Replacement Study [HERS], JAMA 1998;280:605-13; HERS II, JAMA 2002;288:49-57). iii. Estrogen primary prevention: no overall increase in cardiovascular events or death (HR 0.91 [95% CI, 0.75–1.12]) (WHI-ET; JAMA 2004;291:1701-12)

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iv. One factor to consider when evaluating cardiovascular risk: timing (age and years since onset of menopause). No difference in mortality in women that used estrogen therapy/hormone therapy (ET/ HT) for 5–7 years after 18 years of follow-up. When comparing groups by age, patients 50–59 years old had a significantly lower risk of all-cause mortality while using postmenopausal therapy (HR 0.61 [95% CI, 0.43–0.76]) and no difference after 18 years (HR 0.87 [95% CI, 0.76–1.00]) compared with patients 70–79 years old (N Engl J Med 2017;318:927-31). b. Cerebrovascular risk i. Estrogen-progestin: Increased risk with HR 1.41 (95% CI, 1.07–1.85) with absolute risk of 8 per 10,000 person-years (WHI; JAMA 2002;288:321-33) ii. Estrogen: Significant increased risk with HR 1.39 (95% CI, 1.10–1.77). Absolute risk of 12 per 10,000 person-years (WHI-ET; JAMA 2004;291:1701-12) c. Thromboembolism i. Estrogen increases vitamin K–dependent clotting factors. ii. Increased risk adjusted HR 2.11 (95% CI, 1.26–3.55) absolute risk of pulmonary embolism of 8 per 10,000 person-years (WHI; JAMA 2002;288:321-33) iii. Overall, increases risk of deep venous thrombosis by 2–3.5, but the absolute risk is relatively small (20 per 100,000 cases) d. Breast cancer i. Estrogen/progestin: 15% higher rate for the first 5 years (nonsignificant) and 54% higher rate for greater than 5 years of use (WHI; JAMA 2002;288:321-33, Lancet 1997;350:1046-59) ii. Estrogen: Risk of breast cancer increases after 10–15 years of use. e. Endometrial cancer i. Estrogen stimulates endometrial cell mitosis and hyperproliferation. ii. Increased risk after 1 year of unopposed estrogen in patients who still have a uterus iii. Using progestins (medroxyprogesterone acetate 5–10 mg/day or equivalent) 10–14 days/month prevents hyperproliferation. f. Gallbladder dysfunction g. Cognitive decline: Increased risk of dementia in women older than 65 receiving estrogen-progestin. HR 2.05 (95% CI, 1.21–3.48). Absolute risk of 12 per 10,000 person-years (Women’s Health Initiative Memory Study [WHIMS]; JAMA 2003;289:2651-62). HR 2.01 (CI, 1.19–3.42) from JAMA 2013;310:1353-68 h. Ovarian cancer: Meta-analysis, case-control, and cohort trials show that both estrogen and estrogen/ progestin therapy increase the risk of ovarian cancer. However, only one randomized controlled trial evaluated the risk and did not show increased risk. 6. Routes of administration a. Oral i. Advantages: Greater increase in effect on hepatic lipoproteins, ease of administration ii. Disadvantages: Liver effects greater (thromboembolism, harmful lipoprotein changes) b. Transdermal/topical i. Advantages: Decreased or no liver effects, useful in patients with gastrointestinal absorption problems, stable concentrations of estrogen, fewer significant harmful effects on lipids ii. Disadvantages: Skin irritation, still need to give progestins for women with an intact uterus, sunscreen applied near administration time can affect estrogen absorption iii. Less risk (a) Thromboembolism: Meta-analysis compared with non-users (BMJ 2008;336:1227-31) (1) Oral estrogen OR 2.5 (95% CI, 1.9–3.4) (2) Transdermal OR 1.2 (95% CI, 0.9–1.7) (b) Stroke: Nested case-control compared with non-users (BMJ 2010;340:c2519) (1) Oral: OR 1.28 (95% CI, 1.15–1.42) (2) Transdermal: OR 0.95 (95% CI, 0.75–1.20) ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 482

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c. Vaginal i. Advantages: Useful for symptoms of vaginal atrophy ii. Disadvantages: Erratic absorption, long-term use may increase risk of endometrial hyperplasia (especially with ring with systemic effects), no bone density benefit 7. Regimens a. Choice 1: Continuous estrogen and cyclic progestin i. Estrogen is given every day at a set dose. ii. Progestin is added for 10–14 days/month. iii. Advantages: No return of menopausal symptoms because estrogen is given each day iv. Disadvantages: Bleeding each month (usually begins 1–2 days after last progestin dose) b. Choice 2: Continuous estrogen and progestin i. Thought to create an atrophic endometrium and induce amenorrhea ii. Advantages: 75% of women have amenorrhea at 1 year. iii. Disadvantages: Unpredictable spotting or breakthrough bleeding when beginning therapy c. Choice 3: Continuous estrogen and bazedoxifene i. Bazedoxifene is an estrogen agonist/antagonist that provides endometrial protection. ii. Advantages: Relieves moderate to severe vasomotor symptoms and prevents osteoporosis iii. Disadvantages: Limited data d. Unopposed estrogen: Only for women without a uterus

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DETERMINING WHO SHOULD HAVE HT/ET PRESCRIBED Vasomotor or Urogenital symptoms? Less than 60 year old?

No. Do not use HT/ET

Yes Any Contraindications? a,b Absolute Contraindications -Venous thromboembolism/thrombophila -Known or suspected pregnancy -Undiagnosed vaginal bleeding -Breast, estrogen-, or progesterone-dependent cancer (known, suspected, or history of) -Active liver disease or dysfunction -Arterial thromboembolic disease (myocardial infarction, stroke, TIA) -Allergy or angioedema to any ingredient

Warnings/Precautions -Uterine leiomyoma -Migraines with aura (oral products)a -Hypertension (uncontrolled) -Hypertriglyceridemia (oral products) -Hypoparathyroidism (risk of hypocalcemia) -Gallbladder disease (oral products)a -Benign meningiomaa -Hypothyroidism -Fluid retention -Severe hypocalcemia -Ovarian cancer

Yes. Do not use HT/ET. Consider non-estrogen Vasomotor: 1st: SSRI, SNRI, Gabapentin, pregabalin 2nd: clonidine

-Exacerbation of endometriosis, asthma, migraine, lupus, epilepsy, porphyria, and hepatic hemangioma -Intermediate/High breast cancer riska + 5 year National Cancer Institute or IBIS Intermediate 1.67-5%, High >5% -High Cardiovascular Riska +ASCVD >10% -Peripheral arterial diseasea -Abdominal aortic aneurysma -Chronic kidney diseasea -Diabetesa

No

Moderate-Severe symptoms ET, HT, or E+EAA Try to D/C by 5 years

Mild-Moderate symptoms Consider non-estrogen alternatives

Vaginal: 1st: lubricating gels (>2x/wk) Pectin, Polycarboph, Polycarbophil, or hyaluronic acid based 2nd: Add lubricants

STEP 1: Deciding Systemic or Local Therapy

Location of symptoms

Vasomotor symptoms ± urogenital symptoms Systemic Therapy Oral, Transdermal, Topical, Femring STEP 2: Deciding Estrogen or Estrogen/Progestin STEP 2: Deciding Route of Systemic Therapy

Yes. Give ET

Consider ADRs from route Oral-(GI intolerance, ↑ TG, liver disease, gallbladder disease)? Topical/Transdermal-(skin irritation, possible skin to skin transfer) Transdermal/Topicalc Continuous Estrogen & Progestogen

Local Therapy -Any Vaginal product (not Femring) -Ospemifene -Prasterone

TAH or TAH/BSO?

No. Give HT or E+EAA

Oral Continuous Estrogen & Progestogen

Urogenital symptoms only

Consider ADRs from route Oral-(GI intolerance, ↑ TG, liver disease, gallbladder disease)? Topical/Transdermal-(skin irritation, possible skin to skin transfer)

Oral Continuous Estrogen & Cyclic Progestogen

Oral Continuous Estrogen & EAA

Transdermal/ Topicalc Estrogen

Oral Estrogen

Vaginal Systemic Estrogen (Femring)

Figure 2. Determining who could be prescribed hormone therapy/estrogen therapy.

a 2015 Endocrine Society guidelines. Consider non-estrogen therapy because of risk (high-risk CVD and IBIS/NCI score > 5%); caution with use in other conditions and consideration for non-estrogen alternatives.

FDA-labeled contraindications (Dang DK, Wheeler KE, Chen JT. Hormone therapy in women. In: DiPiro JT, Yee GC, Posey M, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 11th ed. New York: McGraw-Hill, 2020. Available at http://accesspharmacy.mhmedical.com.stlcopisa.stlcop.edu/ViewLarge.aspx?figid=2283 44550&gbosContainerID=0&gbosid=0&groupID=0§ionId=228344524).

b

c

The 2017 AACE and 2015 Endocrinology Society guidelines.

ADR = adverse drug reaction; ASCVD = atherosclerotic cardiovascular disease; CAD = coronary artery disease; CVA = cerebrovascular accident; E+EAA = estrogen plus estrogen agonist antagonist; ET = estrogen therapy; GI = gastrointestinal; HT = hormone therapy; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin receptor antagonist; sx = symptoms; TAH = total abdominal hysterectomy; TAH/BSO = total abdominal hysterectomy and bilateral salpingo-oophorectomy; TG = triglycerides; TIA = transient ischemic attack.

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Table 24. Progestin Availability and Minimal Doses for Endometrial Protection

Generic Oral

Medroxyprogesterone Norethindrone Norethindrone acetate Micronized progestin

a

Vaginal/Intrauterine

Levonorgestrel

Progesterone gel Micronized progesterone

Brand Name

Minimal Dose for Continuous Estrogen and Progestin, mg

Minimal Dose for Continuous Estrogen and Cyclic Progestin, mg

Available, mg

Provera

Micronor, Nor-QD

2.5

5

2.5, 5, 10

0.35

0.35

0.35

Prometrium

5

100

5

200

5

100, 200

Mirena IUD

0.20 mcg

N/A

20 mcg/day

Crinone many

45 mg 100 mg/day

45 mg

(4%) 45 mg

Aygestin

Product contains peanut oil.

a

IUD = intrauterine device.

B. Nonhormonal Options for Vasomotor Symptoms (Domain 1, Task 3) 1. First line: antidepressants a. Venlafaxine 75 mg/day: Efficacy in patients with breast cancer b. Paroxetine 7.5–30 mg/day: Avoid in patients taking tamoxifen. The only FDA-approved non-estrogen therapy for vasomotor symptoms c. Sertraline 25–50 mg/day d. Fluoxetine 20 mg/day: Avoid in patients taking tamoxifen. 2. First line: other a. Gabapentin 300–1200 mg/day (usually divided twice daily) b. Pregabalin 75–150 mg/day 3. Second line: antihypertensives a. Clonidine oral 0.1 mg every day or twice daily b. Clonidine patch which delivers 0.1 mg per day 4. No longer recommended: herbal products 5. Soy (isoflavones) 6. Black cohosh: studies have not shown efficacy in patients with breast cancer. C. Options for Vulvovaginal Symptoms (Domain 1; Task 3) 1. Lubricating gels (pectin, polycarboph, or hyaluronic acid based) 2. Vaginal estrogen (cream, tablet, non-systemic ring) 3. Ospemifene 60 mg daily 4. Prasterone 0.5 mg vaginal suppository nightly D. Resources: North American Menopause Society (www.menopause.org/) (Domain 1, Task 5) 1. Patient information 2. Position statements 3. Certified menopause provider

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VII.  GENERAL RESOURCES FOR WOMEN’S HEALTH A. Patient Resources (Domain 1, Task 5) 1. American College of Obstetricians and Gynecologists (www.acog.org): Patient information 2. FDA Office of Women’s Health: Patient information 3. MedlinePlus: Patient information 4. National Women’s Health Network: Patient information 5. Massachusetts General Hospital Center for Women’s Mental Health a. Patient information b. Clinical trial information 6. Association of Reproductive Health Professionals: Patient education 7. Infant Risk Center B. Provider Resources (Domain 1, Task 5) 1. American College of Obstetricians and Gynecologists (www.acog.org): Practice bulletins 2. FDA Office of Women’s Health a. Approval information b. MedWatch updates 3. Association of Reproductive Health Professionals Practice Points • When selecting a contraceptive for a patient, consider plans for future pregnancy – patient-specific factors including medical history, medications, adherence, and blood pressure – to help determine eligibility. • Hormonal contraceptives are first-line treatment for amenorrhea, anovulatory bleeding, and heavy menstrual bleeding for patients not desiring pregnancy. NSAIDs are first line for dysmenorrhea and heavy menstrual bleeding for patients desiring pregnancy. In PMS and PMDD, antidepressant therapies are often used first line for moderate to severe symptoms. • Treatment of infertility because of ovulatory and unknown causes is initiated with clomiphene and/or aromatase inhibitors. It is important to review the patient’s medications and optimize to preferred therapy during pregnancy to decrease risks as well as start folic acid supplementation. • Educate pregnant patients about the purpose, proper use, and potential risks of both the mother and the fetus when considering medications during pregnancy. It is important to discuss potential fetal malformations risk with respect to timing of exposure to the stage of gestation. • Postmenopausal estrogen and hormone therapy should be only used to treat moderate to severe vasomotor and genitourinary symptoms of menopause as well as prevention of osteoporosis. Selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, and gabapentin are nonhormonal options to treat vasomotor symptoms. Lubricating gels are nonhormonal options to treat vulvovaginal symptoms.

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Obstetrics and Gynecology

REFERENCES Contraception 1. Abdollahi M, Cushman M, Rosendale FR. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use. Thromb Haemost 2003;89:493-8. 2. American College of Obstetricians and Gynecologists (ACOG). ACOG practice bulletin No. 110: noncontraceptive uses of hormonal contraceptives. Obstet Gynecol 2010;115:206-18. 3. American College of Obstetricians and Gynecologists (ACOG). Practice bulletin No. 152: emergency contraception. Obstet Gynecol 2015;126:e1-11. 4. Archer JSM, Archer DF. Oral contraceptive efficacy and antibiotic interaction: a myth debunked. J Am Acad Dermatol 2002;46:917-23. 5. Blumenthal PD, Edelman A. Hormonal contraception. Obstet Gynecol 2008;112:670-84. 6. Centers for Disease Control and Prevention (CDC). Update to CDC’s U.S. medical eligibility criteria for contraceptive use, 2016: revised recommendations for the use of contraceptive methods during the postpartum period. MMWR 2016;65:1-104. 7. Centers for Disease Control and Prevention (CDC). U.S. selected practice recommendations for contraceptive use, 2016. MMWR 2016;65:Appendix B. 8. Dickey RA. Managing Contraceptive Pill Patients, 16th ed. New Orleans: Emis Medical Publishers, 2021. 9. Dinger J, Minh TD, Buttmann N, et al. Effectiveness of oral contraceptive pills in a large U.S. cohort comparing progestogen and regimen. Obstet Gynecol 2001;117:33-40. 10. Edelman AB, Cherala G, Munar MY, et al. Correcting oral contraceptive pharmacokinetic alterations due to obesity: a randomized controlled trial. Contraception 2014;90:550-6. 11. El-Ibiary SY, Raney EC. Prevention of pregnancy and sexually transmitted infections. In: Krinsky DL, Ferreri SP, Hemstreet B, et al., eds. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care, 19th ed. Washington DC:American Pharmacists Association, 2017:159-78. 12. Hatcher RA, Trussell J, Stewart F, et al. Contraceptive Technology, 20th ed. New York: Ardent Media, 2011. 13. Leung VWY, Levine M, Soon JA. Mechanisms of action of hormonal emergency contraceptives. Pharmacotherapy 2010;30:158-68.

14. Pomp ER, le Cessie S, Rosendaal FR, et al. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol 2007;139:289-96. 15. Rosenberg M, Waugh MS. Causes and consequences of oral contraceptive noncompliance. Am J Obstet Gynecol 1999;180:S276-9. 16. Selbert C, Barbouche E, Fagan J, et al. Prescribing oral contraceptives for women older than 35 years of age. Ann Intern Med 2003;138:54-64. 17. World Health Organization (WHO). Reproductive Health and Research. Medical Eligibility Criteria for Contraceptive Use, 5th ed. Geneva: WHO, 2015. Menstrual Disorders 1. American College of Obstetricians and Gynecologists (ACOG). Management of acute uterine bleeding in nonpregnant reproductive-aged women. Obstet Gynecol 2013;121:891-6. 2. American College of Obstetricians and Gynecologists (ACOG). ACOG practice bulletin No. 110: noncontraceptive uses of hormonal contraception. Obstet Gynecol 2010;115:206-18. 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington DC: American Psychiatric Association, 2003. 4. Cheang KI, Umland EM. Menstruation-related disorders. In: DiPiro JT, Yee GC, Posey M, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 11th ed. New York: McGraw-Hill, 2020. Available at http://accesspharmacy.mhmedical.com.stlcopisa.stlcop.edu/content.aspx?bookid=2577§io nid=230460240#1174435469. Accessed November 19, 2020. 5. Cohen LS, Soares CN, Lyster A, et al. Efficacy and tolerability of premenstrual use of venlafaxine (flexible dose) in the treatment of premenstrual dysphoric disorder. J Clin Psychopharmacol 2004;24:540-3. 6. Freeman EW, Sondheimer SJ, Sammel MD, et al. A preliminary study of luteal phase versus symptomonset dosing with escitalopram for premenstrual dysphoric disorder. J Clin Psychiatry 2005;66:769-73. 7. Gordon CM, Ackerman KE, Berga SL, et al. Functional hypothalamic amenorrhea: an Endocrine Society practice guideline. J Clin Endocrinol Metab 2017;102:1413-39.

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8. 9. 10.

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Hofmeister S, Bodden S. Premenstrual syndrome and premenstrual dysphoric disorder. Am Fam Physician. 2018;94:236-40. Klein DA, Paradise SL, Reeder RM. Amenorrhea: a systematic approach to diagnosis and management. Am Fam Physician 2019;100:39-48. Krinsky DL. Handbook of Nonprescription Drugs. An Interactive Approach to Self-Care. Available at https://pharmacylibrary.com/doi/ book/10.21019/9781582122656. Accessed December 2, 2019. Lanza di Scalea T, Pearlstein T. Premenstrual dysphoric disorder. Med Clin North Am 2019;103:613-28. Matteson KA, Rahn DD, Wheeler TL II, et al. Nonsurgical management of heavy menstrual bleeding: a systematic review. Obstet Gynecol 2013;121:632-43. Osayande AS, Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician 2014;89:314-6. Schlaff WD, Ackerman RT, Al-Hendy A, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med 2020;382:328-40. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018;110:364-79. Triantafilo N, Castro-Gutierrez V, Rada G. Cabergoline or bromocriptine for prolactinoma? Medwave 2016;16(suppl3):e6545. Webster J, Pisciteli G, Polli A, et al. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 1994;331:904-9. Woodhead N, Pounds R, Irani S, et al. Ulipristal acetate for uterine fibroids: 2 years of real world experience in a UK hospital. J Obstet Gynecol 2018;38:813-7.

3.

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Infertility 1. American College of Obstetricians and Gynecologists (ACOG). Infertility workup for the women’s health specialist. Obstet Gynecol 2019;133:e377-84. 2. American Society for Reproductive Medicine (ASRM). Ovarian Hyperstimulation Syndrome (OHSS). Available at https://www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/ fact-sheets-and-info-booklets/ovarian-hyperstimula-

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tion-syndrome-ohss/#:~:text=Women%20should%20 notify%20their%20doctor,Difficulty%20tolerating%20fluids. Accessed August 30, 2020. Aubuchon M, Yao MWM, Fuji DT, et al. Infertility. In: Berek JS, ed. Berek and Novak’s Obstetrics and Gynecology, 16th ed. Philadelphia: Wolters Kluwer, 2019:942-1001. Badawy A, Shokeir T, Allam AF, et al. Pregnancy outcome after ovulation induction with aromatase inhibitors or clomiphene citrate in unexplained infertility. Acta Obstet Gynecol Scand 2009;88:187-91. Franik S, Eltrop SM, Kremer JA. Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev 2018;5:CD010287. Hughes E, Collins J, Brown J, et al. Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev 2010;1:CD000057. Hughes E, Collins J, Vandekerckhove P. Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea. Cochrane Database Syst Rev 2008;4:CD000056. Lindahl S. A review of infertility for the primary care provider. Physician Assist Clin 2018;3:423-32. Nugent D, Vanderkerchove P, Hughes E, et al. Gonadotrophin therapy for ovulation induction in subfertility associated with polycystic ovary syndrome. Cochrane Database Syst Rev 2009;1:CD000410. Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril 2020;113:533-5. Practice Committee of the American Society for Reproductive Medicine. Evidence-based treatments for couples with unexplained infertility: a guideline. Fertil Steril 2020;113:305-22. Practice Committee of the American Society for Reproductive Medicine. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. Fertil Steril 2017;108:426-41. Practice Committee of the American Society for Reproductive Medicine. The role of immunotherapy in in vitro fertilization: a guideline. Fertil Steril 2018;110:387-400. Practice Committees of the American Society for Reproductive Medicine and Society for Reproductive Endocrinology and Infertility. Use of exogenous gonadotropins for ovulation induction

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15. 16.

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in anovulatory women: a committee opinion. Fertil Steril 2020;113:66-70. Pritts EA. Letrozole for ovulation induction and controlled ovarian hyperstimulation. Curr Opin Obstet Gynecol 2010;22:289-94. Qin F, Zhou Y, Huan L, et al. Comparison of clomiphene and letrozole for superovulation in patients with unexplained infertility undergoing intrauterine insemination. A systematic review and meta-analysis. Medicine 2020;99:e21006. Sene AA, Ghorbani S, Ashrafi M. Comparison of the pregnancy outcomes and the incidence of fetal congenital abnormalities in infertile women treated with letrozole and clomiphene citrate. J Obstet Gynaecol Res 2018;44:1036-41. Smith C, Grimm M, Schwegel M. Treatment of infertility in women. J Am Pharm Assoc 2012;52:e27-42. Stachnik JM, Krueger CD. Infertility in women. In: Murphy JE, Lee MW, eds. Pharmacotherapy Self-Assessment Program, 2013, Book 2, Special Populations. Lenexa, KS: American College of Clinical Pharmacy, 2013:61-79. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018;110:364-79. Usadi RS, Merriam KS. On-label and off-label drug use in the treatment of female infertility. Fertil Steril 2015;113:583-94.

7.

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Selak V, Farquhar C, Prentice A, et al. Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst Rev 2009;1:CD000068. Vercellini P, Trespidi L, Colombo A, et al. A gonadotropin-releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis. Fertil Steril 1993;60:75-9. Vest K, Lynch SE. Endometriosis. In: DiPiro JT, Yee GC, Posey M, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 11th ed. New York: McGraw-Hill, 2020. Available at http://accesspharmacy.mhmedical.com.stlcopisa.stlcop.edu/content. aspx?bookid=2577§ionid=226724883. Accessed November 19, 2020.

Pregnancy and Lactation 1. American Academy of Pediatrics (AAP). Committee on Genetics: folic acid for the prevention of neural tube defects. Pediatrics 1999;104(2 pt 1):325-7. 2. American College of Obstetricians and Gynecologists (ACOG). Practice bulletin No. 187: neural tube defects. Obstet Gynecol 2017;130:e279-90. 3. American College of Obstetricians and Gynecologists (ACOG). Practice bulletin No. 159: management of preterm labor. Obstet Gynecol 2016;127:e29-38. 4. American College of Obstetricians and Gynecologists (ACOG). ACOG practice bulletin No. 107: induction of labor. Obstet Gynecol 2009;114:386-97. 5. American College of Obstetricians and Gynecologists. ACOG practice bulletin No. 189: nausea and vomiting of pregnancy. Obstet Gynecol 2018;131:315-30. 6. American College of Obstetricians and Gynecologists (ACOG). ACOG practice bulletin No. 203: chronic hypertension in pregnancy. Obstet Gynecol 2019;133:e26-50. 7. American College of Obstetricians and Gynecologists (ACOG). ACOG practice bulletin No. 131: gestational diabetes. Obstet Gynecol 2018;131:e49-64. 8. American College of Obstetricicians and Gynecologists (ACOG). ACOG practice bulletin No. 90: asthma in pregnancy. Obstet Gynecol 2008;111:1001-20. 9. American College of Obstetricians and Gynecologists (ACOG). ACOG practice bulletin No. 196: thromboembolism in pregnancy. Obstet Gynecol 2018;132:e1-17. 10. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy. Chest 2012;141(suppl):e6915-7365.

Endometriosis 1. Alison E, Gallo MF, Jensen JT, et al. Continuous or extended cycle vs. cyclic use of combined hormonal contraceptives for contraception. Cochrane Database Syst Rev 2010;3:CD004695. 2. American College of Obstetricians and Gynecologists (ACOG). Practice bulletin no. 114: management of endometriosis. Obstet Gynecol 2010;116:223-36. 3. Prentice A, Deary AJ, Bland E. Progestogens and anti-progestogens for pain associated with endometriosis. Cochrane Database Syst Rev 2000;2:CD002122. 4. Prentice A, Deary AJ, Goldbeck-Wood S, et al. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev 2000;2:CD000346. 5. Selak V, Farquhar C, Prentice A, et al. Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst Rev 2000;2:CD000068.

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of Endocrinology position statement on menopause-2017 update. Endocr Pract 2017;23:869-80. 2. Feig DS, Donovan LE, Zinman B, et al.; MiTy Collaborative Group. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2020;8:834-44. 3. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57. 4. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: Heart and Estrogen/Progestin Replacement Study (HERS) research group. JAMA 1998;280:605-13. 5. American College of Obstetricians and Gynecologists (ACOG). ACOG practice bulletin No. 141: management of menopausal symptoms. Obstet Gynecol 2014;123:202-16. 6. Manson JE, Aragaki AK, Rossouw JE. Menopausal hormone therapy and long-term all-cause and causespecific mortality. The Women’s Health Initiative randomized trials. N Engl J Med 2017;318:927-31. 7. North American Menopause Society. The 2017 hormone therapy position statement of the North American Menopause Society. Menopause 2017;24:728-53. 8. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021;143:e72-e227. 9. Rapp SR, Espeland MA, Shumaker SA. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2663-72. 10. Schierbeck LL, Rejnmark L, Toffeng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomized trial. BMJ 2012;345:e6409. 11. Shumaker SA, Legault C, Rapp SR. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651-62.

11. Briggs GG, Freeman RK, Towers CV, et al. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation, 11th ed. Philadelphia: Wolters Kluwer, 2017. 12. Briggs GG, Nageotte M. Diseases, Complications, and Drug Therapy in Obstetrics. Bethesda, MD: ASHP, 2009. 13. Claire R, Chamberlain C, Davey MA, et al. Pharmacological interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev 2020;3:CD010078. 14. Gerard EE, Meador KJ. Managing epilepsy in women. Continuum 2016;22:204-26. 15. Hale TW. Lactational pharmacology. In: Walker M, ed. Core Curriculum for Lactation Consultant Practice. Sudbury, MA: Jones & Bartlett, 2002:356-91. 16. Harden CL, Meador KJ, Pennell PB, et al. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidencebased review): teratogenesis and perinatal outcomes. Neurology 2009;73:133-41. 17. Loebstein R, Lalkin A, Koren G. Pharmacokinetic changes during pregnancy and their clinical relevance. Clin Pharmacokinet 1997;33:328-43. 18. Lucas S. Migraine and other headache disorders: ACOG clinical updates in women’s health care primary and preventive care review summary Volume XVIII, Number 4. Obstet Gynecol 2019;134:211. 19. Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77:193-8. 20. Parker SE, Van Bennekom C, Anderka M, et al. Ondansetron for the treatment of nausea and vomiting of pregnancy and the risk of specific birth defects. Obstet Gynecol 2018;132:385-94. 21. Pennell PB. 2005 AES annual course: evidence used to treat women with epilepsy. Epilepsia 2006;47(suppl 1):46-53. 22. Sachs CH, Committee on Drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics 2013;132:e796-809. 23. Tatum WO. Use of antiepileptic drugs in pregnancy. Expert Rev Neurother 2006;6:1077-86. Menopausal Symptoms 1. Cobin RH, Goodman NF. American Association of Clinical Endocrinologists and American College

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12. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of symptoms of the menopause: an endocrine society clinical practice guidelines. J Clin Endocrinol Metab 2015;100:3875-4011. 13. Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities recorded in the Women’s International Study of Long Duration Oestrogen After Menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ 2007;335:239. 14. Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291:1701-12. 15. Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;273:199-208. 16. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-33.

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Obstetrics and Gynecology

ANSWERS AND EXPLANATIONS TO PATIENT CASES 1. Answer: D This patient currently has contraindications to using an estrogen-containing contraceptive because her systolic blood pressure is greater than 160 mm Hg (Answers B and C are incorrect). Medroxyprogesterone acetate (Answer A) would not be the best choice because the patient is already overweight, and this product causes significant weight gain. In addition, medroxyprogesterone has an average return of fertility of 9 months after the last injection. Because the patient wants to attempt conception in 12 months, she would receive only a few injections and would then need to consider alternative agents. Norethindrone (Answer D) does not contain estrogen and is not associated with significant weight gain.

Answer D is second line in patients who are not wanting contraceptive therapy; however, this patent is contraindicated because of her DVT history. 5. Answer: B Because this patient has WHO class 2 infertility, letrozole would be the best initial treatment. However, because the patient’s letrozole therapy has failed with an adequate 3-month trial, the next step would be to add gonadotropin therapy (Answer B is correct). This will provide FSH. Answer C is incorrect because letrozole has higher efficacy than clomiphene in this population. Answer A is incorrect because metformin can be added to clomiphene as an alternative therapy but is not recommended with letrozole. Answer D is incorrect because the patient’s menses started 3 days ago. Short courses of progesterone can be used to induce menses for patients; however, newer evidence has shown that providers can start another cycle without inducing bleeding if it is certain the patient is pregnant.

2. Answer: A Late-cycle breakthrough bleeding is a result of progestin deficiency. The patient must start using a different product that has higher progestin activity (+++) than her current product (++) (Answer A). Answers B, C, and D do not increase progestin activity, so these are incorrect.

6. Answer: A Lamotrigine is associated with an increased risk of cleft palate/lip; however, the palate and lip are developed by 9 weeks’ gestation. The patient is currently at 18 weeks’ gestation, so lamotrigine could not cause cleft palate/lip (Answer A). Lamotrigine has not been associated with intrauterine growth restriction, cardiac abnormalities, or neurodevelopment delays (Answers B, C, and D).

3. Answer: C Answer A is incorrect because this patient is past the optimal dosing window of 72 hours for Plan B One-Step. Studies have shown continued efficacy for up to 120 hours after unprotected intercourse, but efficacy may be decreased when used past 72 hours. The dosing in Answer A is also incorrect. Dosing should be levonorgestrel 1.5 mg for one dose. Answer B, recommend a levonorgestrel IUD today, is incorrect because she has an active chlamydia infection. Medical eligibility criteria state that initiating an IUD when the patient has a current purulent cervicitis, chlamydia, or gonococcal infection is a category 4 rating; hence, this is contraindicated. Ulipristal (Answer C) can be given up to 120 hours after unprotected intercourse and can be initiated immediately. Answer D is incorrect because she can still receive EC, given that it has been fewer than 120 hours since unprotected intercourse.

7. Answer: B The patient does not require progestin therapy because she has had her uterus removed (Answer C). Testosterone therapy is not required because she is not experiencing decreased libido with a diagnosis of hypoactive sexual dysfunction disorder (Answer D). A non-oral route would be preferred because of her elevated triglyceride values (Answer B). Oral therapy has the highest effects on the cholesterol panel, including increasing the concentration of triglycerides (Answer A). 8. Answer: D The options in Answers A and C are contraindicated for this patient because of her history of myocardial infarction. In addition, Answer A is incorrect because this patient still has her uterus and would need a progestogen with the estrogen for protection against endometrial hyperplasia. Although ospemifene is indicated for moderate to severe

4. Answer: A This patient has heavy menstrual bleeding, and her NSAID therapy has failed. If patients are interested in using a contraceptive, LNG-IUD have the highest efficacy in improving symptoms, Answer A. Answers B and C are second-line options but are contraindicated in this patient because of her history of deep venous thrombosis (DVT).

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 492

Obstetrics and Gynecology

dyspareunia, it would be inappropriate for this patient (Answer C). Answer B is incorrect because this is a nonhormonal product used for vasomotor, not genitourinary, symptoms. Patients with mild to moderate genitourinary symptoms should start with a vaginal lubricating gel (Answer D).

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Obstetrics and Gynecology

ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS 1. Answer: D Depot medroxyprogesterone acetate (Answer A) causes considerable weight gain, making it a less-than-optimal choice for this patient. Cerebrovascular accident is also a relative contraindication (medical eligibility criteria category 3) for progestin-only contraceptives of depot medroxyprogesterone and continuation of POPs and implants. The levonorgestrel IUD (Answer B) should not be used because the patient has structural abnormalities of the uterus. The contraceptive sponge (Answer C) should be avoided because of the patient’s uterine structural abnormalities and because she is recently postpartum. The polyurethane condom (Answer D) is the best option because the patient has no contraindications or allergies that would prohibit its use.

that birth defect (Answer B is correct). The half-life of a medication does not affect the risk of medication exposure during pregnancy (Answer D is incorrect). 5. Answer: A The best recommendation is to delay the treatment until after she stops breastfeeding (Answer A is correct). The drug is likely to cross into breast milk, but exact concentrations are unknown. Because of its long half-life and therapy duration, the infant would be exposed to the drug. The patient, who is currently asymptomatic, is seeking treatment only for cosmetic reasons. Itraconazole is an option for treating onychomycosis; however, it has decreased efficacy compared with terbinafine (Answer B is incorrect). Topical terbinafine is not effective for treating onychomycosis (Answer C is incorrect). Scheduling the doses right after feedings is recommended to minimize infant exposure; however, because the half-life is long and the baby is feeding every 2 hours, this recommendation is unlikely to decrease infant exposure (Answer D is incorrect).

2. Answer: A The patient has no contraindications or allergies to the female condom (Answer A). However, she has a latex allergy, so the male latex condom (Answer B) would not be a good choice. Estrogen-containing contraceptives (Answer C) are contraindicated (medical eligibility criteria category 4) for patients with stroke, according to the CDC and the World Health Organization. Ulipristal (Answer D) is a form of EC; it should not be used as a regular form of contraception.

6. Answer: D Because the patient has a BMI >30, Xulane is not recommended because of decreased efficacy and increased thromboembolic risk, making Answer A and Answer B incorrect. Estrogen-progestin contraceptives (Answer C and Answer D) are second-line agents after NSAIDs for treating dysmenorrhea because they can decrease menstrual length and volume. Extended-interval dosing is preferred because it decreases the frequency of menses, making Answer D correct.

3. Answer: D Analysis of variance (Answer D) would be most appropriate because the trial consists of more than two groups and involves continuous data that are most likely normally distributed (n=600). Although the Student t test (Answer A) is for continuous data, it should be used only if two groups are being compared. Both the Fisher exact test (Answer B) and the Kruskal-Wallis test (Answer C) are for nonparametric data.

7. Answer: C Natazia is a quadriphasic hormonal contraceptive that requires 9 days of backup contraception. The first two pills contain only estrogen, and ovulation protection does not occur until after the seventh dose. The egg is only viable for up to 48 hours after ovulation, so 9 days (Answer C) are required to provide pregnancy protection.

4. Answer: B Although molecular weight is important in determining whether a drug will cross the placenta, the risk of malformations is not directly addressed (Answer C is incorrect). Information from studies of animals helps determine the potential risks of drugs in humans but does not confer exact risks in humans (Answer A is incorrect). Educating the patient on the gestational timing of risks and on the current stage of pregnancy is imperative to understanding whether the patient has any chance of experiencing

8. Answer: B Estrogens should be avoided because of the patient’s active breast cancer (Answer A is incorrect). Venlafaxine has shown efficacy in decreasing vasomotor symptoms in patients with and without breast cancer (Answer B is correct). Clonidine improves vasomotor symptoms but may not be the best choice because this patient’s blood pressure

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is low (Answer C is incorrect). Black cohosh has not been effective in reducing vasomotor symptoms in patients with breast cancer (Answer D is incorrect). 9. Answer: C The Endometriosis Association (Answer C) provides contact information for local support groups and patient information. The Association of Reproductive Health Professionals (Answer A), ACOG (Answer B), and the National Women’s Health Network (Answer D) provide patient information and health care–related information.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 495

Pulmonary Disorders Jean Y. Moon, Pharm.D., FCCP, BCACP University of Minnesota Minneapolis, Minnesota

Pulmonary Disorders

Pulmonary Disorders Jean Y. Moon, Pharm.D., FCCP, BCACP University of Minnesota Minneapolis, Minnesota

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 499

Pulmonary Disorders

Learning Objectives 1. Compare and contrast between common features of patients with asthma or chronic obstructive pulmonary disease (COPD). 2. Select appropriate evidence-based treatment for patients with asthma, COPD, and/or nicotine dependence based on specific patient factors and comorbidities. 3. Develop a comprehensive education plan with monitoring parameters for patients on therapy for asthma, COPD, and/or smoking cessation. 4. Compare and contrast the different respiratory inhaler devices and holding chambers. 5. Integrate brief behavioral counseling and smoking cessation best practices when assisting a patient with quitting smoking.

Abbreviations in This Chapter

Baseline Knowledge Statements

ACO Asthma COPD overlap ATS American Thoracic Society COPD Chronic obstructive pulmonary disease CV Cardiovascular CYP Cytochrome P450 DPI Dry powder inhaler EPR-3 National Asthma Education and Prevention Program Expert Panel Report 3 FDA U.S. Food and Drug Administration FeNO Fractional exhaled nitric oxide FEV1 Forced expiratory volume in 1 second FVC Forced vital capacity GINA Global Initiative for Asthma GOLD Global Initiative for Chronic Obstructive Lung Disease HFA Hydrofluoroalkane ICS Inhaled corticosteroid LABA Long-acting β2-agonist LAMA Long-acting antimuscarinic LTRA Leukotriene receptor antagonist MDI Metered dose inhaler NRT Nicotine replacement therapy OCS Oral corticosteroid PCV13 Pneumococcal conjugate vaccine PEFR Peak expiratory flow rate PPSV23 23-Valent pneumococcal polysaccharide vaccine SABA Short-acting β2-agonist

• Underlying pathophysiology of asthma, COPD, and nicotine dependence. • Pharmacology of common respiratory medication classes such as short-acting β2-agonist (SABA), long-acting β2-agonist (LABA), long-acting antimuscarinic (LAMA), inhaled corticosteroid (ICS), oral corticosteroid (OCS), and biologic agents (anti-immunoglobulin E [IgE], anti-interleukin [IL]5, anti-IL-5R, anti-IL-4/IL-13). • Pharmacology of common medications used for smoking cessation including varenicline, bupropion, and nicotine replacement therapy (NRT). Additional Readings 1. National Heart, Lung, and Blood Institute. Guidelines for the Diagnosis and Management of Asthma. National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3. NIH Publication 08-5846. 2007. Available at www.nhlbi.nih.gov/sites/default/files/media/docs/ asthgdln_1.pdf. Accessed August 20, 2021. 2. National Heart, Lung, and Blood Institute. 2020 Focused Updates to the Asthma Management Guidelines. National Asthma Education and Prevention Program (NAEPP) Expert Panel Report. NIH Publication. 2020. Available at https://www. nhlbi.nih.gov/health-topics/all-publications-andresources/2020-focused-updates-asthma-management-guidelines. Accessed August 20, 2021.

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Self-Assessment Questions Answers and explanations to these questions can be found at the end of the chapter.

3. Cloutier MM, Dixon AE, Krishnan JA, et al. Managing asthma in adolescents and adults: 2020 asthma guideline update from the National Asthma Education and Prevention Program. JAMA 2020;324:2301-17. 4. Global Initiative for Asthma (GINA) [homepage on the Internet]. Available at www.ginasthma.org. Accessed August 20, 2021. 5. National Institute for Health and Care Excellence (NICE). Asthma: Diagnosis Monitoring and Chronic Asthma Management. NICE Guideline (NG80). Updated February 2020. Available at www.nice.org.uk/guidance/ng80. Accessed August 20, 2021. 6. Parsons JP, Hallstrand TS, Mastronarde JG, et al. An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction. Am J Respir Crit Care Med 2013;187:1016-27. 7. Global Initiative for Asthma (GINA). Asthma, COPD and Asthma-COPD Overlap Syndrome (ACOS). 2015. Available at http://goldcopd.org/ asthma-copd-asthma-copd-overlap-syndrome. Accessed August 20, 2021. 8. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Prevention, Diagnosis and Management of COPD. 2021 GOLD Report. Available at www.goldcopd.org/. Accessed August 20, 2021. 9. Rajat SB, Rigotti NA, Benowitz NL, et al. 2018 ACC expert consensus decision pathway on tobacco cessation treatment: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2018;72:3332-65.

Questions 1–3 pertain to the following case: A.S. is a 23-year-old woman who has been wheezing and coughing for the past year. In the past few months, she has used her albuterol inhaler about four times daily during the day and about twice weekly for coughing that awakens her during the night. Spirometry is consistent with an asthma diagnosis. Fractional exhaled nitric oxide (FeNO) is greater than 50 ppb. 1. Which best classifies A.S.’s asthma severity using the National Asthma Education and Prevention Program Expert Panel Report 3 (EPR-3) guidance? A. B. C. D.

Intermittent. Mild persistent. Moderate persistent. Severe persistent.

2. Which is the best controller therapy for A.S.’s asthma using the 2020 Focused Updates guidance? A. Fluticasone (110 mcg/actuation) two inhalations twice daily by metered dose inhaler (MDI). B. Montelukast 10 mg 1 tablet orally daily. C. Salmeterol 1 inhalation (50 mcg) twice daily by dry powder inhaler (DPI). D. Budesonide/formoterol (160 mcg/4.5 mcg) 1 inhalation twice daily by MDI.

3. The physician would like to start single maintenance and reliever therapy (SMART) for A.S. Which is the most accurate education for the physician? A. Albuterol should be prescribed for reliever therapy. B. Any inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) combination inhaler can be prescribed. C. ICS monotherapy is preferred to SMART. D. Insurance coverage should be checked.

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4. A patient being initiated on a DPI has only used MDIs in the past. Which is the most appropriate instruction for the patient?

A. B. C. D.

A. When using a DPI, the actuation will feel the same as that from an HFA inhaler. B. DPIs require a quick and forceful inhalation technique. C. DPIs should be shaken before each use. D. DPIs should be used with a holding chamber.

8. A 20-year-old woman wants to quit smoking. She has never attempted to quit before and is determined to quit “cold turkey.” You provide her with education regarding withdrawal symptoms. Which of the following is the most likely symptom of smoking cessation withdrawal?

5. A 70-year-old woman has persistent shortness of breath, cough, and sputum production that has gradually worsened during the past year. Her COPD assessment test score is 12. She has been using albuterol HFA two inhalations several times per day for persistent shortness of breath. Her spirometry showed a forced expiratory volume in 1 second (FEV1) equal to 70% of predicted and an FEV1/forced vital capacity (FEV1/FVC) equal to 60% of predicted after a bronchodilator. Her blood eosinophil count is 50 cells/ mm3. She has never had a COPD exacerbation. Which is the best medication to initiate? A. B. C. D.

Liraglutide. Nicotine patch. Bupropion. Varenicline.

A. B. C. D.

Sedation. Increased concentration. Increased heart rate. Weight gain.

9. A 40-year-old man presents to the clinic wanting to quit smoking. He rates how much he wants to quit as 10/10 and believes he can quit with help. Together, you decide to use varenicline to help him quit smoking. Which is most accurate regarding medication use and counseling for this patient?

Tiotropium DPI. Beclomethasone MDI. Montelukast orally. Fluticasone plus salmeterol MDI.

A. A combination of behavioral counseling and drugs is more effective than either behavioral counseling or medication alone. B. Varenicline is contraindicated in patients with renal impairment. C. Varenicline should be taken on an empty stomach. D. Avoid using varenicline longer than 3 months.

6. A 65-year-old man with COPD (baseline FEV1 of 45% predicted) presents with a 3-day history of worsening shortness of breath and increased cough, which has been keeping him up all night. His coughs have been bringing up more sputum, which is mostly clear. He denies cloudy, purulent sputum. Which is the most appropriate treatment at this time? A. No additional therapy needed. B. Albuterol by nebulization. C. Albuterol by nebulization plus oral prednisone burst. D. Albuterol by nebulization plus oral prednisone burst plus oral antibiotics.

7. A 50 year-old woman has been smoking for over 35 years, about 1–1.5 packs/day. Her medical history is significant for COPD and obesity. She is reluctant to quit smoking. Which of the following options would be best to recommend for this patient for smoking cessation?

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I.  ASTHMA A. Definition: Asthma is a common chronic inflammatory disorder of the airways characterized by episodic airflow limitation, bronchial hyperresponsiveness, and underlying inflammation causing recurrent varying symptoms of wheezing, breathlessness, cough, and chest tightness. Increased bronchial hyperresponsiveness can occur with a variety of stimuli. Airway obstruction is often reversible spontaneously or with treatment (Domain 1). 1. Phenotypes of asthma: Recognizable clusters of demographic, clinical, and/or pathophysiological characteristics and include the following (per Global Initiative for Asthma [GINA]): Allergic asthma, nonallergic asthma, adult-onset asthma, asthma with persistent airflow limitation, and asthma with obesity 2. Simplified: Phenotypes associated with Type 2 inflammation versus non-Type 2 inflammation type B. Guidelines (Domain 1) 1. National Asthma Education and Prevention Program (NAEPP) EPR-3, 2020 Focused Updates a. EPR-3 published in 2007; main reference for this chapter as this is widely used in the United States b. 2020 Focused Updates was released in December 2020 with focus on updating EPR-3 guidance in the following areas; both EPR-3 (to designate what was not reviewed/changed) and 2020 Focused Updates are referenced throughout: i. Intermittent inhaled corticosteroids (ICS) ii. Add-on long-acting muscarinic antagonists (LAMAs) iii. Fractional exhaled nitric oxide (FeNO) iv. Indoor allergen mitigation v. Immunotherapy vi. Bronchial thermoplasty 2. GINA a. Updated annually since 2002; twice annual review of literature b. Significant changes in 2019 for treatment recommendations in mild asthma c. Global committee; includes socioeconomic considerations d. 2019 report specific for difficult-to-treat and severe asthma 3. National Institute for Health and Care Excellence a. Last updated in 2021 b. Widely used in the United Kingdom for primary care physicians and patients with mild to moderate asthma 4. American Thoracic Society (ATS) a. Specific guidance to therapeutic areas of pulmonary management and health b. Examples include obesity and asthma, asthma management in the elderly, severe asthma, interpretation of FeNO levels, and exercise-induced bronchoconstriction 5. Global Initiative for Chronic Obstructive Lung Disease/GINA asthma COPD overlap (ACO): a. Last updated in 2015; updated chapter in GINA b. Collaboration between GOLD and GINA; both recommend prioritizing asthma treatment c. Stepwise approach for primary care providers treating patients with features of both asthma and COPD C. Diagnosis (Domain 1) 1. Clinical history (symptoms and family history) 2. Confirmed variable expiratory airflow obstruction; ideally, before respiratory therapy is initiated; poorly controlled asthma is associated with greater variability a. Positive bronchodilator test; reversible airway obstruction is rapidly improved (defined as forced expiratory volume in 1 second [FEV1] improvement by 12% or more in patients 12 years and older and 15% or more in those younger than 12 years after 200–400 mcg SABA) b. Positive exercise challenge test ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 503

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c. d. e. f.

Positive bronchial challenge test (e.g., histamine or methacholine) Significant increase in lung function after 4 weeks of anti-inflammatory treatment Excessive variability in twice-daily peak expiratory flow rate (PEFR) function over 2 weeks or in 1 day Excessive variation in lung function between visits (less reliable)

Table 1. Interpreting Spirometry Component

FEV1

What It Measures

Normal Values

The maximum volume of air that can be exhaled after full inspiration

Reported in L and as a percentage of predicted value on the basis of sex, age, height, and race/ethnicity Normal lungs can empty 80% of air in < 6 s

Volume of air exhaled Normal is 80% or greater of predicted value forcefully in the first second Reported in L/min and as a percentage of predicted value on the of maximal expiration basis of sex, age, height, and race/ethnicity In asthma, reversibility is shown by an increase in FEV1 ≥ 12% after SABA in patients > 12 yr and > 15% in those < 12 yra

FVC FEV1/FVC ratio

Differentiates between obstructive, normal, and restrictive disease

Normal: Within 5% of predicted range, which varies with age; usually 75%–80% in adults Decreased in obstructive disease (asthma, COPD) (< 70%) Normal/high in restrictive disease (e.g., pulmonary fibrosis)

Reversibility may not be present during viral infections or with fixed airway limitation.

a

COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity; SABA = short-acting β2-agonist.

3. Alternate testing a. Peak flow measurement b. Blood eosinophil c. FeNO: Non-invasive and relatively inexpensive test; marker of blood and sputum eosinophil levels; measures the amount of nitric oxide in the exhaled breath i. National Institute for Health and Care Excellence recommends FeNO if equipment is available and testing will not compromise acute treatment. The following patient levels have more eosinophilic inflammation and likely response to corticosteroids: (a) FeNO 40 ppb or greater (17 years of age and older) (b) FeNO 35 ppb or greater (5–16 years of age) ii. GINA does not recommend FeNO for diagnosis of asthma. FeNO can indicate Type 2 airway inflammation, but can also be positive or negative for nonasthma conditions or not elevated in some phenotypes (e.g., neutrophilic). Recommends using FeNO greater than 20 ppb as a factor in increasing ICS dosing or initiating other add-on therapy. iii. ATS provides clinical guidance for the FeNO measurements and recommends use for diagnosis and responsiveness to corticosteroids. The following patient levels have more eosinophilic inflammation and a more likely response to corticosteroids: (a) FeNO 50 ppb or greater (adults) (b) FeNO 35 ppb or greater (children) iv. 2020 Focused Updates recommends FeNO as an adjunct for diagnosing asthma and for ongoing management of therapeutic selection for patients 5 years and older (conditional recommendation). Specifically, FeNO is recommended when a diagnosis is uncertain because of history, physical examination, or spirometry or if spirometry cannot be performed. Similar to GINA, 2020 Focused

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Updates outlines clinical situations when FeNO can be increased or decreased. FeNO is not recommended for predicting future exacerbations or exacerbation severity. More specifically: (a) FeNO less than 25 ppb: Can indicate taking an ICS, non-type 2 asthma, patients with obesity, or those who smoke (b) FeNO 25–50 ppb: Difficult to assess but can indicate partial adherence to ICS or inadequate control (c) FeNO greater than 50 ppb: Found in type 2 inflammation, eosinophilic bronchitis, or patients without asthma with allergic sensitization. These patients will likely respond to corticosteroids. 4. Alternative diagnoses are excluded; most common features in asthma, COPD, or ACO (Table 2) a. Considerations i. Age of onset: These are typical age groupings, but asthma can present later in life. ii. Pattern of symptoms: Cough is usually non-productive with asthma and productive with COPD; isolated cough is seldom consistent with asthma. iii. Asthma is often related to allergies/environmental triggers, family history, obesity, and gastroesophageal reflux disease; patients with COPD often have a common history of smoking. iv. Lung function: FEV1 is often reversible in asthma but is unlikely in COPD unless FEV1 is very low and/or both asthma and COPD are present. Even with a post-bronchodilator response in COPD, obstruction (FEV1/forced vital capacity (FVC) less than 70%) is still present. v. Between testing, patients with asthma may have normal lung function; patients with COPD have persistent airflow limitations. vi. Exacerbations: May be more common in COPD; asthma exacerbations occur, but risk is reduced by treatment vii. Airway inflammation: Asthma: Eosinophils and/or neutrophils; COPD: Neutrophils and positive or negative eosinophils in sputum Table 2. Syndromic Diagnosis in Adults for Asthma COPD Overlap Features

Asthma

Age of onset

COPD

Before 20 years old

After 40 years old

Pattern of symptoms

Variation over min, hr or days Worse during the night or early morning Triggered by exercise, emotions including laughter, dust, or exposure to allergens

Lung function

Record of variable airflow limitation (spirometry or peak flow)

Record of persistent airflow limitation (FEV1/ FVC < 70% post-BD)

Previous diagnosis of asthma Family history of asthma, and other allergic conditions

Previous doctor diagnosis of COPD, chronic bronchitis, or emphysema Heavy exposure to risk factor: Tobacco smoke, biomass fuels

Lung function between symptoms Past history or family history

Normal

Persistent despite treatment Good and bad days but always daily symptoms and exertional dyspnea Chronic cough and sputum preceded onset of dyspnea, unrelated to triggers

Abnormal

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Table 2. Syndromic Diagnosis in Adults for Asthma COPD Overlap (continued) Features

Asthma

Time course

No worsening of symptoms over time; variation in symptoms either seasonally, or from year to year May improve spontaneously or have an immediate response to bronchodilators or to ICS over weeks

Chest radiograph

Normal

COPD

Symptoms slowly worsening over time (over yr) Rapid-acting bronchodilator treatment provides only limited relief Severe hyperinflation

Diagnostic Criteria Based on the Number of Features in Each Column 3 or more features of asthma is consistent with an asthma diagnosis 3 or more features of COPD is consistent with COPD diagnosis Features of both could indicate ACOS

ACOS = Asthma, COPD and Asthma-COPD Overlap Syndrome; BD = bronchodilator; ICS = inhaled corticosteroid.

Information from: Global Initiative for Asthma (GINA). Asthma, COPD and Asthma-COPD Overlap Syndrome (ACOS). 2015. Available at https://goldcopd.org/ wp-content/uploads/2016/04/GOLD_ACOS_2015.pdf. Accessed August 20, 2021.

5. Comorbidities with similar symptoms a. Evaluate allergic rhinitis, eczema (sleep disturbances), food allergy, obesity, gastroesophageal reflux disease (cough) 6. Exercise-induced bronchospasm a. ATS published clinical practice guidelines for exercise-induced bronchospasm in 2013. b. Diagnosis can be challenging in patients with obesity, lack of fitness, or inducible laryngeal obstruction because symptoms are similar. c. Can be confirmed by an exercise challenge in which there is a 15% decrease in FEV1 or peak expiratory flow before and after exercise, measured at 5-minute intervals for 20–30 minutes. GINA recommends this testing as an option; National Institute for Health and Care Excellence does not. ATS recommends serial lung function testing. D. EPR-3 Classification of Asthma Severity and Control (Domains 1, 3). Table 3. EPR-3 Classification of Asthma Severity in Adults and Childrena Age Group (yr) Intermittent

Components

Frequency of symptoms Nighttime awakening

All ages

≤ 2 days/wk

≥ 12

≤ 2 times/mo

Mild Persistent

Severe Persistent

> 2 days/wk, but not daily

Daily

Throughout the day

More than once weekly, but not nightly

Often 7 times/wk

3 or 4 times/mo Daily

Several times a day

3 or 4 times/mo

5–11

SABA; used for symptom control

Moderate Persistent

0–4

0

1 or 2 times/mo

All ages

≤ 2 days/wk

> 2 days/wk, but not daily

More than once weekly

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Table 3. EPR-3 Classification of Asthma Severity in Adults and Childrena (continued) Components

Interference with normal activity FEV1/FVCb

Age Group (yr) Intermittent

Minor limitation Some limitations

Extremely limited

≥ 12

Normal

Normal

Reduced 5%

Reduced > 5%

0–4

N/A

> 80% (normal)

> 60% to < 80%

< 60%

0 or 1/yr

≥ 2/yr

2/yr

≥ 2/yr

0 or 1/yr

≥ 2 in 6 mo or ≥ 4 wheezing episodes a yrc

5–11

Recommended step for initiating treatment (see Table 5)

Severe Persistent

None

≥ 12

Exacerbations requiring oral steroids

Moderate Persistent

All ages

5–11

FEV1 (% of normal)

Mild Persistent

0–4

≥ 12

5–11 0–4

≥ 12

> 85%

> 80% (normal)

N/A

Step 1

> 80%

75%–80%

Step 2

Step 3, and consider short course of oral steroids

5–11 0–4

< 75%

Step 4 or 5, and consider short course of oral steroidsd

Step 3 or 4, and consider short course of oral steroidsd Step 3, and consider short course of oral steroidsd

The patient is classified according to the sign or symptom in the most severe category.

a

b

Normal FEV1/FVC: 8–19 yr, 85%; 20–39 yr, 80%; 40–59 yr, 75%; 60–80 yr, 70%.

Episodes lasting more than 1 day and risk factors for persistent asthma.

c

d

Other systemic corticosteroids such as hydrocortisone and dexamethasone given in equipotent daily doses are likely to be as effective as oral treatment.

EPR-3 = NAEPP Expert Panel Report 3; N/A = not applicable.

Adapted from: National Heart, Lung, and Blood Institute. Guidelines for the Diagnosis and Management of Asthma. National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3. NIH Publication 08-5846. 2007. Available at www.nhlbi.nih.gov/files/docs/guidelines/asthsumm.pdf. Accessed August 20, 2021.

Table 4. EPR-3 Assessing Asthma Control in Adults and Children Age Group (yr)

Component

Symptoms

≥ 12

5–11

0–4

Nighttime awakenings

≥ 12

5–11

Interference with normal activity

0–4

All ages

Well Controlled

Not Well Controlled

Very Poorly Controlled

≤ 2 days/wk

> 2 days/wk

Throughout the day

≤ 2 times/mo

1–3 times/wk

≥ 4 times/wk

> 1 time/mo

> 1 time/wk

≤ 2 days/wk but not > 1 time each day

> 2 days/wk or > 1 time/day on any day

≤ 1 time/mo

≥ 2 times/mo

None

Some limitations

≥ 2 times/wk Extremely limited

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Table 4. EPR-3 Assessing Asthma Control in Adults and Children (continued) Component

Short-acting β2-agonist use for symptom controla

Age Group (yr)

All ages

Well Controlled

Not Well Controlled

Very Poorly Controlled

≤ 2 days/wk

> 2 days/wk

Several times a day

> 80% of predicted/ personal best

60%–80% of predicted/ personal best

< 60% of predicted/ personal best

0–4

N/A

N/A

N/A

Exacerbations requiring oral steroids

≥ 12

0 or 1 time/yr

≥ 2/yr

≥ 2/yr

Recommended action for treatment

All ages

FEV1 or peak flow ≥ 12 5–11 Questionnaires: ATAQ, ACQ, ACT

≥ 12 (N/A if < 12)

5–11 0–4

0 ≤ 0.75 ≥ 20

1 or 2 ≥ 1.5 16–19

Maintain current step; regular follow-up every 1–6 mo; consider step-down if well controlled ≥ 3 mo

2 or 3 times/yr

Step up one step; re-evaluate in 2–6 wk

3 or 4 N/A ≤ 15

> 3 times/yr

Consider short course of oral steroidsb; step up one or two steps; re-evaluate in 2 wk

Does not include β2-agonist used to prevent exercise-induced asthma.

a

b

Other systemic corticosteroids such as hydrocortisone and dexamethasone given in equipotent daily doses are likely to be as effective as oral treatment.

ACQ = Asthma Control Questionnaire (Eur Respir J 1999;14:902-7); ACT = Asthma Control Test (Allergy Clin Immunol 2004;113:59-65); ATAQ = Asthma Therapy Assessment Questionnaire (Am J Respir Crit Care Med 1999;160:1647-52).

Adapted from: National Heart, Lung, and Blood Institute. Guidelines for the Diagnosis and Management of Asthma. National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3. NIH Publication 08-5846. 2007. Available at www.nhlbi.nih.gov/files/docs/guidelines/index.htmasthsumm.pdf. Accessed August 20, 2021.

E. Treatment Goals (Domains 1, 2). 1. Reducing impairment a. Minimal or no chronic symptoms day or night b. Minimal or no exacerbations c. No limitations on activities; no school/work missed d. Maintain (near) normal pulmonary function e. Minimal use of SABA 2 times or less per week (not including pre-treatment of exercise-induced bronchospasm). 2. Reducing risk a. Minimal need for emergency department visits or hospitalizations b. Prevent progressive loss of function c. Minimal or no adverse effects from medications F. Pharmacologic Therapy for Asthma (Domains 1, 3, 4) 1. 2020 Focused Updates notable treatment updates and treatment recommendations (Table 5) a. Step therapy is initiated according to severity classification and age grouping. b. Each step therapy includes preferred treatment and alternative options accounting for maintenance of asthma control and reliever therapy.

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c. Preference for ICS/formoterol therapy in a single inhaler therapy (SiT) as both controller and quick reliever steps 3 and 4 for those 4 years and older compared with higher doses of ICS and same-dose ICS/LABA (with a SABA as needed); see Tables 5 and 6. Recommendation is specific to formoterol (onset of action 1–3 minutes for initial response vs. salmeterol 1–20 minutes) with preference for single maintenance and reliever therapy (SMART); SMART is more effective in reducing exacerbations; SMART dosing for for patients 12 years and older is 1 or 2 puffs (4.5 mcg of formoterol per puff) every 4 hours as needed and a maximum of 12 puffs (54 mcg) per day (8 puffs [36 mcg] per day for patients 5–11 years of age). Current therapy need not be changed if it is providing adequate control. Not FDA approved for use as reliever therapy. Studies of SMART have been conducted for budesonide and beclomethasone combinations with formoterol. d. An add-on LAMA (onset of action 35 minutes) is recommended with ICS/LABA in step 5 for those 12 years and older; secondary alternative to SMART in steps 3 and 4. Preference for adding a LABA (vs. a LAMA) to ICS treatment for uncontrolled persistent asthma; however, preference is for adding a LAMA compared with same doses of ICS. Adding a LAMA to severe persistent asthma (step 6) is not reviewed in this update; insufficient evidence comparing adding a LAMA with adding montelukast e. For patients 5 years and older with mild to moderate allergic asthma, subcutaneous immunotherapy is recommended as adjunctive therapy; sublingual immunotherapy is recommended against in those with persistent allergic asthma; omalizumab is specifically recommended in patients 5–11 years of age because of approval in this age range. f. Specific recommendation is to add short course of a daily ICS at the start of a respiratory tract infection for patients age 0–4 years. g. 2020 Focused Updates focuses on specific areas of treatment; cromolyn, nedocromil (unavailable), leukotriene receptor antagonists (LTRAs), theophylline, and biologics are not considered in the update. 2. GINA notable treatment recommendations compared with 2020 Focused Updates a. Simplified treatment steps (5 vs. 6); less reliant on classification to determine treatment and instead classification is determined by level of treatment needed i. Start with step 1 for mild asthma unless more severe symptoms, noting that low-dose ICS provides most of the clinical benefit in most patients ii. Continuous cycles of assess, adjust treatment, and review response iii. Two tracks for adolescents and adults created for those using low-dose ICS/formoterol (track 1) versus SABA (track 2) as reliever; track 1 preferred b. Preference for ICS/formoterol for each step (adolescents and adults) as either intermittent therapy or SMART i. Early initiation of ICS is emphasized for greater improvement in lung function and reduction in SABA overuse. ii. Budesonide/formoterol has been studied the most for use; beclomethasone/formoterol is also established for use in SMART. c. SABA as needed only in mild asthma is not recommended for adolescents and adults; low-dose ICS/ formoterol as needed is preferred and is a reliever option in children 6–11 years of age. i. SABA alone does not target inflammation; may be training patients to rely on SABA alone. ii. Steroid Treatment as Regular Treatment (START) 3-year study: Patients (5–66 years) on budesonide versus placebo for mild persistent asthma and measuring time to first severe asthma-related event; fewer severe asthma-related events for patients on budesonide d. Low-dose ICS/formoterol is a reliever medication option for patients 6 years and older (preferred in age 12 and older) who are already taking low-dose budesonide/formoterol or beclomethasone/formoterol (not available in the United States) for maintenance therapy; 2020 Focused Updates recommendation is for those 4 years and older in steps 3 and 4.

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e. Consider adding tiotropium soft mist inhaler (SMI) for patients 6 years and older (vs. 12 years and older for 2020 focused updates) with a history of exacerbation. f. Biologic agents i. 2020 Focused Updates considers adding on at step 5 or 6 for patients 5 and older. Recommended for patients whose disease is uncontrolled despite step 4 or 5 as add-on therapy ii. GINA includes stepwise guidance for difficult-to-treat or severe asthma. 3. ACO initial treatment considerations for patients a. For patients with 3 or more asthma features, LABA or LAMA as monotherapy should be avoided. b. For patients with 3 or more COPD features, ICS as monotherapy should be avoided. c. For patients with ACO (3 or more features of both asthma and COPD), treat as asthma, use low/mediumdose ICS, and add LABA and/or LAMA. 4. Exercise-induced bronchospasm (EIB): Prevention and treatment of symptoms a. Regular physical activity recommended; warming up before activity can help reduce EIB b. Pretreatment with an SABA 15 minutes before exercise; patients can develop tolerance with more than daily use; GINA also supports low-dose ICS/formoterol before exercise c. Long-term control therapy, if otherwise appropriate (initiate or step up); daily ICS can reduce EIB d. LTRAs can attenuate symptoms in 50% of patients; take 2 hours before exercise and can be taken as needed or daily. e. ATS supports stepping up to a daily controller if daily SABA is needed; does not support daily LABA use but supports daily ICS use (2–4 weeks for effect) and daily LTRA.

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Table 5. NHLBI Treatment Guidelines with 2020 Focused Updates Step

1 2

3

Age Group (yr) Long-Term Control All ages ≥ 12 5-11 0–4

≥ 12

5–11 0–4

4

≥ 12

5

Use SABA PRN; up to 3 treatments at 20-min intervals PRN

Preferred: Low-dose ICSa

For patients using ICS/ formoterol as controller in steps 3 and 4, ICS/ formoterol PRN use for quick relief is preferred

Preferred: Low-dose ICS or PRN concomitant ICS plus SABAa Preferred: Low-dose ICS

Preferred: Low-dose ICS/formoterola

Preferred: Low-dose ICS plus formoterola

Low-dose ICS/LABA or low-dose ICS plus montelukast or mediumdose ICS; see step 3 (5–11 yr) for patients 4 yr of age Preferred: Medium-dose ICS/formoterola

Preferred: Medium-dose ICS/formoterola

≥ 12

Preferred: Medium-high-dose ICS/LABA plus LAMA; consider biologics for patients with allergic asthma

5–11 6

No controller needed; 0–4 add short course of daily ICS at start of respiratory tract infection

5–11 0–4

0–4

≥ 12 5–11 0–4

Quick Relief

Preferred: Medium-dose ICS plus LABA; see step 4 (5–11 yr) for patients 4 yr old

Preferred: High-dose ICS plus LABA and consider omalizumab

Quick relief use > 2 times/wk (excluding pre-exercise doses) indicates inadequate control and need for step-up treatment; consider step-down if well controlled ≥ 3 mo

Preferred: High-dose ICS plus LABA

High-dose ICS plus LABA plus systemic corticosteroids and consider biologics for patients with allergic asthma Preferred: High-dose ICS plus LABA plus systemic corticosteroids and consider omalizumab Preferred: High-dose ICS plus LABA plus systemic corticosteroids

Conditionally recommend use of subcutaneous immunotherapy as an adjunctive therapy in those ≥ 5 yr whose asthma is controlled at initiation, build-up, and maintenance phases of immunotherapy. a

LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; LTRA = leukotriene receptor antagonist; PRN = as needed.

Adapted from: National Heart, Lung, and Blood Institute (NHLBI). 2020 Focused Updates to the Asthma Management Guidelines. National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 4. NIH Publication. 2020. Available at https://www.nhlbi.nih.gov/health-topics/all-publications-and-resources/2020focused-updates-asthma-management-guidelines. Accessed August 20, 2021. National Heart, Lung, and Blood Institute. Guidelines for the Diagnosis and Management of Asthma. National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3. NIH Publication 08-5846. 2007. Available at www.nhlbi.nih.gov/files/docs/ guidelines/index.htmasthsumm.pdf. Accessed August 20, 2021.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 511

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

512

Rescue therapy

Controller therapy

Severity (based on treatment level)

Rescue therapy

Controller therapy

Severity (at diagnosis)

Group

Alternative: LTRA, theophylline, zileuton, nedocromil, or cromolyn

Low dose ICS or PRN concomitant ICS plus SABA

Mild persistent

Step 2

or low dose ICS plus theophylline (or zileuton)

or medium dose ICS plus LTRA, or medium dose ICS plus theophylline, or medium dose ICS plus zileuton

Alternative: Medium dose ICS/LABA or medium dose ICS plus LAMA

Alternative: Medium dose ICS or low dose ICS/ LABA or low dose ICS plus LAMA or low dose ICS plus LTRA

Medium dose ICS/ formoterol

Step 4

Low dose ICS/ formoterol

Moderate persistent

Step 3

Track 2: Lowdose ICS

Track 2: Low dose ICS when SABA is taken

Track 2: Low-dose ICS/LABA

Track 1: Low dose ICS/formoterol

Moderate asthma

Track 1: Low dose ICS-formoterol as needed Track 2: SABA PRN

Track 1: Low dose ICS/ formoterol PRN

Track 1: Low dose ICS/ formoterol PRN

Mild asthma

Track 2: Medium/highdose ICS/LABA

Track 1: Medium dose ICS/formoterol

Severe asthma

SABA PRN; PRN for rescue is preferred for those using ICS/formoterol

SABA PRN

Intermittent

Step 1

Refer for phenotypic assessment and addon tiotropium, antiIgE, anti-IL5/5R, anti-IL4R

Add-on LAMA; consider high-dose ICS/formoterol

Alternative: Medium-high-dose ICS/LABA or highdose ICS plus LTRA

Medium-high-dose ICS/LABA plus LAMA, and consider biologics in patients with allergies

Severe persistent

Step 5

High dose ICS/LABA plus systemic corticosteroids and consider biologics in patients with allergies

Step 6

Table 7. Pharmacologic Agent Use for Asthma and COPD

Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Available at https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf. Accessed August 20, 2021.

GINA = Global Initiative for Asthma; HDM SLIT = house dust mite sublingual immunotherapy; IgE = immunoglobulin E; IL = interleukin; OCS = oral corticosteroid.

GINA

2020 Focused Updates

Guideline

Table 6. Comparison of GINA and 2020 Focused Updates Stepwise Treatment 12 years and Older

Pulmonary Disorders

Brand

Generic

513

Flovent HFA

Mometasone HFA 100, 200 mcg/puff

Mometasone DPI 110, 220 mcg/dose

Fluticasone furoate DPI 100, 200 mcg/dose

Asmanex HFA

Asmanex Twisthaler

Arnuity Ellipta

Flovent Diskus Fluticasone propionate DPI 50, 100, 250, 55, 113, ArmonAir RespiClick 210 mcg/dose ArmonAir Digihaler

Fluticasone propionate MDI 44, 110, 220 mcg/ puff

Alvesco (HFA)

Pulmicort Respules

Budesonide nebulizer solution 0.25, 0.5, 1 mg/2 mL

Ciclesonide MDI 80, 160 mcg/puff

Pulmicort Flexhaler

Budesonide DPI 90, 180 mcg/dose

Beclomethasone MDI 40, QVAR (HFA) 80 mcg/puff QVAR RediHaler

Corticosteroid inhalers

Brand

Generic

See ICS dosing table

Dose

Dose

Table 7. Pharmacologic Agent Use for Asthma and COPD (continued)

Drug interactions: caution use with potent CYP450 inhibitors (e.g. antifungals and protease inhibitors); specifically fluticasone, budesonide, and mometasone

May slow bone growth in children, but small reduction in adult height with persistent asthma

Hoarseness

Oral candidiasis

Adverse Effects

Adverse Effects

Asmanex, Arnuity Ellipta, and Alvesco are indicated as once-daily dosing for asthma

Budesonide is only nebulized corticosteroid available

QVAR RediHaler device is breathactuated MDI

Rinse mouth with water after inhalations; peak response in 1-2 weeks; additional benefit may be seen throughout several weeks

Use holding chambers to improve total dose delivered; holding chambers are only for MDIs; cannot be used for DPIs; holding chambers with a mask can be used for young children

Comments

Comments

Pulmonary Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Brand

Combivent Respimat

Atrovent HFA

Albuterol/ipratropium SMI (20 mcg/100 mcg)

Ipratropium MDI 17 mcg/puff

Ipratropium nebulizer solution 0.5 mg/2.5 mL

DuoNeb

Albuterol/ipratropium nebulizer solution 0.5 mg/3 mg/3 mL

SAMA and SAMA/SABA Combination

Generic Tremor, tachycardia, electrolyte effects (rare)

Adverse Effects

1 nebulizer every 6-8 hr PRN

2–4 puffs TID-QID (up to 12 puffs/24 hr)

Dry mouth, blurred vision, tachycardia, palpitations

Drug interactions: 1 puff QID; max 6 puffs/day caution with B-blockers, non-potassium-sparing diuretics, monoamine oxidase inhibitors, xanthine derivatives, steroids

1 vial QID PRN

Dose

Table 7. Pharmacologic Agent Use for Asthma and COPD (continued)

Duration: 2–8 hr

Used mainly for COPD or for acute asthma exacerbations requiring emergency treatment

DuoNeb solution is also available as generic

Comments

Pulmonary Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

514

Incruse Ellipta

Spiriva Respimat

Tiotropium SMI 1.25/2.5 mcg/puff

Umeclidinium DPI 62.5 mcg/dose

Spiriva HandiHaler

Tiotropium DPI 18 mcg/ dose

515

1 inhalation daily

Respimat asthma dose: 1.25 mcg 2 puffs daily; COPD dose: 2.5 mcg 2 puffs daily

Inhale 1 capsule QD, 2 puffs daily

1 vial QD

Yupelri

Revefenacin 175 mcg/3 mL

1 inhalation BID

Dose

1 vial BID

Tudorza Pressair

Brand

Glycopyrrolate inhalation Lonhala Magnair solution 25 mcg/1 mL

Aclidinium bromide DPI 400 mcg/dose

LAMA

Generic

Table 7. Pharmacologic Agent Use for Asthma and COPD (continued)

Dry mouth, blurred vision, tachycardia, palpitations, bitter or sweet taste

Adverse Effects

Do not use with severe allergy to milk proteins

Long-acting anticholinergic for COPD DPI with counter

Must insert powder-filled capsules with each dose for DPI

Duration: > 24 hr

Long acting; not for rapid relief

Respimat may be used in COPD or asthma > 6 yra

HandiHaler used for COPD only

Only indicated for COPD; duration of action: 24 hr

Long-acting anticholinergic for COPD; for use in Magnair device only; 2- to 3-min administration time

Long-acting anticholinergic for COPD DPI with counter

Comments

Pulmonary Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

516

2 puffs every 4–6 hr PRN 1 vial every 6-8 hr PRN

Xopenex HFA Xopenex

Levalbuterol nebulizer solution 0.31 mg/3 mL, 0.63 mg/3 mL, 1.25 mg/0.5 mL, 1.25 mg/3 mL

ProAir Digihaler

Albuterol DPI 117 mcg/ puff

1 vial every 6-8 hr PRN

2 puffs every 4–6 hr PRN

Dose

Levalbuterol MDI 45 mcg/puff

ProAir RespiClick

Proventil HFA Ventolin HFA ProAir HFA

Brand

Albuterol DPI 90 mcg/ puff

Albuterol nebulizer solution 0.63 mg/3 mL, 1.25 mg/3 mL, 2.5 mg/0.5 mL, 2.5 mg/3 mL

Albuterol MDI 90 mcg/ puff

SABA

Generic

Table 7. Pharmacologic Agent Use for Asthma and COPD (continued)

Drug interactions: caution with nonselective β-blockers, non-potassium-sparing diuretics, and monoamine oxidase inhibitors

Tremor, tachycardia, hypokalemia, hypomagnesemia, hyperglycemia, tachyphylaxis

Adverse Effects

Contains only R-enantiomer of albuterol

Digihaler is a digital inhaler with built in sensors to measure inspiratory flow and inhaler use

RespiClick is breath activated

Do not use RespiClick with severe allergy to milk proteins

Duration of effect (MDI): 3–4 hr (up to 6)

Also available as a solution for inhalation

Used for acute bronchospasm; regular use indicates poor control

Comments

Pulmonary Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Brovana Striverdi Respimat

Olodaterol SMI 2.5 mcg/ puff

2 puffs QD

1 vial BID

1 vial BID

Perforomist

Formoterol nebulizer solution 20 mcg/2 mL

Arformoterol nebulizer solution 15 mcg/2 mL

Inhale 1 blister/puff BID

Dose

Serevent Diskus

Brand

Salmeterol DPI 50 mcg/ dose

LABA

Generic

Table 7. Pharmacologic Agent Use for Asthma and COPD (continued)

Drug interactions: caution with B-blockers, non-potassium-sparing diuretics, monoamine oxidase inhibitors, xanthine derivatives, steroids

Tremor, tachycardia, electrolyte effects (rare)

Adverse Effects

Only indicated for COPD; duration of action: 24 hr

Arformoterol is the R,R-enantiomer of racemic formoterol

Only indicated for COPD

Onset of action ~ 5 min

CYP3A4 substrate

Duration: 8–12 hr

Should not be used as monotherapy for asthma

Not for acute symptoms

Comments

Pulmonary Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

517

Brand

518

Mometasone/formoterol MDI 100/5, 200/5 mcg/ puff

Fluticasone furoate/ umeclidinium/vilanterol DPI 100/62.5/25 mcg/ inhalation

Fluticasone furoate/ vilanterol DPI 100/25, 200/25 mcg/inhalation 1 puff daily

1 or 2 puffs BID

Dulera (HFA)

1 puff daily

2 puffs BID

1 puff BID

2 puffs BID

2 puffs BID

Dose

Trelegy Ellipta

Breo Ellipta

Advair HFA

AirDuo RespiClick AirDuo Digihaler

RespiClick 55/14 mcg, 113/14 mcg, 232/14 mcg

Fluticasone/salmeterol MDI 45/21, 115/21, 230/21 mcg/puff

Advair Diskus

Fluticasone/salmeterol DPI 100/50, 250/50, 500/50 mcg/inhalation

Budesonide/formoterol Symbicort (HFA) MDI 80/4.5, 160/4.5 mcg/ puff

Budesonide/ Breztri Aerosphere glycopyrrolate/formoterol MDI 160/9/4.8 mcg/puff

Corticosteroid combination inhalers

Generic

Table 7. Pharmacologic Agent Use for Asthma and COPD (continued)

See previous adverse events

Adverse Effects

Trelegy Ellipta is approved for asthma and COPD (> 18 yr)

Symbicort is approved (> 6 yr)

Dulera (HFA) is approved in asthma (> 4 yr)

Breo Ellipta is approved for asthma and COPD (> 18 yr)

Advair Diskus is available in generic

Breztri Aerosphere is approved for COPD

Comments

Pulmonary Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Brand

519

Methylxanthines

Epinephrine (HFA) MDI 0.125 mg

Over-the-counter

Umeclidinium/vilanterol DPI 62.5/25 mcg/puff

Tiotropium/olodaterol SMI 2.5/2.5 mcg/puff

Glycopyrrolate/ formoterol fumarate MDI 9/4.8 mcg/puff

Aclidinium/formoterol 400/12 mcg/inhalation

Primatene Mist

Anoro Ellipta

Stiolto Respimat

Bevespi Aerosphere

Duaklir Pressair

LABA/LAMA combination inhalers

Generic

1–2 puffs every 4 hours, maximum 8 per day

1 puff QD

2 puffs QD

2 puffs BID

1 puff BID

Dose

Table 7. Pharmacologic Agent Use for Asthma and COPD (continued)

Hypertension, tachycardia

See previous adverse events

Adverse Effects

Do not use with MAOI (or 2 wk after)

Only for > 12 yr

OTC

Must be shaken/primed (4 sprays)/ cleaned with each use

Indicated for intermittent asthma

Only indicated for COPD

Comments

Pulmonary Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

520

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Zithromax

Daliresp

Leukotriene receptor antagonistb

Azithromycin

Macrolide

Roflumilast

Phosphodiesterase Inhibitors

Dyphylline tablets 200, 400 mg

Lufyllin

Elixophyllin

Oral solution 80 mg/15 mL

Extended-release 12-hr tablets 100, 200, 300, 450 mg

Theochron

Theo-24 Theo-Dur

Brand

Extended-release 24-hr tablets 100, 200, 300, 400, 450, 600 mg

Theophylline extendedrelease 24-hr capsules 100, 200, 300, 400 mg

Generic

COPD exacerbation: 500 mg daily for 3 days or 500 mg daily followed by 250 mg/day for 4 days COPD prophylaxis (offlabel): 250 mg daily or 500 mg three times/wk

250 mcg daily for 4 wk; increase to 500 mcg daily

Adults: 15 mg/kg every 6 hr

Smokers: may need higher doses at more frequent intervals

Children (1–15 yr): Start at 10 mg/kg/ day

Usual dose 400–600 mg/ day

Adults: 300 mg/day initial dose, divided according to formulation

Dose

Table 7. Pharmacologic Agent Use for Asthma and COPD (continued)

Bacterial resistance, QTc prolongation, impaired hearing

Weight loss, decreased appetite, diarrhea, nausea, suicidal thoughts

At therapeutic levels: Insomnia, GI upset, increased hyperactivity in some children, difficult urination in BPH

At toxic levels: Nausea, vomiting, CNS stimulation, headache, tachycardia, SVT, seizures, hematemesis, hyperglycemia, hypokalemia

Adverse Effects

Less benefit in active smokers

Not for use in moderate to severe liver impairment

Caution with other CYP inducers

Indicated for patients with bronchitis and severe COPD

Excreted unchanged by the kidneys with no liver metabolism

Several drug interactions

Some generic formulations available

Duration: Variable; up to 24 hr

Not for acute relief

Beneficial for night symptoms

Drug clearance declines with age

Achieve concentrations of 5–15 mcg/mL; check trough levels before increasing dose or concerns of toxicity

Comments

Pulmonary Disorders

Zileuton 600-mg CR tablet

Montelukast chewable tablet 10 mg, 4-, 5-mg tablets, oral granules 4 mg/packet

Zafirlukast 10-mg tablet, 20-mg tablet

Generic

Zyflo CR

Singulair

Accolate

Brand Generic available

Headache, GI upset

Adverse Effects

521

1200 mg BID

Zafirlukast: Monitor symptoms, regular LFT monitoring not required

Zileuton: Monitor LFTs (baseline, every mo × 3 mo, every 2–3 mo for remainder of first yr)

Montelukast: Monitor for neuropsychiatric symptoms (black box warning)

Hepatotoxicity (zileuton and zafirlukast):

Drug interactions: Phenobarbital FDA approved Adults and children ≥ 15 yr: for use in ≥ 1 yr old; used in 6 mo and older Churg-Strauss 10 mg/day syndrome associated with Children age 1 to < 6: 4 mg/ tapering doses of steroids; day warfarin and theophylline Children age 6 to < 15: 5 mg/day

10–20 mg BID

Dose

Table 7. Pharmacologic Agent Use for Asthma and COPD (continued)

Also indicated for EIB and seasonal and perennial allergic rhinitis

Dose in the evening for asthma

Bioavailability decreases with food; take 1 hr before or 2 hr after meals

Drug interactions: Warfarin, erythromycin, theophylline

Comments

Pulmonary Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Nucala

Cinqair

Reslizumab

Dupixent

Fasenra

Brand

Mepolizumab

Dupilumab

Benralizumab

Monoclonal antibody

Generic

522

Use in > 12 yr

Used in severe persistent asthma with eosinophilic asthma; AEC > 400 cells/ uL

Anti-interleukin-5/5R

Comments

Injection-site reactions, headache, back pain, fatigue, urticaria, antibody development

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Half-life: 24 days

Use in > 18 yr

Used in severe persistent asthma with eosinophilic phenotype

Anti-interleukin-5

Half-life: 16–22 days

Use in ≥ 6 yr

AEC > 150–300 cells/uL

Used in severe persistent asthma with eosinophilic phenotype

Anti-interleukin-5/5R

Daily OCS affects dosing

Use in ≥ 12 yr

AEC > 150 cells/uL; FeNO > 25 ppb

Injection-site reactions, dental Anti-interleukin-4R α pain, hypereosinophilia, Used in severe persistent asthma with antibody development eosinophilic asthma

Injection site reactions, headache, pharyngitis

Adverse Effects

3 mg/kg IV infusion (20–50 Anaphylaxis black boxed min) every 4 wk warning, injection-site reactions, musculoskeletal, throat pain, antibody development

100 mg SC every 4 wk

200–300 mcg SC every 2 wk (maintenance)

30 mg SC every 4 wk for the first 3 mo then every 8 wk (maintenance)

Dose

Table 7. Pharmacologic Agent Use for Asthma and COPD (continued)

Pulmonary Disorders

Brand Xolair

Do not inject > 150 mg per injection site

Dose and frequency based on baseline IgE and weight in kg

150–375 mg SC every 2–4 wk

Dose Injection-site reactions, urticaria, thrombocytopenia (transient), anaphylaxis (rare), slight risk of TIA/ MI

Adverse Effects

Daily OCS affects dosing

Half-life: 26 days

Use in ≥ 6 yr

Used in severe persistent allergy-related asthma

Anti-IgE

Comments

AEC = absolute eosinophil count; BID = twice daily; BPH = benign prostatic hyperplasia; CNS = central nervous system; CR = controlled release; DPI = dry powder inhaler; FDA = U.S. Food and Drug Administration; FeNO = fractional exhaled nitric oxide; GI = gastrointestinal; HFA = hydrofluoroalkane; ; IV = intravenous; LAMA = long acting muscarinic agent; LFT = liver function test; MAOI = monoamine oxidase inhibitor; MDI = metered dose inhaler; MI = myocardial infarction; QD = once daily; QID = four times daily; SAMA = short acting muscarinic agent; SC = subcutaneously; SMI = soft mist inhaler; SVT = supraventricular tachycardia; TIA = transient ischemic attack; TID = three times daily.

b

FDA Caution: Risk of neuropsychiatric events (behavior and mood changes: aggression, agitation, anxiousness, dream abnormalities, hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior, and tremor)

a

GINA recommends tiotropium use in steps 4 and 5 as another controller medication (GINA 2021).

Omalizumab

Monoclonal antibody (continued)

Generic

Table 7. Pharmacologic Agent Use for Asthma and COPD (continued)

Pulmonary Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

523

Pulmonary Disorders

Table 8. ICS Daily Dosing in Children and Adults ICS

Low Dose (mcg/day)

Age (yr)

Beclomethasone HFA Budesonide DPI

0–5

5 yr of age: 50 N/A

6–11

50–100

≥ 12

Medium Dose (mcg/day)

0–5

6–11

≥ 12

High Dose (mcg/day)

0–5

6–11

≥ 12

100–200

N/A

> 100–200

> 200–400

N/A

> 200

> 400

100–200 200–400

N/A

> 200–400

> 400–800

N/A

> 400

> 800

Budesonide suspension for nebulization

0.5 mg

0.25–0.5 mg

N/A

> 0.5–1 mg

0.5–1 mg

N/A

> 1 mg

> 1 mg

N/A

N/A

80

80–160

N/A

> 80–160

> 160–320

N/A

> 160

> 320

Fluticasone propionate HFA, DPI

5 yr of age: 50

50–100

100–250

N/A

> 100–200

> 250–500

N/A

> 200

> 500

Flovent furoate DPI

N/A

50

100

N/A

50

100

N/A

N/A

200

5 yr of age: 100

100

200–400

N/A

100

200–400

N/A

200

> 400

N/A

200

N/A

N/A

200

N/A

N/A

400

Ciclesonide HFA

Mometasone HFA Mometasone DPI Note: 110 mcg DPI delivers 100 mcg, and 220 mcg delivers 200 mcg

N/A

Adapted from: Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Available at https://ginasthma.org/wp-content/uploads/2021/05/ GINA-Main-Report-2021-V2-WMS.pdf. Accessed August 20, 2021. National Heart, Lung, and Blood Institute. Guidelines for the Diagnosis and Management of Asthma. National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3. NIH Publication 08-5846. 2007. Available at www.nhlbi.nih.gov/files/docs/ guidelines/index.htmasthsumm.pdf. Accessed August 20, 2021.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 524

Pulmonary Disorders

Patient Cases Questions 1–3 pertain to the following case: A 23-year-old woman (B.T.) has been coughing and wheezing about twice weekly, and she wakes up at night about three times per month. She has never been given a diagnosis of asthma, and she has not been to a physician “in years.” She uses an old albuterol inhaler but recently ran out, so she is seeking care. Her activities are not limited by her symptoms. 1. Spirometry is done today, and B.T.’s FEV1 is 82% of predicted. From the EPR-3 guidelines, which is the best classification of her asthma? A. B. C. D.

Intermittent. Mild persistent. Moderate persistent. Severe persistent.

2. In addition to albuterol MDI 1 or 2 puffs every 4–6 hours as needed, which medication is best to recommend for B.T. using 2020 Focused Updates? A. B. C. D.

No additional therapy needed. Montelukast orally 10 mg daily. Mometasone HFA 200 mcg/puff, 1 puff daily Budesonide/formoterol 80/4.5 mcg/puff, 2 puffs twice daily

3. At first, B.T.’s symptoms were well controlled on the recommended therapy. However, when winter arrived, she started having symptoms and using her albuterol 3–4 days per week during the day. Which is the preferred treatment change using EPR-3 and 2020 focused updates? A. B. C. D.

No change in therapy is needed. Change to fluticasone furoate/umeclidinium/vilanterol (100/6.25/25 mcg/puff) DPI, 1 puff daily. Change to budesonide/formoterol 80/4.5 mcg/puff, 2 puffs twice daily. Increase mometasone HFA to 200 mcg/puff, 2 puffs daily.

4. An 8-year-old boy has had daytime asthma symptoms once or twice weekly and is awakened twice weekly during the night with coughing. In addition to albuterol MDI 1 or 2 puffs every 4–6 hours as needed, which is the best initial therapy for this patient using 2020 Focused Updates? A. B. C. D.

Fluticasone HFA 44 mcg/puff, 1 puff twice daily. Montelukast 10 mg daily. Fluticasone/salmeterol 100/50 mcg/puff, 1 puff twice daily. Budesonide/formoterol 80/4.5 mcg/puff, 1 puff twice daily.

G. Monitoring (Domain 1) 1. Regular follow-up every 1–6 months a. Use validated questionnaires: Asthma Control Test and Asthma Control Questionnaire to assess level of control. b. Consider step-down if well controlled for 3 months or more. c. For uncontrolled, consider inhaler technique (see later in this chapter), adherence, incorrect diagnosis, comorbidities, and ongoing exposure. d. Uncontrolled vs. severe asthma; if still uncontrolled after 3–6 months on high dose ICS/LABA, consider referral to specialist.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 525

Pulmonary Disorders

e. FeNO-guided treatment (see alternative testing in diagnosis section earlier in this chapter) i. Found to be beneficial for children in reducing exacerbation rates ii. More evidence needed, but may be helpful 2. Peak flow monitoring a. Symptom- and peak flow-based monitoring have similar benefits; either is appropriate for most patients. Symptom-based monitoring can be more convenient. b. Consider daily home peak flow monitoring for moderate to severe persistent asthma, history of severe exacerbations, or poor perception of worsening asthma symptoms. c. Personal best PEFR, not predicted PEFR, should be determined if using a peak flow-based asthma action plan. i. Personal best PEFR is the highest number obtained after daily monitoring for 2 weeks twice daily when asthma is under control; can consider 2-week diary for patients with no clear diagnosis. ii. Predicted PEFR is based on population norms using sex, height, and age. 3. Spirometry (5 years or older) a. At initial assessment (diagnosis) or after treatment has started and symptoms have stabilized; recognizing treatment can impact results b. If there is prolonged or progressive loss of asthma control c. At least annually, or more often, depending on response to therapy

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 526

Pulmonary Disorders

H. Asthma action plan (Domain 2): Usually symptom based (equal benefits of symptom-based or peak flow-based monitoring); home treatment of an asthma exacerbation Table 9. Adolescent and Adult Asthma Action Plan

Zone

Green

Yellow

Red

Signs/Symptoms

Treatment Example

Doing well; no/minimal symptoms of coughing, wheezing, and/or dyspnea

Take long-term asthma control agent only (if one is prescribed); use 2 puffs of SABA 5–15 min before exercise with exercise-induced asthma and before known triggers

PEFR 80%–100% of personal best

Or: ICS/formoterol 1 or 2 puffs 15 min before exercise

Getting worse; increased frequency Use SABA: 2–4 puffs by inhaler (up to 6 puffs if needed) or 1 of symptoms of coughing, nebulizer treatment; may repeat in 20 min if needed; reassess 1 hr wheezing, and/or dyspnea after initial treatmenta Or: ICS/formoterol 2 puffs (up to 54 mcg daily, if needed)b PEFR 50%–79% of personal best If complete response at 1 hr, contact clinician for follow-up instructions and consider OCS burstc If incomplete response in 1 hr (still some coughing, wheezing, and/or dyspnea), repeat SABA and add OCS burstc; contact clinician that day for further instructions If poor response in 1 hr (marked coughing, wheezing, and/or dyspnea), repeat SABA immediately; add OCS burstc; contact clinician immediately; and continue to the ED if the distress is severe and unresponsive to treatment; consider calling 911 May continue to use SABA every 3–4 hr regularly for 24–48 hr

Medical alert; marked coughing, Begin treatment and consult clinician immediately wheezing, and/or dyspnea; inability Use SABA 2–6 puffs by inhaler (higher dose of 4–6 puffs usually to speak more than short phrases; recommended), or 1 nebulizer treatment; repeat every 20 min up to use of accessory respiratory three times; add OCS bursta,c Or: ICS/formoterol 2–6 puffs (up to 54 mcg daily, if needed) by inhalerb muscles; drowsiness If still in the red zone after 15 min and have not reached the PEFR < 50% of personal best physician, continue to the ED or call 911 Call 911 or go to the ED immediately if lips or fingernails are blue or gray or if there is trouble walking or talking because of shortness of breath

a After initial treatment, immediate medical attention is required if patient is at high risk of a fatal attack. Risk factors: asthma-related (history of severe attack [previous intubation or intensive care unit admission for asthma], two or more hospitalizations for asthma in past year, three or more ED visits for asthma in past year, hospitalization or ED visit for asthma in past month, using more than two canisters of SABA a month, difficulty perceiving asthma symptoms), social (low socioeconomic status or innercity residence, illicit drug use, major psychosocial problems), and comorbidities (CV disease, other chronic lung disease, chronic psychiatric disease). b

For patients using ICS/formoterol for controller therapy. 2020 Focused Updates dosing is based on 12 yr and older, steps 3 and 4.

OCS burst: prednisone (or equivalent); 40–60 mg/day for 5–10 days (18 years or older) or 1–2 mg/kg/day (maximum 60 mg/day) for 3–10 days (younger than 18 years). May also use dexamethasone 0.3–0.6 mg/kg (maximum 16–18 mg/dose) for 1–5 days (younger than 18 years) or 0.5 to 9 mg daily for 1–5 days (18 years or older). c

CV = cardiovascular; ED = emergency department; PEFR = peak expiratory flow rate.

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Patient Cases 5. An asthma action plan is being developed for a 22-year-old man using fluticasone/salmeterol 250/50 mcg 1 inhalation twice daily and albuterol HFA 1 or 2 puffs every 4–6 hours as needed. His personal best peak flow is 500 L/minute. Which set of asthma action plan instructions is best for when he has no asthma symptoms (peak flow readings 400–500 L/minute)? A. B. C. D.

Hold fluticasone/salmeterol when asthma is under control. Use fluticasone/salmeterol regularly; he may use albuterol HFA 1 or 2 puffs 5–15 minutes before exercise. Use albuterol HFA 2 puffs; repeat in 20 minutes if needed; and then reassess. Use albuterol HFA 6 puffs; repeat in 20 minutes; start prednisone 50 mg once daily for 5 days; and then reassess.

6. A 45-year-old woman with a diagnosis of moderate persistent asthma since her teenage years is currently taking albuterol 1–2 puffs every 4–6 hours as needed and fluticasone 220 mcg 1 puff twice daily. She is also a smoker for over 20 years and has been unable to quit. The physician assistant has diagnosed asthma and COPD, as evidenced by spirometry and exam. She has had no hospitalizations related to her breathing, but does report some increased sputum and dyspnea over the past year. Her FeNO is less than 25 ppb; Asthma Control Test is 20; COPD assessment test score is 8. What is the best therapy to recommend for this patient? A. B. C. D.

Add an LABA inhaler. Add an SAMA inhaler. Add an SAMA/SABA inhaler. Add an LABA/LAMA inhaler.

7. A 5-year-old boy is being treated for moderate persistent asthma. He is currently taking budesonide 1 mg nebulized once daily and albuterol 1–2 puffs every 4–6 hours as needed. He is following up in the clinic from a recent exacerbation and has completed a steroid burst. The nurse practitioner would like to step up therapy. What is the best recommendation for this patient? A. B. C. D.

Add LTRA. Add LAMA. Add LABA. Add omalizumab.

I. Asthma Education for Patients (Domain 2) 1. Control: Patients need to know what it means for their asthma not to be well controlled. 2. Medications a. Controllers versus quick-reliever medications b. How to use medication delivery devices (revisit every visit) 3. Self-management/asthma action plan once a year or with medication changes 4. The need for continuous ongoing interaction with the clinician to step up and step down therapy 5. Triggers/environmental changes a. Dust mite interventions i. Impermeable encasings for pillows/mattresses ii. Wash linens in hot water. iii. High-efficiency particulate air filtration b. Animal allergens i. Keep outside/out of bedroom. ii. High-efficiency particulate air filtration

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c. Roach control i. Integrated pest management ii. Clean up food, spills, trash, and leaks. d. Mold and mildew interventions i. Air conditioning ii. Avoid humidifiers. iii. Repair pipes and leaks. e. Air pollution (includes secondhand smoke) f. Exercise (pre-exercise treatment) g. Extreme temperatures J. Inhaler and Device Education (pertinent for both asthma and COPD) (Domain 2) 1. Education on proper technique with MDIs and DPIs is critically important. a. Studies have shown MDI and DPI techniques to be poor. b. Important to demonstrate correct technique to patient and to assess patient’s technique with initial instruction and often thereafter 2. MDIs: Propellant and solution a. Patient education of MDIs i. All MDIs must be primed before first use. ii. Priming: Number of sprays before first use varies; range two to four times. (a) First, shake the MDI (although Alvesco, QVAR, and Atrovent HFA need not be shaken; may be a confusing teaching point). (b) Spray into the air, away from the face. (c) Shake in between each spray. (d) Must be re-primed after dropping inhaler or if not used for a certain 3–28 days. b. Cleaning MDIs i. Clean most once weekly. ii. Some require removal of canister and cap; rinse plastic case/mouthpiece under lukewarm water and let air dry. iii. Advair HFA and Flovent HFA (a) Do not run under water or remove the canister. (b) Open cap and swab small opening with a cotton swab where medicine sprays out (dry for Advair and wet for Flovent). (c) Wipe mouthpiece with wet tissue and let air dry. iv. Symbicort HFA (a) Do not remove the canister. (b) Wipe the mouthpiece with a clean, dry cloth weekly. 3. Respimat delivery devices: Propellant-free SMI; slower velocity a. Patient education for Respimat devices i. Assemble and ready inhaler for first-time use. ii. If the inhaler has not been used: (a) For 3 days: Spray 1 puff to prepare the inhaler. (b) For more than 21 days: Prepare inhaler for first-time use until a spray is visible, and repeat three more times to prepare the inhaler. iii. Do not disassemble cartridge after use; discard 3 months after assembly. b. Cleaning: Using a damp cloth/tissue, wipe the mouthpiece and metal part inside once weekly.

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4. DPIs: Powders contain lactose; caution in patients with lactose allergies. a. Types of DPIs i. Multidose and preloaded DPIs (e.g., Diskus, Flexhaler, Twisthaler, Pressair, Ellipta, Inhub) ii. Single dose (e.g., Handihaler, Neohaler) iii. Breath-activated (e.g., Digihaler, RespiClick, Redihaler) b. Patient education for DPI devices i. Different feel; no “spray” or “puff” ii. Do not shake. iii. Once dose is “prepped,” breathe out fully (away from the mouthpiece); the only DPI that has to be primed once is budesonide (Pulmicort Flexhaler). iv. Close lips around mouthpiece and inhale (quick, deep, forceful inhalation). v. Hold breath for 10 seconds, and then exhale. 5. Valved holding chambers (e.g., AeroChamber, OptiChamber) a. Holding chambers improve total dose delivered and reduce oropharyngeal non-inhalable larger particle deposition with MDIs; not for use with Respimat or DPI delivery devices. b. Technique same as with MDIs, but can inhale up to 5 seconds after actuation c. One puff into chamber per inhalation d. For facemask: 5 inhalations/exhalations per puff e. Children i. In general, children 5 years and older are possible candidates for an MDI with holding chamber or an MDI alone. Must first assess their ability. Some younger children may be able to adequately use an MDI with holding chamber. ii. Most children younger than 5 years (and many 5 years and older) require a holding chamber with facemask when an MDI is used. Nebulizers are also appropriate options, especially for ICSs; however, a more portable option of an MDI plus holding chamber/facemask for an SABA is a good idea. iii. Children should always be educated on inhaler technique, and they should demonstrate proper use before MDIs are prescribed, with or without holding chambers and facemasks. Table 10. Educating Patients About How to Use an MDI

Getting ready

Breathe in slowly

Hold your breath

Take off the cap and inspect for loose objects in the mouthpiece Shake the inhaler Breathe out all the way Either put your inhaler mouthpiece in your mouth or use a holding chamber

Press down on the inhaler once as you start breathing in slowly through your mouth; be sure not to breathe in through your nose (if you use a holding chamber, first press down on the inhaler; within 5 s, begin to breathe in slowly) Keep breathing in slowly, as deeply as you can, about 3–5 s Hold your breath for 10 s (if possible) Wait about 30 s between puffs Exhale

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Box 1. Educating Patients About How to Use DPIs

• • • • • • • •

Contain a small amount of powder; does not contain aerosol Will feel different from an MDI; will not feel a spray; may not feel/taste anything Do not shake before inhalation DPIs that come in foil pouches have expiration dates once opened Protect DPIs from moisture Each specific DPI has slightly different instructions for preparing the inhaler for a dose Once the dose is prepped, breathe out fully, away from the mouthpiece Close lips around the mouthpiece and inhale quickly, forcefully, and deeply; this is different from the method used with an MDI (which is a slow, deep inhalation) • Hold breath for 5–10 seconds; and then exhale Box 2. Educating Patients About How to Use Peak Flow Meters

• • • • • • •

Move the indicator to the bottom of the numbered scale Stand up; take a deep breath, filling your lungs completely Place the mouthpiece in your mouth and close your lips around it; keep your tongue out of the way Blow out as hard and fast as you can in a single blow Write down the number you obtain If you cough or make a mistake, do not write down the number; repeat action Repeat steps 1–5 twice more and write down the best of the three blows in your asthma diary K. Vaccines: Patients with Asthma and COPD Should Receive per the CDC (Domain 5): 1. Pneumococcal a. Patients age 2–5 years should complete the pneumococcal conjugate vaccine (PCV13) series. Those who are unvaccinated or who have incomplete PCV13 series should receive two doses of PCV13 (8 weeks apart). Give one dose of PCV13 if the series is complete, but none after 12 months of age. Patients should also receive one dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23 or Pneumovax) at least 8 weeks after PCV13. b. Patients age 6–18 years should receive 1 dose of PPSV23 if not received earlier in childhood. c. Patients 19–64 years should receive one dose of PPSV23 if not received before (also, for anyone who smokes). i. PCV13 is not specifically indicated for adults (19–64 years) with asthma or COPD unless the patient has received long-term systemic corticosteroids. ii. Special situations in specific immunocompromised conditions d. Patients 65 years and older should receive PPSV23, with consideration for PCV13. i. Consider PCV13 for patients without immunocompromised conditions, cochlear implant, or cerebral spinal fluid leak. ii. Pneumococcal-vaccine naive (or with an unknown history): Consider PCV13 followed by PPSV23 1 year or more later (do not administer the two vaccines at the same time). iii. Previous pneumococcal vaccinations before age 65: Should receive PPSV23 5 years after most recent PPSV23 and 1 year after PCV13 has been given. iv. GOLD recommends that patients with COPD in this age group should receive both PPSV23 and PCV13. 2. Influenza: Vaccinate every fall/winter 3. Pertussis, tetanus, and diphtheria (Tdap): Adults with COPD should receive Tdap vaccination if not vaccinated in adolescence

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4. COVID-19 vaccination per GINA: a. Recommend COVID-19 vaccination for all people with asthma. b. Wait 14 days between COVID-19 and influenza vaccination (and any other vaccine). c. In patients with asthma taking biologic therapy, avoid administration on the same day.

II.  CHRONIC OBSTRUCTIVE PULMONARY DISEASE A. Definition (Domain 1) 1. COPD is a condition characterized by persistent airflow limitation and respiratory symptoms. 2. Other associated conditions defined: a. Chronic bronchitis consists of a persistent cough plus sputum production for a majority of days over a 3-month span in at least 2 consecutive years. b. Emphysema is an abnormal, permanent enlargement of the airways distal to the terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis. B. Guidelines (Domain 1) 1. Global Strategy for Prevention, Diagnosis, and Management of COPD (GOLD) a. Updated annually b. Significant changes in 2017 c. Global committee d. Focus of this chapter 2. 2. American Thoracic Society (ATS) a. Several guidelines and reports for COPD, including pharmacologic management of COPD, reducing COPD hospital readmissions, optimizing home oxygen therapy, preventing and managing COPD exacerbations, stable management, and overall clinical practice guidelines b. Updated as needed; most recent 2020 guideline sought to answer six specific questions C. Diagnosis and Assessment (Domains 1, 3) 1. Diagnosis of COPD is based on a history of exposure to risk factors and the presence of airflow limitation that is not fully reversible, with or without the presence of symptoms. a. GOLD guidelines: Consider COPD if an individual is older than 40 years and has any of the following: i. Chronic cough that is present intermittently or every day; often present throughout the day; seldom only nocturnal. May be nonproductive. It is usually the first symptom. ii. Dyspnea that is progressive (worsens over time), persistent (present every day), and worse with exertion is considered a cardinal symptom of COPD. iii. Chronic sputum production in any pattern iv. History of exposure to risk factors, especially tobacco smoke (most common risk factor), occupational dusts and chemicals, and smoke from home cooking and heating fuels v. Presence of comorbidities that may restrict activity (e.g., heart failure, heart disease, musculoskeletal disorders) b. For the diagnosis of COPD, spirometry is the gold standard. i. Spirometry showing an FEV1/FVC less than 70% of predicted is the hallmark of COPD. ii. Measuring arterial blood gas tension should be considered for all patients with an FEV1 less than 50% of predicted or with clinical signs suggestive of respiratory failure or right heart failure.

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2. Determine severity of airflow limitation: Based on FEV1 a. GOLD grade 1: Mild; FEV1 80% or greater of predicted b. GOLD grade 2: Moderate; FEV1 50% or greater and less than 80% of predicted c. GOLD grade 3: Severe; FEV1 30% or greater and less than 50% of predicted d. GOLD grade 4: Very Severe; FEV1 less than 30% of predicted 3. Use ABCD Assessment Tool: Based on risk of exacerbations and symptoms, patients are placed into letter groups A–D (Table 11). Patients are designated by airflow limitation severity and letter group (e.g., GOLD grade 2, group C). The assigned letter group is used to guide initial therapy (Table 12). 4. Assess risk of exacerbations: Based on number of past exacerbations in past year a. 0–1 in the past year (not leading to hospitalization) b. Two or more or 1 or more (leading to hospitalization) 5. Assess symptoms: Validated symptom scales/questionnaires a. The COPD assessment test score measures health status impairment in COPD (www.catestonline.org). b. The clinical COPD questionnaire is a self-administered questionnaire that measures clinical control in patients with COPD (www.ccq.nl). c. Modified [British] Medical Research Council breathlessness scale for assessing severity of breathlessness (Thorax 1999;547:5816); less comprehensive 6. α1-Antitrypsin 7. Comorbidities (cardiovascular disease [CVD], skeletal muscle dysfunction, metabolic syndrome, osteoporosis, depression, anxiety, and lung cancer) should be treated appropriately. D. Therapy Goals (Domain 2) 1. Reduce symptoms a. Relieve symptoms. b. Improve exercise tolerance. c. Improve health status. 2. Reduce risk a. Prevent disease progression. b. Prevent and treat exacerbations. c. Reduce mortality. Table 11. GOLD Guidelines: ABCD Assessment Patient Group A B C D

Characteristic

Low risk Less symptoms

Low risk More symptoms High risk Less symptoms

High risk More symptoms

Exacerbations per Yr ≤ 1 not leading to hospitalization ≤ 1 not leading to hospitalization ≥ 2 or > 1 with hospitalization ≥ 2 or > 1 with hospitalization

Symptom Score

mMRC 0–1 CAT < 10 mMRC ≥ 2 CAT ≥ 10

mMRC 0–1 CAT < 10 mMRC ≥ 2 CAT ≥ 10

CAT = COPD Assessment Test (validated questionnaire); GOLD = Global Initiative for Chronic Obstructive Lung Disease; mMRC = modified Medical [British] Research Council breathlessness scale (validated questionnaire).

Adapted from: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Prevention, Diagnosis and Management of COPD. 2021 GOLD Report. Available at www.goldcopd.org/. Accessed August 20, 2021.

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Table 12. GOLD Guidelines Initial Treatment Patient Group

Recommended Treatment

A

Bronchodilator

C

LAMA

B

D

LABA or LAMA LAMA or LAMA+LABAa or ICS+LABAb

Consider if highly symptomatic (e.g., COPD assessment test score > 20)

a

b

Consider if blood eosinophil count > 300 cells/mm3

Adapted from: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Diagnosis, Management and Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease. 2021 GOLD Report. Available at www.goldcopd.org/. Accessed August 20, 2021.

E. Management of Stable COPD (Domains 1, 3) 1. Key management strategies a. Smoking cessation is a critical component of COPD management. b. Pharmacologic therapy should be individualized to reduce symptoms, reduce frequency and severity of exacerbations, reduce burden on patient (e.g., combination inhalers), and improve health and exercise tolerance. c. Follow-up management i. Review: Symptoms and risk ii. Assess: Inhaler technique, adherence, and non-pharmacological approaches iii. Adjust: Treatment (escalation and de-escalation) d. Influenza and pneumococcal vaccination decrease lower respiratory tract infections; see Asthma section for more details on scheduling (Domain 5). e. Blood eosinophil count: COPD-associated inflammation has limited responsiveness to corticosteroids. Blood eosinophil counts can predict the magnitude of the ICS effect in preventing further exacerbations (in addition to a bronchodilator). i. Fewer than 100 cells/mm3 likely indicates that ICSs have little to no effect. ii. More than 300 cells/mm3 likely indicates that ICSs have greatest likelihood of effect. f. Pulmonary rehabilitation improves symptoms, quality of life, and participation in everyday activities. g. Quick-reliever short-acting bronchodilators should be prescribed for immediate symptom relief. 2. Pharmacotherapy a. GOLD follow-up treatment algorithm (Figure 1) based on predominant dyspnea or exacerbation trait i. If both traits need to be targeted, follow exacerbation pathway. ii. No dependence on ABCD assessment at diagnosis

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Dyspnea

Exacerbation LABA or LAMA

LABA or LAMA

LABA + LAMA

LABA + ICS*

**

LABA + LAMA

LABA + ICS*

**

**

Consier switching device or molecules, investigate other causes

**

LABA + LAMA + ICS

Consider if eos ≥ 100 cells/ul

*

LABA + LAMA + ICS*

Consider if eos < 100 cells/ul Consider starting ICS if eos ≥ 300 cells/ul or eos ≤ 100 and ≥ 2 moderate exacerbations/1 hospitalization.

*

Roflumilast FEV1 < 50% & chronic bronchitis

Consider de-escalation of ICS or switch if pneumonia, inappropriate original indication or lack of response to ICS. **

If former smokers: Azithromycin

Figure 1. Follow-up treatment eos = eosinophils.

Adapted from: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Prevention, Diagnosis and Management of COPD. Global Initiative for Chronic Obstructive Lung Disease. 2021 GOLD Report. Available at www.goldcopd.org/. Accessed August 20, 2021.

Box 3. Summary of the Pharmacy/American Thoracic Society Clinical Practice Guideline: Pharmacologic Management of COPD

• For patients with concerns of dyspnea or exercise intolerance, recommend LABA + LAMA over LABA or LAMA monotherapy (strong recommendation; moderate certainty) • For patients with concerns of dyspnea or exercise intolerance despite LABA + LAMA, recommend LABA + LAMA + ICS over LABA + LAMA if ≥ 1 exacerbation in past year with antibiotics, oral steroids, or hospitalization (conditional recommendation; moderate certainty) • Patients receiving LABA + LAMA + ICS with no exacerbations in the past year, recommend that ICS be withdrawn (conditional recommendation; moderate certainty) • For patients with blood eosinophilia and ≥ 1 exacerbation in past year with antibiotics, oral steroids, or hospitalization, recommend ICS additive therapy to long-acting bronchodilators (conditional recommendation; moderate certainty) • For patients with a history of severe and frequent exacerbations while receiving optimal therapy, recommend against maintenance OCS therapy (conditional recommendation; low certainty) • For patients with advanced refractory dyspnea while receiving optimal therapy, consider opioid-based therapy with a personalized shared decision-making approach (conditional recommendation; very low certainty)

Nici L, Mammen MJ, Charbek E, et al. Pharmacologic management of COPD: an official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med 2020;201:e56-369.

b. Bronchodilators improve FEV1 (but do not conclusively prevent rate of decline), symptoms, and exercise capacity. Combination bronchodilators may be superior to either component alone. i. β2-Agonists (a) LABAs have been shown to improve health status and exacerbation rates. (1) Salmeterol/Formoterol: Improves FEV1 and lung volumes, dyspnea, and number of hospitalizations

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(2) Vilanterol/Olodaterol: Improves lung function and symptoms (3) Indacaterol: Improves breathlessness (b) Adverse effects: Resting sinus tachycardia, somatic tremor (higher doses), hypokalemia (especially with thiazide diuretic), cough (indacaterol) (c) Drug interactions: LABAs are cytochrome P450 (CYP) 3A substrates, caution with strong inhibitors (increased adverse effects), increased QT prolongation in high doses (avoid with other QT prolongation medications) ii. Antimuscarinic (a) Adverse effects: Dry mouth, bitter metallic taste (ipratropium), small increase in CV events (ipratropium) (b) Drug interactions: Caution use with other anticholinergics (increased adverse effects) (c) LAMA versus SAMA: LAMA showed improved lung function, health status, and OCS need compared with SAMA. (d) Tiotropium improved effectiveness of pulmonary rehabilitation and reduced exacerbations and hospitalizations. (e) Conflicting differences found between tiotropium Respimat SMI and the DPI on mortality rates. Most recent study shows no difference. iii. LAMA versus LABA: Cochrane review concluded: Tiotropium is more effective than LABAs in preventing COPD exacerbations and COPD-related hospitalization but not in overall hospitalization or mortality. Symptom and lung function improvement are similar. However, there are only a few studies. There were fewer serious adverse events and withdrawals from studies with tiotropium than with LABAs. iv. LAMA/LABA and ICS combination (a) May increase bronchodilation with less risk of adverse effects (vs. increasing the dose of single therapy). (b) Reduces exacerbations compared with ICS/LABA. (c) Adding tiotropium to ICS/LABA (triple therapy) improves lung function and health-related quality of life and reduces the number of exacerbations (1) Retrospective data show decreased mortality, fewer hospital admissions, and fewer OCS bursts. (2) Recent randomized trial (InforMing the Pathway of COPD Treatment) with over 10,000 patients shows triple therapy (fluticasone furoate, umeclidinium, vilanterol) showed lower rates of moderate to severe exacerbation than fluticasone/vilanterol or umeclidium/ vilanterol; lower rate of hospitalization than umeclidinium/vilanterol. v. Theophylline is also a bronchodilator, but it is not recommended unless other long-term bronchodilators are unavailable or unaffordable. c. Anti-inflammatory agents have clinically relevant effects on exacerbations (e.g., rates, time to first exacerbation). Inhaled corticosteroid and OCS should not be used outside their indications in long-term treatment because of the risk of pneumonia after long-term exposure. See Table 13. i. ICS (a) The dose response with ICS in COPD is unknown (in contrast to asthma treatment); moderate to high doses have been used in COPD clinical trials. (b) Blood eosinophil counts may be a predictor for likelihood of efficacy in using ICS for preventing exacerbation. (c) Monotherapy with ICS is not recommended; in combination, may not provide much benefit in patients with frequent exacerbations in severe COPD. (d) Combined with a LABA, ICS is more effective for lung function, health status, and reducing exacerbations (in patients with exacerbations in moderate to very severe COPD) than alone; see above on triple therapy. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 536

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(e) Adverse effects: Oral candidiasis, hoarse voice, skin bruising, pneumonia (risk factors), increased risk of withdrawal with discontinuation. Regular treatment increases the incidence of pneumonia. (f) Drug interactions: Caution with strong CYP3A inhibitors and high ICS doses (increased adverse effects of ICS) Table 13. Initiation of ICS Treatment Considerations Strong Support

History of hospitalization(s) for COPD exacerbationa ≥ 2 moderate COPD exacerbationsa Blood eosinophils > 300 cells/mm3 History of or concomitant asthma

Consider Use

1 moderate exacerbation of COPD per yeara Blood eosinophils 100–300 cells/ mm3

Against Use

Repeated pneumonia events Blood eosinophils < 100 cells/mm3 History of mycobacterial infection

Despite long-acting bronchodilator therapy.

a

Adapted from: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Prevention, Diagnosis and Management of COPD. 2021 GOLD Report. Available at www.goldcopd.org/. Accessed August 20, 2021.

ii. Oral glucocorticoids: Chronic treatment with OCSs should be avoided because of an unfavorable benefit-risk ratio (Evidence A). iii. Phosphodiesterase-4 inhibitors: Roflumilast (Daliresp) (a) In patients with severe to very severe COPD, history of exacerbations, and chronic bronchitis, phosphodiesterase-4 inhibitors improve lung function and reduce moderate to severe exacerbations (Evidence A). It also improves lung function and decreases exacerbations for patients with fixed dose ICS/LABA combination (Evidence B). (b) Dose: 250 mcg for 4 weeks, then 500 mcg orally once daily (c) Contraindications: Do not use in moderate to severe liver impairment or in nursing mothers. (d) Precautions (1) Weight loss (monitor), 20% of patients studied had weight loss of 5%–10% of body weight compared with 7% with placebo; average weight loss is 2 kg. (2) Psychiatric events including suicidality (monitor; weigh risks vs. benefits in patients with preexisting psychiatric illness) (e) Adverse effects: Diarrhea, weight loss/decreased appetite, nausea, headache, back pain, influenza, insomnia, and dizziness (f) Drug interactions: Use with strong CYP enzyme inducers is not recommended (e.g., rifampin, phenobarbital, carbamazepine, phenytoin); use with CYP3A4 inhibitors or dual inhibitors of CYP3A4 and 1A2 (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) increases roflumilast exposure and adverse effects (risk-benefit must be weighed). iv. Antibiotics (a) In non-smoking patients with exacerbations despite appropriate therapy, macrolides (specifically azithromycin) can be considered. (b) Chronic azithromycin for prevention of COPD exacerbations (1) Daily azithromycin lengthens time to first exacerbation, decreases rate of exacerbations, and improves quality of life in patients with COPD at increased risk of exacerbations for 1 year; no safety and little benefit are seen at 5 years. (2) More effective in older patients and in milder COPD (3) However, the GOLD guidelines do not recommend general treatment with macrolide antibiotics, especially greater than 1 year, except when indicated during acute exacerbations or patients on triple therapy with continued exacerbations (i.e., azithromycin, erythromycin). ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 537

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(c) Adverse effects: Increased bacterial resistance, QT prolongation, and possible hearing test impairments v. Mucolytics (carbocisteine and N-acetylcysteine): Patients not on ICS may have reduced exacerbations and improved health status vi. α1-Antitrypsin augmentation therapy (Evidence C) (a) Characteristics of patients with α1-antitrypsin deficiency include: white race, development of COPD at a young age (younger than 45 years), and strong family history of COPD. All patients should be tested for α1-antitrypsin deficiency. (b) Treatment for young patients with severe hereditary α1-antitrypsin deficiency and established emphysema; expensive (c) Augmentation therapy found to be most suitable in nonsmokers or never smokers with a FEV1 35%–60% predicted. 3. Non-pharmacologic therapy: a. Home oxygen therapy i. Pulse oximetry should be used to assess all COPD patients for oxygen supplementation. ii. Indicated for patients with severe resting hypoxemia. iii. Titrate to keep SaO2 greater than or equal to 90% iv. Long-term (more than 15 hours a day) use in patients with chronic respiratory failure improves survival in patients with severe resting hypoxemia; does not lengthen lifespan in moderate resting hypoxemia. b. Pulmonary rehabilitation is recommended for patient groups B and D: Includes exercise training, nutrition counseling, and education c. All patients should be offered guidance on self-management of breathlessness, energy conservation, and stress management; should be given a written action plan Patient Cases Questions 8 and 9 pertain to the following case: A 62-year-old man (T.M.) was recently given a diagnosis of COPD. Spirometry shows he has an FEV1/FVC 60%, pre-bronchodilator FEV1 70% of predicted, and post-bronchodilator FEV1 72% of predicted. His symptoms are very bothersome. He is walking slower than others because of shortness of breath and is having to stop to catch his breath every so often when walking on level ground (Modified [British] Medical Research Council = 2). He had one exacerbation in the past year without hospitalization. 8. According to the GOLD guidelines, which is the most appropriate grade and patient group classification for T.M.? A. B. C. D.

Grade 2, group A. Grade 2, group B. Grade 3, group C. Grade 3, group D.

9. In addition to albuterol HFA 2 puffs every 4–6 hours as needed, which pharmacotherapy option is most appropriate to initiate for T.M.? A. B. C. D.

No additional therapy needed. Formoterol solution 20 mcg: Inhale solution twice daily. Salmeterol/fluticasone 50/500 one inhalation twice daily. Salmeterol/fluticasone 50/500 one inhalation twice daily plus roflumilast 250 mcg orally once daily.

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Patient Cases (continued) 10. A 52-year-old woman with COPD has experienced a gradual worsening in shortness of breath during the past few years. Spirometry shows FEV1/FVC 55% and FEV1 63% of predicted. Her COPD assessment test score is 10. She has not had a COPD exacerbation or received systemic corticosteroids in the past 2 years. Her current COPD medications are tiotropium inhaler once daily and albuterol HFA as needed. According to the GOLD guidelines, which is the most appropriate course of action? A. B. C. D.

Discontinue tiotropium, and start tiotropium/olodaterol 2.5 mcg/2.5 mcg, 2 inhalations daily. Add long-term azithromycin 250 mg once daily. Add fluticasone 110 mcg, 2 puffs twice daily. Discontinue tiotropium, and start salmeterol/fluticasone 250/50, one puff twice daily.

F. Management of Exacerbations of COPD (Domain 1) 1. A COPD exacerbation is an acute worsening of a patient’s baseline respiratory symptoms (dyspnea and/or cough and/or an increase in quantity or purulence of sputum) that is worse than normal day-to-day variation and results in a change in medication. Diagnosis is based on clinical presentation and classified as mild, moderate, and severe. a. Common precipitating factors include viral upper respiratory tract infections (most common), air pollution, bacterial infections, and ambient temperatures; but one third of exacerbations are idiopathic (Evidence B). b. Spirometry is not accurate during an exacerbation and is not recommended. c. Pulse oximetry can be used to determine the need for supplemental oxygen, which should be given to those with severe exacerbations. 2. Goal: To minimize negative impact of current exacerbation and prevent further ones 3. Pharmacotherapy a. Inhaled SABA with or without SAMA is the preferred initial treatment for COPD exacerbations (Evidence C). Usual doses of albuterol are 2.5 mg by nebulizer (air-driven preferred) every 1–4 hours as needed, or 4 to 8 puffs by an MDI with holding chamber every 1–4 hours as needed. b. Systemic corticosteroids are effective and shorten recovery time, improve FEV1, and improve hypoxemia (Evidence A). They also lower the risk of treatment failure and early relapse, and reduce the length of a hospital stay. i. Prednisone 40 mg once daily for 5–7 days (Evidence B). ii. In patients with a COPD exacerbation presenting to the hospital, a shorter course of systemic corticosteroids (5 days) was non-inferior to a longer (14 days) course with respect to re-exacerbation within 6 months (JAMA 2013;309:2223-31). iii. Associated with increased risk of pneumonia, sepsis, and death (even with short bursts); may be less efficacious in those with low blood eosinophilia counts c. Most common pathogens in COPD exacerbations: Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. In patients with GOLD stage 3 and GOLD stage 4 severity, Pseudomonas aeruginosa infection is more common. i. Antibiotics should be given if all three cardinal symptoms are present (Evidence B): (a) Increased dyspnea (b) Increased sputum volume (c) Increased sputum purulence ii. Antibiotics should be given if two of the three cardinal symptoms are present and if increased sputum purulence is one of the symptoms (Evidence C). C-reactive protein and procalcitonin may indicate appropriate use; sputum color as an indicator remains highly sensitive and specific.

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iii. Antibiotics should be given to patients with a severe exacerbation requiring mechanical ventilation (Evidence B). iv. Recommended duration of antibiotic treatment is usually 5–7 days (Evidence D); American College of Physicians recommends 5 days (Ann Intern Med 2021;174:822-7). v. Recommended antibiotics (a) Optimal antibiotic therapy has not been determined and should be based on local resistance patterns. (b) If recent (less than 3 months) use of antibiotics, use alternative class. (c) Usual initial antibiotics for uncomplicated COPD: Azithromycin, clarithromycin, doxycycline, or amoxicillin, with or without clavulanate. (d) In complicated COPD with risk factors: Amoxicillin/clavulanate, levofloxacin, moxifloxacin. Risk factors: Comorbid diseases, severe COPD (FEV1 less than 50% of predicted), more than 3 exacerbations/year, antibiotic use in past 3 months (e) If at risk of Pseudomonas infection: High-dose levofloxacin (750 mg) or ciprofloxacin; obtain sputum culture. Risk factors: Four or more courses of antibiotics in past year, recent hospitalization (past 90 days), isolation of Pseudomonas during past hospitalization, severe COPD (FE11 less than 50% of predicted) (f) If exacerbation does not respond to initial antibiotic, sputum culture and sensitivity should be performed. Patient Case 11. A 64-year-old woman with COPD in GOLD grade 3 group C presents for a clinic visit. In the past few days, she has had a worsening in shortness of breath and a productive cough with more “cloudy” and more copious sputum than usual. Pulse oximetry is 95% with room air. She is currently taking glycopyrrolate/formoterol twice daily. She has a nebulizer at home. In addition to regular use of albuterol plus ipratropium by nebulizer every 1–4 hours, which is the best course of action? A. B. C. D.

No additional therapy is necessary. Add oral prednisone 40 mg once daily for 5 days. Add trimethoprim/sulfamethoxazole double strength one tablet twice daily for 7 days. Add oral prednisone 40 mg once daily for 5 days and azithromycin 500 mg one tablet for 5 days.

III.  SMOKING CESSATION A. Tobacco Trends (Domain 1) 1. 2020 U.S. Surgeon General reports that 34 million adults currently smoke cigarettes (https://www.hhs.gov/ sites/default/files/2020-cessation-sgr-executive-summary.pdf). a. Most cigarette smokers (over one-half) make a quit attempt each year; less than one-third use cessation medications or behavioral counseling; less than one-tenth successfully quit. b. 40% of those who smoke do not receive advice to quit from a health care professional. 2. 2017 National Health Interview Survey data shows: a. Cigarettes most commonly used (14% of the population) b. Cigars (3.8% of the population) c. E-cigarettes (2.8% of the population)

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d. Smokeless tobacco (2.1% of the population) e. Pipes (1% of the population) f. Of current tobacco users, 19% use two or more tobacco products i. Most common combination were cigarettes and e-cigarettes ii. Cigarettes and cigars were second g. Higher rates of using tobacco “everyday” or “some days” by demographic data i. Sex: Men more than women ii. Ages: 25–44 years more than 45–64 years more than 18–24 years more than 65 and over iii. Ethnicity: Non-Hispanic American Indian/Alaska Natives more than multiracial more than whites more than blacks more than Hispanics more than non-Hispanic Asians iv. Residence: Midwest more than South more than West more than Northeast v. Insurance: Uninsured more than Medicaid more than other public more than private more than Medicare only B. Decision Pathway for Treatment (Domain 1) 1. Nicotine dependence; physical and psychological addiction a. Symptoms of withdrawal: Depressed mood, insomnia, irritability, frustration, anger, anxiety, difficulty concentrating, restlessness, impatience, decreased heart rate, increased appetite, weight gain b. Symptoms of withdrawal may start within 24 hours and last 1–2 weeks. 2. Patient assessment and education (U.S. Public Health Service coined the “The 5 A’s”: Ask, Advise, Assess, Assist, and Arrange; modified by the American College of Cardiology in 2018 to Ask, Assess, Advise, Offer & Connect to Treatment, and Follow-up) (Domain 2) a. Ask i. At every visit, ask about daily or nondaily tobacco use and document it in the patient’s chart. ii. Consider making “tobacco use” a vital sign. b. Assess (ACC modification in order) i. Tobacco use; nicotine dependence: Consider smoking history, quit attempt history, smoking/tobacco habits, motivators for quitting, barriers to quitting, and triggers (Box 4). (a) Number of cigarettes used (b) Time to first cigarette (1) Assists with dosing of the NRT lozenges and gum. (2) How soon after you wake up do you smoke your first cigarette of the day? 30 minutes or less, or greater than 30 min (c) Assess risk of relapse and secondhand smoke exposure in former or never-smokers. ii. Patient’s willingness to quit; readiness to quit/stage of smoking cessation (a) Assess patient’s readiness to quit/stage of smoking cessation; belief that he or she can quit. (1) “How motivated are you to quit smoking in the next 30 days (1–10)?” (2) “How confident are you that you can quit smoking (1–10)?” (b) If the patient does not want to quit (pre-contemplative) (1) Discuss his or her personal barriers to quitting. (2) “What do you like about smoking?” and “What scares you about quitting?” (3) “Have you tried to quit in the past? If so, why?” (4) Build a patient’s confidence about quitting. (5) Use motivational interviewing strategies (see Table 14). (c) Discuss the five “R’s” (enhances future quit attempts) (1) Relevance (why quitting is personally relevant for them) (2) Risks (health risks of smoking) (3) Rewards (potential benefits of quitting tobacco; tailor to individual patients)

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(4) Roadblocks (ask patients to identify barriers; why they are reluctant to quit or what scares them about quitting) (5) Repetition (motivational intervention should be repeated at each clinic visit)

c. Advise i. Advice should be clear, strong, and personalized to patient situation (e.g., concurrent conditions, risks to children). ii. Focus on CV benefits; even a few strong statements show you care and may help patients decide that they want to quit. iii. Brief behavioral counseling (less than 10 minutes) significantly increases cessation rates. iv. Shorter interventions (less than 3 minutes) are less effective, but they still increase quit rates. Box 4. Heaviness of Smoking Index (points per question)a

1) How soon after waking up do you smoke your first cigarette of the day? > 1 hr (0), 31–60 min (1), 6–30 min (2), within 5 min (3) 2) How many cigarettes do you smoke? < 10 (0), 11–20 (1), 21–30 (2), ≥ 31 (3) 0–2 = low nicotine dependence; 3 or 4 = moderate nicotine dependence; 5 or 6 = high nicotine dependence.

a

Table 14. Using Motivational Interviewing Strategies in Patients Unwilling to Quit

Express empathy

Use open-ended questions to explore: —The importance of addressing smoking or other tobacco use (e.g., “How important do you think it is for you to quit smoking?”) —Concerns and benefits of quitting (e.g., “What might happen if you quit?” “What would be the best part of being a nonsmoker?”) Use reflective listening to seek shared understanding: —Reflect words or meaning without adding your own information or assessment (e.g., “So it sounds like you find smoking helps you to maintain your weight.”) —Summarize what you heard the patient say Normalize feelings and concerns (e.g., “Many people worry about managing without cigarettes.”)

Develop discrepancy

Support the patient’s autonomy and right to choose or reject change (e.g., “I hear you saying you are not ready to quit smoking right now. I’m here to help you when you are ready.”)

Highlight the discrepancy between the patient’s present behavior and expressed priorities, values, and goals (e.g., “It sounds like you are very devoted to your family. How do you think your smoking is affecting your children?”) Reinforce and support “change talk” and “commitment” language: —“It’s great that you are going to quit when you get through this busy time at work.”

Roll with resistance

Build and deepen commitment to change: —“We would like to help you avoid a stroke like the one your father had.” Back off and use reflection when the patient expresses resistance: —“Sounds like you are feeling pressured about your smoking.”

Express empathy: —“You are worried about how you would manage withdrawal symptoms.” Ask permission to provide information

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Table 14. Using Motivational Interviewing Strategies in Patients Unwilling to Quit (continued)

Support self-efficacy

Help the patient to identify and build on past successes; offer options for achievable small steps toward change: —Call the quit line (1-800-QUIT-NOW) for advice and information —Read about quitting benefits and strategies —Change smoking patterns (e.g., no smoking in the home) Ask the patient to share his or her ideas about quitting strategies

From: Tobacco Use and Dependence Guideline Panel. Treating Tobacco Use and Dependence: 2008 Update, Clinical Practice Guideline. U.S. Department of Health and Human Services; 2008. Available at www.ncbi.nlm.nih.gov/books/NBK63952/. Accessed August 20, 2021.

d. Assist (offer and connect to treatment) i. Longer counseling sessions improve quit rates (U.S. Preventive Services Task Force). Quit rates plateau after 90 minutes of total counseling contact time. ii. Combination of drugs and counseling is more effective than either drugs or counseling alone (Evidence A). iii. After the patient has decided to quit (planning stage) (a) Help patient with a quit plan (“STAR”). (1) Set a quit date. (A) This is a vital step to do with the patient. (B) Within 2 weeks is ideal. (C) Do not do it on a stressful, difficult day. (D) Consider having a “contract.” (2) Tell family, friends, coworkers. (3) Anticipate challenges (including withdrawal). (4) Remove tobacco products/paraphernalia from environment; clean home and car. (b) Help patient get ready for the quit date. (c) Help patient recognize danger signs (stress, being around other smokers, alcohol, after meals, lighters, ashtrays, and other triggers). (d) Help patient develop coping skills. (1) Identify triggers. (2) Anticipate and avoid triggers, if possible. (3) Plan ahead: Learn cognitive and behavioral activities to cope with triggers. (e) Alcohol use: Alcohol use is related to relapse. Drinkers should limit/abstain from alcohol while quitting. (f) Caffeine: The metabolism of caffeine decreases with tobacco cessation. (1) Patients stopping smoking can have increased caffeine concentrations by up to 203% of baseline. (2) Recommend that patients reduce caffeine intake after quitting smoking; abrupt abstention of caffeine can worsen withdrawal. (g) Support system: Have patients identify people in their lives whom they can count on for support, and have patients call these people when difficult times arise. (h) Avoid slips, and plan ahead. (1) This is a lifetime commitment. (2) Total abstinence is essential but difficult. Cannot even have “just one puff”; just say NOPE (Not One Puff Ever) (3) If a slip occurs, renew commitment, and do not use tobacco again.

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e. Arrange (follow-up) i. Arrange a follow-up contact (e.g., visit, phone call, e-mail, or text). (a) Call or visit within the 2–4 first weeks of quit date, if possible. (b) Second follow-up contact in first month ii. A follow-up contact is important because of the risk of relapse. (a) Sixty-five percent of self-quitters relapse during the first week. (b) Most smokers who relapse do not return to the pre-contemplation stage; 85% of smokers who relapse cycle to the contemplation or preparation stage. (c) After 1 year of abstinence, 40% relapse. (d) After 4–5 years of abstinence, only 7% relapse. (e) After 5 years of abstinence, most quit permanently. Patient Case 12. A 39-year-old woman with obesity, type 2 diabetes, and hypertension smokes two packs of cigarettes per day but is uninterested in quitting. Which is the best intervention at this time? A. Do nothing at this time because she is uninterested in quitting. B. Provide individualized messages for a minimum of 10 minutes on how quitting smoking will improve her specific diseases. C. Use motivational interviewing strategies to discuss her concerns and the benefits of tobacco cessation. D. Initiate bupropion, and set a quit date.

C. Pharmacologic Treatment for Tobacco Cessation (Domains 1, 2, 3, 4) 1. General approach to pharmacotherapy a. Smokers should be offered medications, with rare exceptions, even those who are not ready to quit immediately (“preloading”). i. Certain populations with limited evidence of effectiveness (e.g., pregnant women, breastfeeding women, smokeless tobacco users, light smokers, adolescents) ii. Pharmacotherapy works synergistically with behavioral counseling to increase quit rates. iii. Assess past attempts: What worked and what did not. How they used the medication. Involve patients in the decision of which therapy to use. (a) Previous success with a drug may be helpful in a subsequent quit attempt. (b) For previous failure with a drug, it is unclear whether the drug should be retried for future quit attempts; data are conflicting on this issue; discuss with the patient. b. Guidelines: i. U.S. Department of Health and Human Services (DHHS); U.S. Public Health Service: Treating Tobacco Use and Dependence (2008 update) ii. U.S. Preventive Services Task Force iii. American College of Cardiology (ACC): Expert Consensus Decision Pathway on Tobacco Cessation Treatment (2018) iv. American Thoracic Society (ATS): Initiating Pharmacologic Treatment in Tobacco-Dependent Adults (2020) (a) Specifically answered seven clinical questions (b) Recommendations and evidence rating summary (Box 5) 2. All FDA-approved therapies (NRT, bupropion, varenicline) are more effective than placebo in promoting smoking cessation for 6 months or more and are safe in patients with CVD. See Table 15. a. ACC recommends combination NRT therapy or varenicline as first line and monotherapy as second line. DHHS recommends all as first-line options. ATS has specific guidance for specific treatment options. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 544

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i. NRT (a) NRT should be initiated in combination and is considered the standard of care when using NRT. (b) Patch has the most patient adherence. (1) Tapering does not necessarily improve cessation rates and is optional. (2) Can continue longer durations than 12 weeks because no harm from long-term NRT has been reported. (c) As needed NRT products can provide quicker relief because they are absorbed faster than patches; require frequent use to relieve withdrawal (every 1–2 hours) (d) Efficacy: Doubles the abstinence rates at 1 year compared with placebo; reduces withdrawal symptoms but does not replicate pleasurable effects of smoking; may reduce satisfaction from smoking in relapse (e) Safety: (1) Adverse effects: skin irritation, gastrointestinal discomfort, sympathomimetic properties (much lower levels than from smoking) (2) Drug interactions: cimetidine may inhibit hepatic metabolism of nicotine; use with niacin may increase flushing and dizziness (3) Inhaled nicotine may reduce theophylline levels and tricyclic antidepressant medications may require a dose adjustment once inhaled NRT is stopped. (4) Oral NRT is buffered to be alkaline to maintain freebase form and maximize absorption in mucosa; drinking acidic liquids (e.g., coffee) acidifies the mouth and impairs absorption. (f) Convenience: OTC NRT covered by many insurance plans with a prescription ii. Varenicline (a) Efficacy: Partial agonist of the nicotinic receptor mediating brain dopamine release; when activated produces about 50% of maximal effects of nicotine (reducing intensity of withdrawal); also blocks activation by cigarette smoke (reducing reward) (1) More effective than single NRT or bupropion in several trials (2) Similar efficacy to combination NRT (3) Mixed results for varenicline plus NRT; ATS recommends varenicline plus NRT patch over varenicline alone (4) ATS also recommends for those not ready to stop smoking (“preloading”) or for those with comorbid psychiatric conditions (over NRT patch). (b) Safety (1) Neuropsychiatric risk: The FDA issued public health advisories on psychiatric risks and a 2009 black box warning following case reports; however, this was removed in 2016 because the risk was not found to be greater vs. placebo (Lancet 2016;387:2507-20). (A) Neuropsychiatric effects for all medications are most common among smokers with a history of psychiatric disease. (B) Patients should be instructed to discontinue the drug if they experience any symptoms of depressed mood, agitation, or behavior changes that do not seem to be from nicotine withdrawal or if they experience suicidal thoughts. (C) Despite this possible risk, the ATS update specifically recommends that patients with comorbid psychiatric conditions be treated with varenicline over a nicotine patch when treatment is initiated. (2) CV risk: Currently varenicline is thought to be safe in stable CV disease and caution in patients with acute coronary syndrome (A) Several large meta-analyses in smokers with acute coronary syndrome have found no increase in CV risk (B) One meta-analysis found small but significant increased risk of CV adverse events

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(C) American College of Cardiology recommends varenicline or combination NRT first line for outpatient with stable CV disease; patch or combination NRT for inpatient with acute coronary syndrome to be discharged with combination NRT or varenicline (3) Drug interaction: may enhance adverse effects of nicotine patch; may increase intoxicating effects of alcohol iii. Bupropion sustained release (a) Considered second line in CVD; similar efficacy to single NRT, regardless of depression diagnosis (b) Efficacy: Works by relieving withdrawal symptoms and reduces reward from smoking (blocking neuronal uptake of dopamine and norepinephrine [to a lesser extent]) (1) Treatment longer than 6 months, up to 1 year (reduces relapse rates) (2) ATS recommends varenicline over bupropion. (3) Has not shown efficacy in smokers hospitalized with acute coronary syndrome, thought to be too brief a time course (c) Safety: Check liver function, renal function, and drug interactions (may decrease clearance of varenicline) b. Combinations (6-month abstinence rate) i. Patch and gum (36.5%) ii. Patch and nasal spray (36.5%) iii. Patch and inhaler (25.8%) iv. Patch and bupropion sustained release (28.9%); bupropion and NRT is more effective than bupropion alone (J Am Coll Cardiol 2018;72:3332-65) v. Bupropion and varenicline are more effective at 12 and 26 weeks, but not at 52 weeks (JAMA 2014;311:155-63). vi. Patch and varenicline (65.1%) (JAMA 2014;312:155-61) vii. Combination of varenicline and NRT was found to be more effective than varenicline alone (BMC Public Health 2015;15:689). 3. Third-line treatments for tobacco cessation (i.e., for those who are unable to use or for whom second-line treatment failed); assess for contraindications, precautions, and adverse effects to the following options: a. Clonidine b. Nortriptyline 4. Specific patient populations a. Heavier smokers/more dependent/history of more severe withdrawal i. Use higher-dose preparations of NRT ii. Evidence that combination NRT is effective (e.g., nicotine patch plus as-needed nicotine gum) iii. Can use two 21-mg patches initially in heavy smokers (more than two packs/day; off-label) b. Light smokers (fewer than 10 cigarettes per day) i. Many smokers are light smokers because of the known health consequences, high cost, and nonsmoking laws ii. Cessation medications have shown mixed results with efficacy; treatment recommended for withdrawal symptoms. iii. Use time to first cigarette of the day to dose NRT gum and lozenge; amount of cigarette smoking for the NRT patch; symptoms for NRT inhaler and nasal spray; doses for varenicline or bupropion do not change. iv. Monotherapy may be sufficient for treatment unless the patient recently decreased to less than 10 cigarettes/day. v. Behavioral modifications may be more important to address than withdrawal in light smokers.

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c. Patients concerned about weight gain i. 80% of patients gain weight (average of 3–6 kg in first 3 months) ii. Exercise interventions showed long-term weight loss, but not in the short-term. Weight management education was not shown to be effective; personalized weight management support may be effective. iii. Bupropion, varenicline, NRT all delay (but do not prevent) weight gain at 12 months. (a) NRT may show the largest weight gain delay (up to 4.3 kg), limited evidence in Cochrane review. (b) There may be a modest long-term effect. (c) A side effect of bupropion is decreased appetite while the patient is taking the medication. d. Pregnancy: The U.S. Preventive Services Task Force concluded that evidence is inadequate to evaluate the safety or efficacy of smoking cessation pharmacotherapy during pregnancy. Table 15. Medications for Smoking Cessation Medications and 6-mo Dose and Mechanism Abstinence Rate of Action

Nicotine patch (OTC): 15.7%– 23.4%

Nicotine gum (OTC) 2 and 4 mg:

Dosing based on amount of daily cigarette use: > 10 cigarettes/day, start with 21 mg patch; < 10 cigarettes/ day, start with 14 mg patch 21 mg/24 hra 14 mg/24 hra 7 mg/24 hr

TTFC approach for dosing: Within 30 min of waking, use 4 mg; otherwise use 2 mg

19% (6–14 wk use); 26.1%, (> 14 Chew on a fixed schedule: wk use) 1 piece of gum every 1 to 2 hr (max 24 pieces/day)

Duration

Precautions/ Cautions/AEs

Patient Education

6 wk ; then 2 wk; then 2 wk or no taper

AEs: Local skin reaction (rotate), insomnia, vivid dreams (can remove at night)

Apply to clean, dry, hairless area between neck and waist; rotate sites; no lotion

Up to 12 wk (longer-term use PRN up to 6 mo may be helpful if needed)

AEs: Mouth soreness and irritation, dyspepsia, nausea

Do not eat or drink anything except for water 15 min before and while gum is in mouth

b

Caution with dental work or dentures

If sleep disruption occurs, remove at night

Directions: Chew until “peppery” taste emerges; then “park” between gum and cheek; rechew every few minutes and park again on other side; chew each piece for 30 min 4-mg strength delays weight gain

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Table 15. Medications for Smoking Cessation (continued) Medications and 6-mo Dose and Mechanism Abstinence Rate of Action

Nicotine lozenge (OTC) 2 and 4 mg: 23.6% (2 mg); 24.2% (4 mg)

Duration

TTFC approach for dosing: Up to 12 wk (longer-term Use 2 mg if first morning use PRN up cigarette ≥ 30 min after to 6 mo may waking; use 4 mg if first be helpful if morning cigarette < 30 min needed) after waking

Precautions/ Cautions/AEs

AEs: Throat irritation, Do not eat or drink anything hiccups, indigestion/ except for water 15 min heartburn, nausea before and while lozenge is in mouth Directions: Place the lozenge in the mouth and allow to dissolve over 20–30 min; do not chew

Use 1 lozenge every hr (max 20 lozenges/day) Nicotine inhaler (Nicotrol; no generic): 24.8%

Use light inhalations to Up to 6 mo deliver the liquid vapor to the inside of the mouth; use 6–16 cartridges a day; each cartridge lasts for 20 min of continuous puffing

Patient Education

AEs: Local irritation of mouth and throat, coughing Avoid use in severe reactive airway disease

4-mg strength delays weight gain

Special inhalation technique; do not use like smoking a cigarette Do not eat or drink anything except for water 15 min before and during use Delivery decrease if < 40°F (4.4°C) in winter; keep in warm area or coat pocket (not in car)

Nicotine nasal spray (Nicotrol NS; no generic): 26.7%

8–40 doses/day

3–6 mo

AEs: Nasal irritation (94% have moderate to severe nasal irritation), rhinitis, sneezing, coughing, tearing

0.5 mg/spray; one in each nostril (1 mg per dose; 200 sprays per bottle) 1 or 2 doses per hr for 6–8 wk (at least 8 doses per day); gradually decrease throughout 4–6 wk

Menthol flavor

Tilt head slightly back; do not sniff, inhale through nose, or swallow while spraying

Most adverse effects of all NRT products Avoid use in severe reactive airway disease and allergic rhinitis

Maximum dose of 5 doses per hr or 40 doses per day

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Table 15. Medications for Smoking Cessation (continued) Medications and 6-mo Dose and Mechanism Abstinence Rate of Action

Varenicline (Chantix; no generic): 21.8%– 33.5%

Bupropion SR (Wellbutrin SR): 16.2%–22.6%

0.5 mg QD for 3 days; then 0.5 mg BID for 4 days; then 1 mg BID starting on quit date (start 1 wk before quit date or between 8 and 35 days of treatment)b; decrease dose in CKD Binds to neuronal nicotine receptors (α4β2 subtype); agonist/antagonist

150 mg every morning for 3 days; then BID (start 1–2 wk before quit date)

Duration

3 mo; maintenance up to 6 mo

Precautions/ Cautions/AEs

AEs: Nausea, insomnia, vivid dreams, headache

Patient Education

Avoid bedtime dosing Report any depression symptoms Patients may experience impaired ability to drive or operate machinery Take with food to reduce nausea

7–12 wk; maintenance up to 6 mo

Adjust dosing for impaired renal or liver function Blocks dopamine and/or norepinephrine reuptake

AEs: Dry mouth, insomnia Contraindications: History of seizure, eating disorder; use of MAOIs in past 14 days; abrupt discontinuation of alcohol, corticosteroids, benzodiazepines, barbiturates, or antiepileptic drugs

Take evening dose before 6:00 p.m. instead of at bedtime to avoid insomnia (doses should be ≥ 8 hr apart) Delays weight gain Check for drug interactions

Dose and duration are for smokers smoking one pack/day; if smoking one-half pack/day, start with 14-mg patch.

a

“Preloading” for 4 weeks before quit date significantly increased abstinence rates, especially in those who reduced nicotine use before quit date (Arch Intern Med 2011;171:770-7).

b

AE = adverse effect; NRT = nicotine replacement therapy; NS = nasal spray; OTC = over the counter; SR = sustained release; TTFC = time to first cigarette.

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Patient Cases 13. A 50-year-old woman presents for smoking cessation. She has COPD, eating disorder, depression, and anxiety. She currently smokes 1.5 packs/day and has smoked one to 2 packs/day for 24 years. She smokes within 30 minutes of waking. Her depression and anxiety are both well controlled on medications; no admissions to the hospital for mood disorders or changes in her medications in the past year. Her renal and liver function are normal. She has tried nicotine patches, inhalers, and lozenges, none of which have helped her quit. She would like to try something different. Which would be the most appropriate pharmacotherapy recommendation? A. B. C. D.

Bupropion sustained release 150 mg once daily for 3 days; then twice daily. Varenicline 0.5 mg once daily for 3 days; then twice daily for 4 days; then 1 mg twice daily. Nicotine gum 2 mg; 1 piece every 1–2 hours for 6 weeks; then as needed. Nicotine patch 14 mg; 1 patch every day for 2 weeks; then decrease to 7 mg daily for 2 weeks.

14. A 27-year-old woman wants to quit smoking and is interested only in NRT for smoking cessation. She does not want to take any “pills.” She smokes 1 pack/day. Her first cigarette is 1 hour after waking up. She has tried quitting “cold turkey” about four times in the past, however, she was unsuccessful except for a few days. She is now more serious because her son’s asthma is getting worse because of her smoking. Which is the most appropriate first-line therapy for her? A. B. C. D.

Nicotine patch 21 mg daily for 6 weeks; then 14 mg daily for 2 weeks; then 7 mg daily for 2 weeks. Nicotine inhaler 6 cartridges per day; use regularly for 6 weeks; then use as needed. Nicotine gum 4 mg use regularly for 6 weeks; then use as needed (maximum 10 pieces per day). Nicotine patch 21 mg daily for 4 weeks; then 14 mg daily for 2 weeks; then 7 mg daily for 2 weeks plus nicotine gum 2 mg (use as needed).

Box 5. Summary of ATS Initiating Pharmacologic Treatment Recommendations (1)  Recommend varenicline over a nicotine patch (strong recommendation; moderate certainty) (2)  Recommend varenicline over bupropion (strong recommendation; moderate certainty) (3)  Recommend varenicline plus nicotine patch over varenicline alone (conditional recommendation; low certainty) (4)  Recommend varenicline over electronic cigarettes (conditional recommendation; very low certainty) (5)  For those who are not ready to stop smoking, recommend varenicline rather than waiting until they are ready (strong recommendation; moderate certainty) (6)  With comorbid psychiatric conditions, including substance use disorder, depression, anxiety, schizophrenia, and/or bipolar disorder, recommend varenicline over a nicotine patch (strong recommendation; moderate certainty) (7)  For those being treated with a controller, recommend extended duration (> 12 wk) over standard duration (6–12 wk) (strong recommendation; moderate certainty) Leone FT, Zhang Y, Evers-Casey S, etc. al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med 2020;202:e5-e31.

D. Electronic Nicotine Delivery Systems; Electronic Cigarettes (e-cigarettes) (Domains 1, 2, 4) 1. Highly advertised battery-operated devices, available in the United States since 2007 a. Deliver a vapor that typically contains nicotine and/or other chemicals for inhalation; some reports have shown them to include propylene glycol, glycerin, and flavorings that can pose risk. b. Pod-mod devices (e.g., JUUL) contain nicotine salts, which create more protonated nicotine at a lower pH than the free base form of nicotine (e.g., other devices, as needed NRT) making it less irritating when inhaled at a higher concentration.

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2. Safety a. Under FDA regulatory authority as of May 2016; allows law enforcement to prevent sale to those younger than 18 years, ban free product samples, and regulate labeling and content. b. U.S. Surgeon General Report on e-cigarette use in youth and young adults states nicotine exposure during adolescence can cause addiction and can harm the developing brain; it is not harmless. Electronic nicotine delivery system use is on the rise in youth and young adults. Available in flavors such as chocolate and mint, which could appeal to young people and increase risk of addiction in children c. National Academies of Science, Engineering, and Medicine (NASEM) conducted 2018 systematic evidence review: Concluded risks could be less than with traditional smoking; insufficient evidence for long-term effects, but found substantial evidence for short-term effects (acute endothelial cell dysfunction, DNA damage, oxidative stress, temporarily increased heart rate) d. Centers for Disease Control and Prevention reports in October 2019 over 1400 cases of lung disease and 33 deaths; most affected report vaping a cannabis product. e. GOLD discusses vaping-associated lung injury. E-cigarette, or vaping, product use- associated lung injury (EVALI) has decreased since the identification of vitamin E acetate (an additive in some THCcontaining e-cigarettes). f. Royal College of Physicians revised position that e-cigarettes should be promoted as harm-reducing substitutes (to combustible tobacco); more risky than NRT products; monitor use in tobacco-naive (adolescents). United Kingdom products are regulated to not contain cannabis or vitamin E. 3. A few studies have shown increased smoking cessation rates at the population level or in comparison to NRT; more evidence is needed before this can be recommended. Several observational studies show electronic nicotine delivery systems promote dual use and continued nicotine addiction. 4. Refill cartridges are a risk if used improperly; risk of nicotine toxicity if the cartridge malfunctions; amount of nicotine may vary from cartridge to cartridge. 5. Treatment should be offered to those trying to quit. Conventional treatments are recommended, however the effectiveness of e-cigarettes is unknown. E. Complementary and Alternative Medicine: Guidelines state that evidence is insufficient to support the use of acupuncture or hypnosis for tobacco use treatment (U.S. Department of Health and Human Services). F. Vaccinations: All smokers 19–64 years of age should receive the PPSV23 vaccine once and a one-time revaccination 5 years or more after the first vaccination at 65 years and older, in addition to the influenza vaccine every fall (Domains 1, 5).

IV.  PUBLIC HEALTH A. Pharmacist role (Domain 4,5). Pharmacists can play a specific role by connecting patients to the public health resources available, serving as experts within these associations, and advancing the evidence of climate change as it relates to pulmonary health. Specifically, pharmacists can support efforts and educate about the following: 1. Tobacco and nicotine exposure 2. Clean air (pollution) 3. Radon testing 4. Obesity prevention 5. Vaccination

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B. U.S. Surgeon General’s Report 1. Combines studies and reports, and provides evidence and recommendations 2. Provides interactive messaging around risk and safety concerns 3. Recommends increasing the price of cigarettes, adopting comprehensive smoke-free policies, implementing mass media campaigns, requiring pictorial health warnings, and maintaining comprehensive statewide tobacco control programs that support and increase smoking cessation Table 16. Agencies/Associations Specific to Asthma, COPD, and/or Smoking Cessation with Resources/Educational Programs for the Public Agency/Association

American Lung Association

Website/Telephone Numbers

www.lung.org

Programs/Resources

Information on management of asthma, COPD, and smoking cessation Can enter zip code and search for local associations; many local programs available Better Breathers Club (COPD), Breathe Well/Live Well SelfManagement Program (asthma), Freedom From Smoking Online program Lung help line 1-800-LUNGUSA to help with any questions on asthma, COPD, smoking cessation

American Thoracic Society

www.thoracic.org

Asthma and Allergy Association of America

www.aafa.org/

Allergy & Asthma Network; Mothers of Asthmatics

www.aanma.org/

CDC Office on Smoking www.cdc.gov/tobacco and Health COPD Foundation

www.copdfoundation.org

Online chat available

Resources for health professionals, patients, and for advocacy Educational programs (online, classroom), resources, materials, tools (e.g., asthma action plans/cards), publications, and educational materials Local educational support groups, including parent support groups “Ask a Nurse” patient support center, educational tools and materials, and asthma and allergy topics in the news Help for parents dealing with children with asthma and allergies Patient educational materials Data and statistics Links to state and community resources

Nonprofit with the purpose to prevent and cure COPD and to improve the lives of all people affected by COPD Patient, caregiver, and provider educational materials Support resources

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Table 16. Agencies/Associations Specific to Asthma, COPD, and/or Smoking Cessation with Resources/Educational Programs for the Public (continued) Agency/Association

National Heart, Lung, and Blood Institute

Website/Telephone Numbers

www.nhlbi.nih.gov

Programs/Resources

Area for public; includes information on asthma, COPD, and smoking cessation National Asthma Control Initiative Publications, fact sheets

Nicotine Anonymous

Smokefree.gov

www.nicotine-anonymous. org

Demonstration projects around the country addressing guideline implementation and dealing with asthma disparities 12-step program offering support to those who want to quit smoking; similar to AA

Links to local support groups and meetings; information on telephone meetings

www.smokefree.gov From the NCI (Tobacco Control Research Branch) Online 1-800-QUIT-NOW step-by-step research guide (connects to state quit lines) Local and state telephone quit lines; NCI national telephone quit line; NCI instant messaging service Publications; resources such as a craving journal; discovering reasons for quitting

AA = Alcoholics Anonymous; CDC = Centers for Disease Control and Prevention; NCI = National Cancer Institute.

V.  PRACTICE MANAGEMENT: CERTIFICATION (Domains 4, 5) A. Certified Asthma Educator 1. National Asthma Educator Certification Board (www.naecb.org/) 2. National examination based on a detailed content outline: Pathophysiology, contributing factors, obtainment of history from a patient with asthma, physical signs, objective measures, educational needs, asthma management (medications, delivery devices), behavioral and environmental modifications, asthma education plan, organizational issues (needs assessment, program development, implementation, evaluation), referrals, and professional networking 3. Many local associations offer review classes. B. National Certificate in Tobacco Treatment Practice (www.naadac.org) 1. National certificate to unify and standardize tobacco competencies, knowledge, and skills. 2. In partnership with the Association for Treatment of Tobacco Use and Dependence (www.attud.org), Association for Addiction Professionals and Council of Tobacco Treatment Training Programs (www.ctttp. org)

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VI.  PATIENT ADVOCACY A. For asthma and COPD, cost and coverage of inhalers may be an issue for patients (Domain 4). 1. Assist patients by checking insurance formularies and recommending inhalers that are covered. This inhaler coverage may change every 6 months for some insurance plans and create confusion and non-adherence. 2. Patient assistance programs are available from manufacturers (Domain 4). e.g.,: www.rxassist.org and www. needymeds.com; can search by name of drug to find criteria and instructions on enrolling patients in the program. Discounts are available for certain medications using www.needymeds.com. 3. Nebulized formulations may be more cost-effective for some patients with Medicare. 4. Some manufacturers offer coupons on their websites. B. Advanced technology tools for inhalers and other devices/apps to track adherence, symptoms, and inspiratory flow rates are currently available. Depending on the patient and their specific needs, the pharmacist can evaluate the benefit of these devices against the cost/burden, especially as evidence becomes more readily available. C. Smoking Cessation 1. Comprehensive, barrier-free smoking cessation insurance coverage; see earlier text for resources 2. Pharmacist prescriptive authority for smoking cessation medications

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REFERENCES Asthma 1. Ajimura CM, Jagan N, Morrow LE, et al. Drug interactions with oral inhaled medications. J Pharm Technol 2018;34:273–80. 2. Bodzenta-Lukaszyk A, Dymek A, McAulay K, et al. Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an openlabel, randomized study. BMC Pulm Med 2011;11:28. 3. Chong J; Haran C; Chauhan BF; Asher I. Intermittent inhaled corticosteroid therapy versus placebo for persistent asthma in children and adults. Cochrane Database Syst Rev 2015;7:CD011032. 4. Cloutier MM, Dixon AE, Krishnan JA, et al. Managing asthma in adolescents and adults 2020 asthma guideline update from the National Asthma Education and Prevention Program. JAMA 2020;324:2301-17. 5. Global Strategy for Asthma (GINA) [homepage on the Internet]. 2020. Available at www.ginasthma.org/. Accessed August 20, 2021. 6. Global Initiative for Asthma (GINA). Asthma, COPD and Asthma-COPD Overlap Syndrome (ACOS). 2015. Available at http://ginasthma.org/asthma-copdand-asthma-copd-overlap-syndrome-acos/. Accessed August 20, 2021. 7. Juniper EF, O’Byrne PM, Guyatt GH, et al. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902-7. 8. Kew KM; Karner C; Mindus SM; Ferrara G. Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children. [Review] Cochrane Database of Systematic Reviews. 12:CD009019, 2013. 9. Kobayashi M, Bennett NM, Gierke R, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2015;64:944-7. 10. Lohia S, Schlosser RJ, Soler ZM. Impact of intranasal corticosteroids on asthma outcomes in allergic rhinitis: a meta-analysis. Allergy 2013;68:569-79. 11. Martinez FD, Chinchilli VM, Morgan WJ, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomized, double-blind, placebo-controlled trial. Lancet 2011;377:650-7.

12. Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey of assessing asthma control. J Allergy Clin Immunol 2004;113:59-65. 13. National Heart, Lung, and Blood Institute. Guidelines for the Diagnosis and Management of Asthma. National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3. NIH Publication 08-5846. 2007. Available at www. nhlbi.nih.gov/files/ docs/guidelines/asthgdln.pdf. Accessed August 20, 2021. 14. National Heart, Lung, and Blood Institute. 2020 Focused Updates to the Asthma Management Guidelines. National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 4. NIH Publication. 2020. Available at https://www. nhlbi.nih.gov/health-topics/all-publications-andresources/2020-focused-updates-asthma-management-guidelines. Accessed August 20, 2021. 15. Nelson HS, Weiss ST, Bleecker ER, et al. The salmeterol multicenter asthma research trial (SMART): a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15-26. 16. Perera BJ. Salmeterol multicentre asthma research trial (SMART): interim analysis shows increased risk of asthma-related deaths. Ceylon Med J 2003;48:99. 17. Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma (TALC study). N Engl J Med 2010;363:1715-26. 18. Price D, Musgrave SD, Shepstone L, et al. Leukotriene antagonists as first-line or add on asthma-controller therapy. N Engl J Med 2011;364:1695-707. 19. Quirce S, Domínguez-Ortega J, Barranco P. Anticholinergics for Treatment of Asthma. J Investig Allergol Clin Immunol 2015;25:84-93. 20. Vollmer WM, Markson LE, O’Connor E, et al. Association of asthma control with health care utilization and quality of life. Am J Respir Crit Care Med 1999;160:1647-52. Chronic Obstructive Pulmonary Disease 1. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689-98.

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2. 3.

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6.

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14.

Beasley R, Singh S, Loke YK, et al. Call for worldwide withdrawal of tiotropium Respimat mist inhaler. BMJ 2012;345:e7390. Bestall JC, Paul EA, Garrod R, et al. Usefulness of the Medical Research Council (MRC) dyspnea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999;547:5816. Calverley PMA, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease (the TORCH study). N Engl J Med 2007;356:775-89. Chong J, Karner C, Poole P. Tiotropium versus longacting beta-agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012;9:CD009157. Ernst P, Gonzalez AP, Brassard P, et al. Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia. Am J Respir Crit Care Med 2007;176:162-6. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Prevention, Diagnosis and Management of COPD. 2021 GOLD Report. Available at www.goldcopd.org/. Accessed August 20, 2021. Heffner JE, Mularski RA, Calverley PM. COPD performance measures: missing opportunities for improving care. Chest 2010;137:1181-9. Lee RA, Centor RM, Humphrey LL, et al. Appropriate use of short-course antibiotics in common infections: best practice advice from the American College of Physicians. Ann Intern Med 2021;174:822-7. Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA 2013;309:2223-31. Lipson DA, Barnhart F, Brealey N, et al. Once-daily single-inhaler triple verses dual therapy in patients with COPD. N Engl J Med 2018;378:1671-80. McEvoy CE, Neiwoehner DE. Adverse effects of corticosteroid therapy for COPD: a critical review. Chest 1997;111:732-43. Nannini LJ, Cates CJ, Lasserson TJ, et al. Combined corticosteroid and long-acting beta-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2007;4:CD003794. Nici L, Mammen MJ, Charbek E, et al. Pharmacologic management of COPD: an official American Thoracic

15.

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Society clinical practice guideline. Am J Respir Crit Care Med 2020;201:e56-369. Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society (ACP/ACCP/ATS/ERS guidelines). Ann Intern Med 2011;155:179-91. Parri G, Nieri D, Roggi M, et al. Fluticasone furoate, umeclidinium bromide, and vilanterol as a combination therapy for chronic obstructive pulmonary disease. Expert Rev Respir Med. 2018;12:997-1005. Qiu S, Zhong X. Macrolides: a promising pharmacologic therapy for chronic obstructive pulmonary disease. Ther Adv Respir Dis 2017;11:147-55. Rutten FH, Zuithoff NP, Hak E, et al. Beta-blockers may reduce mortality and risk of exacerbations in patients with chronic obstructive pulmonary disease. Arch Intern Med 2010;170:880-7. Salpeter SR, Ormiston T, Salpeter E, et al. Cardioselective beta blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2002;2:CD003566. Singh S, Amin AV, Loke YK. Long term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease. Arch Intern Med 2009;169:219-29. Van Grunsven PM, van Schayck CP, Dereene JP, et al. Long-term effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis. Thorax 1999;54:7-14. VanDerMolen T, Willemse BW, Schokker S, et al. Development, validity and responsiveness of the Clinical COPD Questionnaire. Health Qual Life Outcomes 2003;1:13. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD (POET-COPD study). N Engl J Med 2011;364:1093-103. Welte T, Miravitlles M, Hernandez P, et al. Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180:741-50. Wise RA, Anzueto A, Cotton D, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med 2013;369:1491-501.

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Smoking Cessation 1. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patches in smokers with and without psychiatric disorders (EAGLES): a doubleblind, randomized placebo-controlled trial. Lancet 2016;387:2507-20. 2. Bhatnagar A, Payne TJ, Robertson RM. Is there a role for electronic cigarettes in tobacco cessation? J Am Heart Assoc. 2019;8e012742. 3. Campaign for Tobacco Free Kids. State Excise and Sales Tax per Pack of Cigarettes Total Amounts & State Rankings. Available at www. tobaccofreekids.org/research/factsheets/pdf/0202. pdf. Accessed August 20, 2021. 4. Chang P, Chiang C, Ho W, et al. Combination therapy of varenicline with nicotine replacement therapy is better than varenicline alone: a systemic review and meta-analysis of randomized controlled trials. BMC Public Health 2015;15:689. 5. Ebbert JO, Hatsukami DK, Croghan IT, et al. Combination varenicline and bupropion SR for tobacco-dependence treatment in cigarette smokers: a randomized trial. JAMA 2014;311:155-63. 6. Farley AC, Hajek P, Lycett D, et al. Interventions for preventing weight gain after smoking cessation. Cochrane Database Syst Rev 2012;1:CD006219. 7. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. 2008. 8. Hajek P, McRobbie HJ, Myers KE, et al. Use of varenicline for 4 weeks before quitting smoking. Arch Intern Med 2011;171:770-7. 9. Jha P, Ramasunderahettige C, Landsman V, et al. 21stcentury hazards of smoking and benefits of cessation in the United States. N Engl J Med 2013;368:341-50. 10. Koegelenberg C, Noor F, Bateman ED, et al. Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation— a randomized clinical trial. JAMA 2014;312:155-61. 11. Kuehn B. New reports examine psychiatric risks of varenicline for smoking cessation. JAMA 2012;307:129-30. 12. Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med 2020;202:e5-e31.

13. Rajat SB, Rigotti NA, Benowitz NL, et al. 2018 ACC expert consensus decision pathway on tobacco cessation treatment. J Am Coll Cardiol 2018;72:3332-65. 14. Singh S, Loke YK, Spangler JG, et al. Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ 2011;183:1359-66. 15. Slomski, A. E-cigarettes for smoking cessation. JAMA. 2019;321:1149. 16. Swanson JA, Lee JW, Hopp JW, et al. The impact of caffeine use on tobacco cessation and withdrawal. Addict Behav 1997;22:55-68. 17. Tobacco Use and Dependence Guideline Panel. Treating Tobacco Use and Dependence: 2008 Update, Clinical Practice Guideline. U.S. Department of Health and Human Services; 2008. Available at www.ncbi.nlm.nih.gov/books/NBK63952/. Accessed August 20, 2021. 18. U.S. Preventive Services Task Force. Behavioral and pharmacotherapy interventions for tobacco smoking cessation in adults, including pregnant women: U.S. Preventative Services Task Force Recommendation Statement. Ann Intern Med 2015;163:8. 19. U.S. Preventive Services Task Force. Counseling and interventions to prevent tobacco use and tobaccocaused disease in adults and pregnant women: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med 2009;150:551-5. 20. Wackowski OA, Delnevo CD, Steinberg MB. Perspectives for clinicians on regulation of electronic cigarettes. Ann Intern Med. 2016;165:665-6. 21. Wang TW, Asman K, Gentzke AS, et al. Tobacco Product Use Among Adults – United States, 2017. MMWR Morb Mortal Wkly Rep 2018;67:1225-32.

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ANSWERS AND EXPLANATIONS TO PATIENT CASES 1. Answer: B Her symptom frequency of twice weekly, her FEV1 more than 80% of predicted (normal), and the lack of interference with her activities are consistent with intermittent asthma. However, her nighttime awakenings for asthma symptoms occur three times a month, which is consistent with mild persistent asthma. In addition, mild persistent asthma still has normal spirometry. The specific level of persistent asthma is based on the most severe category met, so even though only one of her signs/symptoms falls under mild persistent and the rest under intermittent, she would be categorized as mild persistent (Answer B is correct).

combination with a low-dose ICS. Fluticasone/salmeterol 100/50 twice daily is a medium-dose ICS plus an LABA, which is step 4 in this age group (Answer C is incorrect). 5. Answer: B In an asthma action plan, this would be the green zone instructions (doing well, no symptoms, peak flow meter of 80% or greater of personal best). Instructions should be to take the controller agent only (and the patient may use albuterol HFA 1 or 2 puffs every 4–6 hours only if needed for periodic symptoms). In this case, the controller is fluticasone/salmeterol 250/50 one puff twice daily (Answer B is correct).

2. Answer: C Because she has mild persistent asthma, step 2 is recommended for initial treatment (Answer A is incorrect). In addition to an inhaled SABA as needed, she would need to use a low-dose ICS (preferred treatment): mometasone 200 mcg once daily (Answer C is correct). Montelukast is alternative therapy (not first line) for step 2 (Answer B is incorrect). Budesonide/formoterol, in the dose listed, is a low-dose ICS plus an LABA, which is a step 3 therapy (Answer D is incorrect).

6. Answer: A This patient has both asthma and COPD and is already on appropriate treatment for asthma, which appears to be well controlled. Patients with ACO should be treated with an ICS and can consider adding an LABA and/or LAMA for COPD treatment (Answers B and C are incorrect). The patient’s FeNO level indicates adherence to ICS. Although the guidelines also state an LABA/LAMA combination is a recommended option, adding an LABA first would be the next best step before jumping to triple therapy based on her symptoms and history (Answer A is correct; Answer D is incorrect).

3. Answer: C Using EPR-3, her asthma falls in the “not well controlled” category because of the frequency of her daytime symptoms and because albuterol use is more than 2 days a week. The recommended action for treatment is to go up to step 3: a low-dose ICS plus formoterol is preferred (Answer C is correct; Answer A is incorrect). Fluticasone furoate/umeclidinium/vilanterol is not preferred until step 5 (Answer B is incorrect). Medium-dose ICS, though an alternative in step 3, is not preferred (Answer D is incorrect).

7. Answer: C The patient is currently using a medium-dose ICS, placing him at step 3 therapy. Although adding tiotropium is FDA indicated in use for asthma, the patient is too young (Answer B is incorrect), and 2020 Focused Updates does not recommend adding a LAMA at step 4 for this age group. Adding omalizumab is a consideration for step 5 (2020 Focused Updates) after step 4 of adding an LABA or LTRA or theophylline (Answers A and D are incorrect). As a step up in therapy is indicated; adding an LABA is the best option (Answer C is correct).

4. Answer: D This patient has moderate persistent asthma because of his twice weekly nighttime symptoms and requires step 3 therapy. A medium-dose ICS alone is an alternative initial therapy (low-dose ICS/formoterol preferred) in this age group (5–11 years) (Answer D is correct). Fluticasone 44 mcg 1 puff twice daily is a low-dose ICS for this age group and is considered step 2 treatment (Answer A is incorrect). Montelukast is not recommended for moderate persistent asthma in this age group as monotherapy (Answer B is incorrect); montelukast is recommended only in

8. Answer: B This patient is in GOLD grade 2 group B because his postbronchodilator FEV1 is 50%–79% (grade 2) and he has had 1 or no exacerbations in the past year without hospitalizations with a Modified [British] Medical Research Council score of 2 or more, placing him in group B (Answer B is correct).

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13. Answer: B Bupropion is contraindicated because of her eating disorder (Answer A is incorrect). Nicotine gum 2 mg would be an inappropriate dose; she would need to use the 4-mg dose because she smokes within 30 minutes of waking (Answer C is incorrect). The nicotine patch was not a preference of the patient and she would need at least the 21-mg patch in combination with another NRT (Answer D is incorrect). Varenicline is more effective than the nicotine patch alone and should be considered first line, if possible, and/or not contraindicated (Answer B is correct). Although the patient has depression, it is well controlled, so varenicline may still be used. The patient should be monitored for any worsening depression. She should be instructed to discontinue the agent if she experiences any symptoms of depressed mood, agitation, or behavior changes that do not seem to be from nicotine withdrawal or if she experiences suicidal thoughts. Family members and caregivers should also be educated about worsening mood.

9. Answer: B According to the GOLD guidelines, the recommended treatment for patient group B is regular treatment with a long-acting bronchodilator (either an LABA or an LAMA) (Answer A is incorrect; Answer B is correct). Inhaled corticosteroids are recommended only for group D. Roflumilast is recommended only if FEV1 is less than 50% of predicted with chronic bronchitis and a history of frequent exacerbations (Answers C and D are incorrect). 10. Answer: A This patient is in GOLD grade 2 group B, and is already on the first-choice therapy. Because she is experiencing dyspnea, an LABA should be added to her LAMA (Answer A is correct). Azithromycin is recommended to prevent exacerbations for patients already on LAMA and LABA or ICS/LABA/LAMA (Answers B is incorrect). Inhaled corticosteroids are only recommended for exacerbations and increased eosinophils (Answers C and D are incorrect).

14. Answer: D The combination of a nicotine patch and as needed NRT is more effective than the nicotine patch alone (Answer D is correct). In addition, the patient does not want to use varenicline or this combination as first-line therapy (Answers A, B and C are incorrect). Because she smokes one hour after waking, the 2-mg gum is recommended with the patches.

11. Answer: D According to the latest GOLD guidelines, OCSs are indicated in most exacerbations (Answers A and C are incorrect). The recommended dose is oral prednisolone (or equivalent) 40 mg daily for 5 days. Prednisolone has a dose equivalent to prednisone. Antibiotic treatment is also indicated because the patient has all three cardinal symptoms of airway infection: (1) increased sputum purulence, (2) increased sputum volume, and (3) increased dyspnea. Azithromycin is one of the recommended antibiotics (Answer B is incorrect; Answer D is correct). 12. Answer: C This patient does not want to quit smoking right now. Current ATS 2020 guidance recommends starting varenicline, even when the patient is not ready (strong recommendation, moderate certainty). However, bupropion is not recommended (Answer D is incorrect). The steps to take when individuals are not ready to quit include using motivational interviewing strategies, discussing reasons they should quit (in a supportive manner), discussing their personal barriers to quitting, and discussing the five “R’s” (relevance, risks, rewards, roadblocks, and repetition) (Answer A is incorrect; Answer C is correct). Less than 10 minutes is effective in increasing quit rates; however, even 3 minutes of strong, clear, and personalized statements can increase quit rates (Answer B is incorrect).

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ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS 5. Answer: A The patient is in GOLD grade 2 group B. A single longacting bronchodilator is the first choice for medication treatment. Tiotropium is an appropriate long-acting bronchodilator to initiate in this patient (Answer A is correct). A LABA would also be appropriate, but it was not one of the choices. Montelukast is recommended for asthma, not COPD (Answer C is incorrect). An ICS is recommended only in patient groups C or D (Answers B and D are incorrect).

1. Answer: D EPR-3 classification of asthma severity is based on several criteria, including short-acting inhaler use and nighttime awakenings. The frequency of her nighttime awakenings indicates that she falls into the moderate persistent category, because these are occurring more than one time per week but not daily. However, because she uses her inhaler four times daily, indicating frequency of symptoms is throughout the day, this puts the patient in the severe persistent category. Her nighttime symptoms are not in the severe persistent category, but a patient should be classified by the most severe category in any given area (Answer D is correct).

6. Answer: C For all acute exacerbations of chronic COPD, albuterol with or without ipratropium by nebulization should be given (Answer A is incorrect). For most exacerbations, a burst of OCSs should be given (Answer B is incorrect; Answer C is correct). Antibiotics are only recommended if all three cardinal symptoms of COPD exacerbations (increased dyspnea, increased sputum volume, and increased sputum purulence) are present or if two cardinal symptoms are present and increased sputum purulence is one of the symptoms. This patient does not meet these criteria, so antibiotics are not indicated. He has only two of the cardinal symptoms (increased dyspnea and volume), and increased sputum purulence is not one of his symptoms (Answer D is incorrect).

2. Answer: D Initial treatment of the severe persistent asthma class is step 4 or 5 (Answer B is incorrect). Step 4 preferred is an inhaled steroid (medium dose) with formoterol daily (Answer A is incorrect). Step 5 preferred is an inhaled steroid (medium-high dose) with formoterol (Answer D is correct). Monotherapy with an LABA (salmeterol) is not recommended in asthma (Answer C is incorrect). 3. Answer: D The premise of SMART is to use a single inhaler for both daily control and reliever therapy (Answer A is incorrect). Use of SMART is specific to using formoterol as the LABA because this has a much quicker onset than salmeterol that is similar to albuterol (Answer B is incorrect). In neither guideline is ICS monotherapy preferred to combination therapy, except for step 2. Because this patient should be initiated on step 4 or 5, this would be inaccurate (Answer C is incorrect). Each patient’s insurance coverage should be verified before prescribing SMART, when possible (Answer D is correct).

7. Answer: D At this time, we do not have enough information to recommend liraglutide for preventive weight loss use in smoking cessation (Answer A is incorrect). All three medication classes have been found to delay, but not prevent, weight gain and may be helpful because the patient has obesity. Although NRT is an option, single NRT is less effective than varenicline, making varenicline the best option to recommend for this patient (Answer B is incorrect; Answer D is correct). Bupropion is an option; however, in the ATS 2020 update, varenicline is recommended over bupropion (Answer C is incorrect).

4. Answer: B The inhaler technique with DPIs is very different from that with MDIs. The inhalation must be quick, forceful, and deep, rather than slow and deep (Answer B is correct). When using a DPI, the “puff” feels different from that of the MDIs; no aerosol puff is felt; the patient may not feel anything (Answer A is incorrect). Dry powder inhalers should not be shaken or used with a holding chamber (Answers C and D are incorrect).

8. Answer: D Patients quitting smoking can experience withdrawal symptoms such as insomnia, difficulty concentrating, and decreased heart rate (Answers A, B, and C are incorrect). Patients quitting smoking can gain up to 4.3 kg on average (Answer D is correct).

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 560

Pulmonary Disorders

9. Answer: A Patients with mild to moderate renal impairment can use varenicline and those with severe impairment or dialysis should use a reduced dose (Answer B is incorrect). Varenicline can be used for six months per the package insert (Answer D is incorrect). Patients are advised to take varenicline after meals with a full glass of water; this can help reduce nausea (Answer C incorrect). A combination of behavioral counseling and drugs is more effective than either behavioral counseling or drugs alone (Answer A is correct). Longer counseling sessions are more effective than shorter ones, with efficacy plateauing at 90 minutes.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 561

Practices and Processes of Care Jessica Tilton, Pharm.D., BCACP University of Illinois at Chicago College of Pharmacy Chicago, Illinois

Practices and Processes of Care

Practices and Processes of Care Jessica Tilton, Pharm.D., BCACP University of Illinois at Chicago College of Pharmacy Chicago, Illinois

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 565

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Learning Objectives 1. Discuss issues with transitions of care, including a pharmacist’s role in achieving quality measures and improving the process. 2. Describe different types of patient care services or practice models provided by a pharmacist within an ambulatory practice, along with any applicable regulatory requirements. 3. Apply tools and resources to detect, classify, report, analyze, and reduce preventable and non-preventable adverse drug events. 4. Use formulary management activities and other resources to improve the prescribing of and access to safe, effective, and affordable treatments in an organization. Self-Assessment Questions Answers and explanations to these questions can be found at the end of the chapter.

Abbreviations in This Chapter CDTM CMM ED HRSA

Collaborative drug therapy management Comprehensive medication management Emergency department Health Resources and Services Administration MTM Medication therapy management P&T Pharmacy and therapeutics (committee)

1. A 77-year-old man is referred to the pharmacy for medication therapy management (MTM) under Medicare Part D. Which best describes why the patient is eligible for MTM under Medicare Part D? A. He pays at least $4376 per year for his Part D covered medications, has at least one chronic disease state, and takes one medication. B. He pays at least $3996 per year for his Part D covered medications, has at least four chronic disease states, and takes two medications. C. He pays at least $4696 per year for his Part D covered medications, has at least two chronic disease states, and takes three medications. D. He pays at least $4044 per year for his Part D covered medications, has at least three chronic disease states, and takes four medications.

Baseline Knowledge Statements Readers of this chapter are presumed to be familiar with the following: • What medication reconciliation is and how to effectively perform a medication reconciliation • Basic understanding of the elements of an ambulatory care collaborative practice agreement or protocol

2. A 64-year-old man is referred to the pharmacist by his provider for management of uncontrolled diabetes as dictated by the established collaborative drug therapy management (CDTM) agreement. Which best describes the pharmacist’s general scope of practice under a CDTM agreement?

Additional Readings The following free resource has additional background information on this topic: • https://www.jointcommission.org/assets/1/6/ NPSG_Chapter_HAP_Jan2019.pdf

A. Diagnose the patient with peripheral neuropathy, and initiate gabapentin. B. Discontinue the patient’s glyburide, and initiate glargine. C. Order and obtain the patient’s chemistries and A1C. D. Order continuous positive airway pressure (CPAP) machine for the patient’s obstructive sleep apnea.

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3. A 57-year-old woman has an anticipated hospital discharge for tomorrow. She was admitted because of a mild asthma exacerbation requiring steroids and nebulizer treatments. Which best describes how a pharmacist could improve the patient’s transition of care?

A. Scheduling the patient for a comprehensive medication review (CMR) in 3 months with the pharmacist. B. Completing medication reconciliation for the patient on hospital admission and discharge. C. Providing recommendations to the inpatient team on outpatient pharmacies that will deliver the patient’s medications to her home. D. Conducting an Asthma Control Test with the patient at a follow-up visit in the clinic.

4. Which method of medication safety analysis is best for prospectively identifying the risk of error in a process and for estimating the likelihood of a process failure? A. B. C. D.

Root cause analysis. Failure modes and effects analysis. Safety culture assessment. Analysis of medication error trends.

5. A pharmacist who is a member of the organization’s pharmacy and therapeutics (P&T) committee needs to determine whether a new drug that came to market should be placed on the drug formulary. Which best depicts what the pharmacist should consider before recommending that the drug be placed on formulary? A. Ease of preparation, cost-effectiveness, time on the market. B. Adherence, manufacturer, variety of dosage forms. C. Storage requirements, somnolence potential, convenience. D. Safety, physician demand, efficacy.

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I.  PHARMACIST SCOPE OF PRACTICE A. Profession of Pharmacy’s Mission: To improve public health through ensuring the safe, effective, and appropriate use of medications B. Scope of Practice for Pharmacists: Ultimately regulated at the state level, creating inconsistency; www.nabp.net/ (Domain 3; Task 1; Knowledge a, b, c, d, Task 2; Knowledge a) C. Model State Pharmacy Act and Model Rules of the National Association of Boards of Pharmacy (NABP) (Domain 3; Task 1; Knowledge a, b; Domain 3 Task 3; Knowledge a) 1. “Practice of Pharmacy” includes but not limited to interpretation, evaluation, dispensing, and/or implementation of medical orders, and the initiation and provision of Pharmacist Care Services 2. “Pharmacist Care Services” a. Defined as the provision of patient care activities with or without the dispensing of drugs/devices intended to achieve outcomes related to the cure or prevention of disease, elimination or reduction of a patient’s symptoms, halting or slowing of a disease process b. Should be provided by all pharmacists to the extent of their abilities, irrespective of practice setting 3. “Patient Counseling” is the oral communication by the pharmacist of information to the patient or caregiver to ensure proper use of drugs and devices. 4. “Patient Intervention Program” is any structured activity that complements or supplements the existing responsibilities regarding the dispensing of prescriptions and associated patient counseling, and uses protected health information to contact the patient or caregivers by way of phone, print, electronic media, or other means to discuss, inform, and/or affect patient therapy or choice of medications. 5. “Pharmacist’s Scope of Practice Pursuant to the Collaborative Pharmacy Practice Agreement” includes duties and limitations of duties placed on one or more pharmacists by the collaborating practitioner(s), the Board, and applicable law, and includes the limitations implied by the scope of practice of the collaborating practitioner(s). 6. The Model State Pharmacy Act and the Model Rules of the NABP are updated every August to provide state boards of pharmacy with language that may be used when creating state laws or board rules for regulating the practice of pharmacy and the distribution of drugs and related devices. 7. The NABP Survey of Pharmacy Law provides summary data on issues such as prescribing and dispensing authority, pharmacy technicians, facsimile and electronic transmission of prescriptions, and patient counseling requirements. It is revised and published annually. D. Pharmacist’s Direct Patient Care Scope of Practice in All 50 States in Any Setting (Domain 3; Task 1; Knowledge a, b) 1. Obtain medication histories. 2. Review the patient’s medications to identify medication-related problems. 3. Intervene with the physician to resolve identified problems. 4. Educate the patient about the proper use of medications. 5. Encourage adherence to prescribed medications. 6. Document and communicate information to the physician. E. Council on Credentialing in Pharmacy’s Contemporary Scope of Pharmacy Practice: The scope of practice is evolving from a model in which pharmacists primarily supervise medication distribution and counsel patients to a model in which pharmacists play an expanded, team-based clinical role of providing patient-centered MTM, health improvement, and disease prevention services.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 568

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F. The Joint Commission of Pharmacy Practitioners’ (JCPP’s) Vision for Pharmacy Practice: “Patients achieve optimal health and medication outcomes with pharmacists as essential and accountable providers within patientcentered, team-based healthcare.” G. Pharmacist Recognition of Expanded Services (Domain 3; Task 1; Knowledge a, b; Domain 3 Task 3; Knowledge a) 1. CDTM 2. Licensure as clinicians (i.e., New Mexico’s Pharmacist Clinician) 3. Legislation (i.e., North Carolina’s Clinical Pharmacist Practitioner and California’s Advanced Practice Pharmacist) H. Recommended Reading: The Expanding Role of Pharmacists in a Transformed Health Care System. Available at https://jcpp.net/wp-content/uploads/2015/09/NGA-TheExpandingRoleOfPharmacists.pdf.

II.  AMBULATORY CARE PHARMACY PRACTICE MODELS A. Medication Management Services (MMS) (Domain 3, Task 3, Knowledge a) 1. Definition: A spectrum of patient-centered, pharmacist provided, collaborative services that focus on medication appropriateness, effectiveness, safety, and adherence with the goal of improving health outcomes. 2. Background: Definition was developed under the direction of a JCPP workgroup consisting of representatives from 13 national pharmacy organizations and feedback from a public comment period. 3. Definition approved by the JCPP Board of Governors in February 2018. 4. Each pharmacy organization has the opportunity to sign on in support of the definition. 5. The new term is intended to promote better understanding of MMS and provide consistency in how those services are defined. 6. MMS was chosen to encompass a variety of terms, such as Medication Therapy Management (MTM), Comprehensive Medication Management (CMM), Collaborative Medication Management, etc. 7. As noted by JCPP, terms classified in state and federal laws and regulations (Part D MTM, CMM, etc.), are likely to remain in use and to be recognized under the new definition if they meet the definition’s key elements. 8. Key elements of MMS a. Patient-centered approach to care – the service is individualized for a specific patient, focuses on the patient’s needs and concerns, and involves the patient in the care process b. Assessment of medication appropriateness (indication), effectiveness, safety, and adherence. Consideration should be given to accessibility and cost of medications. c. Collaborative approach to care that involves the patient, caregiver(s), pharmacists, and other health care providers d. Focus on health outcomes 9. MMS is not intended to be used for all services provided by pharmacists, i.e., as safe and accurate provision of medications, medication access services, and medication administration services, etc. B. Pharmaceutical Care (Domain 3, Task 3, Knowledge a) 1. Background: Pharmaceutical care was best defined in 1990 by Hepler and Strand, expanding the pharmacist’s role from dispensing to managing drug-related effectiveness, resolving drug-related adverse events, and preventing potential drug-related problems.

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2. Definition: “Patient-centered, outcomes-oriented pharmacy practice that requires the pharmacist to work together with the patient and other health care providers to promote health, prevent disease, and assess, monitor, initiate, and modify medication use to ensure that drug therapy regimens are safe and effective” 3. Goals a. Optimize the patient’s health-related quality of life. b. Achieve positive clinical outcomes. i. Cure of a disease ii. Eliminate or reduce a patient’s symptomatology. iii. Stop or slow disease progression. iv. Disease prevention or symptomatology 4. Principles a. Can be accomplished by a pharmacist in any practice setting b. Establish and maintain a professional relationship with the patient. c. Patient-specific medical information is to be collected, organized, recorded, and maintained. i. Subjective and objective information: Health status, medical history, medication history, social history, diet and exercise, history of present illness, and economic situation ii. The information source can include, but is not limited to, medical records, pharmacist assessment, patient’s family or caregivers, insurer, and other health care professionals. d. Patient-specific medical information is to be evaluated, and a drug therapy plan should be developed collaboratively with the patient. i. A focus should be placed on medication-related problems. (a) Untreated indications (b) Improper drug selection (c) Subtherapeutic dosage (d) Failure to receive medications (e) Overdosage (f) Adverse drug reactions (g) Drug interactions (h) Medication use without indication ii. The plan should improve and ensure the safety, effectiveness, and/or cost-effectiveness of current or planned drug therapy and minimize current or potential future health-related problems. iii. The plan and desired outcomes should be documented in the patient’s medical and/or pharmacy record. e. Ensure the patient has all the necessary supplies, information, and knowledge to carry out the plan. i. The pharmacist assumes ultimate responsibility for the patient’s ability to obtain and use any drug, products, or equipment in the drug therapy plan. ii. The pharmacist should verify that the patient and/or caregivers understand the disease and the corresponding medications prescribed in the plan. iii. After appropriate education has been provided, the patient is responsible for engaging in behavior that will contribute to the achievement of the positive outcomes outlined in the plan. iv. Steps taken to implement the plan should be documented in the patient’s medical and/or pharmacy record, including monitoring values, barriers, and follow-up. f. Review, monitor, and modify the therapeutic plan, when appropriate, in collaboration with the patient and the health care team. i. The pharmacist should monitor the patient’s progress and coordinate modifications to the therapeutic plan with the patient and health care team to enhance the drug’s safety and effectiveness, in addition to minimizing overall health care costs.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 570

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ii. The pharmacist should help ensure continuity of care by sharing information with other providers as the patient moves between care settings. iii. Progress and modifications to the plan should be documented in the patient’s medical and/or pharmacy record. 5. Structural elements for quality pharmaceutical care a. Knowledge, skill, and function of personnel i. The pharmacist must have knowledge and skills in the area of patient assessment, clinical information, communication, adult teaching and learning principles, and psychosocial aspects of care. ii. Personnel include pharmacists, technicians, automation, and technology. iii. A process to certify and credential the implementation of pharmaceutical care should be created. b. A system for data collection, documentation, and transfer of information i. Pharmaceutical care is supported by data collection and documentation systems that allow patient care communication, interprofessional communications, quality assurance, and research. ii. A documentation system is necessary for reimbursement considerations. c. Effective workflow d. References, resources, and equipment i. Tools to support patient care, equipment to assess medication adherence, clinical resources, and patient educational materials are required. ii. Additional tools include computer software support, drug-use evaluation programs, and disease management protocols. e. Good communication skills f. Commitment to quality improvement and assessment procedures Patient Case 1. A patient has been referred to the pharmacist for albuterol inhaler and spacer technique education. Which best describes the pharmacist’s responsibility as part of pharmaceutical care? A. B. C. D.

Inform the patient’s physician that the patient came to their appointment. Call the patient in 1 week to see if the patient still has albuterol at home. Ensure the patient thoroughly understands the inhaler technique before leaving the visit. Document the interaction in a personal file, should the patient return again.

C. MTM (Domain 3, Task 3, Knowledge a) 1. Background: Medicare Modernization Act of 2003 required Medicare Part D to provide an MTM program as part of its drug benefit program offered to Medicare beneficiaries. 2. Consensus definition a. A distinct service or group of services that optimizes therapeutic outcomes for individual patients b. MTM services are independent of, but can occur in conjunction with, the provision of a medication product. c. Created in collaboration with 11 national pharmacy organizations 3. Goals of MTM according to the Centers for Medicare & Medicaid Services (CMS) a. Optimize therapeutic outcomes through improved medication use. b. Reduce the risk of adverse events and drug interactions. c. Improve medication adherence. 4. CMS requirements of MTM programs – 2022 Plan Year a. Enrollment i. Opt-out method: Plans must auto-enroll targeted beneficiaries who meet the eligibility criteria, and they are considered enrolled unless they decline enrollment. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 571

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ii. Plans must target beneficiaries for enrollment at least quarterly during each plan year. iii. Plans are expected to use more than one approach, when possible, to reach eligible beneficiaries. b. Targeted beneficiaries i. Several chronic disease states, with three chronic diseases being the maximum number a Part D plan sponsor can require for targeted enrollment (a) Most plans require two or three chronic disease states for eligibility. (b) Plans that specify which chronic diseases apply must select at least five of the nine distinct core chronic diseases: Alzheimer disease, chronic heart failure, diabetes, dyslipidemia, endstage renal disease, hypertension, respiratory disease, bone disease-arthritis, and mental health disease AND ii. Multiple covered Part D medications: Eight Part D drugs is the maximum number of drugs a Part D plan sponsor can require for targeted enrollment; most plans require two to eight medications for eligibility AND iii. Costs of Part D medications are $4696 per year or greater AND/OR iv. At-risk beneficiaries under a drug management program c. Required MTM services i. Interventions for both patient and prescriber on optimal medication use ii. Information regarding safe disposal of controlled medications, drug take-back programs, in-home disposal, and cost-effective means to safely dispose of such drugs iii. Annual CMR with written summaries in CMS’s standardized format (a) Must be interactive, person-to-person, or telehealth consultation (b) Can be provided by a pharmacist, pharmacy intern under direct supervision of a pharmacist, or other qualified health care provider (e.g., physician or registered nurse) (c) If the beneficiary cannot accept participation, the CMR may be performed with the beneficiary’s prescriber, caregiver, or other authorized individual. (d) Offered no later than 60 days after being enrolled in Medicare Part D (e) Adapted from the National MTM Advisory Board definition; builds on the American Pharmacists Association (APhA) medication therapy review (MTR) core element (f) Designed to improve patients’ knowledge of their medications, identify and address patients’ problems or concerns, and empower patients to self-manage iv. Quarterly targeted medication reviews (TMRs) plus follow-up reviews as needed (a) If the beneficiary declines the TMR, the pharmacist or other health care provider must still complete a TMR at least quarterly and communicate the interventions to the prescriber. (b) Communication with the prescriber can be interactive or passive (e-mail or facsimile). d. Plans required to have a process in place to measure, analyze, and report outcomes of their MTM program e. Plans must have attestation of their MTM program done by their chief executive officer, chief operating officer, or the chief financial officer. 5. APhA core elements of MTM (www.pharmacist.com/sites/ default/files/files/core_elements_of_an_mtm_ prac­tice.pdf) a. Medication therapy review i. Definition: Systematic process of collecting patient-specific information, assessing medication therapies to identify medication-related problems, developing a prioritized list of medication-related problems, and creating a plan to resolve them ii. Comprehensive (all medications/therapy problems) or targeted (specific therapy problem) iii. Preferably face-to-face (in-person visit); however, person-to-person (by phone) is acceptable

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iv. Interview patient to gather data on demographics, medication history, and general health; should ideally assess the following: (a) Patient’s overall health, including previous and current health conditions (b) Patient’s values, preferences, goals, and quality of life (c) Cultural issues, education level, literacy level, and language barriers (d) Laboratory values and vital signs (e) Medication-related problems (1) Adverse events (2) Appropriateness of each medication (3) Adherence to therapy (4) Untreated conditions (5) Costs and access to medications and health care (6) Duplication of therapy v. Develop a plan for each problem identified, and provide patient education. b. Personal medication record (PMR) i. Definition: Comprehensive record of the patient’s medications, including, but not limited to, herbal products, over-the-counter medications, and other dietary supplements ii. Intended for patients to use in medication self-management iii. Collaborative effort among patients, pharmacists, and other health care professionals iv. Preferably electronic; however, can be handwritten v. An updated PMR should be created with any medication change. vi. May include the following: (a) Patient name, date of birth, and telephone number (b) Name and telephone number of physicians and pharmacy or pharmacies (c) Allergies (d) Date last updated (e) Medication information: Medication name, dose, indication, instructions for use, start and stop date, ordering prescriber, and special instructions c. Medication-related action plan (MAP) i. Definition: Patient-centric document containing a list of actions for the patient to use in tracking progress for self-management ii. Critical component of MTM documentation iii. Collaborative effort between the patient and the pharmacist iv. Includes only information the patient can act on and is within the pharmacist’s scope of practice or agreed on by relevant health care team members v. Does not include outstanding action items that still require physician approval, such as changes in medication regimen that are pending approval vi. The MAP, in conjugation with education, encourages the patient’s active participation in the health care plan. vii. May include the following: (a) Patient name (b) Name and telephone number of physician and pharmacy (c) Date of MAP creation (d) Action steps for the patient (e) Notes for the patient (f) Follow-up information

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d. Intervention and/or referral i. Definition: The pharmacist provides consultative services and intervenes to address medicationrelated problems; when necessary, the pharmacist refers the patient to a physician or other health care professionals. ii. Pharmacist interventions within the health care team are important in improving patient outcomes; documentation of the interventions and outcomes supports the impact of pharmacists on patient outcomes. iii. Any medication-related problems identified should be documented and communicated to the patient’s physician. iv. Suggestions to address medication problems and recommendations on follow-up are also integral to the intervention. v. The intent of this core element is to optimize medication use, enhance continuity of care, and encourage patients to use health care services to prevent future adverse events. e. Documentation and follow-up i. Definition: MTM services are documented in a consistent manner, and follow-up MTM visits are scheduled depending on the patient’s medication-related needs or if the patient is transitioning from one care setting to another. ii. Ideally, electronic; alternatively, paper iii. Documentation may include, but is not limited to, the following: (a) Patient demographics (b) Subjective and objective observations, assessment, and plan (SOAP) note format (c) Education (1) Disease state and medication management education (2) Goal setting (d) Collaboration: Communication with other health care professionals, including recommendations and referrals (e) PMR and MAP (f) Follow-up (1) Transition plan (2) Schedule follow-up visit. (g) Billing (1) Time spent on patient care (2) Level of complexity determined by the interventions documented iv. The purpose of proper documentation (a) Facilitate communication between the pharmacist and other health care professionals regarding recommendations to resolve medication-related problems. (b) Should be appropriate for evaluating patient progress and sufficient for billing purposes (c) Improve patient care and outcomes. (d) Enhance continuity of patient care. (e) Ensure compliance with laws and regulations. (f) Protect against professional liability. (g) Justification of reimbursement (h) Demonstrate the value of MTM services. 6. Barriers to and challenges of MTM a. Reimbursement and billing b. Adequate staffing and devoted time in daily workflow c. Lack of access to complete patient information d. Patients’ lack of perceived benefit and interest in MTM services e. State variations in pharmacist’s scope of practice ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 574

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7. Billing for MTM services: See the chapter titled “Managing a Clinical Practice.” 8. Benefits of MTM a. Improved health outcomes, including, but not limited to, a reduction in hemoglobin A1C (A1C), blood pressure, and lipid values b. Reduction in overall health care expenditure c. Improved medication adherence d. Decreased hospitalizations and emergency department (ED) visits e. Accurate and appropriate medication use f. Patient achievement of health-related goals Patient Case 2. According to the CMS criteria, which best describes a targeted patient for MTM services?

A. A patient with asthma and an upper respiratory tract infection who is taking tiotropium, albuterol, budesonide/ formoterol, monetlukast, and azithromycin; his medications cost $3995 per year. B. A patient with diabetes, hypertension, and hyperlipidemia who is taking metformin, lisinopril, and rosuvastatin; his medications cost $3587 per year. C. A patient with diabetes and occasional headaches who is taking acetaminophen, insulin glargine, and insulin lispro; his medications cost $4631 per year. D. A patient with a kidney transplant and diabetes who is taking metformin, tacrolimus, and mycophenolate; his medications cost $5129 per year.

D. Comprehensive Medication Management (CMM) (Domain 3, Task 3, Knowledge a) 1. Developed by Patient-Centered Primary Care Collaborative (PCPCC) Medication Management Task Force to describe the contribution of clinical pharmacists in patient-centered, team-based care (i.e., patient-centered medical homes and accountable care organizations) 2. Definition: The standard of care that ensures each patient’s medications are individually assessed to determine that each medication is appropriate, effective, safe, and able to be taken a. Philosophy of practice i. Meeting a societal need ii. Assuming responsibility of optimizing medication use iii. Embracing a patient-centered approach iv. Caring through an ongoing patient-pharmacist relationship v. Working as a collaborative member of the health care team b. Patient care process (see Pharmacists’ Patient Care Process, section IIIa) c. Practice management system 3. Logistics of providing CMM a. Qualifying patients i. Have medical conditions associated with high-cost and multiple medications; examples of such conditions: (a) Diabetes (b) Cardiovascular disease (c) Chronic obstructive pulmonary disease (d) Asthma, particularly in children (e) Cancer chemotherapy (f) Depression (g) Pain (h) Hypothyroidism ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 575

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ii. iii. iv. v.

Difficulty reaching goals of therapy Experiencing adverse effects from medications Difficulty understanding and following a medication regimen Require monitoring for a high-risk medication, such as the following: (a) Warfarin (b) Phenytoin (c) Methotrexate (d) Insulin vi. Have frequent hospital readmission, which is usually measured as within 30 days of original hospitalization for the same medical reason b. Referrals i. Given to a qualified clinical pharmacist (a) Clinical pharmacist (1) Licensed professional (2) Residency trained or equivalent post-licensure experience (3) Board certified, once meets eligibility criteria (4) Practice in a team-based, direct patient care environment (b) Meet ACCP’s clinical pharmacist competencies in direct patient care, pharmacotherapy knowledge, systems-based care and population health, communication, professionalism, and continuing professional development; https://www.accp.com/docs/positions/guidelines/ Competencies_Saseen_Early%20View.pdf ii. Patients continue to be provided CMM until the goals of therapy are achieved or until the referring practitioner determines that the care is not necessary. c. Visits i. Communication during visits must be bidirectional. ii. Face-to-face iii. Telemedicine or virtual clinic (a) Ensure that both patient and provider have appropriate technology to conduct the visit and exchange all necessary information. (b) Practitioner must have experience with these media. (c) Quality of service is ensured by defining the standards of care and if or how they differ from a face-to-face visit. d. Documentation i. Electronic medical record preferred; paper charting is acceptable but less desirable (a) Patient’s medication experience (b) Medication allergies (c) Medication history, including immunizations (d) Active medication list (e) Active drug therapy problem list, including the cause of the problem (f) Therapeutic treatment plan ii. Facilitates communication between pharmacists and other health care providers iii. Enhances continuity of patient care iv. Protects against professional liability v. Captures services provided for justification of billing and reimbursement vi. Demonstrates clinical, economic, and humanistic outcomes 4. Benefits of CMM a. Solves medication-related problems i. Current electronic systems of dispensing and e-prescribing records often have an incomplete list of the patient’s home medications and omit 40%–50% of the medications taken by a patient. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 576

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ii. These pharmacy records contain idealized prescription information (e.g., how the prescription was written but not how the medication was taken). b. Helps patients achieve their health-related goals c. Prevents ED visits, hospital admissions, and hospital readmissions; studies show a decrease in 30-day readmission rates, effective transitions of care, and medication reconciliation 5. Differences between CMM and MTM a. CMM includes an assessment of the patient’s clinic status or therapeutic response to treatment. b. CMM incorporates an evaluation to assess the patient’s progress toward treatment goals. c. CMM requires collaborations with the health care team. d. CMM has more stipulations to be considered a qualified pharmacist. Patient Cases 3. A 67-year-old woman was referred to the pharmacist by her primary care physician for CMM as part of a patientcentered medical home (PCMH). Which best qualifies this patient for CMM?

A. Recent admission for an upper respiratory tract infection and taking levofloxacin and albuterol. B. Hospitalized 8 months ago for atrial fibrillation with rapid ventricular response, for which she is taking aspirin and metoprolol. C. Hospitalized twice in the past month, once for chest pain and once for symptomatic anemia. D. Having uncontrolled hypertension without any admissions in the past year.

4. The pharmacist is setting up a CMM appointment for a newly referred patient. The patient asks if she has to come into the clinic to talk with the pharmacist. Which most appropriately describes how CMM can be delivered? A. B. C. D.

Face-to-face only Face-to-face and telephonic visit Face-to-face, telephonic, or virtual visit Face-to-face, telephonic, virtual, or written communication

E. Collaborative Drug Therapy Management (Domain 3, Task 1 Knowledge a, b; Domain 3, Task 3, Knowledge a) 1. Description a. The American College of Clinical Pharmacy (ACCP) defines CDTM as “a collaborative practice agreement between one or more physicians and qualified clinical pharmacists who work within the context of a defined protocol that permits the clinical pharmacist to assume responsibility for performing patient assessments; ordering drug therapy-related laboratory tests; administering drugs; and selecting, initiating, monitoring, continuing, and adjusting drug regimens.” b. The partnership with the prescriber permits the pharmacist to function outside the traditional pharmacy practice laws. c. Can be provided in the retail, inpatient, and outpatient settings d. Forty-nine states have legislative provisions for CDTM. e. Each state is required to establish its own laws regarding CDTM; defined in the state’s pharmacy practice act f. State laws outline different requirements for pharmacists engaging in CDTM, depending on the practice setting. States may require the following: i. Pharmacists to have special training or certification ii. Protocols to be approved by the board of pharmacy iii. Pharmacists to carry liability insurance

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 577

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2. Agreements a. The terms collaborative practice agreement and CDTM are often used interchangeably. b. Agreements can also be called protocols, standing orders, collaborative practice agreements, etc. c. The NABP Model State Pharmacy Act and Model Rules outline the process and required elements for agreements but do not define the clinic activities a pharmacist should be given authority to perform. d. Activities under CDTM must be documented in the patient’s medical record and available to the patient’s health care providers. 3. Pharmacist responsibilities under a CDTM agreement may include all or a combination of the following items: a. Initiate, modify, and discontinue drug therapy for an individual patient or group of patients. b. Order and interpret laboratory results. c. Administer medications (including immunizations). d. Collect and review medication history. e. Obtain vital signs. f. Evaluate and provide education regarding medication regimen. g. Perform a physical assessment consistent with disease state and drug therapy. h. Communicate, provide feedback, and report to the physician about the action plan, which can occur in the prescription record, patient profile, separate logbook, or other appropriate system outlined in the written agreement. 4. Common areas of practice for CDTM a. Emergency contraception b. Asthma therapy management c. Immunization administration d. Hypertension therapy management e. Dyslipidemia therapy management f. Warfarin/anticoagulation therapy management g. Diabetes therapy management h. Depression therapy management i. Smoking cessation therapy management j. Flu/antiviral therapy management 5. Key elements to effective CDTM a. Access to the patient’s medical records b. Knowledge, skills, and ability to perform authorized functions c. Documentation in the patient’s medical records d. Accountability for quality measures e. Ability to be reimbursed for drug therapy management f. Committed time and resources 6. Benefits of CDTM a. Patient specific i. Extends the provision of health education, health screening, and medication management to underserved populations where physician access is limited ii. Improves the quality of drug therapy management by decreasing medication-related problems (e.g., adverse drug reactions, drug interactions, poor adherence) by allowing the pharmacist to make immediate therapeutic interventions when necessary iii. Decreases cost through optimal use of medications – Specifically, by discontinuing inappropriate medications and closely monitoring for adverse drug reactions with the aim of decreasing unnecessary physician and hospital visits b. Physician specific i. Reduces clinic visits for patients with chronic conditions, allowing more time for complex case management ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 578

Practices and Processes of Care

ii. Encourages continuity of care by having the pharmacist refer patients to physicians (a) Ensuring that patients are up to date with clinic visits with all established physicians (b) Providing or encouraging referrals to physicians to resolve newly identified medical issues iii. Increases the number of patients achieving pay-for-performance goals c. Pharmacist specific i. Reinforces relationship between pharmacist and physician (a) Recognized by the American College of Physicians, American Society of Internal Medicine, and Infectious Diseases Society of America (b) Each of the listed organizations has issued a statement of support demonstrating the value of CDTM. ii. For pharmacists working in the community setting, it can shift them from product-oriented service to patient-focused practice to improve outcomes. iii. Permits pharmacists to demonstrate value as part of the health care team d. Health plans/managed care organizations i. Decrease high-cost physician visits for medication-related issues ii. Optimize drug therapy management through the pharmacist’s ability to make therapeutic decisions at the time of service, resulting in improved outcomes iii. Encourage more targeted physician referrals Patient Case 5. A pharmacist has created a CDTM plan in agreement with a physician group. Which of the following settings is most likely to produce successful CDTM? A. A pharmacist working in a community pharmacy who has access to the patient’s electronic medical record B. A pharmacist working in the physician group’s clinic who just started and came from industry working with cancer drugs C. A pharmacist working in the hospital who sees patients whenever she isn’t busy checking prescriptions D. A pharmacist working for the college of pharmacy and placed in the general medicine clinic to gain pharmacy notoriety.

III.  PROCESSES OF CARE A. Pharmacists’ Patient Care Process (Domain 1, Task 1, Knowledge b; Domain 1, Task 2, Knowledge a-g; Domain 1, Task 3, Knowledge a-f; Domain 1, Task 4, Knowledge a-e; Domain 1, Task 5, Knowledge a, b, c, e) 1. Created by a workgroup, under the JCPP, to provide a consistent process of care framework for delivering patient care in any practice setting 2. A cyclical model that has the patient at the core 3. For the model to succeed, it must have collaboration, communication, and documentation. a. Engagement and effective communication is supported by the establishment of a patient-pharmacist relationship. b. Pharmacists continually collaborate, document, and communicate with other members of the health care team to deliver safe, effective, and coordinated care. c. The process is strengthened by interoperable information technology systems that enable efficient and effective communication.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 579

Practices and Processes of Care

4. The process contains five main actions a. COLLECT subjective and objective information. i. Current medication list and medication history ii. Health data, such as medical history, biometric tests, etc. iii. Lifestyle preferences/beliefs, health goals, factors that could impair access to medications, etc. b. ASSESS the collected information. i. The medications’ appropriateness, efficacy, safety, and adherence ii. Health/functional status, cultural factors, health literacy, access to medications, etc. iii. Need for preventive care and other services c. In collaboration with other health care providers and the patient, create an evidence-based, cost-effective PLAN. i. Address medication problems and optimize the drug regimen. ii. Create achievable goals to improve patient outcomes. iii. Empower the patient through education and self-management. iv. Ensure continuity of care through follow-up and transitions of care. d. IMPLEMENT the care plan in conjunction with the patient and other health care providers. i. Address patient issues and implement preventive care (i.e., immunizations). ii. Start, change, stop, and administer appropriate medication. iii. Provide education and self-management training. iv. Schedule follow-up as appropriate. e. FOLLOW-UP: MONITOR AND EVALUATE the effectiveness of the treatment plan, and modify it as needed. i. Through health data, test results, and the patient, ensure medication appropriateness, efficacy, safety, and adherence. ii. Evaluate clinical end points and outcomes of care: control of chronic conditions, patient quality of life, reduction in hospitalizations, and preventive care. 5. JCPP is currently working on a standardized documentation format for the pharmacists’ patient care process through health information technology; www.pharmacyhit.org 6. Implementation a. Outreach b. Basic toolkit being developed c. Accreditation Council for Pharmacy Education (ACPE) has incorporated the process into the revised Pharm.D. standards; www.acpe-accredit.org/pdf/Guidance forStandards2016FINAL.pdf d. American Society of Health-System Pharmacists incorporated into pharmacy postgraduate year 1 (PGY1) residency standards e. Being incorporated into the nation’s projects, grant programs, CMS innovations, some MTM services, and several different training programs B. Transitions of Care (Domain 3, Task 1, Knowledge e) 1. Definition a. The National Health Care for the Homeless Council defines care transitions as “the movement of patients between health care locations, providers, or different levels of care within the same location as their conditions and care needs change” which frequently involves multiple persons, including the patient, the family member or other caregiver(s), nurse(s), social worker(s), case manager(s), pharmacist(s), physician(s), and other providers b. Set of actions designed to ensure the coordination and continuity of health care as patients transfer between health care practitioners, settings, or different levels of care within the same organization during an acute or chronic illness (e.g., hospital, long-term care facilities, patient’s home, primary and specialty care offices) ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 580

Practices and Processes of Care

c. Comprehensive plan of care that includes logistic arrangements, education of the patient and family, and coordination among the health care professionals involved in the transition d. Encompasses both the sending and receiving aspects of the transfer 2. Background a. One in five Medicare patients discharged from a hospital is readmitted within 30 days. b. Unplanned rehospitalizations cost Medicare more than $17 billion. c. Half of Medicare patients do not follow up with an outpatient provider within 30 days of hospital discharge. d. About 60% of medication errors arise during transitions of care. e. In 2011, inadequate transitions of care were responsible for $25 billion–$45 billion in wasteful spending. f. Greater than 50% of patients have at least one medication discrepancy on hospital admission; 40% have the potential to cause harm. g. Thirty percent of patients have at least one medication discrepancy with the potential to cause harm. 3. Possible areas of ineffective transitions of care: from Inpatient to outpatient a. Health care providers i. Poor communication between inpatient and outpatient providers ii. Difficulty transmitting medical records secondary to differences in documentation systems; only 12%–37% of hospital discharge summaries are sent to the outpatient physicians before the followup clinical visit iii. Lack of standardized procedures in conducting successful handoffs to providers and discharge instructions to patients iv. Inadequate amount of time to ensure transitions of care have been performed v. Lack of accountability b. Patients i. Not included in planning for transitions ii. Lack understanding about their medical conditions or plan of care iii. Confusing medication regimen iv. Unclear instructions about follow-up care c. Community pharmacies i. Challenges of maintaining an accurate medication list are secondary to patient use of several pharmacies. ii. Pharmacies often located away from medical centers and physician offices iii. Inadequate communication between the community pharmacist and the physician iv. Lack of access to patient’s medical chart 4. CMS Hospital Readmissions Reduction Program (HRRP) a. Implemented in October 2012 b. Provides incentives for hospitals to decrease unnecessary hospital readmissions, defined as an unplanned admission within 30 days of a hospital discharge c. Medical conditions include acute myocardial infarction, heart failure, pneumonia, chronic obstructive pulmonary disease, and elective hip and knee replacement d. Penalties i. Excess readmission ratio for specified medical conditions is a measure of a hospital’s readmission performance compared with the national average for that condition. ii. About half of hospitals in the program will always face a penalty. iii. Overall magnitude of the penalty will remain the same even as hospitals improve. iv. Penalty was initially set at 1%; it was then increased to 2% in 2014 and to 3% in 2015. e. Providers and patients can view readmission ratios on the Medicare Hospital Compare website: www. medicare.gov/hospitalcompare/search.html.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 581

Practices and Processes of Care

5. Role of the pharmacist a. Inpatient setting i. Obtain admission medication history. ii. Complete medication reconciliation at every care level transition. iii. Assess appropriateness of medication regimen. iv. Resolve medication-related problems before transition. v. Educate patient and caregivers about discharge medications. vi. Conduct telephone follow-up calls 24–48 hours after discharge to review medications, identify medication discrepancies, and assist with coordination of care. b. Community setting (ambulatory care clinic or community pharmacy) i. Help patients interpret discharge paperwork. ii. Clarify medication discrepancies between home regimen and new regimen after transition. iii. Create complete medication list. iv. Provide MTM, including a CMR. v. Assist with third-party formulary problems, assist with prior authorizations, and see medication assistance programs for patients without insurance. c. Home i. Live or virtual visit ii. Provide appropriate post-discharge care, including medication reconciliation, medication adherence, monitoring of adverse events, access to medications, medication and disease state management, and communication to health care providers on patient progress and barriers. Table 1. Established Transitions of Care Models Model

Project RED (Re-engineered Discharge)

Care Transitions

Target Population

Adult general medicine patients

Patients with complex care needs who are discharged from the hospital to home

Intervention

Outcomes

Transitions coach teaches self-management for 4 weeks Sets up home visit and three telephone interactions after discharge from the hospital to home Medication self-management Personal health record Follow-up with primary and/or specialty care Support for patient recognition of symptoms necessitating follow-up

There was a statistically significant difference for the adjusted p value in 30 (p=0.04), 90 (p=0.002), and 180 (p=0.02) day readmissions in addition to a reduction in ED or observation unit visits within 90 days (p=0.03) and time to first re-hospitalization (p=0.003)

Nurse discharge advocate sets up follow-up appointments, provides patient education, completes medication reconciliation, and facilitates transmission of discharge summary to clinicians accepting care of the patient Clinical pharmacist conducts telephone follow-up 2–4 days after discharge

Reduced ED visits and hospitalizations within 30 days of discharge in the intervention group: 0.695 relative risk reduction (95% CI, 0.15–0.99)

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 582

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Table 1. Established Transitions of Care Models (continued) Target Population

Model

Transitional Care

Patients 65 years or older hospitalized for medical or surgical reasons and transitioning to another setting

Guided Care

Patients with many chronic conditions

Intervention

Outcomes

Trained registered nurse in the primary care coordinates patient-centered care: Comprehensive assessment Evidence-based care planning Proactive monitoring Care coordination Transitional care Coaching for self-management Caregiver support Access to community-based services Not specific to patients undergoing transitions, but care coordination assists with transitions when they occur

Lower home health services used Higher patient-rated quality of care

Transitional care nurse coordinates by providing 10 essential elements, including the following: Patient-centric, multidisciplinary, collaborative, comprehensive plan of care Home care Post-acute care clinic follow-up visit support

Lower single and multiple readmission rates Greater number of days between discharge and readmission Shorter lengths of stay during readmission Fewer hospital days Longer time to first readmission or death Reduced cost of care Short-term improvements in quality of life and patient satisfaction

CI = confidence interval.

Information from: (1) Jack BW, Chetty VK, Anthony D, et al. A reengineered hospital discharge program to decrease rehospitalization: a randomized trial. Ann Intern Med 2009;150:178-87; (2) Coleman EA, Smith JD, Frank JC, et al. Preparing patients and caregivers to participate in care delivered across settings: the Care Transitions Intervention. J Am Geriatr Soc 2004;52:1817-25; (3) Naylor M, Brooten D, Jones R, et al. Comprehensive discharge planning for the hospitalized elderly: a randomized clinical trial. Ann Intern Med 1994;120:999-1006; (4) Naylor MD, Brooten D, Campbell R, et al. Comprehensive discharge planning and home follow-up of hospitalized elders: a randomized clinical trial. JAMA 1999;281:613-20; (5) Naylor M, McCauley K. The effects of a discharge planning and home follow-up intervention on elders hospitalized with common medical and surgical conditions. J Cardiovasc Nurs 1999;14:44-54; (6) Naylor MD, Brooten DA, Campbell RL, et al. Transitional care of older adults hospitalized with heart failure: a randomized, controlled trial. J Am Geriatr Soc 2004;52:675-84; (7) Boult C, Reider L, Leff B, et al. The effect of guided care teams on the use of health services: results from a cluster-randomized controlled trial. Arch Intern Med 2011;171:460-6; (8) Boult C, Leff B, Boyd CM, et al. A matched-pair cluster-randomized trial of guided care for high-risk older patients. J Gen Intern Med 2013;28:612-21; (9) Boyd CM, Reider L, Frey K, et al. The effects of guided care on the perceived quality of health care for multi-morbid older persons: 18-month outcomes from a cluster-randomized controlled trial. J Gen Intern Med 2010;25:235-42.

6. Quality measures a. Customary metrics include readmissions, length of stay, ED visits, medication-related problems at medication reconciliation, and patient satisfaction. b. Cost-savings analysis to determine potential economic benefit c. Process indicators i. Percentage of patients who have a completed medication history within 24 hours of admission ii. Percentage of home medication lists reconciled on admission iii. Frequency of pharmacist-physician communication regarding medication discrepancies with respect to admission orders from the total number of home medications

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 583

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iv. The Physician Consortium for Performance Improvement approved a care transitions performance measurement set from the inpatient to the outpatient setting. (a) Measure 1: Reconciled medication list received by discharged patients (b) Measure 2: Timely transmission of transition record (transition record should be transmitted to the facility or primary physician or other health care professionals designated for follow-up care within 24 hours of discharge) Table 2. Metrics to Evaluate Transitions of Care Performance Measure

The Joint Commission – National Patient Safety Goal 03.06.01

Description

Obtain and document current medication information when patients are admitted to the hospital or seen in an outpatient setting Compare the patient-provided medication information with the medications ordered for the patient to identify and resolve discrepancies Provide the patient with written instructions on how to take medications when discharged from the hospital or at the end of an outpatient encounter, including name, dose, route, frequency, and purpose Explain to patients the importance of managing medication information when discharged from the hospital or at the end of an outpatient encounter

Hospital Consumer Assessment of CTM-3 Patient Questions Healthcare Providers and Systems The hospital staff took my preferences and those of my family or caregiver into Survey account in deciding what my health care needs would be when I left the hospital When I left the hospital, I had a good understanding of the things I was responsible for in managing my health When I left the hospital, I clearly understood the purpose for taking each of my medications Physician Consortium for Performance Improvement Quality Measures

Centers for Medicare & Medicaid Services Hospital Readmission Reduction Program National Committee for Quality Assurance Healthcare Effectiveness Data and Information Set – Plan All-Cause Readmissions

Care Transitions Performance Measurement Set Percentage of patients discharged from an inpatient facility to home or any other site who received a reconciled medication list and transition record Percentage of patients for whom a transition record was transmitted within 24 hours of discharge to a facility/health care professional responsible for follow-up care Percentage of patients discharged from the ED to ambulatory care or home health care who received a transition record on ED discharge Readmission rates for acute myocardial infarction, heart failure, pneumonia, chronic obstructive pulmonary disease, and elective hip or knee replacement surgery The percentage of discharges over one year for which medications were reconciled from the date of discharge through 30 days after discharge (total of 31 days)

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Table 2. Metrics to Evaluate Transitions of Care Performance (continued) Measure

National Committee for Quality Assurance Healthcare Effectiveness Data and Information Set – Medication Reconciliation Measure

Description

Percentage of hospital discharges during the measurement year for patients 66 years and older for whom medications were reconciled in the outpatient medical record within 30 days of discharge

CTM-3 = three-item care transition measure.

Information from: (1) The Joint Commission. 2017. National Patient Safety Goals Effective January 1, 2017: Hospital Accreditation Program. Available at https://www. jointcommission.org/assets/1/6/NPSG_Chapter_AHC_Jan2017.pdf. Accessed November 22, 2016; (2) National Quality Forum (NQF). Care Transitions Measure Tools: The CTM-3. Available at http://caretransitions.org/wp-content/uploads/2015/08/CTM-3.pdf. Accessed November 22, 2016; (3) Physician Consortium for Performance Improvement (PCPI). PCPI-Stewarded Measures. Available at http://www.thepcpi.org/programs-initiatives/measurement-science/measure-directory/pcpi-stewardedmeasures/. Accessed November 22, 2016; (4) Centers for Medicare & Medicaid Services (CMS). Readmissions Reduction Program (HRRP). Available at https://www. cms.gov/medicare/medicare-fee-for-service-payment/acuteinpatientpps/readmissions-reduction-program.html. Accessed November 22, 2016; (5) Agency for Healthcare Quality and Research (AHRQ). National Quality Measures Clearinghouse, October 2015. Available at https://www.qualitymeasures.ahrq.gov/summaries/summary/49833. Accessed November 22, 2016; (6) Agency for Healthcare Quality and Research (AHRQ). National Quality Measures Clearinghouse, November 2014. Available at https:// www.qualitymeasures.ahrq.gov/summaries/summary/48847/medication-reconciliation-postdischarge-percentage-of-discharges-from-january-1-to-december-1-of-themeasurement-year-for-patients-66-years-of-age-and-older-for-whom-medications-were-reconciled-on-or-within-30-days-of-discharge?q=medication+reconciliation+mea sure. Accessed November 22, 2016.

7. Methods to improve transitions of care a. Multidisciplinary communication, collaboration, and coordination i. A care team that includes a physician, pharmacist, nurse, social worker, and others begins at admission and continues until the patient is discharged home, to ensure successful transitions. ii. Include patient/caregiver education. iii. At every point during the transition, a responsible coordinating clinician (e.g., a primary care physician or nurse practitioner) is identified by the patient to ensure thorough communication and follow-up. b. Patient-centered process focusing on patient safety c. Shared accountability by sender and receiver d. Comprehensive planning and risk assessment throughout the hospital stay i. Discharge planning begins immediately after admission. ii. During the hospital stay, patients are assessed for risk factors that may limit their ability to perform necessary aspects of self-care, including low literacy, several hospital admissions, and several chronic conditions or medications. e. Standardized transition plans, procedures, and forms i. The following components are included in a written transition plan or discharge summary: active issues, diagnosis, medications, required services, warning signs of a worsening condition, whom to contact in an emergency. ii. The transition plan should be communicated to the outpatient provider. f. Timely follow-up, support, and coordination after the patient leaves a care setting g. Standardized training of health care providers h. Data to justify resources i. Requires a process of continuous quality improvement 8. Medication reconciliation (Domain 3, Task 1, Knowledge d) a. Definitions i. According to the Agency for Healthcare Research and Quality (AHRQ): “The process of avoiding inadvertent medication discrepancies by reviewing a patient’s current medication regimen and comparing it with the regimen being considered for the new setting of care” ii. According to TJC: “Compares medications a patient should be using (and is actually using) with the new medications that are ordered” ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 585

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b. Goal: Decrease medication errors and patient harm c. Accreditation standards i. TJC National Patient Safety Goal 03.06.01 ii. NCQA Healthcare Effectiveness Data and Information Set Medication Reconciliation PostDischarge measure (a) Reconciling the most recent medication list in the outpatient medical record. (b) Measures the percentage of discharges for members for whom medications were reconciled by a prescribing practitioner, clinical pharmacist, or registered nurse on or within 30 days of discharge (c) Includes only Medicare special-needs patients 66 years and older d. Effectiveness of medication reconciliation poorly studied i. Hospital-based medication reconciliation (Arch Intern Med 2012;172:1057-69) (a) Studies have shown a reduction in medication discrepancies, potential adverse drug events, and adverse drug events. (b) Inconsistent reduction in post-discharge health care use (only two of eight studies showed improvement) (c) Successful interventions (1) Intensive pharmacy staff involvement (2) Targeting high-risk patients (3) Studies are needed to determine the most effective interventions. ii. Medication reconciliation in primary care (Ann Pharmacother 2009;43:1667-75) (a) Pharmacist medication review at hospital discharge showed no benefit. (b) Medication reconciliation at each ambulatory care visit revealed mixed results. (c) No good evidence showing the effectiveness of medication reconciliation in the primary care setting (d) Improving medication list accuracy alone may not improve clinical status or prevent adverse drug events; may also need to provide CMM e. Patients are the common factor involved in medication reconciliation between settings of care. i. Patients need to be empowered to be more active participants. ii. Health literacy is defined as “the degree to which individuals can obtain, process, and understand the basic health information and services they need to make appropriate health decisions.” (a) Inadequate or marginal health literacy has been found in 60% of hospitalized medical patients. (b) Within 48 hours of hospital discharge, 56% of elderly patients had a medication discrepancy between the discharge instructions medication list and the patient’s actual home medication use. (c) Teach-back method can be used to explain information to patients and caregivers. (1) Used to make sure patients understand what you have just taught (2) Ask patients in a caring way to show or explain in their own words what they need to know or do. (3) Avoid simply asking patients if they understand. (4) Use open-ended questions instead of closed-ended questions that can be answered with “yes” or “no.” (5) Provides opportunity to re-explain in a different way if misunderstood iii. Even if health care providers were able to reliably access all prescription records, there would still be a need to discern how patients are actually taking their medications. iv. Emphasize the need for patients to maintain an accurate medication list and the importance of sharing the list with all health care providers in all settings.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 586

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f. Electronic Health Information Exchange, including prescription data from community pharmacies and patient-interfacing health information technology tools, could improve the accuracy and efficiency of obtaining accurate medication histories. i. Pharmacy prescription records identified 41.5% more prescribed medications than medication histories obtained in the ED (J Am Med Inform Assoc 2014;21:391-8). ii. Factors contributing to omissions from the ED medication list (a) Patients who filled prescriptions at more than one pharmacy (b) Patients who took more than 12 medications iii. Secure messaging within a patient web portal may assist with medication reconciliation after an inpatient-to-outpatient care transition and identify medication discrepancies and potential adverse drug events (J Am Med Inform Assoc 2014;21:e157-62). iv. Creating a business case of electronic solutions (Academy of Managed Care Pharmacy 2014) (a) Electronic efficiency (b) Readmission penalties (c) HCAHPS (Hospital Consumer Assessment of Healthcare Providers and Systems) incentives (d) Duplicative efforts by several health care providers (e) Payer costs for readmissions g. Multi-Center Medication Reconciliation Quality Improvement Study (MARQUIS) Toolkit i. A study funded by the Agency for Healthcare Research and Quality ii. Goal is to develop better ways for medication to be prescribed, documented and reconciled correctly and safely during transitions of care at hospital admission and discharge iii. Toolkit materials (a) The MARQUIS Medication Implementation Manual: A Guide for Medication Reconciliation Quality Improvement (b) Training videos illustrating strategies for taking a medication history and providing discharge medication counseling (c) A return-on-investment calculator for medication reconciliation quality improvement investments (d) http://www.hospitalmedicine.org/Web/Quality___Innovation/Implementation_Toolkit/ MARQUIS/Med_Rec_Resources_Medication_Reconciliation.aspx 9. Challenges in implementing transitions of care/barriers in implementing transitional care a. Financial resources b. Staffing resources c. Electronic transfer of patient information and data partner groups d. Difficulty developing a partnership with inpatient and outpatient providers 10. Reimbursement by Medicare transitional care management codes a. For specifics on billing, see the chapter titled “Managing a Clinical Practice.” b. The following health care professionals may furnish transitional care management services: i. Physicians (any specialty) ii. The following nonphysician practitioners are legally authorized and qualified to provide the services in the state in which they are furnished: certified nurse-midwives, clinical nurse specialists, nurse practitioners, and physician assistants. iii. Any health care provider, including pharmacists, can furnish the 2-day post-discharge communication.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 587

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Patient Cases 6. Which would be the best quality measure for evaluating a transition of care service from the inpatient to the outpatient setting? A. B. C. D.

The number of patients adherent to their medications 1 year after discharge. The number of patients who had medication reconciliation within 30 days after discharge. The number of patients who are knowledgeable about their medications 6 months after discharge. The number of patients who have a medication error during hospitalization.

7. G.H. is an older adult with chronic medical conditions who takes 14 prescription medications. She has had several hospital and ED admissions this year, and she receives care from a family physician, cardiologist, nephrologist, and endocrinologist. The medication regimen for treatment of heart failure and diabetes is regularly adjusted by several providers in many settings. Which strategy is most likely to maintain the accuracy of the medication list for this patient? A. Provide pharmacist-led medication reconciliation in the primary care clinic after each hospital discharge. B. Evaluate the patient’s electronic medical record for all medication changes the providers wanted to take place. C. Contact all pharmacies that have filled prescriptions for the patient each time she is seen in the primary care clinic. D. Educate her on how to keep an up-to-date medication list and to share it with all health care providers.

C. Patient Assistance (Domain 1, Task 2, Knowledge b) 1. Lowering patients’ prescription drug costs a. Switch to generic or other lower-cost drugs. b. Use pharmacies’ discounted drug formularies or coupon cards (i.e., GoodRx). c. Pharmaceutical manufacturer assistance programs i. Not all manufacturers offer assistance programs. ii. Qualifications vary by program. iii. Program information and applications can be obtained by calling pharmaceutical manufacturers or searching the Internet. iv. Typical application requirements (a) Proof of income (b) Valid prescription signed by prescriber (c) Patient information (d) Prescriber information (e) Financial information (f) Insurance information (g) Completed application with patient attestation and signature v. Medicare offers a pharmaceutical assistance program website with information for Medicare beneficiaries about pharmaceutical manufacturer assistance programs (www.medicare.gov/ pharmaceutical-assistance-program). vi. Assistance from pharmaceutical manufacturer assistance programs will not count toward Medicare Part D TrOOP costs. d. State pharmaceutical assistance programs i. State-administered programs that help Medicare recipients with limited income and resources afford prescription drugs

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 588

Practices and Processes of Care

ii. Currently offered by 21 states and the U.S. Virgin Islands; www.medicare.gov/pharmaceuticalassistance-program/state-programs.aspx iii. Some programs require patients to join a specific plan or may even enroll patients. iv. Most state pharmaceutical assistance programs work with Part D plans. (a) Pay for drugs not covered by a plan (b) Provide discounts on prescriptions (c) Offer certain medications for a low, fixed copayment v. Always the payer of last resort vi. Assistance provided by some of these programs may count toward Medicare Part D TrOOP costs. e. Medicare Part D Low-Income Subsidy (also known as Extra Help) for assistance with prescription drug plan costs i. Estimated to be worth $4000 per year ii. Qualifications (a) Medicare recipient (b) Reside in one of the 50 states or the District of Columbia (c) Annual income limited to $17,655 for an individual ($23,895 for a married couple living together) (d) Total resources must be limited to $13,640 for an individual ($27,250 for a married couple living together). Resources include the value of the things the patient owns. (1) Real estate (other than primary residence) (2) Bank accounts, including checking, savings, and certificates of deposit (3) Stocks (4) Bonds, including U.S. savings bonds (5) Mutual funds (6) Individual retirement accounts (7) Cash iii. Can be applied/reapplied any time if income status or resources change iv. Some patients automatically qualify for the Extra Help subsidy. (a) Have full Medicaid coverage (b) Get help from a state Medicaid program paying the patient’s Part B premiums (c) Receive supplemental security income benefits v. Patients are notified each October if there is a change in their Extra Help copayments. f. National and local charitable groups i. National Patient Advocate Foundation; www.npaf.org ii. National Organization for Rare Disorders; www.rarediseases.org iii. National Council on Aging; www.benefitscheckup.org iv. Assistance provided by some of these programs may count toward Medicare Part D TrOOP costs. 2. 340B drug pricing program a. Background i. Created by the U.S. federal government in 1992; section 340B of the Public Health Service Act of 1992 ii. Requires drug manufacturers participating in the Medicaid Drug Rebate Program to sign a pharmaceutical pricing agreement with the Secretary of Health and Human Services, which limits the price manufacturers can charge certain covered entities for outpatient drugs iii. Administered by the Office of Pharmacy Affairs, which falls under the Healthcare Systems Bureau within the Health Resources and Services Administration (HRSA) (a) Enrollment, recertification, compliance (b) Must recertify annually, attesting to compliance with all requirements

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 589

Practices and Processes of Care

b. Purpose: Enables covered entities to stretch scarce federal resources as far as possible by expanding the services and volume of care provided to the most vulnerable patient populations c. Covered entities (CE) – entities must recertify their eligibility yearly and notify the Office of Pharmacy Affairs whenever there is a change in eligibility. i. Federally qualified health center or look-alikes ii. Ryan White grantees iii. State AIDS drug assistance programs iv. Medicare/Medicaid disproportionate share hospitals v. Children’s hospitals vi. Critical access hospitals vii. Freestanding cancer hospitals viii. Rural referral centers ix. Sole community hospitals x. Black-lung clinics xi. Comprehensive hemophilia diagnostic treatment centers xii. Title X family planning clinics xiii. Sexually transmitted disease clinics xiv. Tuberculosis clinics xv. Native Hawaiian health centers xvi. Tribal/urban Native American health centers d. Pharmacies i. Not considered a CE ii. A CE can contract with a pharmacy to provide comprehensive pharmacy services to 340B-eligible patients. iii. Contract pharmacies dispense discounted drugs purchased under the 340B program by the CE to eligible patients. iv. The contracted pharmacy collects the reimbursement from the payers and shares with the CE. e. Patient eligibility i. The CE is responsible for the patient’s health care (i.e., the patient has a medical record number). ii. Care is provided and maintained from a health care provider while working in a 340B-eligible outpatient clinic. iii. Prescription originated from a provider while working in a 340B-eligible outpatient clinic or is a discharge prescription from a CE hospital. iv. The patient does not have a Medicaid or Medicaid managed care plan; this eliminates a duplicate discount, up-front 340B discount, and back-end Medicaid rebate. v. Prescriptions are for outpatient medications. f. Eligible drugs i. FDA-approved prescription drugs ii. Over-the-counter drugs written on a prescription iii. Biological products dispensed only by a prescription (other than vaccines) iv. FDA-approved insulin v. Orphan drugs used for non-orphan conditions to cancer hospitals, critical access hospitals, rural referral centers, and lone community hospitals g. Anti-diversion i. Diversion occurs if 340B drugs are used for ineligible patients. ii. Auditing by HRSA (a) Began in fiscal year 2012 (b) Risk-based audits (c) Targeted audits ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 590

Practices and Processes of Care

(d) HRSA released “Mega Guidance” for review; proposed guidance to the 340B program iii. Diversion can have severe penalties, including large fines and revocation of the 340B drug pricing program. Patient Case 8. Your pharmacy is contracted to dispense 340B medications. You have a patient who presents a prescription from a physician who you know works for the covered entity your pharmacy is contracted with; however, the prescription is written on a prescription pad from a different facility. Which best describes how the prescription should be processed? A. Using 340B medications because the physician works for the covered entity. B. Using non-340B medications because the physician did not write the prescription while working at the covered entity. C. Using 340B medications because the patient receives some of her care at the covered entity. D. Using non-340B medications because the patient’s insurance is a Medicare Part D plan.

IV.  SPECIAL ISSUES IN PHARMACY PRACTICE A. Medication Safety (Domain 3, Task 1, Knowledge d; Domain 3, Task 1, Knowledge b) 1. Definitions a. Errors: Failures of planned actions to be completed as intended or the use of incorrect plans to achieve aims b. Medication errors: Any errors occurring in the medication use process c. Close calls: Errors that occurred but did not reach the patient d. Adverse events: An event resulting in unintended harm to the patient by an act of commission or omission rather than by the underlying disease or condition of the patient e. Adverse drug events: Injuries caused by medications f. Preventable adverse drug events: Considered medication errors g. Non preventable adverse drug events: Considered adverse drug reactions 2. Medication errors a. Medication errors are the most common type of medical error. b. Error of commission i. Doing something wrong ii. Example: Ordering a medication for a patient who has a documented allergy to that medication c. Error of omission i. Failing to do the right thing ii. Is considered to reach the patient (i.e., not a close call) iii. Example: Failing to order venous thromboembolism prophylaxis for a patient after hip replacement surgery

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 591

Practices and Processes of Care

Procurement

Monitoring

Prescribing

Administration

Transcribing

Dispensing

Order Entry

Preparation

Figure 1. Steps of the medication use process during which errors can occur. 3. Adverse drug events, error reporting, and detection a. Safety reporting is very uncommon in ambulatory care. b. Reporting must be easy and efficient, yet it must provide useful data. c. Internal voluntary reporting i. Traditional efforts to detect adverse events have focused on voluntary reporting and tracking of errors. ii. Only 10%–20% of errors are ever reported. (a) Complex reporting process (b) Culture of fear (c) Culture of risk tolerance (d) Concern of liability (e) Perception reporting is not a priority iii. Most hospitals and large health systems have a confidential error reporting system for front-line staff. iv. Ideally, internal reports are conveyed externally into a larger data pool for broader analysis. d. External voluntary reporting i. MedWatch: The FDA Safety Information and Adverse Event Reporting Program (a) Voluntarily report product problems or unexpected adverse effects (b) Anyone may report – Online (https://www.accessdata.fda.gov/scripts/medwatch/index. cfm?action=professional.reporting1), mail, telephone, fax (c) Why to report (1) Not all products have clinical data/trials before clearance to market. (2) Clinical trials have limitations in identifying safety signals before marketing. (3) Number of patients studied may be too small to detect rare, serious problems. (4) Trials are brief. (d) Events to report (1) Fatal (2) Life threatening (3) Permanent harm or disability

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 592

Practices and Processes of Care

(4) Require or prolong hospitalization (5) Birth defect (6) Intervention required to prevent permanent damage or impairment ii. Vaccine Adverse Event Reporting System (VAERS); http://vaers.hhs.gov (a) National Vaccine Safety Surveillance Program (b) Report non preventable adverse reactions to a vaccine product (c) Cosponsored by the CDC and the FDA (d) Online, fax, mail iii. Institute for Safe Medication Practices (ISMP) (a) 501(c)(3) nonprofit organization; founded in 1994 (b) Federally certified patient safety organization (PSO) – Provides legal protection and confidentiality for data and error reports (c) Newsletters: ISMP Medication Safety Alert!; https://www.ismp.org/newsletters/ (1) Community/ambulatory care edition (2) Acute care edition (d) Mission: to advance patient safety worldwide by empowering the health care community, including consumers, to prevent medication errors (e) ISMP Medication Errors Reporting Program (MERP); https://www.ismp.org/report-medicationerror (f) ISMP Vaccine Error Reporting Program (VERP) (1) http://verp.ismp.org/ (2) Information confidentially forwarded to the VAERS, the manufacturer, or both (g) All reports sent to ISMP are sent to the FDA; however, not always the other way around. (1) There is a memorandum of understanding (MOU) between the FDA and ISMP. (2) They develop some educational materials together. Patient Case 9. A community pharmacist overrode a serious drug-drug interaction computer alert involving warfarin; subsequently, the patient developed a stroke with permanent functional impairment because of the drug interaction. To support process improvements in the pharmacy, which would be the most appropriate reporting system to use? A. B. C. D.

FDA MedWatch The pharmacy’s internal voluntary reporting system ISMP reporting program FDA Vaccine Adverse Event Reporting System

e. Methods for detecting adverse drug events i. International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnosis codes obtained through administrative data query (a) Adverse drug events are not reliably or consistently coded. (b) Health care providers may not recognize a medical problem as being an adverse drug event. ii. Global Trigger Tool for Measuring Adverse Events (a) Developed by the Institute for Healthcare Improvement (IHI): www.ihi.org/resources/pages/ ihiwhitepapers/ihiglobaltriggertoolwhitepaper.aspx (b) Various versions have been developed: Danish, German, Swedish, United Kingdom (c) Use of “triggers” or clues to identify adverse events (1) Orders for certain drugs (2) Orders for antidotes such as naloxone or vitamin K ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 593

Practices and Processes of Care

(3) Laboratory values such as elevated serum drug concentrations (4) Abrupt medication stop orders (d) Method for measuring the overall level of harm in a health care organization (e) Triggers may be identified using computer programs designed for health information systems. (f) Almost real-time identification of potential adverse events provides an opportunity to reduce the effect on patients. (g) Includes retrospective detailed chart review of patient records to determine whether an adverse event actually occurred; recommends doing a sampling of patients (h) Not intended to identify every single adverse event in a patient record (i) According to one study, the use of the Global Trigger Tool for Measuring Adverse Drug Events increased the rate of adverse drug event detection about 50 times more than traditional reporting methods (Qual Saf Health Care 2003;12:194-200). iii. Examples of outcome measures (a) Adverse events per 1000 patient-days (b) Adverse events per 100 admissions or office visits (c) Percentage of admissions or office visits with an adverse event iv. Other available IHI trigger tools (a) Trigger Tool for Measuring Adverse Drug Events in a Mental Health Setting (b) Trigger Tool for Measuring Adverse Drug Events in the Nursing Home (c) Surgical Trigger Tool for Measuring Perioperative Adverse Events (d) Intensive Care Unit Adverse Event Trigger Tool (e) Pediatric Trigger Toolkit: Measuring Adverse Drug Events in the Children’s Hospital (f) Perinatal Trigger Tool (g) Trigger Tool for Measuring Adverse Events in the Neonatal Intensive Care Unit (h) Outpatient Adverse Event Trigger Tool v. Text searching in electronic medical record notes to find key words indicative of adverse events vi. Methods involving chart review can introduce variability among reviewers. f. Analysis of trends i. A small percentage of errors that occur are voluntarily reported. ii. Need to be careful about using voluntarily reported data as measures of improvement given that reporting rates may change because of factors such as work volume, culture of safety (i.e., fear of repercussions or blame), and reporting system functionality changes. iii. If voluntary reports involving a certain medication error type decrease, it may be that employees are too busy to report or they are fearful of retaliation or “looking bad” for reporting problems. iv. If voluntary reports of a certain medication error type increase, there is not necessarily a new problem; reports may increase because of an augmented focus by the organization or department on a particular error type or on safety reporting in general. 4. Error prevention and management a. Failure modes and effects analysis i. Prospectively identifies the risk of error in a process to prevent harm ii. Process mapping to identify all the steps in a process iii. Identifies the ways each step can go wrong (i.e., the failure modes) iv. Determines the probability that each error will be detected (i.e., so that it can be corrected before causing harm) v. Estimates of the likelihood of a process failure, the chance of detecting such a failure, and its impact are combined numerically to produce a criticality index. vi. The criticality index assists in prioritizing targets for improvement.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 594

Practices and Processes of Care

b. Systematic assessment for error prevention i. Monitor actual and potential medication errors and adverse events. ii. Learn from errors that have occurred, and make continual improvements. c. Root cause analysis i. Structured retrospective method used to analyze serious adverse events ii. Identifies underlying problems that increase the likelihood of errors while avoiding focusing on mistakes made by individuals iii. Goal of root cause analysis is to identify the following: (a) Active errors – Occur at the point of interface between people and systems (b) Latent errors – Hidden problems within health care systems that contribute to adverse events iv. Keys to success (a) Quality of information reported (b) Analysis of available information (c) Subsequent actions taken to improve the system and prevent future patient harm d. Suggested readings i. AHRQ PSNet glossary; https://www.psnet.ahrq.gov/issue/psnet-glossary ii. Failure Modes and Effects Analysis tool; www.ihi.org/resources/Pages/Tools/FailureModes andEffectsAnalysisTool.aspx 5. Examples of strategies to reduce/prevent medication errors a. Avoiding error-prone abbreviations; www.Ismp.org/tools/errorproneabbreviations.pdf b. Tall-man lettering i. Look-alike, sound-alike drug names contribute to errors. ii. Drug names can be modified using mixed-case letters to draw attention to the parts of the drug names that are dissimilar. iii. Highlighting sections of drug names using tall man letters can make medication mix-ups less likely. iv. Promoted by ISMP, FDA, The Joint Commission, and other safety-conscious organizations v. Use supported by the literature vi. Examples of look-alike drug pairs and recommended tall-man lettering ((https://www.ismp.org/ resources/special-edition-tall-man-lettering-ismp-updates-its-list-drug-names-tall-man-letters): (a) BusPIRone and buPROPion (b) ChlorproMAZINE and chlorproPAMIDE (c) glyBURIDE and glipiZIDE c. High-alert medications in community/ambulatory health care; https://www.ismp.org/recommendations/ high-alert-medications-community-ambulatory-list i. Drugs with an increased risk of harm if an error occurs ii. Does not imply errors involving these drugs are more common iii. Special safeguards may include the following: (a) Mandatory patient counseling (b) Improve access to information concerning the drugs. (c) Auxiliary labels and automated alerts (d) Independent double-checks (e) Standardizing the medication use process iv. High-alert drug classes and specific drugs (a) Antiretroviral agents (b) Oral chemotherapeutic agents (excluding hormonal agents) (c) Oral hypoglycemic agents (d) Immunosuppressant agents (e) Insulin

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 595

Practices and Processes of Care

(f) Opioids (g) Pediatric liquid medications that require measurement (h) Pregnancy category X drugs (i) carBAMazepine (j) Chloral hydrate liquid, for sedation of children (k) Unfractionated heparin and low-molecular-weight heparin (l) metFORMIN (m) Methotrexate, non-oncologic use (n) Midazolam liquid, for sedation of children (o) Propylthiouracil (p) Warfarin d. Clinical decision support (CDS) tools in the electronic medical record and pharmacy system may reduce medication errors. i. Designed to deliver knowledge and patient-specific information ii. Intended to improve the quality of health care iii. Include patient safety alerts and reminders (e.g., drug interaction, drug allergies, dose checking) iv. Alert fatigue may result when alerts are too common and excessive. This may lead to alerts being indiscriminately overridden, defeating their purpose. v. If override rates are high, alerts need to be refined to improve their focus and relevance and reduce alert fatigue. vi. Rate of medication-related CDS alert overrides in the outpatient setting at the time of prescribing is 52.6% (J Am Med Inform Assoc 2014;21:487-91). (a) Most common alerts: Duplicate drug (33.1%), patient allergy (16.8%), drug-drug interactions (15.8%) (b) Alerts most likely to be overridden: Formulary substitutions (85.0%), age-based recommendations (79.0%), renal recommendations (78.0%), and patient allergies (77.4%) (c) On average, 53% of overrides are classified as appropriate. 6. Safety culture a. Safety culture is “the set of beliefs, norms, attitudes, roles, and social and technical practices that are concerned with minimizing the exposure of employees, managers, customers and members of the public to conditions considered dangerous or injurious” (Turner 1989). b. Properties of safety culture i. Leadership ii. Teamwork iii. Communication iv. Patient-centeredness v. Evidence based vi. Just culture vii. Learning and improvement viii. Reporting culture c. Just culture is “a culture of trust where people are encouraged for providing essential safety-related information, but in which they are also clear about where the line must be drawn between acceptable and unacceptable behavior” (Reason 1997). i. Promotes a questioning attitude ii. Resistant to complacency iii. Committed to excellence iv. Nurtures personal accountability v. Promotes corporate self-regulation in safety

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 596

Practices and Processes of Care

d. Tools to evaluate safety culture and practices i. ISMP Medication Safety Self-Assessment for Community/Ambulatory Pharmacy, Hospital, Medical Office, and Nursing Home ii. AHRQ Surveys on Patient Safety Culture iii. Safety Attitudes Questionnaire (SAQ) 7. FDA a. The FDA is an agency within the U.S. Department of Health and Human Services concerned with protecting the public health. Table 3. Functions of the FDA

Regulates tobacco products

Ensures the safety, effectiveness, and quality of the following: Human prescription and nonprescription drugs Vaccines, blood products, and biologics Food Dietary supplements

Veterinary drugs Medical devices Cosmetics Products that emit radiation

b. Recalls are actions taken to remove a product from the market. i. May be initiated by the manufacturer, FDA request, or FDA order under statutory authority ii. How the FDA gains awareness of problems (a) Manufacturer contacts the FDA (b) Manufacturing facility inspections (c) Reporting systems (d) CDC Table 4. Classification of FDA Drug Recalls or Market Withdrawal Type

Description

Class I recall

Reasonable probability that exposure to product will cause serious adverse health consequences or death

Class II recall

When exposure to product may cause temporary or medically reversible adverse health consequences or when the probability of serious adverse health consequences is remote

Class III recall

Unclassified recall

Market withdrawal

Exposure to product is not likely to cause adverse health consequences

A pilot program expedites notices of drug recalls that are still in the process of being classified Product has a minor violation that would not be subject to FDA legal action (e.g., product may be removed from the market because of tampering)

iii. Finding recall information (a) When the public must be alerted to serious hazards, the FDA uses press conferences, press releases, and updates to www.fda.gov. (b) FDA Enforcement Reports include all recalls monitored by the FDA; www.fda.gov/Safety/ Recalls/EnforcementReports/ucm181313.htm (c) Sign up to receive e-mail alerts. (d) Not all recalls are announced by the media.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 597

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c. Medication guides i. The FDA determines which drugs/biologics pose a serious and significant public health concern. ii. Requires the distribution of FDA-approved patient medication information that is necessary to ensure patients’ safe and effective use of these drugs and biologics iii. May be a requirement of Risk Evaluation and Mitigation Strategies (REMS) d. REMS i. The Food and Drug Amendments Act of 2007 gave the FDA the authority to require REMS from manufacturers to ensure that the benefits of a drug/biologic outweigh the risks. ii. REMS may include the following: (a) Medication guides (b) Communication plan (c) Elements to ensure safe use, which may include the following: (1) Patient registry (2) Prescriber training, experience, or special certification (3) Patient monitoring (4) Dispensing to patients only in certain health care settings (5) Special certification for pharmacies, practitioners, or health care settings that dispense the drug (d) Implementation system (1) May be required by the FDA (2) Manufacturer may be expected to take steps to monitor, evaluate, and improve implementation by parties in the health care system responsible for implementing the REMS elements. e. Drug safety communications i. Early communication about an ongoing safety review (a) Communicates early with the public when still evaluating data and a conclusion has not been reached (b) Informs about issues under review and anticipated completion ii. Information for Healthcare Professionals (a) Also known as Healthcare Professional Information Sheet (b) The alert summarizes new safety information. (1) Detailed information about the safety issue (2) Factors to consider when making a treatment decision (3) Information for health care professionals to discuss with patients about reducing the risks related to the drug (4) Summary of the facts or data f. Medical device safety alerts are issued when a medical device may present an unreasonable risk of substantial harm; recalls can occur. g. Boxed warnings emphasize significant and serious safety data for prescription drugs. h. Drug shortages i. Primary reasons for drug shortages (a) Quality/manufacturing issues (b) Manufacturer production and raw materials supplier delays (c) Discontinuations ii. Manufacturers are required to report information about shortages on the FDA website that includes the following: (a) Reasons for shortages (b) Expected duration of shortages

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 598

Practices and Processes of Care

iii. Early notification from manufacturers of any issue that could lead to a shortage is critical to preventing or mitigating drug shortages. iv. The FDA Safety and Innovation Act of 2012 enhanced the FDA’s authority regarding drug shortages. (a) Broadened the scope of early notification requirement by demanding that all manufacturers notify the FDA of potential discontinuances (prior law applied only to sole manufacturers) (b) Manufacturers are required to report discontinuations, regardless of whether they are permanent or temporary. (c) May require mandatory reporting of shortages of biologic products (prior law excluded biologics) (d) Notification requirement applies to drugs that are used in emergency medical care or during surgery if intended for use in preventing a debilitating condition. (e) The FDA issues noncompliance letters to manufacturers who fail to comply with the drug shortage notification requirements and makes the letter and the company’s response to the letter available to the public. v. Current and Resolved Drug Shortages and Discontinuations Reported to FDA Database; www. accessdata.fda.gov/scripts/drugshortages/default.cfm i. Compounding i. Title I of the Drug Quality and Security Act, the Compounding Quality Act, removes some provisions from section 503A of the federal Food, Drug, and Cosmetic Act (FDCA) ii. Under 503B, a new section of the FDCA, a compounder can become an “outsourcing facility.” iii. Outsourcing facilities (a) Must comply with current good manufacturing practice requirements (b) Will be able to qualify for exemptions from the following: (1) FDA approval requirements (2) Requirement to label products with adequate directions for use (c) Will be inspected by the FDA according to a risk-based schedule (d) Must report adverse events (e) Provide FDA with information about the products they compound (1) List of all products compounded during the previous 6 months (2) Source of ingredients used to compound iv. State boards of pharmacy have overseen and regulated traditional pharmacy compounding. 8. Agency for Healthcare Research and Quality (AHRQ) a. Lead federal agency for patient safety research b. Offers several patient safety tools and resources; www.ahrq.gov/professionals/quality-patient-safety/ index.html. Surveys on patient safety culture: i. Hospital ii. Medical office iii. Nursing home iv. Pharmacy v. Comparative databases exist for all surveys, except for the pharmacy survey because it is relatively new. c. Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) i. Set of tools to train clinicians in teamwork and communication skills ii. Reduces patient safety risks d. Patient Safety Network is a web-based source for news and resources on patient safety. e. Pharmacy Health Literacy Center; www.ahrq.gov/professionals/quality-patient-safety/pharmhealthlit/ index.html i. Health literacy educational resource for pharmacy personnel

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 599

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ii. Assessment tool to evaluate how prepared pharmacies are to care for patients with limited health literacy 9. Patient safety organizations a. Authorized by the Patient Safety and Quality Improvement Act of 2005 to improve the safety and quality of health care delivery in the United States b. Congress vested authority with AHRQ for implementing the Patient Safety Act. c. Patient safety organizations must meet the criteria established in the Patient Safety Rule. d. Goals i. Encourage health care providers and organizations to voluntarily report safety events without fear of legal discovery ii. Provide secure environment to identify and reduce risks iii. Aggregate and analyze patient safety events locally, regionally, and nationally iv. Gain insights into causes of patient safety events 10. National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) a. Founded by the U.S. Pharmacopeial (USP) Convention in 1995 b. Twenty-seven national organization members c. Promotes reporting, discussion, and communication about safe medication use, medication errors, errorprone processes, and error prevention strategies d. Strategies: Medication error reporting, understanding, and prevention e. Established a standard taxonomy of medication errors and allow the information to be disseminated to peers through its newsletter based on the level of harm f. Harm is impairment of the physical, emotional, or psychological function or structure of the body and/ or pain. Table 5. Categorizing Medication Errors Category A B C D E F G H I

Description

Circumstances or events that have the capacity to cause error

An error occurred, but the error did not reach the patient (an “error of omission” does reach the patient) An error occurred that reached the patient but did not cause patient harm

An error occurred that reached the patient and required monitoring to confirm that it resulted in no harm to the patient and/or required intervention to preclude harm

An error occurred that may have contributed to or resulted in temporary harm to the patient and required intervention An error occurred that may have contributed to or resulted in temporary harm to the patient and required initial or prolonged hospitalization An error occurred that may have contributed to or resulted in permanent patient harm An error occurred that required intervention necessary to sustain life

An error occurred that may have contributed to or resulted in the patient’s death

Adapted from: National Coordinating Council for Medication Error Reporting and Prevention. 2001. NCC MERP Index for Categorizing Medication Errors. Available at http://www.nccmerp.org/sites/default/files/indexBW2001-06-12.pdf. Accessed November 11, 2016.

11. Other organizations that improve patient safety a. Centers for Medicare & Medicaid Services (CMS) i. Hospital Readmissions Reduction Program – Provides incentives for hospitals to decrease unnecessary hospital readmissions (within 30 days of a discharge)

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 600

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ii. Medicare Star Rating System includes quality, safety, and satisfaction measures for Medicare Part C and Part D plans. iii. Overutilization Monitoring System (a) Ensures that Part D sponsors have established reasonable and appropriate drug use management programs to prevent overuse of opioid drugs and acetaminophen-containing prescribed medications (b) Quarterly reports provided to Part D sponsors identifying beneficiaries with potential overuse issues identified through Medicare Part D Prescription Drug Event data (c) Plans are expected to do the following: (1) Develop target criteria to identify beneficiaries who should receive case management (2) Investigate beneficiaries’ potential overuse issues (3) Submit and track responses to CMS regarding overuse issues (4) Monitor progress in reviewing and addressing overuse issues over time iv. Performance and quality measures are used by CMS so that Medicare beneficiaries have the information necessary to make informed enrollment decisions by comparing available health and prescription drug plans. They also provide measures of quality across Part D sponsors. (a) CMS calculates and publicizes eight other patient safety measures. (b) Monthly reports calculated using Medicare Part D Prescription Drug Event data provided to Part D plans (c) Measures allow prescription drug plans (PDPs) or Medicare Advantage Prescription Drug Plans (MA-PDs) to compare performance with overall averages and monitor progress over time. Table 6. CMS Patient Safety Reports Measure

Description

The percentage of Medicare beneficiaries 65 years and older who received two or more fills of at least one drug with a high risk of serious adverse effects in the older adult

High-risk medicationa

The percentage of Medicare Part D beneficiaries 18 years and older dispensed a medication for diabetes and for hypertension whose treatment included an RAS antagonist medication (angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, or direct renin inhibitors)

Diabetes treatmenta

The percentage of Medicare Part D beneficiaries who received a prescription for a target medication during the measurement period and who were dispensed a prescription for a contraindicated medication with or after the initial prescription

Drug-drug interactionb

The percentage of Medicare Part D beneficiaries who were dispensed a dose higher than the daily recommended dose for the following diabetes treatment therapeutic categories of oral hypoglycemic: biguanides, sulfonylureas, thiazolidinediones, and dipeptidyl peptidase–IV inhibitors

Diabetes medication dosageb

The percentage of Medicare Part D beneficiaries 18 years and older who adhere to their prescribed biguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase–IV inhibitors, incretin mimetics, meglitinides, and sodium glucose cotransporter 2 inhibitors

Diabetes medicationsa Hypertension

a

The percentage of Medicare Part D beneficiaries 18 years and older who adhere to their prescribed RAS antagonist medications (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or direct renin inhibitors)

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 601

Practices and Processes of Care

Table 6. CMS Patient Safety Reports (continued) Measure

Description

The percentage of Medicare Part D beneficiaries 18 years and older who adhere to their prescribed statin medications

Cholesterola

The percentage of Medicare Part D beneficiaries 18 years and older who adhere to their prescribed antiretroviral medications

HIV/AIDS

Measure contributes to a plan’s Part D star rating; available at the Medicare Plan Finder at www.medicare.gov.

a

b

Part of the Part D Display Measures. Available at www.cms.gov/Medicare/Prescription-Drug-Coverage/PrescriptionDrugCovGenIn/PerformanceData.html.

IV = intravenous; RAS = renin-angiotensin system.

Adapted from: (1) Acumen, LLC. Patient Safety Analysis: High Risk Medication Measures PDP/MA-PD Contracts Report User Guide. April 2014; (2) Acumen, LLC. Patient Safety Analysis: Diabetes Treatment Measures PDP/MA-PD Contracts Report User Guide. July 2014; (3) Acumen, LLC. Patient Safety Analysis: Drug-Drug Interaction Measures PDP/MA-PD Contracts Report User Guide. April 2014; (4) Acumen, LLC. Patient Safety Analysis: Diabetes Medication Dosing Measures PDP/ MA-PD Contracts Report User Guide. April 2014.

b. Hospital accrediting organizations i. TJC National Patient Safety Goals include medication reconciliation standards for several settings (e.g., hospitals, ambulatory care, home care, long-term care). ii. Healthcare Facilities Accreditation Program iii. Det Norske Veritas Healthcare, Inc. c. NCQA i. Managed care organization accrediting body ii. Healthcare Effectiveness Data and Information Set is the quality, safety, and service measurement data set used to measure performance. d. National Patient Safety Foundation (NPSF) pursues improvement of the safety of care provided to patients. e. National Quality Forum (NQF) reviews, endorses, and recommends use of standardized health care performance measures. f. Pharmacy Quality Alliance (PQA) promotes appropriate medication use and develops strategies for measuring and reporting performance. Patient Cases 10. You are a clinical pharmacist in the community setting. Which resource would best prevent adverse drug events from occurring in your patient population? A. Monitor the FDA safety communications to identify safety concerns, and collaborate with community physicians to ensure appropriate prescribing. B. Submit error reports through the ISMP website. C. Sign up to receive recall notices from the FDA, and establish a standardized response to class III recalls. D. Use a standard taxonomy of medication errors based on the level of harm within your pharmacy’s confidential reporting system.

11. You are a clinical pharmacist who provides CMM in a primary care clinic that uses an electronic medical record. You would like to determine the most common medication errors in your practice setting and design an intervention to reduce those errors. Which would best measure the success of your intervention? A. B. C. D.

Track voluntarily reported medication errors. Monitor the use of diagnosis codes signifying preventable adverse drug events. Use a trigger tool to measure medication errors per 100 office visits. Survey patients on the adverse effects they experience.

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B. Formulary Management and Pharmacy and Therapeutics Committees (Domain 1, Task 2, Knowledge a; Domain 3, Task 1, Knowledge d) 1. Formulary management is defined by the Academy of Managed Care Pharmacy as “an integrated patient care process which enables physicians, pharmacists and other health care professionals to work together to promote clinically sound, cost-effective medication therapy and positive therapeutic outcomes.” 2. Pharmacy and therapeutics (P&T) committees a. Usually oversee all aspects of drug therapy in an institution or organization b. Pharmacists and physicians collaborate. c. Influence cost-effective prescribing, and affect clinical outcomes d. Adverse drug reaction and medication error monitoring e. Quality assurance f. Policy and procedure approval g. Traditionally associated with institutional pharmacy h. Other organizations have P&T committees. i. Managed care organizations ii. Insurance companies iii. Pharmacy benefit management companies iv. Unions and employers v. State Medicaid boards vi. State departments of public institutions vii. Medicare viii. Long-term care facilities ix. Ambulatory clinics x. Community pharmacies 3. Drug formularies a. Formulary committees deal strictly with determining which drugs are carried within an institution or organization. b. A drug formulary contains a list of drugs that are available under that formulary system. i. Also called preferred medication lists or preferred drug lists ii. A drug formulary is published as a hardcopy book, in electronic format, or both. iii. Reflects the clinical judgment of the medical staff after a global evaluation of the drug iv. Listed alphabetically and/or by therapeutic class (usually American Hospital Formulary Service classification) v. Contains information on the dosage forms, strengths, names (e.g., generic, trade, and chemical), and ingredients vi. May include indications, adverse effects, dosing, use restrictions c. Increasingly formulary committees are evaluating both clinical and financial impacts to determine value. i. Safety ii. Efficaciousness iii. Cost-effectiveness iv. Other considerations (a) Variety of dosage forms available for the medication (b) Estimated volume of use (c) Convenience (d) Dosing schedule (e) Adherence (f) Abuse potential (g) Physician demand

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(h) Ease of preparation (i) Storage requirements d. Usually, only two or three drugs from any class are added to avoid therapeutic redundancy. e. Including only one agent per class is probably too restrictive to accommodate intolerances and responsiveness to medications. f. Drugs or drug classes must be objectively assessed according to scientific information, preferably from clinical studies. g. If objective data are lacking, a committee may make a decision and schedule a product for a follow-up review. i. Additional prescribing and patient use data may be available. ii. Clinical trial data may be available. 4. Conflict of interest a. Decision-makers for a drug’s formulary status may have a conflict of interest by receiving direct or indirect compensation from including a drug on the formulary. i. Stock in a company ii. Honoraria for speaking iii. Consulting fees iv. Gifts or grants from a company b. P&T committees are responsible for identifying and addressing conflict-of-interest issues in the decisionmaking process. c. Ways to avoid bias i. Conflict-of-interest policy, requiring regular disclosure of any possible conflicts ii. Regular voting P&T committee members may have to abstain from the vote if they disclose a possible conflict of interest. iii. Committee may vote to decide whether a conflict is significant enough to prevent voting by the individual. 5. Ambulatory drug formulary copayment structures a. Pharmacy benefit managers, together with their health plan clients, place formulary and nonformulary medications into tiers. b. Encourage the use of the most clinically appropriate, cost-effective drug while maintaining quality of care c. The tier copayment structure developed in response to the rising drug costs i. Tier 1 (a) Usually generic drug products (b) Lowest copayment ii. Tier 2 (a) Preferred brand-name drugs (b) Higher copayment because of the added cost of the brand-name drug iii. Tier 3 (a) Usually reserved for nonpreferred brand-name drugs (b) Copayment is significantly higher. (c) Copayments may be calculated as a proportion of the drug cost or require paying for the entire drug cost. iv. Specialty tier (a) Highest copayment or coinsurance (b) Specific, very high-cost prescription drugs 6. Other formulary management activities a. Used to ensure that certain drugs are used correctly and only when medically necessary

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b. Prior authorizations i. Before the drug will be covered by a plan, the prescriber must contact the plan to show the medical necessity for that particular drug. ii. Step therapy is a type of prior authorization in which patients must first try and fail less expensive drugs before a certain medication will be covered. (a) Less expensive alternative was not effective. (b) Less expensive alternative was not tolerated because of adverse effects. c. Quantity limitations may be instituted for safety and cost reasons. i. Appropriate therapy duration for an indication may be proved. ii. Longer treatment courses may not be more effective or may pose more risk than benefit. d. Generic substitutions can be required when a drug entity is available as an approved generic. e. An exception can be requested if a prescriber believes a patient has a medical necessity to be treated with a medication that is not on the formulary. i. Exceptions may be requested under several circumstances. (a) Prescriber believes a patient requires a drug that is not on the formulary. (b) Prescriber believes a coverage rule (such as step therapy) should be waived. (c) Patient believes the copayment for a nonpreferred drug should be lower because the preferred formulary drugs are not effective or tolerated. ii. Prescriber must provide a supporting statement that explains the medical reason for the request, including why a covered medication is not appropriate for the patient. 7. Preventive medications and services covered by private health plans under the Affordable Care Act a. Non-grandfathered group health plans and health insurance coverage offered in the individual or group market are required to cover preventive services without patient cost sharing (e.g., copayment, coinsurance), even if the annual deductible has not been met. b. In general, these services must be delivered by a network provider to be covered. c. These requirements do not apply to grandfathered health plans. d. Covered preventive services are based on the following: i. Evidence-based items or services that have a rating of “A” or “B” in the current recommendations of the U.S. Preventive Services Task Force (USPSTF) ii. Recommendations from the Advisory Committee on Immunization Practices (ACIP) of the CDC in children, adolescents, and adults iii. Evidence-informed preventive care and screenings included in the guidelines supported by HRSA for infants, children, adolescents, and women (if not already included in the current recommendations of the USPSTF) iv. www.uspreventiveservicestaskforce.org/Page/Name/uspstf-a-and-b-recommendations/ e. Immunization vaccines for adults and children can be found at www.healthcare.gov/coverage/preventivecare-benefits/.

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Patient Case 12. Which scenario represents the most appropriate application of formulary management activities?

A. A physician successfully justifies a formulary exception for oxycodone controlled release with the statement, “Patient prefers oxycodone controlled release because she has always tolerated it.” B. A drug plan implements a quantity limit on hydrocodone 5 mg/acetaminophen 325 mg tablets in an effort to prevent patients from taking more than 4 g of acetaminophen per day. C. A physician submits a step therapy prior authorization for a brand-name long-acting oral narcotic to treat a patient’s diabetic neuropathic pain because the physician believes it will work better than the covered options on the patient’s formulary. D. The P&T committee includes only one drug per therapeutic class to contain costs.

Practice Points • There are several practice models with distinct differences. • No matter which practice model pharmacists use, their scope of practice is only as robust as their state’s pharmacy practice act. • It is important to recognize all the resources available to ensure a patient safely receives appropriate medication at an affordable cost. • Proactive reporting and identification of adverse drug events can help prevent future risk. • Pharmacists can play a critical role in the transition of care process.

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REFERENCES Scopes of Practice 1. Council on Credentialing in Pharmacy; Albanese NP, Rouse MJ. Scope of contemporary pharmacy practice: roles, responsibilities, and functions of pharmacists and pharmacy technicians. J Am Pharm Assoc 2010;50:e35-69. 2. Maine LL, Knapp KK, Scheckelhoff DJ. Pharmacists and technicians can enhance patient care even more once national policies, practices and priorities are aligned. Health Aff 2013;32:1956-62. 3. NABP Boards of Pharmacy. Available at www.nabp. net/boards-of-pharmacy/. Accessed May 30, 2017. 4. National Association of Boards of Pharmacy. Model State Pharmacy Act and Model Rules of the National Association of Boards of Pharmacy. 2016;e1-206. Available at https://nabp.pharmacy/ publications-reports/resource-documents/modelpharmacy-act-rules/. Accessed May 30, 2017.

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Medication Management Services 1. JCPP Medication Management Services Definition and Key Points. Available at https://jcpp.net/wp-content/ uploads/2018/05/Medication-Management-ServicesDefinition-and-Key-Points-Version-1.pdf. Accessed September 10, 2018.

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Pharmaceutical Care 1. American Society of Hospital Pharmacists (ASHP). ASHP statement on pharmaceutical care. Am J Hosp Pharm 1993;50:1720-3. 2. Hepler CD, Strand LM. Opportunities and responsibilities in pharmaceutical care. Am J Hosp Pharm 1990;47:533-43. 3. Principles of Practice of Pharmaceutical Care. Available at www.pharmacist.com/principles-practicepharmaceutical-care. Accessed May 30, 2017.

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com/sites/default/files/files/mtm_2011_digest.pdf. Accessed May 30, 2017. American Pharmacists Association and National Association of Chain Drug Stores Foundation. Medication Therapy Management in Pharmacy Practice: Core Elements of an MTM Service Model, Version 2.0. Available at www.pharmacist.com/sites/ default/files/files/core_elements_of_an_mtm_practice.pdf. Accessed May 30, 2017. Bluml BM. Definition of medication therapy management: development of professionwide consensus. J Am Pharm Assoc 2005;45:566-72. Centers for Medicare & Medicaid Services (CMS). CY 2022 Medication Therapy Management Program Guidance and Submission Instructions. Available at https://www.cms.gov/files/document/ memo-contract-year-2022-medication-therapymanagement-mtm-program-submission-v-043021. pdf. Accessed August 13, 2021. Ludvigson N. Medication Therapy Management Contribution to Improved Outcomes and Cost Savings in Health Care. Available at www.drugstorenews. com /ar ticle/medication-therapy-managementcontribution-improved-outcomes-and-cost-savingshealth-care. Accessed May 30, 2017. Pellegrino AN, Martin MT, Tilton JJ, et al. Medication therapy management services: definitions and outcomes. Drugs 2009;69:393-406. Ramalho de Oliveira D, Brummel AR, Miller D, et al. Medication therapy management: 10 years of experience in a large integrated health care system. J Manag Care Pharm 2010;16:185-95.

Comprehensive Medication Management 1. American College of Clinical Pharmacy (ACCP). Comprehensive Medication Management in TeamBased Care. Available at www.accp.com/docs/ positions/misc/CMM%20Brief.pdf. Accessed August 17, 2021. 2. American College of Clinical Pharmacy (ACCP). ACCP Guideline: Standards of Practice for Clinical Pharmacists. Available at https://www.accp.com/ docs/positions/guidelines/StndrsPracClinPharm_ Pharmaco8-14.pdf. Accessed September 5, 2017. 3. Integrating Comprehensive Medication Management to Optimize Patient Outcomes. PCPCC Resource Guide, 2nd ed. June 2012. Available at www.pcpcc.

Medication Therapy Management 1. American Pharmacists Association (APhA). Medication Therapy Management Digest: Perspectives on 2009: A Year of Changing Opportunities. Available at www.pharmacist.com/sites/default/files/files/ mtm_2010_digest_2.pdf. Accessed May 30, 2017. 2. American Pharmacists Association (APhA). Medication Therapy Management Digest: Tracking the Expansion of MTM in 2010: Exploring the Consumer Perspective. Available at www.pharmacist.

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org/sites/default/files/media/medmanagement.pdf. Accessed May 12, 2017. 4. McBane SE, Dopp AL, Abe A, et al. ACCP white paper: collaborative drug therapy management and comprehensive medication management—2015. Pharmacotherapy. 2015;35:e39-50. Available at https://www.accp.com/docs/positions/whitePapers/ CDTM%20CMM%202015%20Final.pdf. Accessed November 23, 2020. 5. McInnis TA, Webb CE. Comprehensive Medication Management in the Patient-Centered Medical Home – Is It Critical for Success? Medical Home News. April 2010. 6. Patient-Centered Medical Home Medication Management Tool Box. Available at www.impactedu.net/pcmh/pdf/Patient-Centered%20Medical%20 Home%20Medication%20Management%20Toolbox. pdf. Accessed May 30, 2017. 7. Pestka DL, Frail CK, Sorge LA, et al. Development of the comprehensive medication management practice management assessment tool: a resource to assess and prioritize areas for practice improvement. J Am Coll Clin Pharm 2020;3:448-54. Available at https://accpjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/ jac5.1182. Accessed August 17, 2021. 8. Pestka DL, Sorge LA, McClurg MR, et al. The philosophy of practice for comprehensive medication management: evaluating its meaning and application by practitioners. Pharmacotherapy 2018;38:69-79. Available at https://https://accpjournals.onlinelibrary. wiley.com/doi/epdf/10.1002/phar.2062. Accessed August 17, 2021. 9. Rosenthal TC. The medical home: growing evidence to support a new approach to primary care. J Am Board Fam Med 2008;21:427-40. 10. Saseen JJ, Bondi D, Burke JM, et al. ACCP guideline: ACCP clinical pharmacist competencies. Pharmacotherapy 2017;36:630-6.

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gov/dhdsp/pubs/docs/translational_tools_providers. pdf. Accessed September 5, 2017. Hammond RW, Schwartz AH, Campbell MJ, et al. Collaborative drug therapy management by pharmacists—2003. Pharmacotherapy 2003;23:1210-25. Kuo GM, Buckley TE, Fitzsimmons DS, et al. Collaborative drug therapy management services and reimbursement in a family medicine clinic. Am J Health Syst Pharm 2004;61:343-54. McBane SE, Dopp AL, Abe A, et al. ACCP white paper: collaborative drug therapy management and comprehensive medication management—2015. Pharmacotherapy. 2015;35:e39-50. Available at https://www.accp.com/docs/positions/whitePapers/ CDTM%20CMM%202015%20Final.pdf. Accessed November 23, 2020. National Association of Boards of Pharmacy. Model State Pharmacy Act and Model Rules of the National Association of Boards of Pharmacy. 2016;e1-206. Available at https://nabp.pharmacy/ publications-reports/resource-documents/modelpharmacy-act-rules/. Accessed May 30, 2017. Practice Advisory on Collaborative Drug Therapy Management. Academy of Managed Care Pharmacy. February 2012. Available at https://www.amcp.org/ sites/default/files/2019-03/Practice%20Advisory%20 on%20CDTM%202.2012_0.pdf. Accessed November 23, 2020.

Pharmacists’ Patient Care Process 1. Joint Commission of Pharmacy Practitioners. The Pharmacists’ Patient Care Process. Available at http://jcpp.net/patient-care-process/. Accessed May 12, 2017. Transitions of Care 1. Agency for Healthcare Research and Quality (AHRQ). National Quality Measures Clearinghouse. October 2015. Available at www.qualitymeasures. ahrq.gov/summaries/summary/49742. Accessed May 12, 2017. 2. Physician Consortium for Performance Improvement (PCPI). PCPI-Stewarded Measures. Available at https://www.thepcpi.org/page/PCPIStewarded-Measures?&hhsearchterms=%22pcpistewarded+and+measures%22. Accessed November 23, 2020.

Collaborative Drug Therapy Management 1. Adam AJ, Weaver KK. The continuum of pharmacist prescriptive authority. Ann Pharmacother 2016;50:778-84. Available at https://journals.sagepub. com/doi/pdf/10.1177/1060028016653608. Accessed November 24, 2020. 2. Centers for Disease Control and Prevention (CDC). Collaborative Practice Agreements and Pharmacists’ Patient Care Services. Available at https://www.cdc.

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12. Coleman E, Boult C; on behalf of the American Geriatrics Society Health Care Systems Committee. Improving the quality of transitional care for persons with complex care needs. J Am Geriatr Soc 2003;51:556-7. 13. Coleman EA, Smith JD, Frank JC, et al. Preparing patients and caregivers to participate in care delivered across settings: the Care Transitions Intervention. J Am Geriatr Soc 2004;52:1817-25. 14. Cornish PL et al. Arch Med 2005; 165:424-9. 15. Hume A, Kirwin J, Bieber H, et al. Improving care transitions: current practice and future opportunities for pharmacists. Pharmacotherapy 2012;32:326-37. 16. Jack BW, Chetty VK, Anthony D, et al. A reengineered hospital discharge program to decrease rehospitalization: a randomized trial. Ann Intern Med 2009;150:178-87. 17. Kirwin J, Canales A, Bentley H, et al. Process indicators of quality clinical pharmacy services during transitions of care. Pharmacotherapy 2012;3:338-47. 18. Kripalani S, LeFevre F, Phillips CO, et al. Deficits in communication and information transfer between hospital-based and primary care physicians. JAMA 2007;297:831-41. 19. Kwan Y et al. Arch Intern Med 2007;167:1034-40. 20. National Health Care for the Homeless Council. October 2012. Improving Care Transitions for People Experiencing Homelessness. Available at https:// nhchc.org/webinars/care-transitions-for-patientsexperiencing-homelessness/. Accessed November 23, 2020. 21. National Quality Forum (NQF). Safe Practices for Better Healthcare–2009 Update: A Consensus Report. Washington, DC: NQF, 2009. 22. Naylor MD, Brooten D, Campbell R, et al. Comprehensive discharge planning and home followup of hospitalized elders: a randomized clinical trial. JAMA 1999;281:613-20. 23. Naylor M, Brooten D, Jones R, et al. Comprehensive discharge planning for the hospitalized elderly: a randomized clinical trial. Ann Intern Med 1994;120:999-1006. 24. Naylor MD, Brooten DA, Campbell RL, et al. Transitional care of older adults hospitalized with heart failure: a randomized, controlled trial. J Am Geriatr Soc 2004;52:675-84. 25. Naylor M, McCauley K. The effects of a discharge planning and home follow-up intervention on elders

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American Society of Health-System Pharmacists and American Pharmacists Association. ASHPAPhA Medication Management in Care Transitions Initiative Best Practices. Available at https:// www.ashp.org/-/media/assets/pharmacy-practice/ resource-centers/quality-improvement/learn-aboutquality-improvement-medication-management-caretransitions.ashx. Accessed September 1, 2020. 4. Boult C, Leff B, Boyd CM, et al. A matched-pair cluster-randomized trial of guided care for high-risk older patients. J Gen Intern Med 2013;28:612-21. 5. Boult C, Reider L, Leff B, et al. The effect of guided care teams on the use of health services: results from a cluster-randomized controlled trial. Arch Intern Med 2011;171:460-6. 6. Boyd CM, Reider L, Frey K, et al. The effects of guided care on the perceived quality of health care for multi-morbid older persons: 18-month outcomes from a cluster-randomized controlled trial. J Gen Intern Med 2010;25:235-42. 7. Care Transitions Measure (CTM) Specifications. Available at http://caretransitions.org/wp-content/ uploads/2015/08/CTM3Specs0807.pdf. Accessed May 30, 2017. 8. Centers for Medicare & Medicaid Services (CMS). Evaluation and Management Services guide. Available at https://www.cms.gov/Outreach-and-Education/ Medicare-Learning-Network-MLN/MLNProducts/ Downloads/eval-mgmt-serv-guide-ICN006764.pdf. Accessed November 23, 2020. 9. Centers for Medicare & Medicaid Services (CMS). April 18, 2016. Readmissions Reduction Program. Available at www.cms.gov/medicare/medicarefe e -for-s e r v ic e -pay m ent /a cut ei npat ient p ps / readmissions-reduction-program.html. Accessed May 30, 2017. 10. Centers for Medicare & Medicaid Services (CMS). Transitional Care Management Services. Available at www.cms.gov/Outreach-and-Education/ Medicare-Learning-Network-MLN/MLNProducts/ Dow n loads/ Tra nsit iona l- Ca re -Ma nagementServices-Fact-Sheet-ICN908628.pdf. Accessed May 30, 2017. 11. Clark K, Doyle J, Duco S, et al. Hot Topics in Health Care: Transitions of Care. Joint Commission Resources. Available at www.jointcommission.org/ assets/1/18/Hot_Topics_Transitions_of_Care.pdf. Accessed May 30, 2017.

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Patient Assistance 1. Centers for Medicare & Medicaid Services (CMS). December 2018. 4 Ways to Help Lower Your Medicare Prescription Drug Costs. Available at www.medicare.gov/Pubs/pdf/114174-Ways-Lower-Prescription-Costs.pdf. Accessed August 4, 2019. 2. Health Resources and Services Administration (HRSA). 340B Drug Pricing Program. Available at www.hrsa.gov/opa/. Accessed May 30, 2017. 3. Social Security Administration. 2017. Understanding the Extra Help with Your Medicare Prescription Drug Plan. Available at www.socialsecurity.gov/ pubs/EN-05-10508.pdf. Accessed May 30, 2017.

hospitalized with common medical and surgical conditions. J Cardiovasc Nurs 1999;14:44-54. 26. Wittkowsky AK. Impact of target-specific oral anticoagulants on transitions of care and outpatient care models. J Thromb Thrombolysis. 2013;35:304-11. Medication Reconciliation 1. Academy of Managed Care Pharmacy. Report of the 2013 AMCP Partnership Forum on electronic solutions to medication reconciliation and improving transitions of care. J Manag Care Pharm 2014;20:937-47. 2. Agency for Healthcare Research and Quality (AHRQ). Multi-Center Medication Reconciliation Quality Improvement Study (MARQUIS) Toolkit. Available at www.innovations.ahrq.gov/ qualitytools/multi-center-medication-reconciliation-quality-improvement-study-marquis-toolkit. Accessed January 4, 2019. 3. Bayoumi I, Howard M, Holbrook AM, et al. Interventions to improve medication reconciliation in primary care. Ann Pharmacother 2009;43:1667-75. 4. Heyworth L, Paquin AM, Clark J, et al. Engaging patients in medication reconciliation via a patient portal following hospital discharge. J Am Med Inform Assoc 2014;21:e157-62. 5. Lindquist LA, Go L, Fleisher J, et al. Relationship of health literacy to intentional and unintentional nonadherence of hospital discharge medications. J Gen Intern Med 2012;27:173-8. 6. Morris NS, Grant S, Repp A, et al. Prevalence of limited health literacy and compensatory strategies used by hospitalized patients. Nurs Res 2011;60:361-6. 7. Mueller SK, Sponsler KC, Kripalani S, et al. Hospitalbased medication reconciliation practices: a systematic review. Arch Intern Med 2012;172:1057-69. 8. Ratzan SC, Parker RM. Introduction. In: Selden CR, Zorn M, Ratzan SC, et al., eds. National Library of Medicine current bibliographies in medicine: health literacy. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2000:v-vi. 9. Tamblyn R, Poissant L, Huang A, et al. Estimating the information gap between emergency department records of community medication compared to on-line access to the community-based pharmacy records. J Am Med Inform Assoc 2014;21:391-8.

Medication Safety 1. Bates DW, Boyle DL, Vander Vliet MB, et al. Relationship between medication errors and adverse events. J Gen Intern Med 1995;10:199-205. 2. Classen DC, Resar R, Griffin F, et al. “Global trigger tool” shows that adverse events in hospitals may be ten times greater than previously measured. Health Aff 2011;30:581-9. 3. Cohen, Michael. “Medication Safety: We’ve Made Great Strides but We still Have A Long Way to Go.” University of Illinois College of Pharmacy Preceptor Conference. Chicago, IL. 19 May 2016. Conference Presentation. 4. Institute for Safe Medication Practices (ISMP). 2011. FDA and ISMP Lists of Look-Alike Drug Names with Recommended Tall Man Letters. Available at www.ismp.org/tools/tallmanletters.pdf. Accessed May 30, 2017. 5. Institute for Safe Medication Practices (ISMP). 2015. ISMP’s List of Error-Prone Abbreviations, Symbols, and Dose Designations. Available at www.ismp.org/ tools/errorproneabbreviations.pdf. Accessed May 30, 2017. 6. Institute of Medicine (IOM). Patient Safety: Achieving a New Standard for Care. Washington, DC: National Academy Press, 2004. 7. Institute of Medicine (IOM). To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press, 2000. 8. ISMP. 2011. List of High-Alert Medications in Community/Ambulatory Healthcare. Available at https://www.ismp.org/recommendations/high-alertmedications-community-ambulatory-list. Accessed November 23, 2020.

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Formulary Management and Pharmacy and Therapeutics Committees 1. ASHP Guidelines on the Pharmacy and Therapeutics Committee and the Formulary System. Available at http://www.ajhp.org/content/65/13/1272. Accessed September 14, 2018. 2. Centers for Medicare & Medicaid Services (CMS). January 2021. Medicare and Medicaid Programs; Contract Year 2022 Policy and Technical Changes to the Medicare Advantage Program, Medicare Prescription Drug Benefit Program, Medicaid Program, Medicare Cost Plan Program, and Programs of All-Inclusive Care for the Elderly. Available at https://www.govinfo.gov/content/pkg/FR-2021-01-19/ pdf/2021-00538.pdf. Accessed November 4, 2021. 3. Kaiser Family Foundation. August 4, 2015. Preventive Services Covered by Private Health Plans under the Affordable Care Act. Available at http://kff.org/health-reform/fact-sheet/preventiveservices-covered-by-private-health-plans/. Accessed May 30, 2017.

ISMP.org [homepage on the Internet]. Horsham, PA: Institute for Safe Medication Practices. Available at www.ismp.org/guidelines. Accessed January 17, 2019. Nanji KC, Slight SP, Seger DL, et al. Overrides of medication-related clinical decision support alerts in outpatients. J Am Med Inform Assoc 2014;21:487-91. National Coordinating Council for Medication Error Reporting and Prevention. 2001. NCC MERP Index for Categorizing Medication Errors. Available at https://www.nccmerp.org/sites/default/ files/indexBW2001-06-12.pdf. Accessed November 23, 2020. Reason J. Managing the Risks of Organizational Accidents. Hants, UK: Ashgate Publishing, 1997. Rozich JD, Haraden CR, Resar RK. Adverse drug event trigger tool: a practical methodology for measuring medication related harm. Qual Saf Health Care 2003;12:194-200. Turner BA, Pidgeon N, Blockley D, et al. Safety Culture: Its Importance in Future Risk Management. Position Paper for the Second World Bank Workshop on Safety Control and Risk Management; 1989; Karlstad, Sweden. U.S. Food and Drug Administration (FDA). Compounding Quality Act: Title I of the Drug Quality and Security Act of 2013. January 1, 2017. Available at https://www.fda.gov/drugs/humandrug-compounding/text-compounding-quality-act. Accessed November 13, 2020. U.S. Food and Drug Administration (FDA). FDA Implementation of the Compounding Quality Act. March 3, 2016. Available at www.fda.gov/Drugs/ GuidanceComplianceRegulator yInfor mation / PharmacyCompounding/ucm375804.htm. Accessed May 30, 2017. U.S. Food and Drug Administration (FDA). Recalls Background and Definitions. Available at https:// www.fda.gov/safety/industry-guidance-recalls/recallsbackground-and-definitions#:~:text=Class%20III%20 recall%3A%20a%20situation,market%20or%20corrects%20the%20violation. Accessed November 25, 2020. U.S. Food and Drug Administration (FDA). Risk Evaluation and Mitigation Strategies REMS. Available at https://www.fda.gov/drugs/drug-safety-and-availability/risk-evaluation-and-mitigation-strategies-rems. Accessed August 17, 2021.

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ANSWERS AND EXPLANATIONS TO PATIENT CASES 5. Answer: A CDTM can be practiced anywhere regardless of place of service. However, the most successful practice will have access to the patient’s medical records, knowledge, skills and ability to perform authorized functions, documents in the medical records, accountability for quality measures, ability to be reimbursed for drug therapy management, and committed time and resources. Answer B is incorrect because the pharmacists currently may not have the knowledge or potentially the skills because they just came from a setting that did not require clinic management of patients and their knowledge surrounded a particular disease state. Answer C is incorrect because the pharmacist does not have devoted time. Answer D is incorrect because not being considered part of the general medicine clinic may limit the pharmacist’s ability to bill for services. Answer A is the best answer because they have access to the patient’s medical records.

1. Answer: C The pharmacist should involve the patient’s physician and other health care providers when necessary. Alerting the referring physician of the patient to the appointment does not alter or assist in a patient’s drug plan, making Answer A incorrect. Calling the patient in 1 week just to see if they still have albuterol on hand does not achieve the goals of pharmaceutical care, which are to optimize the patient’s health-related quality of life and achieve positive clinical outcomes, making Answer B incorrect. Moreover, having documentation that is kept solely for your own personal use does not promote interprofessional communication to benefit the patient, making Answer D incorrect. The pharmacist’s responsibility is to ensure that the patient, caregiver, or both have all the necessary supplies, information, and knowledge to carry out the plan with the patient’s medication, making Answer C correct. 2. Answer: D The CMS criteria for eligibility of MTM services are as follows: chronic disease states, multiple medications for chronic conditions, and Part D drugs costing at least $4696 per year; making Answer D correct and Answers A, B, and C incorrect.

6. Answer: B Quality measures reinforce the need for pharmacist participation during transitions of care. Assessing medication adherence and knowledge does not directly reflect the outcomes from the transitions of care service, making Answers A and C incorrect. The number of patients who had medication reconciliation within 30 days post-discharge is a process indicator that a pharmacist can facilitate and a direct indicator listed by the AHRQ to ensure appropriate transitions in care, making Answer B correct. Measuring the number of patients with a medication error during hospitalization is not beneficial in assessing the quality of the transitional care service, making Answer D incorrect.

3. Answer: D Patients qualify for CMM if they have medical conditions associated with high-cost and multiple medications, have difficulty reaching goals of therapy, are experiencing adverse drug events, have difficulty understanding and following a medication regimen, have high-risk medications that need to be monitored, or have frequent hospital readmissions, making Answer D correct and Answers A, B, and C incorrect.

7. Answer: D Medication reconciliation provided in the primary care clinic after hospital discharge, regardless of the provider of the service, has not shown benefit, making Answer A incorrect. Even if all of the patient’s electronic medical record and prescription claims data were accessible, she would still need to explain how the medications are actually being taken, making Answers B and C incorrect. If the patient keeps an up-to-date list of medications at all times, this will probably be the most accurate medication list available, making Answer D correct.

4. Answer: C To conduct a CMM visit, communication must be bidirectional; thus, written forms of communication, such as sending a letter, are inappropriate, making Answer D incorrect. However, the visit does not have to be face-toface only; telephonic and virtual communication are also acceptable, making Answer C correct and Answers A and B incorrect. Providers of CMM must be comfortable and well trained in all means of communication that are specific to their practice sites.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 612

Practices and Processes of Care

8. Answer B To use a 340B medication, the covered entity should be responsible for the patient’s health care, and care should be provided and maintained by a health care provider while working in a 340B-eligible outpatient clinic. Moreover, the prescription should have originated from a provider while working in a 340B-eligible outpatient clinic, or it should be a discharge prescription from a covered entity hospital. In addition, the patient should not have a Medicaid or Medicaid managed care plan. Because this prescription was not written while the physician was working at a 340B-eligible clinic and was thus written on a different prescription pad, non-340B medications must be used, making Answer B correct and Answers A, C, and D incorrect.

event unless associated with a prescribing or dispensing error; adverse effects are usually considered adverse drug reactions, making Answer D incorrect. 12. Answer: B Answer A is incorrect because the prescriber did not include an explanation for why a covered medication is not appropriate for the patient. Answer B is correct because the drug plan is using quantity limits in an effort to improve medication safety. Step therapy prior authorization should be initiated after the patient’s covered formulary medications have failed, and not just because physicians believe the drug they have chosen will work better, making Answer C incorrect. Answer D is incorrect because including only one agent per class on a formulary is probably too restrictive to accommodate intolerances and responsiveness to medications.

9. Answer: B Answer B is correct because an internal report can be used by the pharmacy to track and trend errors, facilitating improvements in processes and systems. Answers A, C, and D are all external reports, so the pharmacy may be unaware of the error, limiting internal improvements. Answer A is also incorrect because the adverse event was the result of an error rather than an unexpected adverse effect. Answer D is also incorrect because the incident was not a non preventable adverse reaction to a vaccine product. 10. Answer: A Answer A is correct because the FDA safety communications will allow the pharmacist to design a specific plan to reduce adverse events for specific patients who meet certain criteria described in the communication. Submitting error reports to a national organization might raise awareness to a wider audience, but this would not necessarily facilitate a direct change within the local practice, making Answer B incorrect. Establishing a standardized response to class III recalls would not reduce adverse effects because class III recalls are unlikely to cause harm, making Answer C incorrect. Answer D is incorrect because using a standard taxonomy for medication errors might make it easier to analyze errors, but it would not reduce adverse effects without further action. 11. Answer: C A trigger tool is 50 times more effective than voluntary reporting, making Answer C correct and Answer A incorrect. Preventable adverse drug events are considered medication errors, but diagnosis codes are not a reliable indicator of adverse drug events, making Answer B incorrect. Adverse effects are not necessarily an adverse drug

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 613

Practices and Processes of Care

ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS 4. Answer: B Failure modes and effects analysis is useful for identifying potential failures to a new system or process before it is implemented, allowing safety measures to be put in place to prevent those failures or minimize their risks, making Answer B correct. Root-cause analysis is a structured retrospective method used to analyze serious adverse events, and system and process improvements are typically identified, making Answer A incorrect. Safety culture assessment facilitates the identification of problems within the culture of an organization that may not foster a safety culture, but it is not used to analyze processes, making Answer C incorrect. Analysis of medication error trends is not a prospective method, making Answer D incorrect.

1. Answer: C According to CMS’s definition for 2022, the criteria for eligibility of MTM services encompass multiple chronic disease states, multiple Part D–covered medications, and Part D drug costs of at least $4696 per year and/or are at-risk beneficiaries under the plan’s drug management program, making Answer C correct and Answers A, B, and D incorrect. 2. Answer: B The pharmacist’s responsibilities under the CDTM agreement can include initiating, modifying, and discontinuing medications; ordering and interpreting laboratory values; and assessing and providing patient education, depending on the individual practice act covering the state of practice. Furthermore, a pharmacist can place a referral as necessary to improve patient care. The physician is responsible for determining the illness diagnosis; therefore, Answer A is incorrect. Answer C is incorrect; whereas the CDTM agreement allows for ordering labs, it does not have a provision for drawing the actual lab. Answer D is incorrect because sleep apnea is outside the scope of the CDTM agreement. Discontinuing and initiating a medication for diabetes management is in the scope of the CDTM, making Answer B correct.

5. Answer: D There are several aspects that a P&T committee may evaluate, typically both the clinical and financial impacts that could provide value. These could include dosage forms of the medication, volume of use, convenience, dosing schedule, adherence, abuse potential, provider demand, and storage requirements. Making Answer D correct and Answers A, B and C incorrect.

3. Answer: B To ensure a safe and effective transition for the patient, it is important to facilitate a detailed, timely, and thorough handoff from the inpatient to the outpatient setting. Therefore, scheduling the CMR 3 months later may not be as beneficial as scheduling it within 14 days of discharge, making Answer A incorrect. To ensure a smooth transition for the patient, a thorough medication reconciliation must be completed at each transition, whether from the outpatient to inpatient setting or vice versa, and a discharge plan should be communicated to the outpatient provider verbally or in writing, making Answer B correct. Providing recommendations to the inpatient team on pharmacies located in the area may not be beneficial to patients, depending on where they live, and the pharmacy should be tailored to the patient’s preference, making Answer C incorrect. Conducting an Asthma Control Test at a follow-up visit will not assist in transitioning the patient to the outpatient setting, making Answer D incorrect.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 614

Communication Strategies in Pharmacy Jamie L. McConaha, Pharm.D., BCACP Duquesne University Pittsburgh, Pennsylvania

Theresa R. Prosser, Pharm.D., BCPS St. Louis College of Pharmacy St. Louis, Missouri

Communication Strategies in Pharmacy

Communication Strategies in Pharmacy Jamie L. McConaha, Pharm.D., BCACP Duquesne University Pittsburgh, Pennsylvania

Theresa R. Prosser, Pharm.D., BCPS St. Louis College of Pharmacy St. Louis, Missouri

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 617

Communication Strategies in Pharmacy

Learning Objectives 1. Use strategies that develop patient rapport, foster trust, and effectively and efficiently obtain accurate, comprehensive histories, despite potential barriers in communication. 2. Use assessments of patients’ knowledge, health literacy, self-management skills, health beliefs, and attitudes toward medications to tailor educational interventions that will improve adherence and self-efficacy. 3. Communicate patient care activities and medication-related information effectively to other health care professionals verbally and in writing through the medical record. 4. Discuss factors and methods used to assess and select appropriate written educational materials intended for the general public. Self-Assessment Questions Answers and explanations to these questions can be found at the end of the chapter.

Baseline Knowledge Statements Readers of this chapter are presumed to be familiar with the following: • Basic principles of the Indian Health Service (IHS) model counseling techniques • Primary differences between literacy and health literacy and how this affects patient communication • Motivational interviewing techniques to elicit patient change • The five stages of change as defined by the transtheoretical model

1. A Spanish-speaking woman is scheduled for a followup appointment today to assess her recent lifestyle changes. Two hours before her appointment, the patient’s interpreter calls, saying he will not be in until tomorrow because he has a family emergency. The clinic’s receptionist, who speaks fluent Spanish, offers to help fill in for the interpreter. Which would be the most appropriate request for the pharmacist to make of the receptionist? A. Step in for the interpreter during the encounter. B. Call the patient to reschedule the appointment. C. Ask the patient to bring a family member or friend. D. Explain to the patient on arrival why the interpreter will not be there.

Additional Readings The following free resources have additional background information on this topic: • Health Literacy Tool Shed: http://healthliteracy. bu.edu/ • Indian Health Service: https://www.ihs.gov/ipc/ about/models-for-improving-care/ihs-care-model/ • ASHP Guidelines on Pharmacist-Conducted Patient Education and Counseling: https:// www.ashp.org/-/media/assets/policy-guidelines/ docs/guidelines/pharmacist-conducted-patienteducation-counseling.ashx • BeMedWise patient education on medication safety and adherence: https://bemedwise.org/

2. A pharmacist is performing a patient medication history and would like to assess the risk of patient nonadherence to a multidrug diabetes regimen. Which method would be best to use for this purpose? A. The Adherence Estimator questionnaire B. The Morisky questionnaire C. The Background, Affect, Troubling, Handling, Empathy (BATHE) technique D. Motivational Interviewing

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Communication Strategies in Pharmacy

A. B. C. D.

3. An older adult male patient correctly completed the calculation in the Newest Vital Sign (NVS) questionnaire. In the package insert dispensed with his prescriptions, he was able to find relevant facts about adverse effects associated with medications he was taking. He is selecting a Medicare D program and is struggling to compare brochures from several companies to identify the best program for him on the basis of his medications. Which National Assessment of Adult Literacy (NAAL) classification is this patient most likely in? A. B. C. D.

“Inject 15 units daily at bedtime.” “Inject 15 U QD at HS.” “Inject 15 units QD at HS.” “Inject 15 U daily at bedtime.”

7. A pharmacist reads an editorial in the newspaper recommending the rejection of the school board’s latest policy for required vaccinations of new students. The pharmacist strongly agrees with the school board’s plan and carefully writes a 600-word rebuttal to this editorial. Which would be the most effective way to use this rebuttal to advocate for the new policy?

Below basic Basic Intermediate Proficient

A. Send the rebuttal as a letter to the school board to voice support. B. Submit the rebuttal as a letter to the newspaper’s editor. C. Read the rebuttal at the next open school board meeting. D. Offer the rebuttal to the newspaper as an “op-ed” piece.

4. A pharmacist is considering whether a commercially developed multimedia presentation would be appropriate to include as part of his institution’s comprehensive asthma education program for adults. Which would be the most appropriate method to evaluate the usability of this presentation? A. Ask a multidisciplinary group of colleagues to review the presentation’s content. B. Evaluate the presentation by using the Suitability Assessment of Materials (SAM) tool. C. Assess the presentation by using the Patient Education Materials Assessment (PEMAT) tool. D. Play the presentation in a random classroom and perform a survey on patient opinions of the video after class.

5. A pharmacist is asked to give a presentation to a group of physical therapists regarding new methods of pain management. Which topic would likely be of most interest to this audience? A. B. C. D.

Mechanism of action and adverse events Cost and formulary status Pharmacology and pharmacokinetics Dosage and administration

6. In performing medication reconciliation for a patient, the pharmacist detected a discrepancy in the dosage of insulin glargine between the prescriber’s medication orders and the patient’s list. After clarifying the dosage with the prescriber, which would be the most appropriate way to document the correct dose and frequency of insulin in the patient’s medical record? ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 619

Communication Strategies in Pharmacy

I.  COMMUNICATING VERBALLY WITH PATIENTS AND CAREGIVERS A. General Communication Tips (Domain 1) 1. Listen patiently and allow patients to tell their story. If necessary, gently redirect or explain by whom and when the patient’s other concerns might be addressed. 2. Use questions appropriately. a. Open ended: Useful to begin a topic. Permits patients to provide their perspectives on what is important. Helps assess patient knowledge and understanding of the situation, medical problem, and medication. b. Use of prompts: After the initial response, prompts help patients continue or complete their train of thought (e.g., “You mentioned […]; what else do you remember?”). c. Probing questions: Ask for more focused or clarifying information. “Tell me more about…” “How did you feel when…?” d. Closed ended: After patients seem to have completed their story, focused or closed-ended questions can screen for other pertinent positives/negatives. “Did you have any diarrhea or cramping?” e. Avoid compound questions. “How satisfied are you with your pay and job conditions in the pharmacy?” f. Avoid leading questions. “You didn’t have any questions about this new medication, right?” g. Sequence questions in a logical, organized manner to avoid duplication. h. Phrase questions tactfully and respectfully. 3. Use paraphrased summaries to indicate your understanding or for a transition to the next topic; allow the patient to make additions or corrections. 4. Consider your body language. Examples: Make regular eye contact (especially if using electronic documentation during session); interviewer is positioned ideally at eye level with body turned toward, and at an appropriate spatial distance from, the patient. Avoid nervous and annoying habits (e.g., playing with a pencil or tapping foot). 5. Actively listen. Examples: React to ideas (not the person), read the patient’s body language, listen to the patient’s tone of voice as well as to the patient’s words, ask for clarifications as needed, jot notes of follow-up questions to use after the patient finishes talking (do not interrupt), allow the patient to pause before jumping to next question, and permit silence for the patient to gather his or her thoughts. 6. Enunciate clearly. Modulate tone, volume, and rate of speech. B. Developing Relationships and Maintaining Rapport During Patient Interviews (Domain 1) 1. Introduction a. Set aside an appropriate time and place for speaking with the patient so that you may devote your full attention to the patient. b. Warmly greet patients using their preferred mode of address and gender identity. Use their first name only if invited to do so. c. Introduce yourself by name, give your role, and describe the purpose for the interaction. Give an estimate of time so that patient knows what to expect. d. Acknowledge what you know about the purpose for their visit. “The receptionist said you had a question about your asthma medication?” e. Establish a mutual agenda for the visit. “So you believe your pain medication is not working well and you need refills on your other medicines. Blood work is due for your diabetes. Anything else?” f. On closing, summarize joint decisions and verify next steps. Provide contact information and offer assistance with future questions or problems. 2. Incorporate patients’ perspectives and concerns a. Provide opportunities for them to voice concerns throughout the encounter (e.g., during the initial introductions, ask the patient what they hope to accomplish; pause to allow patient to voice concerns throughout the encounter).

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 620

Communication Strategies in Pharmacy

b. Repeat the patient’s concerns or perspective with nonjudgmental language. Allow the patient an opportunity to clarify and make additions or corrections. c. Describe how you will address their concern. If you cannot address their concern, explain why it cannot be addressed, to whom their concern will be referred, or when their concern might better be addressed. d. Encourage and respond to patient questions. Provide the patient with additional sources of reliable information to support answers to their questions when possible. e. Be transparent when incorporating their perspective. “Because you said taking medication several times a day is difficult to incorporate into your schedule…” f. Ask the patient about requests or goals. “What bothers you most about…?” g. Include patients in decision-making, depending on their degree of interest. i. Offer and explain available options and provide resources for them if they wish to research further. ii. Identify any of their desired support partners. Respect their desire to include (or not include) others in the decision-making process. 3. Use health equity principles for inclusive communication. It is important to address all patients inclusively and respectfully. a. Avoid making any assumptions about gender identity and sexual orientation. b. When addressing patients for the first time, avoid using pronouns and other terms that indicate a gender. i. Best practices have a system that allows patients to enter their preferred name, gender identity, and pronouns in registration forms. ii. If this information is not collected, politely ask patients privately what names and pronouns they prefer to use. c. Avoid asking unnecessary questions. d. Maintain a nonjudgmental attitude. 4. Accept emotions and be empathetic and respectful. Ignoring emotions can appear uncaring (e.g., sadness, tears, pain) or can escalate if patients think their concerns are not being heard (e.g., anger, frustration, aggressiveness). a. Respond to emotions by acknowledging the patient’s verbal and nonverbal cues. “You seem very distracted today. Are you concerned about something?” b. Address the emotion by reflecting back. “You are angry that…” c. Encourage the patient to expand as appropriate. “What frustrates you most about having to…?” d. Redirect the conversation tactfully back to the goal of the encounter when needed. “I will see that the receptionist deals with this billing issue after we finish. Let’s get back to…” e. Offer appropriate apologies. “I am sorry we dropped the ball on your request for…. I will make sure that is done today.” In addition, make sure you address all their concerns around a missed item. “Is there anything else that I need to make sure I address that you are concerned about?” f. Maintain composure. g. Offer comfort, compassion, reassurance, or support. “You are worried about how you will do with all of this. I will help you by…” h. Nonverbal cues and empathetic listening can be more genuine and sincere than routine offers of sympathy such as “I am sorry about your loss.” 5. Assessment of pharmacist communication during patient encounters a. Several frameworks and instruments have been developed to teach and assess physician communication skills during patient encounter. Among these frameworks, there are differences between the specific criteria and content. Common areas include organization of the interview, development of patient rapport, and general verbal and nonverbal communication skills (Fam Med 2005;37:184-92).

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 621

Communication Strategies in Pharmacy

b. The Four Habits Model is one of the best-known assessment frameworks of this type (Permanente J 1999;3:79-88). The Four Habits model follows four patterns of behavior (habits) that allows for an efficient framework for organizing the flow of medical visits. i. The various communication tasks that make up each habit are organized into families of skills, techniques, and payoffs. ii. Habits are seen as nested and interrelated. c. A limitation of applying these frameworks to pharmacists is that the terminology, criteria, and examples may not pertain to or be inclusive of pharmacist-patient encounters. A pharmacist-specific communication assessment framework, Patient Centered Communication Tools (PaCT) is similar to the Four Habits Model but relates specifically to pharmacy and utilizes medication-related examples and prompts. C. History Taking (Domains 1, 2) 1. Current problem and chief concern for visit a. Opening question: Usually is open ended (“Tell me about your stomach problem”). b. The PQRST (Provocative/Palliative, Quality/Quantity, Region/Radiation, Severity, Timing/Temporal relationship) method after the patient’s opening story encourages a comprehensive description of the problem. Commonly used for pain but also suitable for a variety of problems. i. Provocative or palliative: “What makes the problem better (or worse)? ii. Quality or quantity: “How many times…?” “Describe the sensation.” iii. Region or radiation: “Point to where you feel…” iv. Severity: “On a scale of 1–10, with 10 the worst, how bad is this?” “How does this compare to usual (state of health)?” “How bothered are you by this problem?” v. Timing/Temporal relationship: “What time did this start?” “How long after you started exercising did…?” c. A variant used for hospice palliative health is the OPQRSTUV method. The additional portions may be useful in other situations as well. i. Onset of the problem ii. Provoking/palliating iii. Quality iv. Region/radiation v. Severity vi. Treatment: “What have you tried so far?” “What has been the effect?” “Has this treatment caused any problems?” “What have you used in the past?” vii. Understanding impact on you: “How is this affecting your daily activities?” “What has been the impact on your family?” “What do you believe is causing this problem?” viii. Value: “What is your goal for this problem?” “What would be an acceptable level for this problem?” d. Another helpful mnemonic is SCHOLAR-MAC, which can be used by pharmacists in assessing patient symptoms. i. Symptoms ii. Characteristics of symptoms iii. History of symptoms iv. Onset v. Location vi. Aggravating factors vii. Remitting factors viii. Medications (prescription, OTC, herbal, dietary supplements) ix. Allergies x. Conditions (medical)

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 622

Communication Strategies in Pharmacy

e. Follow-up or other visits without a chief concern, start with open-ended questions to begin dialogue about what patient hopes to accomplish at this visit. f. The Background, Affect, Troubling, Handling, Empathy (BATHE) method can be useful to gather data and the patient’s perspective on problems that have an emotional component or that affect quality of life. For example, identify how a patient is coping with a new diagnosis (Prim Care Companion J Clin Psychiatry 1999;1:35-8). i. Background: Use an open-ended question similar to the standard question to elicit the chief concern. ii. Affecting: Solicit feelings or effect on quality of life. “How do you feel about this?” or “How is this problem affecting your life?” iii. Troubling: Identify the relative importance or specific areas of concern. “What troubles you the most about…? iv. Handling: “How are you dealing/coping with this problem?” v. Empathy: Reflect back the concern and/or emotion. “You seem frustrated by the lack of…” vi. The BATHE technique is a psychotherapeutic procedure, meaning it seeks to empower patients to trust themselves and others, confirm their positive feelings about themselves, and enhance their ability to control the circumstances of their lives. vii. This method will also serve as a rough screening test for anxiety, depression, and situational stress disorders. Patient Case Questions 1 and 2 pertain to the following case. The pharmacist is meeting today with a 78-year-old man who presents to the pharmacy today with a chief concern of new-onset back pain. 1. Which would be the most appropriate way to begin a discussion about his chief concern? A. B. C. D.

You have been taking your pain medication every day as prescribed, right? How has your back pain been affecting your daily activities? Tell me in your own words about the back pain you are experiencing. Describe your back pain, including other symptoms.

2. This man has returned twice in 6 months with the same concern. His physician has changed his pain medication each time. He currently describes his pain intensity at 3 or 4 (on a 10-point scale, with 10 as the worst). He is able to work, but he limits some of his desired daily activities because of pain. Today, he asks about having back surgery. Instead, his physician prescribes a third pain medication and gives him a referral for physical therapy. After the physician leaves, the man turns to the pharmacist and bursts out: “When my brother had back surgery, it helped the pain right away! If I had better insurance, she would do the surgery.” Which would be the best initial response to the patient? A. B. C. D.

“Surgery is serious, so it is done only if medication and physical therapy don’t work.” “The physician was trying to explain that your back pain is not severe enough for surgery just yet.” “It is common to try two or three medications to find the right one at the right dose.” “You suspect that she is treating your problem differently because she will not get paid as much.”

2. Components of an initial medication history: History should be complete (drug, dose, frequency, route), clear (not missing any information), complete (all drugs including over-the-counter [OTC], supplements, vitamins, natural products, herbs, physician samples), and current (include all recent changes). a. Prescription medications include the following: i. Oral and other routes such as topical, injectable, and inhalation. ii. Both routine and as-needed medications: Note the dose, route, frequency, approximate starting date, and indication for each medication. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 623

Communication Strategies in Pharmacy

b. c. d. e.

f.

iii. Durable medical equipment: Home oxygen (continuous or intermittent), continuous positive airway pressure machine (note adherence), other therapeutic medical devices such as a continuous glucose monitor iv. Past medications, especially those used to treat current problems: Inquire about when the medication was started or stopped (approximately) and for what reason (e.g., lack of effect, problem now resolved, adverse event). v. Vaccinations: Check for specific vaccinations depending on the patient’s age (pediatric, adolescent, adult, or elderly) or current problems (e.g., diabetes). For each, ask for the date of the initial vaccination and any boosters. If patient has not received vaccination, ask the reason why. Obtain a copy of a vaccination card if the patient has one or check your state vaccine registry. vi. Drugs from other sources: Ask about samples, medications from patient assistance programs or clinical research studies, or use of another’s prescription medications. Drugs from these sources are often not documented in the common places (e.g., medical records, community pharmacy profiles, electronic databases from pharmacy benefit managers). OTC medications: Include vitamins, topical products, and herbal and nutritional supplements. Inquire about the frequency of use: Routine, seasonal, or as needed (often patients do not consider these as medications and therefore may omit them when gathering a medication history). Other pharmaceuticals: If a patient is coming from another institution, inquire about recent use of diagnostic, contrast, and radioactive agents; blood derivatives; and intravenous solutions, including any additives. Adverse reactions and allergies i. Differentiate between adverse effects and true allergic reactions. ii. Document any known details, such as the date it occurred, the specific reaction, and its severity. Medication-related social history i. Street drugs: Consider the potential connotations of other terms such as illicit, illegal, or recreational drugs. Inquire about oral, inhaled, and injectable forms. ii. Tobacco products: Phrasing the question as “Do you smoke?” or “Do you use cigarettes?” may narrow the response to exclude non-cigarette forms of tobacco (e.g., pipes, cigars), routes of tobacco (e.g., snuff, chewing tobacco), or nicotine products (e.g., vaporized, patch, lozenges). Ask age at initiation, discontinuation, and average frequency of use per day, week, or month. Calculate packyear history of cigarettes. Ask patients if they would like to quit smoking/determine readiness to quit. iii. If collecting information on a form, consider the use of a multiple choice format to collect information iv. Alcohol: Ask about the amount (ounces), type of alcohol (e.g., beer, wine), and number of drinks per day, week, or month. Note the pattern of use (e.g., seven beers per week could be either one drink daily or seven beers on Saturday night). v. Medical or other sources of marijuana and/or cannabis: Amount, frequency, age at initiation, purpose for use, and source Adherence. Inquire about the following: i. The number of specific doses missed per week in a nonjudgmental fashion. “How often in a typical week do you miss one of your medicines?” Adherence patterns may vary according to the medication, a specific disease, or the time of day. “When is the last time you missed taking this medicine?” Ask patients “What are the reasons you may miss a dose?” ii. Whether the patient has a specific method or system to assist in taking daily medications (e.g., pillbox, timer, calendar) or tracking the doses and frequency of as-needed medications (e.g., journal or logbook). If the patient misses more than a few doses, ask the patient or caregiver what they have tried in the past and what seems to work the best for them to remember doses. iii. The most recent dose of medication taken: This may be important to correctly schedule the next dose when patients are being transferred, admitted, or discharged.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 624

Communication Strategies in Pharmacy

3. Medication reconciliation a. A standardized process should be used for reviewing a patient’s specific medication regimen at transition points in care. Discrepancies should be identified and resolved. The correct regimen should be clearly documented and communicated to all who are involved in care. b. A pictorial tool, Medication Reconciliation Review of Systems Subject (MR ROSS), has been used to increase the number of medications identified by the patient during medication reconciliation (J Am Pharm Assoc 2013;53:652-8). c. The Joint Commission includes medication reconciliation in its National Patient Safety Goals; however, it does not specify procedures or recommend best practices. Table 1 includes a suggested procedure. Table 1. Process for Medication Reconciliation Collect information from available sources Identify discrepancies

Resolve discrepancies

Communicate changes

Patient/caregiver verbal history Any written medication lists from the patient Medical records from the provider, discharge lists, or admission lists

Check for the following: Completeness: All prescription, over-the-counter, and as-needed medications and supplements Clear instructions: For example, dose, route, frequency, therapy duration Currency: Up to date with all new orders and dosage changes; all discontinued medications are deleted Duplicate therapy: Same drug or in same drug class (e.g., brand names or combination products) Compare/verify information from additional sources Family members or caregivers, if appropriate Community pharmacies medication profile(s) Prescriber records Electronic sources with data from pharmacy benefit managers (e.g. Capture Rx, PharmMD, Mirixa, Outcomes, Surescripts, RxHub, etc.)

Identify the cause/reason for the discrepancy. For example: A more recent order for a dosage change, for a new drug, or for discontinuing a drug Formulary substitutions (hospital drug formulary, insurance coverage, etc.) Patient misunderstanding or confusion Changes in patient status (e.g., renal function, worsening disease, laboratory values, patient improvement, weight loss) Make recommendations according to the cause of the discrepancy Obtain prescriber approval Have a methodical process for following up with pending discrepancies until ultimately resolved Document order changes in the medical record Update the medication list Transmit the updated list to other providers as needed Educate ambulatory patients on the reconciled regimen, emphasizing any changes Provide the reconciled list to ambulatory patients; a chart organizing the medications by administration times may be preferred Encourage the patient to maintain a complete and up-to-date list and to bring it to each provider visit

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D. Assessing Patient-Specific Needs When Tailoring Educational Sessions (Domain 1) 1. Health literacy: Defined as the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions (Institute of Medicine 2004). a. The National Assessment of Adult Literacy (NAAL) categorizes health literacy into four performance levels (Kutner 2006). i. Below basic (level 1): Around 14% of the population or about 40 million Americans. These adults may be able to interpret short, simple text to perform routine tasks. However, those at level 1 have trouble matching information or identifying numbers to use in mathematical problems. ii. Basic (level 2): An additional 22% (about 50 million American adults) can solve routine mathematical problems or make simple inferences. However, people with level 1 or level 2 skills would find it difficult to interpret a dose chart on an OTC cold medication to calculate the correct dose for a child (Institute of Medicine 2004). iii. Intermediate (level 3): About 53% of the population can summarize text, find and apply facts from denser text, and identify and apply information to solve arithmetic calculations. iv. Proficient (level 4): Only 12% of the population can analyze and integrate several pieces of information or solve more abstract or multistep mathematical problems. b. Four major health literacy domains have been identified (Health Promot Int 2005;20:195-203). i. Fundamental domain includes reading, writing, speaking, and basic numeracy. This is what most would think of as general literacy. ii. Scientific domain includes the ability to understand basic scientific concepts. Examples include knowledge of the basic purpose and function of various organs, understanding of biologic concepts behind medical tests, and application of higher mathematical concepts such as trends, risk, and statistics. iii. Cultural domain incorporates beliefs, customs, and social identity into personal decision-making. iv. Civic domain requires applying health information to make decisions regarding general public policy. Examples include school board members making policy decisions regarding a nutritious diet for school lunch programs or voters deciding whether tobacco use should be banned in public. c. Risk factors for low or inadequate health literacy i. Include age older than 65 years, less than a high-school education, low income, those for whom English is a second language, and immigrants. However, the largest group numerically consists of white individuals (Institute of Medicine 2004). ii. The presence of risk factors alone does not reliably identify low or inadequate health literacy. iii. Assessment tools have been developed for research or clinical settings. Information regarding screening tools for low health literacy is summarized in Table 2. Table 2. Summary of Common Health Literacy Assessment Screening Tools Tool

REALM

Description

A brief (3–6 minutes) tool; adults pronounce a list of 66 common words related to anatomy or illnesses

Comments

Commonly used in research studies Does not directly measure comprehension of health information but has been highly correlated with reading comprehension (i.e., readinggrade level) Primarily assesses reading skills but not numeracy or mathematical ability Identifies those with inadequate health literacy REALM-R is a shorter version (eleven words) but is not as widely validated

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Table 2. Summary of Common Health Literacy Assessment Screening Tools (continued) Tool

Description

Comments

NVS

Contains six questions regarding interpretation of a standard nutritional label; takes 3 minutes to administer

Assesses both literacy and numeracy (includes arithmetic calculations) Validated in English and Spanish Both versions correlate with the TOFHLA Has been tested in primary care settings

TOFHLA

SILS

Consists of 50 reading and 17 numeracy items involving common medical situations; takes up to 22 minutes to administer

Is only one item: “How often do you need to have someone help you when you read instructions, pamphlets, or other written material from your doctor or pharmacy?”

SAHLSA-50

Involves reading 50 words; choice between two distractors is used to indicate understanding

Commonly used in research studies A shorter version (s-TOFHLA) uses 36 of the reading questions and takes only 7 minutes Results are categorized into inadequate, marginal, or adequate levels of health literacy Spanish versions available for both the full and shorter versions of the TOFHLA; these are not as widely studied as the English version; scores between men and women varied on the shorter version

Response scale is from 1 (never) to 5 (all of the time); response of more than 2 (sometimes, often, always) has a 54% sensitivity and 83% specificity for identifying inadequate health literacy Very brief; easy to integrate into clinical practice Other (individual) questions have also been tested Developed initially and validated in Veterans Affairs clinics but has also been tested in primary care population More reliably identifies those at risk of low/inadequate health literacy compared with confirming those with adequate health literacy; stronger correlation with s-TOFHLA and REALM in detecting inadequate compared with marginal health literacy Does not assess numeracy Based on the REALM (This is for adults who speak Spanish but is not a Spanish translation of REALM)

NVS = Newest Vital Sign; REALM = Rapid Estimate of Adult Literacy in Medicine; SAHLSA-50 = Short Assessment of Health Literacy for Spanish Adults; SILS = Single Item Literacy Screener; TOFHLA = Test of Functional Health Literacy in Adults. Institute of Medicine (IOM). Health Literacy: A Prescription to End Confusion. Washington, DC: National Academies Press, 2004:66-8.

North Carolina Program on Health Literacy. Literacy Assessment Instruments. Available at www.nchealthliteracy.org/instruments.html. Accessed September 26, 2014. Weiss BD, Mays MZ, Martz W, et al. Quick assessment of literacy in primary care: the Newest Vital Sign. Ann Fam Med 2005;3:514-22.

Morris NS, MacLean CD, Chew LD, et al. The Single Item Literacy Screener: evaluation of a brief instrument to identify limited reading ability. BMC Fam Pract 2006;7:21. Consumer Health Informatics Research Resource. Health Literacy. Available at http://chirr.nlm.nih.gov/health-literacy.php. Accessed September 29, 2014.

2. Topic-specific educational needs: With complex diseases (e.g., diabetes, asthma, hypertension), even patients with good health literacy may lack the necessary knowledge, understanding, or skills to optimally care for their condition at home. Educational needs can be assessed by asking the patient open-ended questions such as “Tell me what you know so far about…” or “What do you still need/want to know about…?” Patients may have questions regarding the following: a. Disease or disease process and what they can expect (e.g., prognosis for a cure or developing complications, need for ongoing testing and monitoring). b. Specific medications: For example: How to take them, why they are needed, how they work together, how long they might be necessary, and what options are available. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 627

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c. Nondrug therapy and lifestyle changes, including healthy eating habits and physical activity levels; role of surgery or physical therapy; and pulmonary, cardiovascular, or poststroke rehabilitation programs. 3. Health beliefs: Pharmacists should be alert for aspects of patients’ belief systems that may affect participation in care and adherence to medications and other treatments. Examples include the following: a. General health-related attitudes such as trust in or skepticism about organized or Western medicine, openness to complementary and alternative medications, relative safety or efficacy of prescription versus OTC medications, importance of self-care and healthy lifestyles, or causes of disease. b. The Health Belief Model uses four constructs (perceived susceptibility, severity, benefits, and barriers) to predict whether a patient will participate in disease prevention or treatment. Identifying an individual’s disease-specific beliefs may help identify barriers to adherence and assist in tailoring effective educational messages (Champion 2008). Two additional constructs (cues to action and self-efficacy) were added as the HBM evolved. See Table 3. Table 3. Using the Health Belief Model to Identify Issues and Tailor Educational Messages Construct

Description

Patient Case Example

Tailored Educational Message

Perceived severity

Concern regarding the seriousness of the condition

She says, “Diabetes is not that big of a deal; all my family has it and they are just fine.”

Perceived benefits

Belief that making a suggested change can have an important impact

A tailored message might include the many complications of diabetes and connecting information from her family history (mother’s heart attack at 55 years of age) to a complication from diabetes

Perceived barriers

Beliefs about the negative aspects of change

Cues to action

Factors that trigger action

Self-efficacy

Confidence that one can perform the behavior to reach the desired outcome

Perceived susceptibility

Individuals’ beliefs about their likelihood of contracting the disease or condition

A 35-year-old woman is not interested in learning about how she can prevent type 2 diabetes mellitus; she says, “I will worry about it if it ever happens.”

“There is nothing I can do about my genes; I am going to get diabetes regardless; I’ll just take the pills like my mother.”

“Cooking healthy food with my crazy work schedule would be too hard; I don’t like vegetables and salad.” “I’ve only gained a little bit of weight; it’s not that big of a deal.”

Explaining her many risk factors, such as obesity, history of gestational diabetes, and significant family history may help her understand the high likelihood of her developing diabetes

Explaining how losing weight, eating a healthy diet, and becoming more active can delay or even prevent the onset of diabetes might increase her motivation to change her lifestyle

Help her brainstorm about possible foods that she likes, that are healthier, and that can be successfully integrated into her schedule Point out the connection between her continued weight gain and the rise in her blood glucose into the prediabetic range; reassure her that even small changes in her diet or activity level can help decrease her risk of developing diabetes

“There is no way I am going Explain that coaching and assistance will be available to help her identify affordable to lose 50 pounds, and I can’t afford a gym.” resources, develop a specific plan, and successfully implement it (see more on selfefficacy in Table 7)

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4. Religious or moral beliefs and value systems affecting medication use may include medications from human cell lines (e.g., vaccinations), use of contraceptives, abortion-inducing and psychotropic medicines, decisions related to advanced directives, and practices affecting diet, such as religious fasting and vegetarianism. 5. Adherence a. Terminology (Horne 2005) i. Compliance: The degree to which a patient’s behavior is consistent with the prescriber’s recommendations ii. Adherence: The degree to which a patient’s behavior meets the agreed plan from the prescriber. This is the generally accepted term in the literature in the United States. (a) Persistence: Whether the patient continues a medication beyond the first refill. In general, taking 80% or more of prescribed doses is considered “acceptable” adherence but may vary depending on the prescription medication (e.g., insulin). (b) Primary nonadherence: Patient never fills, or fills but does not initiate the medication or behavior change. (c) Secondary nonadherence (or nonpersistence): Patient begins but subsequently discontinues a medication or behavior change. (d) Improper use: Patient continues to take the medication but in a manner inconsistent with the prescriber instructions (e.g., different dose or frequency, takes intermittently). iii. Concordance: Prescriber and patient in consultation agree on decisions incorporating their respective views. This process begins at prescribing but continues with patient support for taking the medication. (a) This term (i.e., concordance) is more recent and is primarily promoted in the United Kingdom; it describes a higher-level therapeutic partnership between patient and prescriber. (b) It should not be confused with patient coercion (e.g., providing the patient with information in such a way as to influence the outcome). b. Measurement i. Indirect methods include calculating the proportion of days covered (PDC) or the medication possession ratio from prescription refill history. Of these, generally the PDC is the preferred method, because it provides a more conservative estimate of adherence (http://ep.yimg.com/ty/cdn/epill/ pdcmpr.pdf). ii. More direct methods, such as pill counts, are generally too labor intensive for routine assessment of adherence. Like the indirect methods, pill counts only infer the degree of adherence. Even if the appropriate number of doses are missing, one cannot assume that the patient is adherent to prescription instructions; for example, the patient could be taking at different intervals or different amounts. c. Assessing risk of future nonadherence: The medication history or review of the pharmacy patient profile can retrospectively identify nonadherence. It would be helpful to prospectively identify the risk of nonadherence and its potential causes when tailoring educational messages. i. The Adherence Estimator can be used to prospectively assess the likelihood that a patient will adhere to a newly prescribed medicine (Curr Med Res Opin 2009;25:215-38). (a) Scoring: Three questions are answered by the patient by using a 6-point scale from agree completely to disagree completely. Scores range from zero (low risk of nonadherence) to 36 (high risk of nonadherence). See Table 4. (b) Usefulness: This tool is easy to use and quick to administer and to calculate the score. Assesses risk of nonadherence to an individual drug (not to a particular disease regimen or an entire regimen). (c) Targeted messages can be provided to the patient’s specific issue(s). Note that the tool measures patients’ perceptions of the drug rather than its actual toxicity, efficacy, or cost.

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Table 4. The Adherence Estimator Question

Issue

Score

Convinced of the prescription’s importance?

Committed to take the medication because it is necessary

0 (strongly agree), 7, or 20 (strongly disagree) points

Worry the prescription will do more harm than good?

Perception of financial burden? Scoring

Is concerned that the risk of harm exceeds the medication’s potential benefit

The cost is perceived to be affordable

0 (strongly disagree), 4, or 14 (strongly agree) points

0 or 2 (strongly disagree) points

0 points = low risk of nonadherence 2–7 points = medium risk of nonadherence 8–36 points = high risk of nonadherence

McHorney CA. The Adherence Estimator: a brief proximal screener for patient propensity to adhere to prescription medications for chronic disease. Curr Med Res Opin 2009;25:215-38.

ii. The Morisky questionnaire is a predictive adherence measurement tool available in four- and eightquestion formats. It can be used to screen for patient knowledge gaps and motivational issues that may affect adherence. Questions ask about missing doses, stopping medication, or cutting back on medication because of adverse effects or disease control. An advantage is that a single questionnaire can be used to screen a disease-specific regimen involving several drugs (e.g., hypertension). It is also available in languages other than English, including French and Chinese. Patient Case Questions 3–5 pertain to the following case. A pharmacist is initially counseling a 75-year-old, lower-middle-class man of Middle Eastern descent on sliding-scale insulin. He is a native-born American who, after completing high school, worked 40 years as a security officer. He says his wife most often reads the medical information for him that he brings home. The prescriber’s instructions are to take 2 units of insulin for every 100 mg/dL that his blood glucose concentration is higher than 100 mg/dL. To check his understanding, the pharmacist asks him how much insulin he would take if his blood glucose were 300 mg/dL. The man takes several minutes but correctly calculates the dose. 3. Using NAAL levels and interpreting the patient’s response to the Single Item Literacy Screener (SILS), what is the best assessment of this patient’s health literacy? A. B. C. D.

At risk of inadequate health literacy according to SILS; likely NAAL level 2. Adequate health literacy according to SILS; likely NAAL level 3. At risk of inadequate health literacy according to SILS; likely NAAL level 3. Adequate health literacy according to SILS; likely NAAL level 2.

4. Which is most likely a risk factor for low health literacy in this man? A. B. C. D.

His educational level His race/ethnicity His income level His age

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Patient Case (continued) 5. When the patient returns 3 months later, the pharmacist wants to assess the likelihood of his continued adherence moving forward to the insulin sliding-scale regimen to identify further educational needs. Which would be the best method to make this assessment? A. B. C. D.

Check his profile for aspart refill dates to calculate his medication possession ratio. Scan his blood glucose log to see how many times he has used insulin aspart correctly. Ask him to complete the Adherence Estimator questionnaire regarding insulin aspart. Use the Health Belief Model to assess his perception of the importance of insulin aspart.

E. Providing Educational Messages (Domain 1) 1. When starting with a new patient or beginning a new topic, a “universal precautions” approach is recommended (i.e., all patients should be considered at risk of low health literacy until a patient-specific assessment can be made of the individual’s knowledge and skills) (AHRQ 2010). a. Health literacy screening tools (e.g., SILS or REALM) are better at identifying those at risk and are less reliable for assessing the adequacy of an individual’s actual health literacy. Example: In response to the SILS question, a patient responds that he always reads medical information himself. This response normally implies good health literacy. However, someone with low health literacy may make the same response if he has no one to help him. b. Even those with generally good (general) health literacy may have topic-specific misconceptions or gaps in knowledge or skills. 2. Start with an open-ended question to assess the patient’s baseline knowledge. a. Indian Health Service Prime (medication) questions i. What did your prescriber tell you the medication was for? ii. How did your prescriber tell you to take the medication? iii. What did your prescriber tell you to expect? b. To assess baseline knowledge of a disease state, another open-ended question appropriate for the situation may be used. “What has the diabetes educator reviewed with you so far?” “What do you want to learn most about…?” c. From the patient’s responses, the provider can reinforce correct knowledge and make an initial assessment of the patient’s needs to clarify misunderstandings, address misperceptions, fill in information gaps, or demonstrate needed skills. 3. Communicating clearly. See techniques in Table 5.

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Table 5. Techniques to Communicate Clearly Technique

Comments

Limit content

Prioritize key points Limit verbal information to three to five key points; if more, provide written instructions Provide information that can be digested in the time available; this may mean scheduling additional educational sessions

Use visual aids

Draw or show pictures Use dimensional models or placebo devices Explain and demonstrate skills (e.g., respiratory device technique, use of home blood pressure monitor)

Use plain, nonmedical language

Listen and reflect back terms used by the patient for medical and nonmedical terms (e.g., menopause vs. change of life, dinner vs. supper) Use plain language and avoid medical jargon. Consult the Plain Language Thesaurus for suggested medical and nonmedical terms to avoid and for better alternatives to these words Avoid abbreviations (e.g., “Use your ICS medication…”) Be specific: “Take this medication at least 2 hours after eating” vs. “Take on an empty stomach” Give examples: “Dairy includes milk, cheese, ice cream, and yogurt” Use the consistent terms recommended by disease guidelines (e.g., quick relief and long-term controller inhalers for asthma medications)

Tailor the message Adapt to the patient’s motivational or interest levels (e.g., provide sources for additional information if interested, shorten the topic to essential information if less interested) Explain the relevance of the information to the patient’s own situation Provide information in the patient’s preferred style, if possible: “There is a pamphlet I can give you, or there is a great website, or I could show you a video. Which would you prefer?” Increase patient participation

Use familiar analogies to explain concepts Encourage questions “What questions do you have?” “What parts would you like me to go over again?” “That would be a great question to ask your doctor at your visit today” More formal methods can be used to encourage patient questions such as the following: Ask Me 3 (https://www.ihs.gov/sites/healthcommunications/themes/responsive2017/display_ objects/documents/AskMe_8-pg_NatAmer.pd) What is my main problem? What do I need to do? Why is it important? The “Questions Are the Answer” tool on the Agency for Healthcare Research and Quality website helps patients articulate their own questions regarding medications or other therapies (www.ahrq.gov/patients-consumers/patient-involvement/ask-your-doctor/index.html?utm_ source=buffer&utm_campaign=Buffer&utm_content=buffer31ff3&utm_medium=twitter) Ask the patient to personalize the information: “It is important to take this at the same time each day. What is something you do at the same time every day?”

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Table 5. Techniques to Communicate Clearly (continued) Technique

Comments

Chunk and check

Break down complex topics into manageable sections Assess knowledge at the end of each section

Assess knowledge and skills

Emphasize key points

Use the teach-back method to assess understanding In the initial teach-back question, the provider accepts responsibility for communicating clearly and correctly: “To be sure I included everything, tell me how you will…” or “I want to be sure I was clear; when will you…?” Acknowledge correct information If necessary, clarify, supplement, or correct information, and then repeat the teach-back process Many teach-back “loops” may be necessary until the patient understands Use the “show-me” technique as appropriate: “Show me which column you would record this blood glucose number in” or “Show me how many pills you would take tomorrow morning.” Have patient demonstrate each skill (e.g., coding the glucometer, checking the memory, obtaining a blood sample) Provide situation-based “what if” examples: “What would you do if your blood glucose were 70?”

Summarize at the end of the session Write down complex information or provide health literacy–friendly handouts Point out the instruction booklet and any “quick-start guides” for devices Provide patients with disease-specific care plans (e.g., written asthma action plan with instructions based on red-yellow-green zones) Provide a call back number, e-mail, or other form of contact if questions arise after the patient leaves.

Centers for Disease Control and Prevention. Plain Language Thesaurus. Atlanta, GA: CDC, U.S. Department of Health and Human Services, 2007. Available at http:// depts.washington.edu/respcare/public/info/Plain_Language_Thesaurus_for_Health_Communications.pdf. Accessed September 26, 2014.

F. Specific Topics (Domain 1) 1. Medication labels are often misinterpreted (Am J Health Syst Pharm 2006;63:1048-55). Common issues include the following: a. Several instructions included in one sentence are complex and easily misread. For example: “Take 1 tablet by mouth twice daily for seven days or as directed.” b. Instructions can be vague or misunderstood: For example, “take two tablets daily” could mean two tablets in the morning, one tablet every 12 hours, or one tablet in the morning and evening. c. Words within instructions are commonly misread. For example, teaspoon versus tablespoon or 1 versus 2 versus ½ tablet. d. For patients with low literacy, the ability to correctly read the label may not mean full comprehension of instructions. e. Misinterpretation of warning labels is a potential issue. Many patients ignore all warning labels. Labels with many instructions may be written at the 12th-grade reading level. (Goal is fifth-grade reading level.) Pictograms may be misunderstood. f. Labeling does not eliminate the need for verbally reviewing instructions with the patient and assessing patient understanding. Use either the teach-back or the show-me method, as appropriate, to verify comprehension. g. In 2010, the United States Pharmacopeia initially released recommendations for standardizing and improving prescription labeling. See Table 6.

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h. In the area of labeling, pharmacists can be advocates for patient safety by doing the following: i. Working with the appropriate corporate or institutional committees to implement the United States Pharmacopeia labeling recommendations and developing clear medication instructions as the default settings on computerized physician order entry programs. ii. Verbally clarifying instructions during patient education. Pharmacists should be aware of their state board of pharmacy’s regulations regarding pharmacists’ ability to actually change written labeling. Verbally clarifying the medication label instructions from “take twice daily” to “take every 12 hours” may be done during education. Changing the label instructions may require a verbal order from the prescriber. iii. When prescribing or taking verbal orders, write prescriptions consistent with the United States Pharmacopeia labeling recommendations. Table 6. Recommendations of the United States Pharmacopeia on Prescription Labels Recommendation

Comments

Simplify the language

Wording should be concise Information should be clear, using common terms Do not use Latin terms or medical jargon

Organization of the label

Use explicit terms for instructions regarding dosage and interval

Include the purpose for use Provide labeling in the patient’s preferred language Improve readability

Include supplemental information Standardize directions

Include only the patient information critical for understanding and safe use

Use specific frequency intervals (e.g., morning and evening, every 12 hours) Use numbers rather than words (e.g., “take 2 tablets” is preferred to “take TWO tablets”) When possible, the prescriber should include the indication for the medication in lay language (e.g., high blood pressure) Translations should be available, especially for those with low English proficiency Use high-quality process for translation Lettering should be in a minimum of 12-point and sans serif font, such as Arial Sentence punctuation should be used; do not use all capital letters

Auxiliary labels should be limited to evidence-based information that is necessary and important Information should be supplied in a standardized manner Use consistent language in e-prescribing programs

United States Pharmacopeia. USP Advisory Panel Recommends Standardizing Prescription Container Labeling to Improve Patient Understanding of Medication Instructions. Available at http://us.vocuspr.com/ViewAttachment.aspx?EID=2WSh2u7neSpIu2bXW1HJ5VQ48HGFAOGH1NdNBeuPwJE%3d. Accessed September 26, 2014.

2. Building skills and self-efficacy: Self-efficacy is a patient’s confidence in or perception of ability to correctly perform a behavior, and it is one of the concepts in the Health Belief Model (Health Educ Q 1986;13:73-91). a. Self-efficacy varies by a particular behavior, but it is also situationally dependent. For example, a patient may be confident in managing a hypoglycemic reaction normally but may be worried about managing reactions when at work or away from home. b. Low self-efficacy may have the following effects: i. Discourage a patient from learning new skills or changing behaviors ii. Decrease the amount of time or effort a patient would spend attempting to learn a new skill iii. Be a source of anxiety or depression or cause avoidance in dealing with a medical problem c. Methods to improve self-efficacy: See Table 7.

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Table 7. Methods to Improve Self-Efficacy • • • • • • • • • •

Break complex skills into manageable tasks Arrange tasks in a series of logical, progressively difficult steps Implement changes slowly over time as patient is successful Use frequent follow-up to address questions or problems Show that progress is being made (e.g., small weight loss, slight improvement in blood pressure) Acknowledge and encourage even small initial steps in implementing the plan Connect successes to an improvement in the patient’s abilities Assist in setting patient-specific and achievable short- and long-term goals Brainstorm with the patient to identify personalized methods to implement the plan Analyze lapses or problem situations for lessons learned; identify potential solutions for avoiding or dealing with that situation in the future • Identify peer coaches, mentors, or role models for ongoing support 3. Self-management of medications requires the patient to have the ability to optimally integrate the series of steps to independently implement a drug regimen at home (Image J Nurs School 1991;23:231-5). a. Medication management is a term that encompasses a series of steps, starting with obtaining the medications (initially and then refills), remembering to take the medications, correctly interpreting labels and instructions, integrating several label instructions to develop a personal medication schedule, correctly measuring and preparing dosages, following supplemental administration instructions, and monitoring for efficacy and toxicity. b. Problems with medication management are more common in patients with low executive functioning (the ability to plan, organize, and complete tasks) or low health literacy, those receiving complex medical regimens, or those who are elderly. Poor medication management skills may result in unintentional nonadherence. c. Methods have been developed to assess individuals’ capacity to manage their own medications. Tools such as the Drugs Regimen Unassisted Grading Scale (DRUGS) may be useful in identifying patients who need more assistance in handling their medication regimen at home (Ann Pharmacother 2008:42:1026-36). d. Pill boxes, medication organizers and reminder aids, automatic refills, and prescription delivery may address only some types of medication management issues. e. Patients with low medication management skills may need extra assistance with the following. i. Correctly interpreting label instructions ii. Developing a simple regimen with the minimal number of administration times iii. Integrating any medication changes into their current regimen (e.g., adding new medicines, making dosage changes, and discontinuing medications) iv. Updating and maintaining a current medication list 4. Addressing adherence behaviors: Often, health care professionals narrowly view nonadherence as unintentional (i.e., the patient did not understand the instructions, has trouble remembering to take medications, or cannot afford the regimen). However, much nonadherence is actually intended and is often logical from the patient perspective. Some of these adherence factors and behaviors are outlined in Table 8.

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Table 8. Adherence Factors and Behaviors Adherence Factors

Physical factors

Adherence Behaviors

Medications are judged “effective” or “ineffective” by whether or not the patient’s desired physical response, such as control of symptoms (e.g., pain relief) or activity level, is reached Medications are discontinued or adjusted according to the patient’s desired goal Regimens are modified to avoid adverse reactions, which are not reported to their provider

Economic aspects

Medications are continued, discontinued, or adjusted according to the patient’s perception of cost to the perceived benefit The actual cost of the medication may not be as important as the perceived financial distress Generic medications may be perceived as less effective

Psychological aspects and self-regulation

Less value may be placed on medications when there is little or no cost to patients; adherence may be better when there is a co-pay

Patient Case Examples

A middle-aged man with diabetes is nonadherent to both diet and oral medications; he takes the medication when his blood glucose concentration is high enough to cause polyuria and discontinues it when urination becomes less frequent; he understands and appears unconcerned that a hemoglobin A1C of 13.5% puts him at high risk of a future heart attack or kidney failure; he begins to take his medication regularly when he understands that his erectile dysfunction and painful neuropathy will more likely worsen when his diabetes is poorly controlled. A middle-aged woman is nonadherent to two generic medications for asymptomatic hypertension ($5 copay each). She is willing to pay $60 each month for a third-tier pain medication that improves her back pain. She becomes somewhat more adherent to the blood pressure medications when shown her systolic blood pressure was 20 mm Hg lower when taking her medication. She was encouraged to do home blood pressure monitoring monthly to see the benefit from the medication.

Testing: Patients test for the continued need for therapy by stopping or adjusting medications

A woman’s cholesterol concentration was well controlled with a low-dose statin; she stopped taking it because she thought her cholesterol was cured; she was willing to restart it after her cholesterol increased 40 points after stopping the medication.

Control: Medications are adjusted because of the patient’s perception of control or dependence

A woman resisted taking insulin twice daily because the regimen was perceived as too rigid for her lifestyle; she was actually more adherent to a more complex regimen requiring several injections and carbohydrate counting because she could adjust it to her variable mealtimes and food intake.

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Table 8. Adherence Factors and Behaviors (continued) Adherence Factors

Psychological aspects and self-regulation

Adherence Behaviors

Patient Case Examples

Being practical: Medications are adjusted to diminish the perceived disruption in the patient’s lifestyle

An elderly woman with heart failure wanted to discontinue her diuretic while on a vacation because she did not want to worry about finding a bathroom while on the side tours; it was explained that if she stopped it, her heart failure would worsen and she would not have the energy to go sightseeing.

Stigmatization: The patient may perceive having the disease or taking medication as a stigma; taking medication may be an acknowledgment to patients or others that they have an illness

Gambling: The perception that short-term “costs” exceed the long-term “gains” of therapy

Medication as a resource: Adherence may improve when therapy is perceived as a resource or when it allows patients to accomplish desired goals

An adolescent with a seizure disorder is resistant to taking his medications; he becomes more adherent when he realizes he can take his driver’s license test like his friends when he has been seizure-free for 2 years.

A man in his 40s smoking 2 packs of cigarettes per day is unconcerned regarding the long-term health risks: “Not everyone who smokes dies from it;” he cut back to 1 pack/day when he realized that his early morning cough was an early indication of COPD. An elderly woman with severe COPD refused to use oxygen when outside of her home; she began to use it when she realized that it could give her enough energy to visit and play with her grandchildren.

COPD = chronic obstructive pulmonary disease.

Morris L, Schulz RM. Medication compliance: the patient’s perspective. Clin Ther 1993;15:593-606.

5. Techniques to improve motivation a. Motivation theory: Many patients lack motivation to make lifestyle changes or adhere to medication on the basis of proposed health benefits alone. Motivational theory proposes that everyone has one or more primary need. Expressing messages in terms of those primary needs may open individuals to hearing messages and implementing behavior changes. One framework of motivational theory is the Open Management Concept (Kafka 1990). Table 9 describes the five “needs” in this framework. Examples are given of tailored messages in the context of a patient’s specific motivating need.

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Table 9. Use of the Open Management Concept The pharmacist asks patients to describe what they dislike most about using tobacco; listening carefully, pharmacists tailor their response to the patient according to their assessment of the individual’s likely motivator Motivator

Patient Case Examples

Need for control

Patient: “Sometimes I wonder who is in charge, me or the cigarettes. I can’t even sit through a movie without going out for a cigarette. After break at work, I start watching the clock to my next cigarette at lunch.” Pharmacist: “Wouldn’t it be nice to go throughout your day without wondering when you can smoke your next cigarette?”

Need for economic or financial security

Need for recognition

Need to belong

Need for personal self-worth

Patient: “Cigarettes are now more than $10.00 a pack, and most of that is taxes! Years ago, they were only a buck.” Pharmacist: “So you spend more than $2500 per year; What would you do with an extra $50 a week?”

Note: If the patient believes that tobacco helps him deal with stress, his need for control could be a barrier to quitting

Patient: “I used to think that smoking was cool in high school; now I am conscious that my clothes smell and I use tooth whiteners.” Pharmacist: “You are right! It used to be really acceptable to smoke, but you don’t see as many people smoking in public anymore; smoking not only yellows your teeth but also causes early tooth loss.” Patient: “At Thanksgiving or Christmas dinner, my sister makes me go outside by myself because she says it stinks.” Pharmacist: “Does that mean you are the only one in the family who now smokes?” Patient: “Yes, they all stopped; even my brother…”

Note: If key family, friends, or colleagues use tobacco, the desire to belong can be a barrier to quitting Patient: “I have three children who hate my smoking.” Pharmacist: “That’s got to be tough. How old are your children?” Patient: “The oldest boy is 13; my daughter is 10; the youngest boy is 6.” Pharmacist: “In general, young children dislike cigarettes. In the preteen years, peer pressure begins; young girls often start smoking because they’ve heard the myth that smoking keeps one thin. What a great example you would be to your children if you chose to stop.”

Kafka VW, Schaefer JH. Working Relationships: Everyone’s Guide to Working with People. Moraga, CA: Effective Learning Systems Press, 1990.

b. Motivational interviewing: When providers try to convince patients to change, it may cause patients to justify why change for them is not possible (i.e., the “righting reflex”). Motivational interviewing uses a series of strategies to encourage the patient (instead of the provider) to articulate/explore reasons for changing behavior (Berger 2013; Rollnick 2008). Some key motivational interviewing concepts are briefly outlined in Table 10.

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Table 10. Motivational Interviewing Concept

Patient Case Example

Explanation

Express empathy

“So you are concerned about the cost and the long-term effects of a daily medicine on a 6-year old; is that right?”

Avoid arguing

“There are no generic controller inhalers for my son’s medication, so the controller seems expensive every month” (restate patient concern); May I tell you of my concerns about Billy’s asthma? (ask permission); You said he awakens often at night; when he has an asthma episode, he misses school, and we give him large doses of prednisone for several days to control his asthma; I think asthma is affecting Billy’s schoolwork (voice medical perspective in context of patient concern); What do you think?” (listen to response)

Reflect back the patient’s concern in a nonjudgmental manner; empathy does not necessarily mean expressing agreement

Roll with resistance

“You are reluctant to give little Billy an asthma controller medicine every day because you don’t think his asthma is bad enough to need a medicine every day. Tell me a little more about that…”

Accept the patient’s reluctance by paraphrasing the concern; encourage the patient to discuss his or her concerns further; a better understanding of the situation may help the provider answer questions, address concerns, or clarify misperceptions

Arguing may just reinforce patients’ reluctance to change; ask permission before challenging their opinions, perceptions, or concerns; then, inform them of your concerns from a medical perspective; listen to their response

Explore their ambivalence about change; Develop “You want him to do well at school and give him the least discrepancy amount of medicine; every episode requires lots of albuterol help them see inconsistencies between their goals and their behavior and prednisone, and the emergency visit is expensive; he is also not keeping up at school; giving a controller medicine in a tiny dose every day might actually expose him to less medication and help him do better at school…Is that worth a try?” Support “I can show you how to track his albuterol use and self-efficacy nighttime asthma episodes, so we can see if his asthma improves during the next several weeks. Do you think that you would be willing to track this information to see if there is any improvement?”

Table 7 lists items to build and support self-efficacy

c. Transtheoretical model i. This is another method for tailoring the patient intervention according to patients’ readiness to change their behavior. (a) The pharmacist assesses the patient’s stage of change and provides an appropriate intervention to encourage or maintain change. (b) Potential interventions include the following: (1) Providing timely information (2) Identifying and emphasizing personal motivators (3) Recognizing progress and encouraging further change (4) Building self-efficacy (see Table 7) (5) Troubleshooting lapses and encouraging continued efforts ii. Definitions of the stages (or constructs) and examples are listed in Table 11. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 639

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Table 11. Transtheoretical Model Stage of Change

Precontemplation

Definition

No plan to implement change in the next 6 months

Patient Case Example

A middle-aged, overweight, sedentary woman develops prediabetes; her pharmacist reviews her latest laboratory results and the health benefits of weight loss

Explanation of Pharmacist Response

The pharmacist seeks the patient’s permission and, with this, explores her potential motivators and attitudes toward healthy eating habits and exercise; he offers to help her whenever she is ready; afterward, she begins to think about her daughter’s wedding next fall

Contemplation Thinking of changing in the next 6 months, but usually does not have a specific plan

At her next visit, she tells the pharmacist that she is looking at mother-of-the-bride dresses with her daughter but that losing weight seems too hard; she has spotted ads for community-based weight-loss support groups

Action

Six weeks later, she has switched a daily afternoon soda to plain iced tea; her daughter offered to pay for the gym membership, she did not like the one aerobics class she tried; the pharmacist congratulates her on making the diet change and notes the 1-kg weight loss

The pharmacist recommends trying out a variety of activities at the gym and to inquire if a personal trainer is available; because she is doing so well with the beverage change, he asks what small diet change she would like to try next; any roadblocks or setbacks are addressed

Her weight loss has leveled off at 8 kg during 8 months; she is happy maintaining her current diet and exercise plan at this time

The pharmacist monitors her weight at each visit and reviews her blood glucose results with her periodically

Preparation

Plans to make a change in the next 30 days and has usually taken some steps toward change Has overtly changed behavior for less than 6 months

Maintenance

Has changed behavior for more than 6 months

Termination

No temptations or lapses and is confident that change can be maintained

The pharmacist helps her explore and evaluate her resources; he explains how small changes in diet and gradual increases in activity can make a significant difference over time; he offers to help her develop a realistic, successful plan

At the next visit, she tells the pharmacist she plans to join the support group at work that is forming next month; she liked the trial session at her friend’s gym, but the monthly fee seems too expensive

The pharmacist brainstorms with her some affordable alternatives for increasing activity

She has lost 5 kg during 6 months; she has kept up with several small diet changes and exercises routinely twice weekly; she is a little discouraged that she regained 1 kg at Thanksgiving

The pharmacist is upbeat regarding her overall progress; he notes that her repeated blood glucose reading is just under the goal of 100 mg/dL; they briefly discuss why she regained weight (holiday baking) and how she might avoid that at Christmas

Prochaska O, Redding CA, Evers KE. Transtheoretical model and stages of change. In: Glanz K, Rimer BK, Viswanath K, eds.

Health Behavior and Health Education: Theory, Research, and Practice, 4th ed. San Francisco: John Wiley & Sons, 2008:97-119.

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iii. Patients may exit and re-enter the model at any stage before successfully reaching the maintenance/ termination stage. G. Special Populations (Domain 1) 1. Older adult patients a. May have different medical educational needs (Centers for Disease Control and Prevention 2009) i. Have complex medical problems that call for higher health literacy and better medication management skills ii. May be less likely to use the Internet and other sources to obtain health information; so are more dependent on family, friends, and providers for health information iii. In general, may process information more slowly and have more trouble recalling information later iv. Are less confident and more easily confused v. Are more likely to have impairments to learning information such as less dexterity or visual or hearing problems b. Cognitive decline may impair the executive functioning necessary for management of their medications. c. General tips for counseling older adults are listed in Table 12. Table 12. Tips for Educating Older Adult Patients Clear communication strategies are especially important, such as the following: Using plain language Demonstrating and allowing patients to practice skills Documenting patient understanding by using the teach-back and show-me techniques to verify understanding Use briefer educational sessions Keep information focused and organized Pause often, and allow the patient more time to process information Information may need to be repeated more often, both during a session and over time Use more face-to-face communication to permit more interaction Use more personal examples for relevancy Follow up more often and at shorter intervals when implementing new plans Develop and use personalized decision-making tools (e.g., disease-related care plans) Ideally, use educational materials designed specifically for older adults (e.g., written material should be large print; high contrast between the print color and paper; essential points should be bulleted or in list formats) Be alert for physical (vision, hearing, and dexterity) and cognitive impairments that might diminish medication management skills; assess medication management capacity as needed Assist in maintaining an accurate medication list Provide medication charts to organize administration times Inquire about support systems and difficulties with activities of daily living Assess for low self-efficacy, and implement strategies as needed Centers for Disease Control and Prevention. Improving Health Literacy for Older Adults: Expert Panel Report 2009. Atlanta: U.S. Department of Health and Human Services, 2009. Available at www.cdc.gov/healthliteracy/pdf/olderadults.pdf. Accessed November 23, 2016.

2. Low health literacy: For these patients: a. Introduce new concepts more slowly. b. Use teach-back more often throughout the session. c. Use more visual aids. d. Inquire if they have a preferred family member or friend to assist them.

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3. Use of interpreters a. The qualifications for a medical interpreter involve more than being bilingual. Interpreters are trained in the expectations of both cultures so that they can anticipate the potential for misunderstandings, be knowledgeable about medical terminology and jargon, and agree to abide by a code of ethics. b. The National Culturally and Linguistically Appropriate Services (CLAS) Standards in Health and Health Care require that timely language assistance be provided to those with limited English proficiency without charge. c. Even patients who initially appear bilingual may not comprehend the complexities of a medical interview or educational session. The services of an interpreter should be used if there is any concern that the patient may not fully understand. The Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) program has training materials for enhancing safety for patients with limited English proficiency (http://teamstepps.ahrq.gov/). d. Tips for speaking to patients through interpreters. A similar process is used whether the interpreter is used for a different language or for hearing impairment. See Table 13. Table 13. Tips for Speaking to Patients with Interpreters Brief the interpreter about the purpose and goals for the encounter Verify that the interpreter will function in a conduit manner (i.e., interpret in the first person without revising, adding, or deleting any of the message) Face the patient, make eye contact with the patient, and talk by using the first person Use a normal speaking tone and volume Expect that the interpreter will do the following: • Greet the patient and introduce himself or herself at the beginning of the encounter • Transmit any exhibited emotion (by you or the patient) • “Step out” of the interpreter role to ask his or her own questions of you or the patient if the interpreter does not understand what is being said • Stand off to the side so that the facial expressions of both parties can be seen Use normal good communicate strategies; for example: Use lay language; the interpreter will not simplify your words Check patient understanding by using the teach-back or show me techniques Be aware of the policies in your institution for using bilingual colleagues as interpreters; asking colleagues to function outside their normal training and responsibilities can be problematic (e.g., asking a receptionist to translate a diabetes education session) Avoid using family members or friends of the patient to interpret • They may have conflicts of interest or trouble being objective • They may have difficulty understanding the information to be translated • Document the patient’s requests to use the interpreter of his or her choice • If a family member or friend functions as an interpreter, first assess his or her English proficiency with informal conversation; then, assess his or her health literacy with a basic question related to the encounter • Be specific with expectations for accurate, complete translation of words from both the patient and the provider • Use minors only in emergencies Document in the medical record that an interpreter was used, together with his or her name and that of his or her company

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H. Communication After a Medication Error or Adverse Event 1. Traditional approaches involved a “deny-and-defend” strategy. 2. Patient-centered approaches now recommend early disclosure and a focus on preventing future events. a. The Communication and Optimal Resolution (CANDOR) toolkit is available through AHRQ to help hospitals implement communication resolution programs: https://www.ahrq.gov/professionals/qualitypatient-safety/patient-safety-resources/resources/candor/index.html b. Principles may be applied to the outpatient setting.

II.  SELECTING WRITTEN PATIENT EDUCATIONAL MATERIALS A. Written Patient Health Educational Materials: Only effective when used as part of your overall patient education strategy (e.g., use in combination with spoken instructions) (Domain 1) B. Understandability: Suitability Assessment of Materials (SAM) (Doak 1996) (Domain 1) 1. Useful tool to qualitatively evaluate materials under consideration for health literacy and understandability 2. Can be used to quantitatively compare different materials by ranking each factor on a 3-point scale: 0 (not suitable) to 2 (superior). The maximum score is 2 points times the number of factors considered. 3. Areas to be evaluated (each area may include one or more factors) a. The purpose is clear, the scope is limited to the purpose, and a summary is provided. b. Literacy demand i. Reading level (a) The desired level for the average population is about the fifth-grade reading level. (b) Various methods, including Flesch-Kincaid, Fry Readability Formula, and Simple Measure of Gobbledygook (SMOG), are available to calculate reading level. One should be aware of the advantages and limitations of the various methods. The calculated reading-grade level can vary depending on the method used (e.g., the Flesch-Kincaid method often results in a lower calculated reading level than other methods). In addition, “reading level” is not a precise concept. (c) Follow the instructions for using the specific tool (e.g., the minimum number of words in the sample to be analyzed). (d) Be cautious when interpreting the results (e.g., the calculation is based on the length of the words and sentences; the assumption that longer words are harder to read and understand is not always true; in addition, the reading level can vary across the document). ii. Writing style: An active voice, using a conversational style and short, simple sentences, is preferred. iii. Vocabulary: Common words are ideally used. Technical words should be limited to keywords that patients should learn. Jargon should be avoided. Examples or definitions should be given for any technical words used. iv. Sentence structure should provide the context for the new information before providing the new information. For example, “To see if your heart function is normal (context), your doctor may perform a test to check (new information)…” v. Content should be organized under headers. c. Graphics i. Type: Illustrations should be real and use familiar images but not distract from the message. Pictures should also be age appropriate. ii. Relevance: Illustrations should present key messages. Borders, backgrounds, and colors should support, rather than distract from, the message.

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iii. Tables, graphs, charts should have the following: (a) Step-by-step instructions, with examples (b) Captions to identify and explain the figure d. Layout should be inviting and easy to read. For example: i. The flow and sequence of the material should be logical. ii. There should be adequate white space. Two (shorter) column texts are preferred to a single (lengthy) column of more than 50 characters in width. iii. Visual cues are used to highlight key points (e.g., arrows, insert boxes). iv. Use low (or no) gloss paper with high contrast to the text. v. Chunk information with bullets and headers, but use no more than five bullets per subheading. e. Typography i. Use sentence case (capitalize only the first word of a sentence). Do not use all capital letters. ii. Font should be readily legible and consistent (e.g., 12-point sans serif font, such as Arial). (a) Boldface or larger font can be used for emphasis. (b) Colored fonts can also be used if they are in sufficient contrast to the paper and not distracting. f. Cultural and gender appropriateness: Images are positive and realistic. Logic, language, and ideas are familiar to the target audience. C. Other Factors to Consider That Are Not Included in SAM Tool (Domain 1) 1. Content: Aspects of content other than health literacy including the following: a. Source is credible. i. The author has suitable expertise or training (e.g., credentials, experience). ii. The sponsoring organization is easily identifiable (e.g., pharmaceutical company, health foundation, or government agency/grant). iii. Facts are easily verified from tertiary sources such as disease guidelines. iv. Ideally, cites the sources and references for the content b. Potential biases are limited and identifiable. i. Any opinions are separate from the evidence and clearly labeled as such. ii. Source of funding, if different from the sponsor, is included (e.g., a foundation grant). iii. Promotes all products in drug class fairly and in similar frequency (a) Appearance in pictures/visuals (b) Inclusion in discussion and examples (c) Discussion in studies and evidence (d) Identifies drugs by generic name with reference to brand name(s) with ® c. Information is current. i. Ideally, lists the date the information was most recently reviewed or updated ii. Dates of the references are within the past 5 years. iii. Content is consistent with current disease guidelines or standards of care. iv. Materials should be reviewed initially and periodically for continued currency. 2. Selecting materials for a comprehensive disease program a. Materials are age appropriate for the target audience. b. Have available a variety of materials for different literacy levels (e.g., low literacy, basic, and high literacy) and across a variety of learning styles (e.g., visual, auditory). c. Select materials across a range of topics. Match content of materials to the desired teaching objectives. d. Consider a focus group from the target audience to provide feedback on the usability of the information.

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D. Other Assessment Tools for Content and Literacy (Domain 1) 1. Other variations of, and scoring sheets for, the SAM tool are available on the Internet. For example: a. Patient Education Materials Assessment Tool (PEMAT): https://www.ahrq.gov/ncepcr/tools/self-mgmt/ pemat.html: Systematic method to evaluate and compare the understandability and actionablility of patient education materials b. PEMAT: This recently published tool contains many criteria similar to those of SAM, such as understandability, layout, and design (www.ahrq.gov/professionals/prevention-chronic-care/improve/ self-mgmt/pemat/pemat-av.html). i. Has an additional domain called “actionability,” which addresses whether the materials encourage, describe, or provide tools for the patient to implement health-related skills and activities ii. Can be used to compare written materials and audiovisual educational materials, such as multimedia presentations 2. The Medical Library Association has published a user’s guide for evaluating medically related websites for the lay public (www.mlanet.org/resources/userguide.html).

III.  ALTERNATIVE METHODS OF COMMUNICATING WITH PATIENTS A. Telephone Tips (Domain 1) 1. Ask for the patient’s preferred phone number and contact them at that number. 2. Before discussing specific patient information, do the following: a. Verify the identity of the caller. b. Ask if this is a convenient time (e.g., if patient is alone and able to talk). c. Protect patient privacy. i. Leave very limited messages. “This is _____, the pharmacist at XYZ pharmacy, with a message for (patient name). Please call me back at (number).” ii. Be aware of whether the telephone number is for a general home phone, personal cell phone, or work phone. 3. Use the teach-back method to verify the correct understanding of messages. 4. For efficiency and consistency, consider developing documentation templates for common encounters in the electronic medical record (e.g., requests for refills, anticoagulation test results). 5. Document the content and results of the interaction in the patient’s medical record. B. E-mail Etiquette (Domain 1) 1. For extra privacy and security, communicating to an individual’s personal account on a Web-based corporate system is preferred to using a patient’s personal e-mail account (i.e., patients send and access messages to and from their health team by a stand-alone personal account on the health system’s website by using a password). 2. Follow the general communication tips in Table 5 (e.g., use plain language, limit amount of content, tailor the message). 3. Apply appropriate criteria from the SAM tool (in section II). For example: a. Literacy demand: Reading level, sentence structure, active voice, and so forth b. Layout: If several points, chunk information with headers and bullets instead of using a paragraph 4. Ask patient to verify by responding to the message. Avoid using request delivery or read receipts. Use teach-back if appropriate. 5. General e-mail etiquette is outlined in Table 14.

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C. Telehealth 1. Look the part. Dress professionally. 2. Be prepared. This includes not only reviewing the patient’s chart ahead of the appointment, but also having ready any equipment that may be needed. 3. Verify with patients that they can see and hear you to ensure effective communication. 4. Establish rapport and communicate empathy. 5. Use technology appropriately. Be aware of body language, even through “virtual” mediums. Maintain eye contact with the camera, not the patient’s image. Table 14. General E-mail Etiquette Balance conciseness with clarity Answer patient questions and anticipate additional questions Be professional • Use correct spelling, punctuation, and grammar • Respond in a timely manner (usually within 24-48 hours) • Do not use medical or texting abbreviations • Restrict to essential information; avoid confidential details • Use complete signature with credentials, organization, position, and contact information • Watch tone to avoid the appearance of being curt or abrupt or the impression that the patient is bothersome • Provide a closure that encourages a follow-up for questions Reread e-mail before sending it Use a clear, meaningful subject in the subject line Do not use e-mail when personal contact is more appropriate Ensure e-mail is compliant with privacy standards before sending any type of information related to a person’s health (e.g., secure send out of information) Silberman L. 25 Tips for Perfecting Your Email Etiquette. Available at www.inc.com/guides/2010/06/email-etiquette.html. Accessed September 26, 2014. Email Etiquette. Available at www.emailreplies.com/. Accessed September 26, 2014.

IV.  COMMUNICATING WITH OTHER HEALTH CARE PROFESSIONALS A. Making Interventions to Implement Medication-Related Recommendations for Patients (Domain 3) 1. Do your homework before making the recommendation. a. Hypothesize the reasons that this situation occurred. Is this likely an oversight or an intended choice by the prescriber? Identifying the possible reasons will help you to anticipate and respond to questions or requests for additional information. b. Is additional information needed to assess the situation, such as blood work or information from the patient history? c. Identify and weigh therapeutic alternatives to identify the best recommendation to resolve the situation. What is the strength of the evidence to support each recommendation? How might the recommendation change depending on the additional patient information requested? d. Consider to whom you will be communicating the recommendation. Knowing your audience will be helpful in framing your recommendation. What will they know or want to know? i. Discipline: Physicians, nurse practitioners, and physician assistants will generally have a different level of knowledge of therapeutics and evidence-based medicine.

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ii. Generalist versus specialist: Is this therapeutic recommendation within or outside their area of specialty? iii. Academic versus nonacademic provider: Academicians may have a greater interest in detailed rationales and the results of clinical research, and they may be open to new evidence. However, they may also be more skeptical of suggestions from those outside their discipline or specialty. iv. Personality of the provider (e.g., confidence in their ability, openness to new ideas) v. Differences in communication styles: According to cultural or ethnic background, age, sex, or generational differences e. Choose an appropriate time: What is the level of urgency? When is a good time to talk? (e.g., “Is this a busy time for you?”) f. What is the optimal method of delivery (e.g., written, verbal, or electronic)? Ideally, verbal recommendations should still be documented as a note in the patient’s medical record. 2. Delivering the message: Be clear, complete, concise, timely, professional, and organized. a. Introduction i. Greet the provider by the preferred method of address. Always use a formal greeting (e.g., Doctor) if a third party is present. ii. Identify yourself and your role, if necessary. iii. The opening should catch the provider’s attention and signal the level of urgency. What do you want the provider to do? b. Define the problem or issue. Support the assessment with patient-specific data. c. Clarify the problem or request additional information. Be prepared to modify your recommendation according to this new information. d. Suggest a solution (with any acceptable alternatives) to the problem. If there are several suitable alternatives, present them objectively. e. Use an appropriate verb according to the strength of your recommendation (e.g., recommend, suggest, consider). f. Provide the rationale and offer evidence to support the recommendation. Clearly separate opinion from published evidence or guidelines. g. Develop rapport while delivering the interventional message. Watch the terminology, tone, and body language. i. If the message is delivered verbally, choose a time that is as convenient as possible (e.g., if nonurgent, wait for the provider to finish current task or ask to speak with the provider after rounds are completed). ii. The message should be patient focused rather than about organizational policy (e.g., explain why your recommendation [based on this policy] would improve the care of this patient). iii. Be calm, respectful, and assertive, but not aggressive. Include patient data to support recommendation. iv. Be tactful. Phrase the recommendation positively. How would this change benefit the patient? v. Be persuasive, but do not overstate the case for change. vi. Use of correct medical terminology, pronunciation, and confident body language will add to credibility. Avoid nervous mannerisms. vii. Revise delivery according to the cues and body language of the provider (e.g., shorten the conversation if the provider appears stressed or hurried). h. Be prepared to modify your recommendation in response to new information or challenges from the provider. i. Answer questions and offer further explanation. Elaborate on justification. ii. Collaborate to identify the best alternative. Sometimes, the best solutions are completely different from the initial recommendations and arise from the synergy between the pharmacist and the provider.

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iii. If the recommendation is partly accepted or rejected, advise whether further or more frequent monitoring might be necessary to avoid future problems. 3. Closure a. Use the check-back technique: Repeat the change in plan or new orders (TeamSTEPPS program) (www. ahrq.gov/professionals/education/curriculum-tools/teamstepps/instructor/essentials/pocketguide.pdf). b. Offer to provide additional information (e.g., copy of clinical study, institutional policy, clinical protocol) or to do a further information search. c. Thank provider for his or her time. 4. Acronym for organized message delivery: SBAR (situation, background, assessment, recommendation) a. S: Situation – Briefly describe the situation or the patient problem. b. B: Background – Add necessary information to understand the problem. c. A: Assessment – Provide an assessment of the problem, such as cause and severity. d. R: Recommendation – Make recommendations to address or resolve the problem. Table 15. Use of SBAR to Organize a Patient-Specific Recommendation Patient Case Example Situation

“Dr. Jones, regarding Mrs. Smith: I am concerned about her potential for hyperkalemia.”

Assessment

“At her age and with her renal function, her potassium concentration could rise pretty quickly during the next several days; there are no current orders to monitor potassium values.”

Background

“Her furosemide dose was cut back by one-half to 20 mg daily today because her edema is better; her current potassium concentration is normal; however, she is still receiving lisinopril 40 mg daily with potassium 20 mEq twice daily, and her estimated creatinine clearance is estimated to be 30 mL/minute/1.73m2.”

Recommendation

“I recommend decreasing her potassium dose to 20 mEq once daily and checking her concentration in 3 days and then again early next week.”

SBAR = situation, background, assessment, recommendation.

Agency for Healthcare Research and Quality (AHRQ) [homepage on the Internet]. TeamSTEPPS® Program. Rockville, MD: AHRQ. Available at http://teamstepps.ahrq. gov/. Accessed September 26, 2014.

5. Special situations a. Dealing with anger, irritation, or frustration i. Stay calm and assertive. ii. Reflect back the emotion (e.g., “So you are feeling frustrated because…”). iii. Keep the focus of conversation on what is best for the patient (vs. personalities). iv. Accept alternative viewpoints. Respect decision-making authority. v. Offer to pass on concerns regarding policies or procedures to those in authority. b. When recommendations are rejected or partly accepted i. Document the initial recommendation made, the provider’s decision, and a brief rationale for the decision. ii. If concerned about the plan, propose compromises to limit the potential for adverse outcomes (e.g., “Because current therapy is to be continued, strongly suggest rechecking potassium in 3 days to be sure it is not still rising”). c. Assertively communicate concerns about safety: TeamSTEPPS program recommends using the CUS technique to structure messages to other team members about potential safety issues. CUS is an acronym for concern, uncomfortable, safety. For example: “I am concerned about… I am uncomfortable that this could… This is a safety issue.” (http://teamstepps.ahrq.gov/)

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Communication Strategies in Pharmacy

B. Providing Health and Educational Programming for Other Health Care Professionals (Domain 3) 1. Tailoring the presentation to the audience a. Content: Specific objectives to be addressed b. Disciplines and level of training of the attendees 2. Logistics: Includes location, room size, available audiovisual equipment, whether the presentation will be virtual or in person, the exact time allotted, deadlines for any slides or handouts, arrival time, reimbursement for travel or expenses, number of attendees 3. Format for the presentation. Examples: Lecture, round table, panel discussion, interactive cases, and question and answer 4. Special circumstances include the following: a. Additional requirements if attendees are to receive continuing education credit b. Whether the presentation is part of a larger conference. Know the topics and credentials of the other presenters. How does this presentation fit in with the other presentations? c. Any particular reasons this topic is of interest to the audience, such as the development of new programs or policies and procedures or the result of a patient care problem

V.  DOCUMENTING IN THE MEDICAL RECORD A. References That Outline Effective Medical Documentation (Domain 1) 1. Psychiatry (Edgmont) 2004;1:26-8 (www.ncbi.nlm.nih.gov/pmc/articles/PMC3010959/pdf/PE_1_3_26.pdf) B. Notes Documented in the Medical Record Should Have the Following Features. (Domain 1) 1. Be clear and concise yet complete. Note should not require further verbal explanation (e.g., “Renewed lisinopril 10 mg daily for 3 months” is better than “Refilled lisinopril x 3”). 2. Be appropriate for all likely target audiences (e.g., prescribers, nurses, physical therapists, dietitians). The 21st Century Cures Act now requires immediate patient access to all medical records, including chart notes. 3. Include the necessary information to be interpreted within the short- and long-term time context in which they were written. For example, “Pending the return of cultures, the empiric antibiotics started are…”; “Awaiting information from the family to clarify drug dose”; “Current first-generation cephalosporin on formulary is…”; “According to the Third Expert Panel Report on Asthma guidelines, suggest…” 4. Include the time and date of the note (unless already electronically time stamped). 5. Write tactfully and persuasively. Document the patient’s concerns, health beliefs, and reasons for declining therapy in a nonjudgmental manner. Objectively document the results of interactions with other health professionals; do not be critical. 6. Use professional terminology and format. a. Avoid abbreviations, especially of drug names. Do not use any abbreviations on The Joint Commission’s “Do Not Use List” (http://www.jointcommission.org/facts_about_do_not_use_list/) and avoid the use of abbreviations on Institute for Safe Medication Practices (ISMP)’s error-prone abbreviation list when possible (available at www.ismp.org/Tools/errorproneabbreviations.pdf). b. Follow the institutional or corporate norms and conventions. Many institutions use a subjectiveobjective-assessment-plan (i.e., SOAP) format. However, this format has many variations. For example, all disease/problem assessments may be written together, followed by the disease plans for all problems, or alternatively, the assessment and plan for each problem may be grouped together.

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Communication Strategies in Pharmacy

7. Document in a timely manner. a. Ideally, charting should be completed at the end of each patient visit or as soon as the encounter has ended. Notes become increasingly less credible the longer the time between the encounter and the writing of the note. It is easy to forget or confuse details regarding the encounter. b. Payment claims may be rejected if submitted 24 hours or more after the encounter. c. In paper charts, notes should immediately follow the most recent note. Do not leave room for others to write their notes. 8. Be transparent when making addendums, corrections, or changes. a. Reasons for addendums, updates, or changes to the chart should be explained (e.g., “Dose of atorvastatin was clarified with community pharmacy as 20 mg daily [not 10 mg daily]).” b. Errors or modifications i. In paper charts (a) For small errors: Draw a single line through the error and continue writing. Do not use correction fluid, heavily cross out, write over, or erase. (b) For larger modifications: If a note has already been completed, an addendum (or a revised note) may need to be generated. The original note is left in the chart, perhaps with a comment showing the date of the revised note. Provide an explanation, if needed (e.g., started note in wrong patient chart). (c) Initial and date the correction. Even if the error was made at the time of the entry, the correction should be initialed and dated. ii. In electronic charts, a separate addendum is generally required. 9. Record formal names and the disciplines of the colleagues involved (e.g., “Referred to S. Jones, RD, for diabetes diet instruction”). 10. Include documentation of even brief interactions, such as telephone calls. 11. Write legibly in paper charts. Be especially careful with writing numbers and inserting decimal points. Rather than squeezing in information, start a new page. 12. Tips for electronic charting a. Developing and using practitioner-specific templates for common types of patient encounters can assist in the efficiency and completeness of documentation. b. Be cautious when routinely cutting and pasting information and assessments from previous notes. For example, do not recopy physical findings unless the physical examination was actually repeated or the actual date of the finding is documented. c. Reread notes carefully before submitting to avoid addendums. Do not rely on automatic spell-check. d. Institutions may encourage practitioners to begin or complete patient notes during the patient encounter to improve the efficiency and timeliness of documentation. However, using the computer during the encounter should not impede patient-practitioner communication (e.g., decrease eye contact, increase physical distance between practitioner and patient). Patient Case 6. A pharmacist is documenting a patient order change for morphine sulfate in her medical record. Which method of writing the order would be most consistent with the Joint Commission’s recommendations? A. B. C. D.

“Morphine sulfate 10.0 mg IV q 6 hours for pain.” “MSO4 10 mg IV every 6 hours for pain.” “Morphine sulfate 10 mg intravenously every 6 hours for pain.” “MSO4 10.0 mg intravenously q 6 hours for pain.”

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Communication Strategies in Pharmacy

C. Documenting Educational Assessments and Interventions (Domain 1) 1. Subjective data obtained from patient interviews, medication histories, and results of medication reconciliation should be documented in the medical record as discussed previously (e.g., adherence behaviors, results of SILS or other health literacy assessments, misperceptions, personal goals and health beliefs about medications, preferred learning styles). 2. List the educational content, skills taught, and verification of the patient’s understanding at the highest level appropriate for that content. a. “Patient verbalized/indicated understanding of…” is generally an inadequate verification of understanding. “Indicated” could merely mean the patient nodded, said “I understand,” or just did not have any questions. b. The minimum level of understanding that should be documented is comprehension (e.g., results from teach-back method). For example, “The patient repeated the new warfarin dose and that she is to return for blood work next week.” c. Ideally, any required skills should be demonstrated by the patient (e.g., using the show-me technique). For example: “Patient correctly showed 8-mg dose from combination of 5-mg and 1-mg warfarin tablets.” “Patient obtained an adequate blood sample and correctly recorded the blood glucose reading.” d. If the instructions are situation-dependent, the documentation should state the patient’s ability to apply the information (e.g., “Given peak flow and symptoms, patient was able to identify the correct zone and corresponding activities on the asthma action plan”). 3. Document both the educational message and the implications for adherence/nonadherence if applicable. For example, “Patient voiced reluctance to return for blood monitoring. Explained the importance of frequent blood work and medication adjustments to minimize the risk of significant bleeding.” 4. Further educational needs and plans for follow-up. Note the patient’s level of difficulty or ease in learning new skills and any particular steps with which the patient struggled. For example: “Patient demonstrated correct inhaler technique on first attempt” or “Patient struggled with timing of the inhalation to the release of medication.” 5. Any specific educational materials or resources such as written pamphlets given (e.g., title and source of material, referrals to websites or support groups). For example: “Patient given American Heart Association pamphlet ‘What Is Hypertension?’” If several versions exist, the version or revision date should be noted. Patient Case 7. A pharmacist is counseling a patient on his or her new insulin regimen. Which would be the best way to document the patient’s full understanding of how to use the sliding-scale insulin in the medical record after the session? The patient: A. B. C. D.

Correctly repeated insulin dose and demonstrated injection technique. Verbalized understanding of dose, route, frequency, and injection technique. Described sliding-scale insulin dosage and the correct injection technique. Showed injection technique and calculated dose for hypothetical blood glucose.

D. Documenting Therapeutic Assessments and Making Persuasive Recommendations (Domain 3) 1. Provide sufficient patient data to support the assessment and plan. 2. Assessments should be clear and consistent with patient’s data. Use appropriate terminology for the disease (e.g., “Patient has stage II hypertension, uncontrolled to goal pressure of…” “Carvedilol is an appropriate β-blocker for heart failure, but current dose is below target of…”). a. Use of ICD-10 terminology b. Complete assessments will support higher billing codes based on patient acuity

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Communication Strategies in Pharmacy

3. Making written recommendations a. Use the active voice whenever possible. The note should reflect the writer’s professional opinion, not that of others. For example, “I recommend…” versus “It was decided…” b. Choose a verb that corresponds to the strength of the recommendation (e.g., recommend, suggest, advise, consider). c. Be specific (e.g., the complete drug regimen, the person who will follow up, what blood work was ordered, time frame for monitoring). d. Clearly document the results of the recommendations; for example: i. Whether recommendations were accepted and whether there were any order changes ii. When recommendations are partly accepted or rejected (a) Document respectfully and objectively. As stated previously, the active voice is usually preferred. However, the passive voice can be useful in situations when one wants to document one’s recommendation and acknowledge provider’s decision without reflecting one’s agreement with it. For example, “Suggested that the ramipril dose be decreased to 5 mg because of rising serum potassium (now at 5 mEq/L). Checked with Dr. Jones. Ramipril to be continued at same dose (10 mg) at this time. Serum potassium to be checked again tomorrow.” (passive voice) (b) Document actions taken to limit the potential for adverse effects. “Verbal order from Dr. Jones to recheck potassium in 3 days and decrease the ramipril to 10 mg daily if still greater than 5 mEq/L.”

VI.  OPPORTUNITIES FOR PATIENT ADVOCACY OUTSIDE THE HEALTH CARE SYSTEM Many people without medical training will be in a position to make decisions about or influence health-related policies (e.g., legislators, school board members, news reporters) but will lack adequate health literacy (i.e., civic domain of health literacy). Pharmacists should seek opportunities to positively influence public policy for safe and efficacious medication use. A. Collaborate with Professional Organizations (e.g., American College of Clinical Pharmacy, American Pharmacists Association, American Society of Health-System Pharmacists, state associations) and Disease Advocacy Groups (e.g., American Lung Association, American Heart Association, American Cancer Society) for legislative days in your state. These groups may also offer training sessions beforehand on how to effectively speak to legislators. (Domain 3) B. Offer to Speak in Public Forums such as town hall or school board meetings on timely topics of interest to the organization as a private citizen, or provide a presentation as a medical expert. (Domain 3) C. Letters to the Editor: These are usually short (100–250 words) and in response to a recent news story. Tips for writing letters are available online (http://ctb.ku.edu/en/table-of-contents/advocacy/direct-action/letters-to-editor/ main). (Domain 3) 1. Follow the organization’s guidelines for length and submission. 2. If the letter is in response to a recent article, include the date and title of the article. 3. Keep a copy of the letter to see whether it was edited when it appeared. 4. Include full contact information. Papers will print the author’s name and city, but most will not print anonymous letters. 5. Choose topics important to you. Most papers will not print letters from the same person more than every few months.

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Communication Strategies in Pharmacy

D. Opposite the Editorial Pieces (also known as “op-ed” pieces) (Domain 3) 1. Can be influential and highly visible in local newspapers. Often written in response to the paper’s editorial or can be unsolicited on a timely topic. 2. A limitation is that only a few are published compared with letters to the editor. a. Timing is critical. Today’s top story is old news tomorrow. Submit quickly if you wish to respond to an editorial or hot news item. If a topic is likely to be brought up in the near future, you might draft a piece in anticipation and then tailor it to the actual event. b. Be concise and to the point. Keep the length to a maximum of 600–750 words. c. Make one carefully crafted main point. Be clear and accurate with facts and evidence. d. Help the readers care about the issue. A personal story about yourself or a patient situation provides human interest. (Be careful to protect patient privacy in examples.) Use an example that readers can understand and that is memorable. e. Write it for a lay audience: Follow the suggestions in the Health Literacy section on written materials (e.g., use short sentences and common words, avoid jargon and abbreviations, use an active voice). f. Follow the rules and guidelines from the newspaper or media source (e.g., length, to whom it is sent, whether or not to use an attachment, preferred method of submission). g. Write a cover letter with key points, state why this topic is timely, and provide your credentials. h. Make a favorable first impression and a memorable last impression. A catchy opening grabs attention, and a good closing is what the reader may remember. E. Letters to Legislators and Senators (Domain 3) 1. Follow guidelines similar to those for letters to the editor with respect to length, style, and preference for electronic submission. 2. Be aware that politicians usually accept only letters from their constituents. 3. Use the appropriate form of address. For example: The Honorable… 4. Note clearly in your letter if your communication is in response to a particular piece of legislation (e.g., House Bill No. —). 5. Include a clear recommendation to support or oppose the legislation. 6. In closing, provide your credentials and contact information with an offer to provide more information if necessary. F. A Speaker’s Bureau for Your Organization: Hospitals and corporations may have public relations/media departments that keep a list of employees who are able to comment on various health-related topics. As issues arise, reporters may contact these organizations when looking for experts to comment. Training by the organization may be provided to learn how to effectively speak to the media. (Domain 3) Practice Points • Assessing a patient’s health literacy, learning style, and barriers to adherence enables pharmacists to adapt educational messages to best meet the patient’s needs. • Obtaining a thorough patient history, including using active listening and motivational interviewing skills, will uncover educational gaps in knowledge and aid in relationship building. • Communication with other health care providers should be clear, concise, and professional.

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Agency for Healthcare Research and Quality (AHRQ). Health Literacy Measurement Tools: Rapid Estimate of Adult Literacy in Medicine Short Form (REALM-SF). Available at www.ahrq. gov/professionals/quality-patient-safety/qualityresources/tools/literacy/index.html. Accessed September 26, 2014. Agency for Healthcare Research and Quality (AHRQ). Patient Education Materials Assessment Tool for Audiovisual Materials (PEMAT-AV): How to Use the PEMAT to Assess a Material. Version 1.0. Available at www.ahrq.gov/professionals/preventionchronic-care/improve/self-mgmt/pemat/pemat-av. html. Accessed September 26, 2014. Agency for Healthcare Research and Quality (AHRQ) [homepage on the Internet]. TeamSTEPPS® Program. Available at http://teamstepps.ahrq.gov/. Accessed September 26, 2014. Berger BA, Villaume WA. Motivational Interviewing for Health Care Professionals. Washington, DC: American Pharmacists Association, 2013. Centers for Disease Control and Prevention (CDC). Improving Health Literacy for Older Adults: Expert Panel Report 2009. Atlanta: U.S. Department of Health and Human Services, 2009. Available at www. cdc.gov/healthliteracy/pdf/olderadults.pdf. Accessed November 23, 2016. Centers for Disease Control and Prevention (CDC). Plain Language Thesaurus. Available at http:// depts.washington.edu/respcare/public/info/Plain_ Language_Thesaurus_for_Health_Communications. pdf. Accessed September 26, 2014. Centers for Medicare & Medicaid Services (CMS). Toolkit for Making Written Materials Clear and Effective. Part 7. Using Readability Formulas: A Cautionary Note. 2012. Available at www. cms.gov/O ut reach-a nd-E ducat ion /O ut reach / WrittenMaterialsToolkit/downloads/toolkitpart07. pdf. Accessed September 26, 2014. Champion VL, Skinner CS. The health belief model (Chapter 3). In: Glanz K, Rimer BK, Viswanath K, eds. Health Behavior and Health Education: Theory, Research, and Practice, 4th ed. San Francisco: John Wiley & Sons, 2008:45-62. Available at. www. med.upenn.edu/hbhe4/part2-ch3.shtml. Accessed September 26, 2014.

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Community Tool Box. Writing Letters to the Editor. Available at http://ctb.ku.edu/en/table-of-contents/ advocacy/direct-action/letters-to-editor/main. Accessed September 26, 2014. Conn VS, Taylor SG, Kelley S. Medication regimen complexity and adherence among older adults. Image J Nurs School 1991;23:231-5. Consumer Health Informatics Research Resource. Health Literacy. Available at http://chirr.nlm.nih.gov/ health-literacy.php. Accessed September 29, 2014. DeWalt DA, Callahan LF, Hawk VH, et al. Health Literacy Universal Precautions Toolkit. AHRQ Publication 10-0046-EF. Rockville, MD: Agency for Healthcare Research and Quality, 2010. Available at www.ahrq.gov/legacy/qual/literacy/. Accessed September 26, 2014. Doak CC, Doak LG, Root JH. Chapter 4: Suitability assessment of materials. In: Teaching Patients with Low Literacy Skills, 2nd ed. Philadelphia: JP Lippincott, 1996:41-61. Available at http://www. ahrq.gov/sites/default/files/wysiwyg/professionals/quality-patient-safety/quality-resources/tools/ literacy-toolkit/healthliteracytoolkit.pdf. Accessed September 9, 2016. Duke University. How to Write an Op-ed Article. Available at http://newsoffice.duke.edu/duke_ resources/oped.html. Accessed September 9, 2016. Fairleigh-Dickinson University. Want to Write an Op-ed Piece? Available a thttps://people.emich.edu/ aross15/math110/socsec/opinion/fdu.html. Accessed September 9, 2016. Farris KB, Phillips BB. Instruments assessing capacity to manage medications. Ann Pharmacother 2008;42:1026-36. Finkbeiner N, Braun B. University of Maryland Extension Materials Assessment Tool. College Park, MD: University of Maryland Extension. Available at http://extension.umd.edu/sites/default/files/_images/ programs/insure/University%20of%20Maryland%20 Materials%20Assessment%20Tool%203-13.pdf. Accessed September 26, 2014. Frankel RM, Stein T. Getting the most out of the clinical encounter: the Four Habits Model. Permanente J 1999;3:79-88.

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19. Fraser Health. Symptom Assessment Acronym. Available at www.fraserhealth.ca/media/ SymptomAssessmentRevised_Sept09.pdf. Accessed September 29, 2014. 20. Grice GR, Prosser TR, Gattas N, et al. Patient-Centered Communication Tools. Available athttp://stlcop.edu/ health-literacy/pact.html. Accessed September 9, 2016. 21. Gutheil TG. Fundamentals of medical record documentation. Psychiatry (Edgmont) 2004;1:26-8. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC3010959/pdf/PE_1_3_26.pdf. Accessed September 26, 2014. 22. Horne R. Concordance, Adherence and Compliance in Medicine Taking. Report for the National Coordinating Centre for NHS Service Delivery and Organization R & D. December 2005. Available at www.nets.nihr.ac.uk/__data/assets/ pdf_file/0009/64494/FR-08-1412-076.pdf. Accessed September 26, 2014. 23. Institute of Medicine (IOM). Health Literacy: A Prescription to End Confusion. Washington, DC: National Academies Press, 2004. Available at www. nap.edu/catalog.php?record_id=10883. Accessed September 26, 2014. 24. Kafka VW, Schaefer JH. Working Relationships: Everyone’s Guide to Working with People. Moraga, CA: Effective Learning Systems Press, 1990. 25. Kutner M, Grenberg E, Jin Y, et al. The Health Literacy of America’s Adults: Results from the 2003 National Assessment of Adult Literacy. Washington, DC: U.S. Department of Education, 2006. National Center for Education Statistics. Publication NCES 2006-483. 26. Lieberman JA, Stuart MR. The BATHE method: incorporating counseling and psychotherapy into the everyday management of patients. Prim Care Companion J Clin Psychiatry 1999;1:35-8. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC181054/ pdf/i1523-5998-001-02-0035.pdf. Accessed September 26, 2014. 27. McHorney CA. The Adherence Estimator: a brief proximal screener for patient propensity to adhere to prescription medications for chronic disease. Curr Med Res Opin 2009;25:215-38. 28. Medical Insurance Exchange of California. Medical Record Documentation for Patient Safety and Physician Defensibility. Available at www.miec.com/

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Portals/0/pubs/MedicalRec.pdf. Accessed September 26, 2014. Medical Library Association. A User’s Guide to Finding and Evaluating Health Information on the Web. Available at www.mlanet.org/resources/userguide.html. Accessed September 26, 2014. Morisky DE, Ang A, Krousel-Wood M, et al. Predictive validity of a medication adherence measure in an outpatient setting. J Clin Hypertens 2008;10:348-54. Morris L, Schulz RM. Medication compliance: the patient’s perspective. Clin Ther 1993;15:593-606. Morris NS, MacLean CD, Chew LD, et al. The Single Item Literacy Screener: evaluation of a brief instrument to identify limited reading ability. BMC Fam Pract 2006;7:21. National Education Association. Writing to Your Legislators. Available at www.nea.org/home/19657. htm. Accessed September 30, 2014. National LGBT Health Education Center. Providing Inclusive Services and Care for LGBT People. Available at https://www.lgbtqiahealtheducation.org/ wp-content/uploads/Providing-Inclusive-Servicesand-Care-for-LGBT-People.pdf. National Patient Safety Foundation (NPSG). Ask Me 3. Available at www.ihs.gov/health c o m m u n i c a t i o n s /d o c u m e n t s /A s k M e _ 8 - pg _ NatAmer.pdf. Accessed September 26, 2014. Nau DP. Proportion of Days Covered as Preferred Method Measuring Medication Adherence. Available athttp://www.pqaalliance.org/images/uploads/files/ PQA%20PDC%20vs%20%20MPR.pdf . Accessed October, 1 2014. North Carolina Program on Health Literacy. Literacy Assessment Instruments. Available at www.nchealthliteracy.org/instruments.html. Accessed September 26, 2014. North Los Angeles County Regional Center. Sample Letter That You Can Use to Write to Your Legislator. Available at https://www.nlacrc.org/modules/showdocument.aspx?documentid=272. Accessed September 30, 2014. Prochaska O, Redding CA, Evers KE. Transtheoretical model and stages of change. In: Glanz K, Rimer BK, Viswanath K, eds. Health Behavior and Health Education: Theory, Research, and Practice, 4th ed. San Francisco: John Wiley & Sons, 2008:97-119.

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40. Rollnick S, Miller WR, Butler CC. Motivational Interviewing in Health Care. New York: Guilford Press, 2008. 41. Schirmer JM, Mauksch L, Lang F, et al. Assessing communication competence: a review of current tools. Fam Med 2005;37:184-92. 42. Silberman L. 25 Tips for Perfecting Your Email Etiquette. Available at www.inc.com/guides/2010/06/ email-etiquette.html. Accessed September 26, 2014. 43. Stein T, Krupat E, Frankel RM. Talking with Patients Using the Four Habits Model [monograph on the Internet]. Oakland, CA: Madison Street Press, 2011. Available at www.madisonstreetpress.com/monograph.shtml. Accessed September 26, 2014. 44. Streacher VJ, DeVellis BM, Becker MH, et al. The role of self-efficacy in achieving health behavior change. Health Educ Q 1986;13:73-9. 45. The Joint Commission. Facts About the Official “Do Not Use List.” Available at https://www.jointcommission.org/facts_about_do_not_use_list/ Accessed September 9, 2016. 46. The Joint Commission. Hospital National Patient Safety Goals. Available at https://www.jointcommission.org/standards_information/npsgs.aspx /. Accessed September 9, 2016. 47. U.S. Department of Health and Human Services (DHHS). The National CLAS Standards. Available atht t p://m inor ityhea lth.h hs.gov/om h / browse. aspx?lvl=2&lvlid=53 . Accessed September 9, 2016. 48. Vouri SM, Marcum ZA. Use of a medication reconciliation tool in an outpatient geriatric clinic. J Am Pharm Assoc. 2013;53:652-8. 49. Weiss BD, Mays MZ, Martz W, et al. Quick assessment of literacy in primary care: the Newest Vital Sign. Ann Fam Med 2005;3:514-22. 50. Wolf MS, Davis TC, Tilson HH, et al. Misunderstanding of prescription drug warning labels among patients with low literacy. Am J Health Syst Pharm 2006;63:1048-55. 51. Zarcadoolas C, Pleasant A, Greer DS. Understanding health literacy: an expanded model. Health Promot Int 2005;20:195-203.

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ANSWERS AND EXPLANATIONS TO PATIENT CASES 1. Answer: C An open-ended question is best used to open a discussion about the patient’s chief concern. Leading and closedended questions (Answer A) should be avoided. Answer B and Answer D are more focused questions, which are better saved for later in the conversation.

likelihood of continued adherence moving forward. The Health Belief Model may be useful to assess reasons for nonadherence, but it does not predict continued adherence (Answer D). 6. Answer: C According to The Joint Commission recommendations, abbreviations, especially those for drug names (MSO4), should be avoided. Trailing zeros (10.0) should not be used with drug doses. Other abbreviations should be avoided (IV, q).

2. Answer: D When dealing with emotions such as anger, it is usually best to first reflect back the emotion and acknowledge the patient’s concerns or complaints. Once this patient believes his concern is understood, he may be willing to listen to one of the other responses as a reason for what appears to him to be a delay in resolving his problem.

7. Answer: D In this case, documentation should include both the ability to perform the necessary skill (i.e., injection) and to apply the sliding scale to calculate a situation-specific dose. Answers A, B, and C are limited to comprehension of the dosing scale and/or technique.

3. Answer: A Patients who respond to the SILS question by stating that they sometimes, often, or always ask others to help them read medical information are considered at risk of inadequate health literacy (either Answer A or Answer C). This patient was able (with some difficulty) to correctly calculate the correct dose when given the specific numbers to use, and only very simple arithmetic was necessary. So he is likely at NAAL level 2 (basic level) (Answer A). Those at level 3 would be able to identify which numbers to use and perform basic calculations (e.g., calculate a pediatric dosage from a chart). 4. Answer: D Adults older than 65 years are at higher risk of inadequate health literacy. Other risk factors are less than a high school education and low income. This patient completed high school, and he is part of the middle class. One should not assume English is the patient’s second language on the basis of his or her ethnicity. It should not be automatically assumed that all in minority groups have low health literacy. 5. Answer: C The Adherence Estimator is a useful tool to assess a patient’s perception of concern, commitment, and cost of an individual medication. Adverse perceptions of a medication likely discourage continued adherence and could therefore be areas for tailored educational messages (Answer C correct). Answer A and Answer B would be ways to assess his past adherence, but would not assess the

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Communication Strategies in Pharmacy

ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS 1. Answer: B Because this routine maintenance medication therapy management is not an emergency, it would be best to use a professional interpreter according to the guidelines for using medical interpreters by the Association of American Medical Colleges. Therefore, only Answer B is the best option of those given.

they would usually be less interested in cost, dosing, formulary status, or pharmacokinetics. Thus the most correct option would be Answer A. 6. Answer: A U is listed on the ISMP error-prone abbreviations list and should not be used if possible. Units is the preferred way to note the insulin dose. The term QD (daily) is also listed on the ISMP list and is often mistaken as QID (four times a day) and should not be used; daily is preferred. The Joint Commission does not state a preference with respect to HS versus bedtime; however, ISMP lists this on the error-prone list because it is often confused with half-strength and, in general, these abbreviations should be avoided.

2. Answer: B The Morisky and the Adherence Estimator questionnaires are both methods to assess the likelihood of adherence. However, only the Morisky questionnaire is intended to evaluate adherence to one or more drugs in a regimen for a particular disease. The Adherence Estimator is used only with individual drugs. The BATHE technique or Motivational Interviewing may help identify reasons for nonadherence, but neither assesses the likelihood of adherence.

7. Answer: D Responses to editorials of between 300 and 750 words are suitable for placement opposite the editorial (or op-ed piece). Letters to the editor can be used to respond to editorials, but they receive less visibility and generally should be fewer than 250 words. The school board would appreciate the support. Ideally, however, the pharmacist’s comments should reach the same readership as the newspaper’s original editorial. Sending them to the school board would not achieve this.

3. Answer: C This patient is able to identify facts from dense text (the package insert) and perform simple calculations, so he is at least at the intermediate literacy level. Because he is having trouble integrating and applying information from several sources, he is unlikely to be considered proficient. 4. Answer: C The PEMAT tool would be most appropriate because it was specifically designed for assessing the usability of audiovisual materials. The SAM tool has similar criteria, but it was designed originally for written materials. Obtaining feedback from either knowledgeable colleagues or typical patients would be useful, but this may not provide a comprehensive assessment of usability. 5. Answer: A Whereas health care professionals typically learn at least some of the aspects of medication therapy, audiences are usually most interested in information related to their job responsibilities. Physical therapists would want to know the neuromuscular effects of a medication and their potential impact on patient movement. For example, the adverse effects of dizziness, hypotension, or sedation might impair a patient’s ability to participate in physical therapy sessions. Because these professionals are typically not responsible for prescribing or administering pain-related medications,

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 658

Developing and Managing a Clinical Practice Elizabeth Van Dril, Pharm.D., BCPS, BCACP, CDCES University of Illinois at Chicago College of Pharmacy Chicago, Illinois

Previous Author: Mary Ann Kliethermes, Pharm.D., FAPhA, FCIOM American Society of Health-System Pharmacists Bethesda, Maryland

Developing and Managing a Clinical Practice

Developing and Managing a Clinical Practice Elizabeth Van Dril, Pharm.D., BCACP, CDCES University of Illinois at Chicago College of Pharmacy Chicago, Illinois

Previous Author: Mary Ann Kliethermes, Pharm.D., FAPhA, FCIOM American Society of Health-System Pharmacists Bethesda, Maryland

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 661

Developing and Managing a Clinical Practice

Learning Objectives 1. Perform an internal and external environmental scan and needs assessment to determine the need for and organizational value of an ambulatory pharmacist–provided patient care service. 2. Discuss steps to implement an ambulatory service, including identifying key stakeholders and developing essential clinic operational activities. 3. Develop a robust and sustainable quality assessment program using the balanced scorecard concept for your clinical service and identifying quality measures important to your organization and patient population. 4. Develop a credentialing and privileging process to ensure the competency of pharmacists providing direct patient care in your ambulatory service. 5. Identify and implement revenue-generating opportunities for pharmacist-provided patient care services in different ambulatory care settings. Abbreviations in This Chapter

PCM PCMH PDP PDSA PFS QHP QPP RVU SWOT

ACO APC APM AWV BCACP

Accountable care organization Ambulatory Payment Classification Alternative Payment Model Annual wellness visit Board Certified Ambulatory Care Pharmacist CCM Chronic care management CLIA Clinical Laboratory Improvement Amendments CPA Collaborative practice agreement CPT Current Procedural Terminology E/M Evaluation and management EHR Electronic health record FFS Fee-for-service FQHC Federally qualified health center HCPCS Healthcare Common Procedural Coding System HEDIS Healthcare Effectiveness Data and Information Set HIPAA Health Insurance Portability and Accountability Act HOPPS Hospital Outpatient Prospective Payment System IPPE Initial preventive physical examination IT Information technology MAC Medicare administrative contractor MACRA Medicare Access and CHIP Reauthorization Act MDPP Medicare Diabetes Prevention Program MIPS Merit-Based Incentive Payment System MSSP Medicare Shared Savings Program MTM Medication therapy management NPI National Provider Identifier

TCM

Principal care management Patient-centered medical home Prescription drug plan Plan, do, study, act Physician Fee Schedule Qualified health care professional Quality Payment Program Relative value unit Strengths, weaknesses, opportunities, threats Transitional care management

Baseline Knowledge Statements Readers of this chapter are presumed to have a basic understanding of the following: • Different types of patient care services that pharmacists provide in the ambulatory setting • Pharmacy services management and standard business terms • Health care structure and operations in the ambulatory setting • Purpose of team-based care, key team members, and team members’ roles • Quality measurement and its importance in the current health care environment • Importance of pharmacist competency in sustaining a practice • Health care payment and reimbursement processes

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 662

Developing and Managing a Clinical Practice

C. Determine the payer mix and current reimbursement opportunities for pharmacist-provided patient care services. D. Focus on your specific training and strengths, such as detailing your role and service in diabetes patient care.

Additional Readings The following resources have additional background information on the topics included in this chapter: • Bodenheimer T. Anatomy and physiology of primary care teams. JAMA Intern Med 2019;179:61-2. • Centers for Medicare & Medicaid Services (CMS). MLN Publications. Available at www. cms.gov/Outreach-and-Education/MedicareLearning-Network-MLN/MLNProducts/ MLN-Publications. • Kliethermes MA, Brown TR, eds. Building a Successful Ambulatory Care Practice: Advancing Patient Care, 2nd ed. Bethesda, MD: American Society of Health-System Pharmacists, 2019. • Schumock GT, Stubbings J. How to Develop a Business Plan for Pharmacy Services, 3rd ed. Lenexa, KS: American College of Clinical Pharmacy, 2018. • Zgarrick DP, Desselle SP, Moczygemba LR, et al., eds. Pharmacy Management: Essentials for All Practice Settings, 5th ed. McGraw Hill, 2020.

2. You recognize that the success of your service depends on the efficiency of your workflow and how effectively it integrates with the workflow of other providers. Which is the optimal implementation strategy for your proposed daily workflow in the clinic?

A. Perform all patient scheduling for the services you provide to prevent losing patients to follow-up. B. Use the clinic’s patient service representatives to perform patient scheduling services. C. Develop a rigid patient visit schedule set at 45 minutes for new patient visits and 30 minutes for follow-up appointments. D. Establish a separate referral process from providers in the ACO to control your schedule.

3. You are developing a Centers for Disease Control and Prevention (CDC)-recognized diabetes prevention program for your community pharmacy. When performing an analysis for strengths, weaknesses, opportunities, and threats (SWOT), which is the best opportunity for you to develop and create the program?

Self-Assessment Questions Answers and explanations to these questions can be found at the end of the chapter.

A. Hiring a new pharmacist with a community postgraduate year one residency (PGY1) and an interest in diabetes management. B. Remodeling your pharmacy for immunizations with a private area to perform the service. C. Identifying that a large percentage of your patient population is of Southeast Asian descent, which is the fastest-growing population with diabetes in the United States. D. Reviewing billing codes that exist for this service, though you have not calculated whether this avenue for directly generating revenue will cover the program costs.

Questions 1 and 2 pertain to the following case. An accountable care organization (ACO) recently hired you as the first clinical pharmacist for its internal medicine clinic. Providers have been overwhelmed with the number and complexity of the medication-related problems in their patient population. They believe they need a pharmacist’s skills; however, they are unclear about your role and service and ask you to develop a proposal. 1. Which is the most important first step in preparing your service proposal?

A. Do an external environmental scan to determine which types of services others have provided to a similar population. B. Do an internal environmental scan to determine which type of medication problems patients are experiencing.

4. To produce the desired health outcomes, pharmacists can use a business tactic known as the balanced scorecard. Which group of organizational measures best reflects a balanced scorecard?

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 663

Developing and Managing a Clinical Practice

use to assure your organization that the best hire has been made?

A. Percentage of providers trained in correct blood pressure measurement technique; percentage of patients with blood pressure values documented at each visit; percentage of blood pressure values less than 140/90 mm Hg; performance reimbursement for meeting blood pressure value goals. B. Number of errors made in computerized provider order entry system; patient satisfaction scores; hospital readmissions for heart failure; weight documentation in chart. C. Number of faxes versus electronic medical record use for communication with the laboratory; A1C values less than 8%; adherence rates to oral antihyperglycemic medications; number of diabetes visits per month per patient. D. “Incident-to” evaluation and management (E/M) code revenue; number of referrals for smoking cessation; documentation of smoking cessation education; maintenance of Board Certified Ambulatory Care Pharmacist (BCACP) credentials.

A. B. C. D.

BCACP credentials. Postgraduate year two (PGY2) training. Peer review of services at 90 days. Medication therapy management (MTM) training certification.

7. You are a pharmacy director of a community hospital that lost 3% of its Medicare revenue this past year because of the readmission penalty. To rectify this problem, the hospital has a strategic plan to improve its ambulatory care presence. You have pharmacists currently in the ambulatory clinic attached to the hospital; however, you have not pursued billing for their services. You believe the current pharmacists’ services will meet the intent of the new strategic plan, but you also know that the ability to generate revenue directly will be a key component in sustaining these services. Which group of codes will be most beneficial to pursue in sustaining and potentially growing these services? A. 99605–99607 MTM service codes. B. 99211–99215 incident-to E/M codes. C. Ambulatory Payment Classification (APC) 5012, G0463 facility fee codes. D. APC 5011, Current Procedural Terminology (CPT) 99490 chronic care management (CCM) codes.

5. Your organization is moving toward value-based payment models and recently became part of the Medicare Shared Savings Program (MSSP). To sustain your services within the organization, you want to ensure that you are contributing to the quality measure set for this Medicare-based Alternative Payment Model (APM). Which measure set is best to review? A. Healthcare Effectiveness Data and Information Set (HEDIS) measures. B. Merit-Based Incentive Payment System (MIPS) measures. C. Interoperability measures. D. ACO measures.

8. Which billing opportunity is currently best for a physician group to use to generate revenue for patient services performed by pharmacists under general supervision? A. B. C. D.

6. Your practice is growing and needs another pharmacist practitioner. Your physician partners have clearly stated their desire for the new hire to have the same level of skills as you in order for them to be comfortable in extending the collaborative practice agreement (CPA) to that practitioner. The risk management team is also concerned with consistency and the same standard of practice and skill. To mimic what the organization uses to ensure highly competent physicians, nurse practitioners, and physician assistants, you develop a credentialing and privileging program for patient care pharmacists. Which tactic is best to

MTM codes. CCM codes. Incident-to codes. Wellness visits.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 664

Developing and Managing a Clinical Practice

I.  IDENTIFYING THE NEED FOR AN AMBULATORY CLINICAL PHARMACY PROGRAM AND ASSOCIATED PATIENT CARE SERVICES (Domain 3, Task 3, Item c) Practice Case 1. You recently completed a residency with an ambulatory care focus and have been hired by the pharmacy department of a health system to start ambulatory services. The health system has an outpatient clinic with primary care and medical specialty services. Historically, the pharmacy department has only provided inpatient services to the organization. The health system’s goal is to expand into ambulatory care in preparation for value-based payment contracts. The director of pharmacy asks you to develop a plan regarding which service would be best to start with: transitional care, MTM, polypharmacy management, or specialty services. Which is your best first step? A. B. C. D.

Review the literature on successful practices for each service. Pursue transitional care services because you had a residency rotation on these. Choose specialty services because of the associated use of high-cost medications. Perform a gap analysis to determine which services are most needed in the organization.

Note: Although the information in this chapter is presented in a certain order, the work described in each section should occur simultaneously as you develop your clinical practice. Please review a suggested timeline in the chapter as a guide to integrating each of these steps as you develop plans for your clinic. In addition, in this document, the terminologies for program and services are differentiated such that a pharmacy program is used to describe the complete set of clinical pharmacy services you plan to offer. In some instances, this offering may only be one service, such as anticoagulation; in others, it may be a variety of services, from MTM to transitional care, wellness, and other services. A. Internal Environmental Scan 1. Perform an internal environmental scan to develop a successful clinical pharmacy program. a. In developing a successful clinical pharmacy program, the initial step is doing the necessary background research and thoroughly evaluating your practice setting. b. It is essential to fully understand the current and future needs of your setting as you start planning your ambulatory patient care services. 2. Become organized by evaluating and prioritizing your opportunities with consideration of the following important factors: a. Gap analysis i. Gap analysis is the comparison of what is presently occurring with what is desired to occur. ii. Perform a gap analysis to determine the services that are needed but not currently provided or those that do not meet the needs of the patients, clinic, or organization. b. Prioritization i. Prioritize potential services that may be offered by your program. ii. Which services or practice models might provide the most value to your organization and make sense for pharmacy to provide in your setting? c. Resources i. What resources are available to you, and what are your resource limitations? ii. Resources to consider may be physical items such as space, support staff, or skill sets of the pharmacy practitioners in your organization.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 665

Developing and Managing a Clinical Practice

3.

4.

5. 6. 7.

d. Culture of the organization i. Key questions: Do any political issues exist? Is there any provider or administrative group that leads the trajectory of your organization (i.e., physicians, nursing, or compliance department)? Assess your relationship with that group. Are patient care pharmacy services usual and customary in your setting? Who else may be providing similar services in different parts of your organization? The answer to these questions will help you know where to focus as you begin developing your service proposal. ii. Value is considered the quality or benefit of your services divided by the cost of providing the services. Do you need to convince stakeholders that pharmacist-provided patient care services provide value, or is the value of pharmacy services already understood? The greater the quality over the cost, the greater the value and the stronger your proposal. e. Practical considerations such as the time needed and the feasibility for you and/or your team to pursue the proposed endeavor Collect data. a. Organizational data showing a need for the services you are proposing are the most important information you will need for your proposal. Examples may include rehospitalization rates and the reasons for hospitalization, frequency and time spent on medication access issues, adverse drug event data, and performance rates on surrogate markers of disease management such as blood pressure and A1C. b. The data collected should unequivocally support the need and financial viability of your pharmacy program and the set of services you propose to offer. In today’s health care environment, your services must improve the quality of patient care. c. Quality should be measured clinically (e.g., disease- and therapy-related outcome measures), humanistically (e.g., patient satisfaction and patient engagement measures), and financially by demonstrating positive economic outcomes (e.g., generating revenue or reducing costs). d. Your services should be synergistic with the quality measures the organization may need to report for value-based contracts and billing or those that the organization chooses to measure for improvement. Develop proposed mission and vision statements for your program that clearly align with the services you plan to offer. They are fundamental for guiding the direction of a service, organization, or business and are critical in directing decision-making. These statements help managers and staff remain focused on the reason for the service and help others understand why your service must exist. a. A mission statement describes in a clear, concise, and informative manner the purpose of your program and explains why it should exist. b. A vision statement defines what the program wants to accomplish in the future, usually at 5–10 years. This statement articulates the value of the service. i. Your statements should align with the organization’s mission, vision, goals, and strategic plan. ii. Articulate the results you expect from your program and explain how they will meet the organization’s needs. Develop suggested goals and objectives for your overall program and each proposed service. a. Goals are indicators of success for your program and its vision. b. Objectives describe how you are going to measure the goals. Describe clearly and accurately what your program will entail, including defining what services the pharmacist will provide (e.g., the pharmacist’s specific roles) to each customer – patients, other providers, the organization, and payers – for each service proposed. Leadership and teamwork a. To be successful, you must assume the role of leader for your initiative and assemble a supportive and functional team. b. Given your work with the internal environmental scan: i. Identify the needs and priorities of the key stakeholders for your initiative.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 666

Developing and Managing a Clinical Practice

ii. Determine how well their needs and priorities are being met. iii. Identify opportunities, risks, and practice or health care service trends. iv. Know best practices, and determine whether the current services in your organization are providing care at that level. v. Know the organizational structure, and understand how your program and proposed services will optimally integrate into the organization’s structure. c. Identify your stakeholders. Depending on your clinic and practice site, key stakeholders may include the following: i. Physicians and other providers who refer patients ii. Billing or the compliance officer who is responsible for compliance with billing practices and the legal ramifications surrounding billing and contracts iii. Practice manager: As a key team member to assist in integrating your service into the current health care team workflow, a practice manager facilitates the planning and procurement of space, equipment, and supplies. iv. Pharmacy colleagues (a) Pharmacy managers or directors who may need to make the initial presentation for your program and services or who have been asked by administration to implement certain services (b) Pharmacy staff who will participate in the program and provide the services v. Program champion (a) Opinion leader or well-known individual within an organization who can influence the opinions of others, often called the program champion (b) Usually a respected physician or administrative leader vi. Patients and/or caregivers within the organization: Their health care stories describe a need for your proposed service(s) and may influence decisions from key stakeholders. vii. Payers who are currently experiencing high costs in a certain area or who have identified quality measures in which your organization may be underperforming viii. Quality improvement managers or those responsible for the quality measures within your organization that are connected with reimbursement on the basis of contracts with government or commercial payers ix. Administrators who are concerned with the organization’s revenue, costs, and financial health: Board of directors or high-level administrators, particularly those who may need to support you at board-level discussions x. Laboratory services (a) Particularly if you plan to do point-of-care testing (b) If your service will increase the volume of patients using laboratory services, discuss how this will affect the laboratory’s workflow. xi. Other clinical staff (e.g., nursing staff, dietitians, social workers): You will want support for your program and services from these practitioners and to avoid any interpretations that your proposal is conflicting or competing with their work. xii. Risk managers: Responsible for minimizing adverse patient events in the organization and may be important allies if drug-related problems are a significant cause of patient dissatisfaction, morbidity, mortality, or legal actions d. Mobilize key participants or stakeholders to create your team. Create a team that has enough stakeholders to move your project forward but that is not too large to be ineffectual. i. Secure a commitment from the key stakeholders and members of your team. ii. Unite the team members by having them contribute to and finalize the service’s mission, vision, and goals. iii. Secure a commitment upfront for anticipated resource needs from the appropriate stakeholders involved with financial approvals. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 667

Developing and Managing a Clinical Practice

e. Engage the stakeholders as champions for your proposed service. i. Establish a relationship by identifying their goals for participating on your team. (a) Identify their roles and contributions to your proposal. (b) When establishing a relationship, remember that the most important characteristics of collaboration are relationship initiation, trustworthiness, and role specification. ii. Nothing captures attention like data: Share and professionally present the data from the internal and external scans. iii. Share your plans for outcome measures, and gather stakeholders’ input. iv. Address all concerns raised by the stakeholders, and develop an agreed-on plan to overcome obstacles, disagreements, and barriers. f. Team members should begin articulating your program and services to others in the organization, particularly your program’s consensus mission, vision, and goals. g. Inspiring and maintaining enthusiasm within the team requires commitment to the following: i. Transparency and honesty in all communication, with no hidden agendas ii. Openness to feedback and ideas from your stakeholders. Listen carefully to their concerns and recommendations, and adjust your proposed service as needed. iii. Clear communication and expectations iv. Integrity in all interactions such that trust, support, and confidence exist among the team and stakeholders. Trust in your knowledge and skills cannot be overstated in this process. v. Creativity, innovation, and an entrepreneurial spirit in solving the challenges that will occur vi. Expertise on the proposed service and the specific details for its implementation Practice Case 2. You have been providing clinical pharmacy services in an antithrombosis clinic in your organization for 2 years and would like to expand your services. You routinely document vital signs and have noticed that blood pressure values are above goal for many clinic patients; however, you have not had time to address this medication-related issue for most patients. At a recent clinic staff meeting, measures where the practice was not performing well were presented. Blood pressure control was one of the measures. You would like to develop a new pharmacist-led blood pressure management service and present the proposal to your clinic administrator. Which information will be most important to obtain from an external environmental scan to use in your initial proposal? A. Literature that supports positive financial and clinical patient outcomes from pharmacist services in blood pressure management. B. Advice solicited from an e-mail list of ambulatory care pharmacists providing blood pressure management services. C. Established practice standards specifically for pharmacists in blood pressure management. D. The advertising brochure from the clinic 2 miles away detailing that it is part of the Million Hearts initiative.

B. External Environmental Scan 1. Identify literature that supports the pharmacy program and services you are considering. When possible, be sure to use literature from the professional journals important to your stakeholders, such as the pharmacy, medicine, family practice, and health administration journals shown in Box 1. 2. Learn from the work of others. a. Understand what helped others succeed. b. Understand the barriers they encountered, and learn how they may have overcome challenges. 3. Review and incorporate into your plans any standards of practice or the best practices for the type of service(s) you plan to provide.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 668

Developing and Managing a Clinical Practice

4. Know what your organization’s competitors are doing. Does your organization need to consider your proposal to remain competitive in your community? Will your proposal help your organization be viewed as innovative and/or cutting edge in your community? Box 1. Key General Literature Resources American College of Clinical Pharmacy (ACCP). Standards of practice for clinical pharmacists. Pharmacotherapy 2014;34:794-7. American Pharmacists Association (APhA). Successful Integration of Pharmacists in Accountable Care Organizations and Medical Home Models: Case Studies. March 2020. Available at https://pharmacist.com/Portals/0/PDFS/Practice/ APhA_Medical_Home_ACO_Report_Final.pdf?ver= 0vbHcscSN_2-3x3UmFLZ5Q%3D%3D. Brummel A, Lustig A, Westrich MA, et al. Best practices: improving patient outcomes and costs in an ACO through comprehensive medication therapy management. J Manag Care Pharm 2014;20:1152-8. Brush JE, Handberg EM, Biga C, et al. 2015 ACC health policy statement on cardiovascular team-based care and the role of advanced practice providers. J Am Coll Cardiol. 2015;65:2118-36. Buxton JA, Babbitt R, Clegg CA, et al. ASHP guidelines: minimum standard for ambulatory care pharmacy practice. Am J Health Syst Pharm 2015;72:1221-36. Castelli G, ed. ACCP Ambulatory Care Pharmacist’s Survival Guide, 4th ed. Lenexa, KS: American College of Clinical Pharmacy, 2019. Centers for Disease Control and Prevention (CDC). Collaborative Practice Agreement and Pharmacist Patient Care Services: A Resource for Decision Makers. Atlanta: CDC, 2013. Chisholm-Burns MA, Lee JK, Spivey CA, et al. U.S. pharmacists’ effect as team members on patient care: systematic review and meta-analysis. Med Care 2010;48:923-33. CMM in Primary Care Research Team. The Patient Care Process for Delivering Comprehensive Medication Management (CMM): Optimizing Medication Use in Patient-Centered, Team-Based Care Settings. Lenexa, KS: American College Clinical Pharmacy, 2018. Available at www.accp.com/docs/positions/misc/CMM_Care_Process.pdf. Dunn SP, Birtcher KK, Beavers CJ, et al. The role of the clinical pharmacist in the care of patients with cardiovascular disease. J Am Coll Cardiol 2015;66:2129-39. Fabel PH, Wagner T, Ziegler, et al. A sustainable business model for comprehensive medication management in a patientcentered medical home. J Am Pharm Assoc 2019;59:285-90. Greer N, Bolduc J, Geurkink E, et al. Pharmacist-led chronic disease management: a systematic review of effectiveness and harms compared with usual care. Ann Intern Med 2016;165:30-40. Get the Medications Right Institute. Get the Medications Right Blueprint For Change Report. Available at https://gtmr. org/blueprint-full/. Get the Medications Right Institute. The Outcomes of Implementing and Integrating Comprehensive Medication Management in Team-Based Care: A Review of the Evidence on Quality, Access and Costs, October 2020. Available at https://16bvl028dn7zhgp35k7rzh5c-wpengine.netdna-ssl.com/wp-content/uploads/2020/11/TheOutcomes-of-Implementing-and-Integrating-PGx-within-CMM-in-Team-Based-Care-A-Review-of-the-Evidence-onQuality-Access-and-Costs-11252020-1.pdf. Isasi F, Krofah E. The Expanding Role of Pharmacists in a Transformed Health Care System. Washington, DC: National Governors Association Center for Best Practices, 2015. Available at www.nga.org/wp-content/uploads/2020/08/1501T heExpandingRoleOfPharmacists.pdf. Joint Commission of Pharmacy Practitioners (JCPP). Pharmacists’ Patient Care Process. Available at http://jcpp.net/wpcontent/uploads/2016/03/PatientCareProcess-with-supporting-organizations.pdf. Kliethermes MA, Brown TR, eds. Building a Successful Ambulatory Care Practice: Advancing Patient Care, 2nd ed. Bethesda, MD: American Society of Health-System Pharmacists, 2019.

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Box 1. Key General Literature Resources (continued) Leavitt Partners. Defining High-Value Pharmacists for ACO Partnerships. Washington, DC: Robert Wood Johnson Foundation, 2016. Available at https://leavittpartners.com/wp-content/uploads/2018/05/LP_RWJF_Pharmacist_brief_ final.pdf. Long P, Abrams M, Milstein A, et al., eds. Effective Care for High-Need Patients: Opportunities for Improving Outcomes, Value, and Health. Washington, DC: National Academy of Medicine, 2017. McFarland MS, Buck ML, Crannage E, et al; writing on behalf of the Get the Medications Right Institute. Assessing the impact of comprehensive medication management on achievement of the Quadruple Aim. Am J Med 2021;134:456-61. McInnis T, Capps K. Get the Medications Right: a nationwide snapshot of expert practices – comprehensive medication management in ambulatory/community pharmacy. Health2 Resources, May 2016. McInnis T, Strand LM, Webb CE. The Patient-Centered Medical Home: Integrating Comprehensive Medication Management to Optimize Patient Outcomes, 2nd ed. Patient-Centered Primary Care Collaborative, 2012. Meyers D, LeRoy L, Bailit M, et al. Workforce configurations to provide high-quality, comprehensive primary care: a mixed-method exploration of staffing for four types of primary care practices. J Gen Intern Med 2019;33:1774-9. Nigro SC, Garwood CL, Berlie H, et al. Clinical pharmacists as key members of the patient-centered medical home: an opinion statement of the Ambulatory Care Practice and Research Network of the American College of Clinical Pharmacy. Pharmacotherapy 2014;34:96-108. Perez A, Doloresco F, Hoffman JM, et al. Economic evaluations of clinical pharmacy services: 2001–2005. Pharmacotherapy 2009;29:128-66. Roth MT, Ivey JL, Esserman DA, et al. Individualized medication assessment and planning: optimizing medication use in older adults in the primary care setting. Pharmacotherapy 2013;33:787-97. Santschi V, Chiolero A, Burnand B, et al. Impact of pharmacist care in the management of cardiovascular risk factors: a systematic review and meta-analysis of randomized trials. Arch Intern Med 2011;171:1441-53. Schottenfeld L, Petersen D, Peikes D, et al. Creating patient-centered team-based primary care. AHRQ Publication No. 16-0002-EF. Rockville, MD: Agency for Healthcare Research and Quality, 2016. Smith M, Bates DW, Bodenheimer TS. Pharmacists belong in accountable care organizations and integrated care teams. Health Aff (Millwood) 2013;32:1963-70. Talon B, Perez A, Yan C, et al. Economic evaluations of clinical pharmacy services in the United States: 2011-2017. J Am Coll Clin Pharm 2020;3:793-806. Thomas-Henkel C, Turner S, Freda B; Center for Health Care Strategies. Opportunities to Enhance Community-Based Medication Management Strategies for People with Complex Health and Social Needs. Hamilton, NJ: Center for Health Care Strategies, 2018. Available at www.chcs.org/media/CMMC_Report_062918-1.pdf. Touchette DR, Doloresco F, Suda KJ, et al. Economic evaluations of clinical pharmacy services: 2006–2010. Pharmacotherapy 2014;34:771-93.

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II.  SPECIFIC APPROACH TO PREPARING YOUR PHARMACY SERVICE PROPOSAL (Domain 3, Task 1, Item b; Domain 3, Task 3, Item c, e) A. Required Attributes of Your Service 1. Your service must have four key attributes to be successful: valuable, scalable, reproducible, and sustainable. a. Value is the quality divided by the cost. Will your service improve quality, decrease cost, or both? b. Scalable is the ability of your program and services to easily be expanded to accommodate the increase in demand as they mature. Growth is generally inevitable and should be planned for in your proposal. c. Reproducible is the ability to be replicated and implemented elsewhere. Larger organizations may look at scalability by piloting your proposed service at a single site and then reproducing it at other sites. d. Sustainable is the ability to maintain a positive quality/cost ratio, or high value, as practice needs shift and its resources fluctuate. B. Determine Your Scope of Practice. 1. The first step is to review your state’s pharmacy practice act and Board of Pharmacy rules. a. Terminology, definitions, and sections vary among states, and you need to pay careful attention to the following: i. Practice of pharmacy: Are the services you intend to provide included in the definition of a pharmacy practice? ii. Scope of practice: What are the activities you can perform under the state’s pharmacy practice act? These activities may include physical examination, clinical decision-making, medication changes, and administration of medication. iii. Collaborative practice: If the services you plan to provide (e.g., ordering or changing medications) must be delegated from a licensed provider, what are the rules for the collaboration? iv. Providing services under protocol: Does your state have statutes that allow expanded services under a statewide protocol? If so, what are the rules for providing these services? The services may include providing immunizations, naloxone, and birth control. v. Medication management: How does the state practice act define patient care services? 2. Be mindful of nuances in the details of state and federal laws and regulations when incorporating processes for pharmacist-led clinical services. a. Requirements for physician oversight and orders b. Allowable pharmacy services, such as medication administration, physical examination, and ordering laboratory tests c. Any differences related to the practice site, such as community pharmacy, hospital, and long-term care d. Develop your proposal in compliance with the specific allowances for managing medication therapy and related care in your state. C. Analyze Your Proposed Patient Care Services. 1. Analysis of strengths, weaknesses, opportunities, threats (SWOT) a. Overview i. Using your review of the literature and your circumstances, your next goal is to perform a SWOT analysis to understand the strengths, weaknesses, opportunities, and threats to your program and proposed patient care services. ii. The SWOT analysis is the most common tool used for this type of analysis. b. Strengths i. Evaluate the current strengths of your core team, your proposed program and services, and/or your organization. ii. Identify those that will increase your chances of successfully initiating and performing the proposed service(s). ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 671

Developing and Managing a Clinical Practice

iii. For example, a strength may be that you have highly trained individuals (PGY2 ambulatory-trained residents) for the proposed service(s) or that a strong physician-pharmacist relationship exists. c. Weaknesses i. Identify the weaknesses that exist within your core team, your service, and/or your organization that may create barriers and make it difficult to provide the proposed service(s). ii. For example, if your organization’s current information technology (IT) department cannot incorporate into its system the specifications you need to measure the success of your services – thus necessitating manual collection – this weakness may impede your ability to receive timely information and add a cost that negatively affects your program. d. Opportunities i. Identify opportunities in your setting that will support the establishment of your proposed program and service(s) as well as their growth at a desired pace. ii. For example, your institution may have a high hospital readmission rate and face significant financial penalties. However, if your program is successful at reducing readmissions, the total cost of your proposed program and service(s) may be more than offset by reducing or eliminating the losses from the associated financial penalty. e. Threats i. Understand the threats that place your proposal or service at risk and that may result in its insolvency. ii. For example, there may currently be discussions of potential mergers of your physician group with another health system that historically has not supported the type of pharmacist-led service model you are proposing. iii. Another example may be that the Medicare Part D plan used by most of your population, which already has an established MTM program, competes with the services you are proposing. 2. Table 1 provides considerations for a general SWOT analysis for the various care delivery models in which pharmacists participate when providing ambulatory direct patient care. Table 1. SWOT Analysis of Care Delivery Models Delivery Model Strengths

Traditional, office-based practice model

• Physician collaboration • Fewer communication barriers • Access to patient medical record

Weaknesses

• Health care provider may not fully use available pharmacistprovided patient care services or understand scope of practice • Limited population • Often limited physical space

Opportunities

• High level of practice • Quality-based payment models to support work • Grants as source of funding

Threats

• Other mid-level providers performing proposed services with established revenue streams (nurse practitioners, physician assistants) • Revenue options may not cover costs if the only source is incident-to billing • State scope-of-practice laws

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 672

Developing and Managing a Clinical Practice

Table 1. SWOT Analysis of Care Delivery Models (continued) Delivery Model Strengths

Weaknesses

Opportunities

Threats

Integrated team- • Core function based models of through a care multidisciplinary team • Strong IT cornerstone, allowing the sharing of patient information

• Payment models that are not well developed and that are potentially risky • Pharmacist not always part of team • IT may not be fully developed to support team

• Improved quality of care • Potential for reduced cost of care and increased revenue • Prime setting for research and grants

• Other team members (advanced practice nurses) may have better quality/cost ratios • Ability to secure contracts • Payment models not fully tested for sustainability

Pharmacy department– based practice model

• Health system has • Physical space • Added services several clinic sites challenges in clinic may improve other in community • Staffing challenges associated business • Serves diverse or and inability to lines entire population consistently staff over • Opportunity for • Health system has and above existing niche or specialty billing option of pharmacy services practices facility fee billing • May lack • Ability to affect model administrative rehospitalization support and financial • More challenging penalties for the communication with health system outside primary care providers

• Billing and collection challenges for expanded services • Outside organizations (community pharmacy) may be able to provide the services • Considered competition to primary care

IT = information technology; SWOT = strengths, weaknesses, opportunities, threats.

D. Evaluate Your Resource Needs. 1. Overview a. The key resource needs for any business are personnel, space, equipment, and supplies. b. Each of these resources will be a cost to your program that you will need to consider and control as you determine the financial cost and value equation for your program and proposed services. 2. Personnel a. The pharmacists and other support personnel anticipated to staff your clinic are the primary resources needed for most models. Their salary and benefits will compose most of the costs of your program. b. The expected patient volume for your proposed service(s) will determine your staffing needs. 3. Determine the duration and frequency of visits. a. It is important to evaluate the required activities during the visit and the estimated time needed to perform those activities. i. Anticoagulation services are generally 30–45 minutes initially, with 15- to 20-minute follow-ups. ii. High-risk patients with complex medical conditions may require 60-minute initial visits and 30- to 45-minute follow-up visits. b. Patients can be seen as often as weekly (not uncommon for patients at high risk or with cognitive or psychiatric conditions), quarterly (patients with more stable, well-managed conditions), or yearly (wellness visit or patients with stable conditions).

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 673

Developing and Managing a Clinical Practice

4.

5.

6.

7.

c. Determine how other team members’ roles may influence your specific role and the time required to deliver your service; for example, will the medical assistant perform vital signs and obtain a current medication list before your patient visits? Will staff be available to help with scheduling appointments and other administrative tasks? d. Estimate the need for patients requiring immediate availability or same-day appointments. Additional time for direct patient care activities a. For example, pre-visit chart review, documentation, and follow-up tasks to implement and communicate the care plan b. These may require an additional 30–40 minutes above the patient visit time, depending on factors such as the service provided, patient complexity and barriers to care, workflow, and system support for scheduling, patient data access, and documentation. Non-patient care activities a. These duties need to be factored into time considerations for staffing. A recent report evaluating the productivity of MTM practices within an integrated health care system noted that 30% of time was not spent in patient care activities (J Am Pharm Assoc 2017;57:95-101). b. Non-patient care time should be accounted for in your planning. Examples include the following: i. Teaching and assuming the role of preceptor to students and residents ii. Quality measurement and outcomes data collection and analysis iii. Research participation and dissemination of your model and lessons learned iv. Meeting attendance within the organization and outside, such as professional development and continuing education v. Leadership service and other professional activities vi. Committee work Support staff a. To be efficient, it is important to use support staff for duties that can be delegated and that do not require a pharmacist’s skills. This approach may require adding duties to the organization’s existing clerical and other staff. It may also be accomplished using pharmacy technicians and trainees in new and innovative ways. Examples of duties that may be delegated include the following: i. Patient scheduling ii. Patient reception, rooming, and vital signs iii. Point-of-care testing (e.g., performing INR testing) iv. Data collection for measuring your goals or quality indicators v. Clerical duties, such as filing and mailing vi. Maintaining and ordering supplies and educational materials vii. Managing medication patient assistance programs (i.e., pharmaceutical manufacturer assistance programs) viii. Submitting the billing for your services ix. Following up on no-shows x. Calling for appointment reminders, if needed IT systems a. You may anticipate using your organization’s established electronic medical record, or you may already have a pharmacist documentation system in your organization; however, you may need to purchase a separate system or need specific software codes written for your services and billing. b. Resources that you may find valuable in navigating IT are the documents created by the Pharmacy Health Information Technology Collaborative. i. These documents include guidance on working with vendors, using structured coding, and working with health information exchanges. ii. All material is available at www.pharmacyhit.org.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 674

Developing and Managing a Clinical Practice

c. Consider the following when assessing your IT needs: i. Patient information retrieval ii. Documentation of your services iii. Patient information exchange between you and other providers iv. Ability to collect quality measurement data v. Additional pharmacist billing needs (i.e., Medicare Part D billing) E. Financial Assessment: Evaluating Expenses vs. Revenue 1. Determining the financial potential of your program a. Return on investment (ROI) i. ROI is often used as a measure of the financial benefit the organization can expect from your services. ii. The ROI equation is as follows: ROI =

gain from investment − cost of investment cost of investment

b. Consider using the literature (see Box 1) to determine the financial potential if no other resources are available. An ROI of 4.81/1 was calculated from a systematic review of the economic impact of clinical pharmacy services reported in studies during 2001–2005 (Pharmacotherapy 2009;29:128-66). In the literature, ROIs for pharmacist-provided patient care services range from 3/1 to 12/1 (Health2 Resources, May 2016). 2. Direct revenue generation opportunities a. Review your payer mix and associated billing opportunities in the context of your practice model. i. Fee-for-service (FFS) (a) Health system–based versus office-based FFS methods (b) The FFS billing method is quickly being replaced by value-based payment models. (c) States where payment is available for pharmacists providing patient care services ii. Direct contracts with payers or insurers that will reimburse for pharmacist-provided patient care services iii. Pay-for-performance revenue iv. Alternative Payment Models (APMs) tied to quality and value contracts and incentives, also termed value-based purchasing b. Evaluate visit types that have billing opportunities according to your service or practice model and payer mix. Reviewed in greater detail in section IX, Reimbursement for Pharmacist Services c. Understand how your organization generates revenue overall: How are other providers paid and incentivized? i. For example, in an FFS model, physicians are not as inclined to refer for clinical pharmacist–provided patient care services because they have their own visit counts and goals to meet for relative value units (RVUs). Referring to pharmacists may detract from attaining their financial goals. Referring to pharmacists may also adversely affect a clinic’s bottom line and often the physician’s paycheck as well. ii. However, in a recent study in an FFS setting, referring to the pharmacist generated more income for the referring physicians because they were then able to see more patients with greater complexity (J Am Pharm Assoc 2019;59:285-90). Physicians may also be motivated to support pharmacist services in this model when their pay or bonus structure is based on meeting the quality measures in their patient panel. d. Estimate the number of visits per visit type for a period and the potential revenue for each visit from your payer mix.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 675

Developing and Managing a Clinical Practice

e. Recognize that the amount billed is not always the amount collected. i. To determine this difference, review your plan with the financial or billing personnel within your organization who will be responsible for managing any revenue generated from your service. They will have an idea of the general percentage collected for the respective billing codes. ii. Some reimbursement levels may be as low as 50% of the billed amounts. 3. Indirect revenue-generating opportunities a. Improved care efficiency i. Relieving services provided by another provider, usually physicians, who may then generate greater revenue by seeing more patients at their higher reimbursement rate ii. Examples include patient education, dose titration of certain medications (e.g., angiotensinconverting enzyme inhibitors, insulin), and disease or high-risk medication management. b. Cost avoidance i. Sometimes called “soft dollars” because it generally produces cost-saving figures on the basis of “what didn’t happen” (e.g., hospitalizations for heart failure, ED visits for hyperglycemia) ii. Soft-dollar contributions are areas where your service can affect cost; however, this contribution is not through collection of direct revenue. iii. Nevertheless, the quality- and value-based billing models are rapidly changing how organizations’ financial officers view soft-dollar contributions. iv. Improving quality, reducing cost, and improving population health are increasingly a major source of revenue. v. Cost savings also result from improved patient safety, efficiency, and effectiveness in management. c. Revenue from improving quality measures as part of value-based payer contracts d. Grant money 4. Create a pro forma financial statement, which is an estimated profit and loss statement, for the next 3–5 years. Use assumptions to predict a point at which your cost value will benefit your organization. a. Estimate growth. b. Estimate expenses. c. Estimate revenues. Practice Cases 3. You have been hired as an assistant professor focused on ambulatory care at a new college of pharmacy. The college has secured a new practice site in a family practice office that is reengineering its practice to align with the Medicare and commercial ACO programs in which it is now participating. The service wants you to begin seeing individuals with diabetes because the practice needs to improve its quality measures for both Medicare and commercial payer contracts. Which best describes the optimal referral process to provide your service with the most appropriate patients to affect the stated quality measures? A. B. C. D.

Referral by a physician for each qualified patient. Automatic referral for patients with A1C 9% or greater. Offer for patients to choose to participate in the pharmacist-provided patient care service. Automatic referral only for individuals with diabetes insured through the commercial ACO.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 676

Developing and Managing a Clinical Practice

Practice Cases (continued) 4. You are creating your referral template for a comprehensive medication management clinic available to all providers in the medical group. Because most of your patients will likely be older, supervision will be provided by the Medicare Part B providers (e.g., physicians, nurse practitioners) in the primary care clinic to meet the Medicare rules for reimbursement. Which is most critical to include in your referral form? A. B. C. D.

Provider generating the referral. Pharmacist for whom the provider is directing the referral. Reason for referral. Expectations of referral.

III.  CREATING YOUR SERVICE MODEL: CLINIC OPERATIONS, POLICIES AND PROCEDURES (Domain 3, Task 3, Item c) A. Clinic Operations 1. Clinic workflow should be easy for patients to maneuver, be efficient for you and your staff, and integrate well with other activities or providers in your workspace. 2. Referral process a. Integrate, when possible, with other providers’ systems for referrals, and follow similar processes used by other providers in the organization. Having providers learn a new referral process can be a barrier to generating referrals to your service. b. Source of the referral: Determine who can refer patients (e.g., physicians, nurses, self-referrals). c. Content of the referral: The most important considerations in determining the content of your referral follow. i. First, it should not be burdensome to the person making the referral or it will not occur. ii. Second, it must contain reasons for the referral, which is required by many payers for mid-level practitioners. CMS terms this documentation a statement of medical necessity and usually requires that it come from an eligible provider for Medicare Part B. iii. Third, it should address any state law requirements or collaborative practice requirements for physician delegation of services to the pharmacist. Using quick checkboxes will aid in this process as follows: (a) Whom the referral is from (b) Whom it is going to (c) Reason for referral (d) Expectations of referral d. Scheduling: Once the referral is made, determine who will schedule patients. 3. Patient scheduling: Integrate scheduling into the processes used by other providers at your location as much as possible. This approach will save you time and cause much less confusion for the patients referred to your service. 4. Patient check-in for face-to-face visits a. Identify who will check in patients. b. Determine the required paperwork and the items you may need, or consider the following: i. Billing information or copays ii. HIPAA (Health Insurance Portability and Accountability Act) form for authorization on sharing patient information and privacy policies ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 677

Developing and Managing a Clinical Practice

iii. Consent for services or agreement to participate in the collaborative practice agreement (CPA) (required by some states and to enroll patients in chronic care management [CCM] services) iv. Patient rights and responsibilities c. Determine where patients will wait until they are directed to the visit room. 5. Vital signs and point-of-care testing a. Determine what you will routinely do at each visit and who will perform each activity. i. Consider medical assistants to perform this function if they are already performing such services for other providers. ii. Consider this a role for a pharmacy technician or students. If pharmacy technicians are used, consider any additional necessary training. b. Determine the flow of where these activities may be done, if not by you, and how the information will be communicated and documented. c. Obtain a Clinical Laboratory Improvement Amendments (CLIA) waiver to perform all point-of-care tests. i. Certain tests are deemed by the FDA and the CDC to have minimal risk. CLIA-waived tests are “simple laboratory examinations and procedures that have an insignificant risk of an erroneous result.” ii. To perform these tests in a clinic, the following should be done: (a) Be sure the point-of-care test you plan to use is CLIA waived at www.cms.gov/Regulationsand-Guidance/Legislation/CLIA (b) Complete an online application. (c) Pay the required fees. (d) Testing procedures: A CLIA waiver requires you to follow the manufacturer’s testing instructions. (e) Waste disposal: Follow OSHA (Occupational Safety and Health Administration) guidelines, and check state rules and regulations because they may vary from state to state. 6. Visit process a. Consistency and efficiency in the process of collecting patient information allow for easier expansion and scalability. b. Should use the Pharmacists’ Patient Care Process such that visits are standardized (Box 2) c. Consider the role of students/residents in the process. 7. Non−face-to-face visits a. Your service may use other methods for patient visits, such as telephonic or video-based visits. Consider which additional resources may be needed in a more virtually based practice model (e.g., using Doxy. me, Doximity, or other telehealth platforms). b. Your service may need to adapt visit processes to the different means of contact. B. Clinic Policies and Procedures 1. General components: Consider including the following information about your service: a. Title stating the document’s policy and procedures for your clinic b. Mission and vision statements c. List of specific services provided d. Hours of operation and off-hour coverage process 2. For service personnel, define: a. Job description, duties, and responsibilities b. Required credentials and preferred experience c. Scope of practice and clinic privilege i. CPAs ii. Description of supervision process ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 678

Developing and Managing a Clinical Practice

3. 4.

5. 6. 7.

8. 9.

d. Continuing education requirements e. Continuing credentialing and/or privileging processes Define the responsibilities of other providers if needed by the pharmacists (i.e., supervising provider for items not within the pharmacist’s scope, collaborative practice, or protocol). Clinic operational processes a. Referral process i. Routine referrals ii. Urgent referrals b. Patient scheduling process i. New visits (length of visits) ii. Follow-up visits (length of visits) c. Follow-up process for patients and recommended intervals d. Coordination of care procedures e. Discharge or transfer from service f. No-show and cancellation policy Documentation standards and processes: How documentation of the care plan will be communicated to the health care team Clinic billing process a. Billing codes used b. Claims process and procedures Emergency management a. Patient emergency or need for acute care procedures b. Patient code procedures c. Environmental emergencies Quality improvement program and processes Point-of-care testing a. CLIA waiver b. Procurement, maintenance, storage of point-of-care machine and supplies c. Training requirements to demonstrate competency using point-of-care tests

C. Billing Requirements 1. Billing requirements may affect the structure and workflow of your service and should therefore be considered. 2. In physician offices or hospital-based clinics, pharmacists function as mid-level providers and must work under a supervising health care provider (usually a supervising physician) to bill. 3. In servicing Medicare beneficiaries, CMS has rules regarding the proximity of the supervising provider when using incident-to or facility fee billing (covered in section IX, Reimbursement for Pharmacist Services). a. Medicare rules stipulate that the supervising provider must be within the same office space for physician office billing. b. For outpatient billing in a hospital or health system, CMS has relaxed this ruling to general supervision.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 679

Developing and Managing a Clinical Practice

Box 2. Pharmacists’ Patient Care Process 1. Collect: Gather patient information from the medical record and interviewing patients or caregivers to obtain the pertinent information needed for patient care 2. Assess: Evaluate the legal and clinical appropriateness of the medication regimen to identify, resolve, and prevent medication-related problems 3. Plan: Participate with health care team members and patients in medication and disease state therapy decisionmaking and development of patient goals and plans of care 4. Implement: Initiate the plan, including educating patients and caregivers on disease, medication therapy, adherence, and preventive health 5. Follow up, monitor, and evaluate the effect of medication therapy on patient health outcomes 6. Document and communicate the services provided, and create and maintain medication profiles, medication-related plans of care, and other needed patient care documentation Joint Commission of Pharmacy Practitioners (JCPP). Pharmacists’ Patient Care Process. 2014. Available at https://jcpp.net/wp-content/uploads/2016/03/PatientCareProcesswith-supporting-organizations.pdf.

Practice Case 5. Both in your proposal and after its approval, you will need a timeline for establishing your program. Which is the optimal time interval from approval to seeing first patients for your service (in months)? A. B. C. D.

3. 6. 12. 18.

IV.  SUGGESTED TIMELINE FOR ESTABLISHING A PRACTICE (Domain 3, Task 3, Items c) A. General Principles 1. Establishing an ambulatory practice requires time to complete all the steps to develop a service. 2. Although you may be the responsible party, it is not an endeavor that you can perform alone and often requires creation of a multidisciplinary team of stakeholders who have certain roles in the process. 3. Because team members have competing priorities, being efficient and organized will minimize the time needed to develop a service from its initial concept. B. Optimal Timeline (Box 3) 1. If the proposed service is straightforward, generally supported, and its mission, vision, and goals are clear to other stakeholders, you may be able to set up your clinic in 6 months or less. 2. Ideally, 6 months is a good goal timeline. 3. Taking longer may subject your clinic to stakeholders’ loss of interest or changes in both internal and external environments that create barriers.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 680

Developing and Managing a Clinical Practice

Box 3. Optimal Timeline for Establishing a Practice

Month 1 • Perform internal and external environmental scans • Draft mission and vision statements and goals for your service • Identify important stakeholders and potential members of your implementation team • Review state and federal rules on scope of practice and payment that may affect your proposed service • Perform a SWOT analysis

Month 2 • Convene your planning and implementation team • Finalize mission, vision, and goals with team • Determine resources together with startup costs • Estimate the operational costs and potential revenue for your service • Develop a timeline for measuring progress on the goals and objectives of your service • Begin developing and writing your service proposal or business plan • Meet with stakeholders and decision-makers to informally discuss your anticipated services, and identify areas and concerns they would like you to address Months 3−4 • Complete your service proposal or business plan • Schedule formal meetings and presentations to stakeholders and decision-makers within your organization

Months 5−6 (You can begin this work while awaiting approval so that you are ready to begin once approval for your service is obtained) • Develop policies and procedures • Develop your marketing plan • Plan the setup of your service • Order the necessary equipment and supplies • Obtain CLIA waivers, as needed CLIA = Clinical Laboratory Improvement Amendments; SWOT = strengths, weaknesses, opportunities, threats.

Practice Cases 6. You have a well-established heart failure clinic and have consistently decreased readmission rates for heart failure. Many of your patients have comorbid diabetes, and you have also begun managing this condition through recommendations to clinic providers. However, treating patients with diabetes is slowing the clinic workflow because of needed approval for any medical decision-making you perform for patients with comorbid diabetes. Which is the best course of action to resolve this inefficiency? A. Adjust your schedule to spend one day in the endocrinologist’s office to further develop professional relationships. B. Work with your medical group to expand your CPA to include diabetes medication management. C. Hire an additional pharmacist to focus solely on diabetes management for these patients. D. Establish an electronic-based communication system to allow for faster communication.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 681

Developing and Managing a Clinical Practice

Practice Cases (continued) 7. An audit by the compliance officer results in a notification that you cannot use incident-to billing for the patients for whom you are managing diabetes and heart failure with sodium-glucose cotransporter-2 inhibitors. Your current CPA and protocol have not been updated since 2015. Which is the most likely reason for the result of this audit? A. B. C. D.

Not within the pharmacist’s state scope of practice. Change in Medicare payment rules. Outdated CPA. Not outlined in your policy and procedure.

V.  GENERAL ONGOING MANAGEMENT (Domain 3, Task 1, Items a, b; Domain 3, Task 3, Item c) A. Maintaining Policies and Procedures 1. Review policies and procedures yearly. a. An annual review will keep the review process manageable. b. Waiting too long for a review will result in outdated policies and procedures that may require a major overhaul, often in turn resulting in a large workload for you and your staff. 2. Collaborative practice agreement a. Update and review your CPA on a yearly basis or as dictated by state laws, rules, and regulations. b. Regularly review clinical practice guidelines and new primary literature, and update your CPA accordingly. 3. Staff to perform review a. Pharmacist staff perform the processes for the service daily and will therefore be able to detect discrepancies or needed updates to policies and procedures. b. Maintain your practice to meet the minimum current standards of an ambulatory care pharmacist practice as described in the steps of the Pharmacists’ Patient Care Process (see Box 2).

VI.  MAINTAINING AN EFFECTIVE TEAM AND FUNCTIONING AS AN EFFECTIVE HEALTH CARE TEAM MEMBER (Domain 3, Task 1, Items a, c, d, e; Domain 3, Task 2, Items b; Domain 3, Task 3, Item e) The triple aim of the Institute for Health Improvement – improve patients’ experience of care (i.e., satisfaction and outcomes), reduce the cost of care, and improve population health – has driven the dramatic changes in health care in the past few years. Recently, pharmacists have demonstrated value in the ambulatory care setting and alleviated physician workload by participating in the management of chronic disease states, which aligns with the recently proposed quadruple aim. The success of the triple aim depends on health care being delivered by teams of health care providers in many disciplines versus sole individual providers. The complexity of health care demands team-based care. However, systems of care, workflow, IT, and means of communication have not kept pace with the needs and demands of team-based care. The sustainability of your service will depend on your ability to overcome these barriers by understanding features of effective teams and establishing standard, reliable methods for workflow, communication, and documentation.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 682

Developing and Managing a Clinical Practice

A. Features of Effective Teams: A 2014 review of extensive research in team performance from across a range of industries identified best models and their respective features to health care team functioning as follows (Postgrad Med J 2014;90:149-54): 1. Team leadership: Team leaders coordinate tasks of team members, plan daily work, and are concerned with developing team members, providing motivation, and establishing a positive atmosphere. Team leaders are usually physicians. 2. Mutual performance monitoring: All team members require sufficient understanding of the environment within the workplace to monitor other team members, such that any member can step in and assist when task overload or lapses are identified. 3. Backup behavior: Team members have sufficient understanding of others’ tasks to enable effective redistribution of workload or needed support with the variances in service demand. 4. Adaptability: This approach enables the team to respond to changes in the environment to adapt patient management and workflow as needed to maintain patient care and the desired outcomes. 5. Team orientation: This approach includes a willingness to consider others’ ideas and perspectives and a belief that team goals should be aligned with what is best for patients, termed patient centeredness. B. Characteristics of Effective Teams: Ambulatory pharmacists should strive to model the following characteristics: 1. Respect and trust to be able to give and receive feedback on performance 2. Good communication skills to accurately convey information 3. Shared mental model, defined as a common understanding of the situation, plan of care, roles, and tasks of individuals on the team, described as being “on the same page” (Postgrad Med J 2014;90:149-54). C. Health Care Communication 1. General principles a. As previously stated, strong communication processes are one of the most vital aspects of ambulatory care. b. The success of the pharmacy service will depend on how effectively you communicate with patients, your immediate health care team, and the individuals involved in a patient’s care. c. Setting up standard communication processes and structures that allow needed flexibility will help create efficiency in the program. d. Communication must occur bidirectionally between all members of the health care team. e. The communication style to strive for is to be conversational versus solely exchanging information. 2. Documentation recommendations: a. Several organizations have developed documentation recommendations with the input of experts from several disciplines, including physicians, regarding the desired content of a pharmacist’s note. i. Patient-Centered Primary Care Collaborative Guidelines for the Practice and Documentation of Comprehensive Medication Management in the Patient-Centered Medical Home (PCMH) available at www.pcpcc.org/sites/default/files/resources/Appendix_A_Guidelines_for_the_Practice_and_ Documentation.pdf ii. American College of Clinical Pharmacy (ACCP) (Pharmacotherapy 2014;34:794-7) b. It is important to establish a consistent documentation process across your team to reduce variability in the services provided.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 683

Developing and Managing a Clinical Practice

VII.  MEASURING THE QUALITY OF YOUR PROGRAM (Domain 2, Task 3, Item b, c; Domain 3, Task 3, Item b, c, d) Practice Case 8. The physician group for whom you practice has secured an alternative payment contract with a large commercial insurer for both Medicare Advantage and commercial beneficiaries. The contract is a set payment per month per patient, with the potential for bonuses on the basis of set outcome measures. Which best describes this valuebased payment model? A. B. C. D.

FFS with pay for performance. Bundled payment model. Risk-sharing model. Global payment model.

A. Alternative Payment Models (APMs): Several emerging models and terms are being used to describe the payment models associated with reimbursement on the basis of the quality of services provided and the resulting patient outcomes. 1. Value-based payment models: Payment models and contracts for services that reward for the quality of the services provided versus the number of patients served, as in the FFS model. Value in these models is the ratio of outcomes that are important to patients to the dollars spent for a service (N Engl J Med 2010;363:2477-81). a. Pay-for-performance model i. Uses payment for health care services aligned with quality measures and performance of the providers, usually through incentives or disincentives ii. Often built on an FFS payment structure b. Global payment i. This model has a requirement to achieve quality benchmarks. ii. A set per-patient fee is paid to the provider that encompasses the total cost of care for the patient’s services during a set time interval. iii. The payment structure may be payment per patient, per month, or per year. c. Episodes of care or bundled payment i. Payment arrangements that include financial and performance accountability for episodes of care, such as a set fee for a hip replacement ii. This model includes meeting required quality metrics. d. Risk sharing i. Full risk describes when the organization and providers are at full financial risk for negative events that increase costs, such as hospitalizations; however, these entities also receive the financial rewards of increasing quality of care with associated cost savings. ii. Partial risk or risk sharing describes when the organization and payer share the financial risk for negative events that increase cost and results that improve quality and reduce cost. The shared percentage is usually pre-negotiated. e. Value-based insurance design i. In this model, payers incentivize patients by reducing or eliminating beneficiary costs for services that are considered high value on the basis of known and accepted medical evidence. ii. Payers disincentivize patients by increasing their costs for the services for which evidence shows little or marginal value. 2. Health Care Payment Learning & Action Network a. Both CMS and commercial payers have articulated their desire and plans for moving most provider payments to be based on quality or value through APMs. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 684

Developing and Managing a Clinical Practice

b. As part of the Medicare Access and CHIP Reauthorization Act (MACRA), which was passed in 2016 and resulted in dramatic changes in payment models, this network was established as a collaborative network of public and private stakeholders, including health plans, providers, patients, employers, consumers, states, and federal agencies within the health care community. c. The APM framework white paper (https://hcp-lan.org/apm-refresh-white-paper/) presents the payment model framework (Figure 1). B. Models of Care That Emphasize Quality vs. Volume 1. ACOs are models of integrated care delivery that are reimbursed through APMs, defined by the following elements: a. Voluntary groups of physicians, hospitals, long-term care providers, and other health care providers b. Assume responsibility for the care of a clearly defined population of beneficiaries assigned to them by a payer, such as Medicare, on the basis of patients’ use of primary care services c. Shared savings: If the triple aim is met at better care and health with reduced costs, the savings are shared between the ACO and the payer. d. Quality and quality measure reports on populations are a major part of the ACO goals. 2. PCMH is a model of primary care with the following principles: a. Comprehensive team-based care i. Team members vary; however, they include a physician, a nurse or nurse practitioner, and a patient coach as core members. ii. Others include pharmacists, dietitians, social workers, and physical and occupational therapists. iii. Members have varied widely and have included almost any health provider. b. Patient-centered or whole-person orientation c. Care that is coordinated d. Superb access to care, which ensures that patients receive their desired care whenever they need it e. Systems-based approach to quality and safety f. Payment is reflective of care given.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 685

Developing and Managing a Clinical Practice

Figure 1. Alternative Payment Model framework. APM = Alternative Payment Model.

Used with permission from: Health Care Payment Learning & Action Network.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 686

Developing and Managing a Clinical Practice

C. Methods Used by Organizations to Evaluate Quality 1. Lean process a. Developed within the Japanese auto industry and subsequently popularized by a Massachusetts Institute of Technology study, the Lean process is often called the Toyota Way. b. Five key principles i. Achieve value outcomes with the least amount of work possible. (a) Define value. (b) Evaluate workflow for inefficiencies. ii. Eliminate waste or remove any activity that does not add value, such as the following: (a) Overproduction or duplication of action (b) Waiting for information or other needs (c) Poor material movement or not having items when and where needed (d) Excessive motion or time wasted in inefficient movement (e) Inappropriate processing (f) Inventory or not having the items needed to provide services (g) Correction or having to fix errors (h) Underuse or when something should have occurred but did not iii. Use Jidoka or “just in time.” (a) Automatically detect and stop the process when a problem occurs. (b) Identify defects as close to the source of the problem as possible, and halt the process until fixed. (c) Ability to respond to day-to-day shifts in demand iv. Identify value streams. (a) Identify the steps most critical and valuable to the service. (b) Understand the complex adaptive system (many interacting points that vary with circumstances). v. Use the Lean approach, which means that every worker needs to be a problem solver. 2. Six Sigma a. Method focused on reducing variation and defects within processes to consistently create a desired outcome and reduce opportunities for error b. Six Sigma is a statistical term of measurement that denotes 0.6 deviations from the mean or 3.4 defects per 1 million opportunities. Six Sigma represents an almost error-free process. c. The steps in the Six Sigma process are as follows: i. Identify and define what has to be improved. ii. Measure what is currently occurring by collecting data; analyze the results. iii. Use creative solutions to improve, and then control, the process with policies, guidelines, and strategies. 3. “Plan, do, study, act” (PDSA) cycle – Quick and manageable process for small groups a. This method uses three key questions: i. What are we trying to accomplish? ii. What change can we make that will result in improvement? iii. How will we know that a change is an improvement? b. Planning stage i. Aims are established according to the outcome desired. ii. Strategies for change are developed. iii. Measures are chosen that will determine whether you achieved your aim. c. Do phase: Implement the change. d. Study phase: The change is tested using the defined measures. e. Act phase: Results are used from the study phase to reenter the cycle for further improvement.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 687

Developing and Managing a Clinical Practice

D. Creating Your Quality Program. Consider using a business concept called the balanced scorecard, which states you should not focus on only one area of your service (e.g., just patient outcomes). Doing so may result in gains in one area but failures in the other areas; this effect, in turn, may sabotage the overall quality of your program. There are four areas you need to measure to ensure quality. 1. Structure. Examples include the following: a. Staff is adequately trained. b. Communication systems work and are efficient. c. Workload is manageable. d. Employee satisfaction and retention 2. Process. Examples include the following: a. Error rates b. Timeliness of services c. Documentation meeting standards d. Task performance to address quality measures 3. Patient outcomes. Examples include the following: a. Clinical markers b. Patient satisfaction (as well as satisfaction of other customers) c. Care experiences 4. Financial outcomes. Examples include the following: a. Clinic growth and referrals b. Cost avoidance c. Reimbursement and revenue capture d. Cost/value ratio E. Focus of Your Quality Measures: Although quality measures in today’s environment are often dictated by payers, it is best to influence measure choices, when possible, by considering the following characteristics: 1. Meaningfulness a. The measure must be meaningful to you and your patients. b. Measure an area known to need improvement. 2. Feasibility a. Can you collect the data needed? b. How disruptive will collecting data be to your workflow? c. Do you have the resources to collect the data? d. Will the collection and analysis be timely for action? 3. Actionable a. You must be able to use the results you obtain. b. Can you make the necessary changes on the basis of results? F. Choosing Measures for Your Practice 1. Most ambulatory pharmacist practice measures for your organization are primarily predetermined by the payer or group of payers. 2. It is important to understand which measures your organization is required to report, which of these measures your service may positively affect, and the subsequent benefit to the organization and your patients. 3. The most appropriate starting points are HEDIS for your commercial payers and CMS programs for Medicare. 4. This information, together with knowledge of your patient population, payer mix, and organizational contracts, will help direct you to the appropriate measures for your service. 5. Looking to the future, CMS rules for MACRA and its implementation over the next few years will be key in how organizations incorporate quality measurement into their workflow and payment methods.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 688

Developing and Managing a Clinical Practice

6. It is important to account for the direction of Medicare quality measurement and address how your services fit into the Medicare quality strategy because these will ultimately determine the sustainability of your services. G. Sources for Quality Measures 1. General principles a. More than 8000 health care quality measures are currently available, and health care organizations that develop measures continue to create more to fill gaps where quality measurement is needed. b. Many of these measures have been tested and evaluated with some rigor to ensure a level of validity and quality. c. Your service may be affected by many of the measures adopted by payers and accreditation organizations. d. It is important to understand measure developers, validators, promoters, and users so that you can understand the measures you and your organization are asked to report on, or the measures you are able to choose that are most meaningful for your practice and organization. 2. Government-related organizations a. Agency for Healthcare Research and Quality (AHRQ) i. Sets national strategy for quality improvement in health care ii. Developed a collection of evidence reports titled “Closing the Quality Gap Series.” Available at www.ahrq.gov/research/findings/evidence-based-reports/er208-series.html b. National Quality Measures Clearinghouse (NQMC) i. NQMC was a public resource for evidence-based quality measures housed by AHRQ. ii. Like the National Guideline Clearinghouse, this repository is no longer being funded by the federal government. iii. To find measures, go to the websites of the measure developer or payer to view the lists of measures being used. iv. CMS has created a site for all quality measures used in its programs (www.cms.gov/Medicare/ Quality-Initiatives-Patient-Assessment-Instruments/QualityMeasures/CMS-Measures-Inventory). c. Centers for Disease Control and Prevention i. Healthy People 2030 ii. National Health Interview survey d. Universal Data System (UDS) i. Established by Health Resources & Services Administration program for Health Center Program grantees (a) Federally qualified health centers (FQHCs) (b) Migrant Health Centers (c) Health Care for the Homeless (d) Public Housing Primary Care Program ii. To reduce measurement burden, the quality requirements for these organizations are updated yearly. The annual updated UDS resources are available at https://bphc.hrsa.gov/datareporting/reporting/ index.html e. National Academy of Medicine, formerly IOM (Institute of Medicine) i. An independent, nonprofit organization established under the National Academy of Sciences ii. Role is to work outside government to provide unbiased and authoritative advice to decision-makers and the public. iii. Almost 200 reports on health care quality and patient safety are available. f. Pharmacy Quality Alliance (PQA) i. Established as public-private partnerships to assist CMS and health care in general in ensuring the provision of quality services to Medicare beneficiaries and all patients ii. Mission is to optimize health by advancing the quality of medication use. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 689

Developing and Managing a Clinical Practice

iii. Workgroups consisting of multidisciplinary representatives from member organizations develop measure concepts that are then tested, voted on, and moved forward for public use. g. Quality improvement organizations (QIOs) i. Independent organizations contracted with CMS to improve the effectiveness, efficiency, economy, and quality of services delivered to Medicare beneficiaries ii. Located in every state iii. Monitor, educate, and assist providers and patients in the delivery and receipt of quality services iv. Have scope-of-work contracts with CMS to focus on certain outcomes v. In the past, QIOs have focused on areas such as immunizations, diabetes care, infection rates, opioids, and adverse drug events. h. Alliance for Integrated Medication Management Collaborative (AIMM, formerly the Patient Safety and Clinical Pharmacy Services Collaborative) i. Initiated by the Health Resources & Services Administration in 2007 to address adverse medication events for uninsured, isolated, or medically vulnerable patients serviced by “safety-net” providers such as FQHCs ii. Uses the PDSA process to integrate clinical pharmacy services into patient care settings to improve patient safety and health outcomes iii. Membership has expanded to include any multidisciplinary, community-based group with high-risk patients that has integrated or can integrate clinical pharmacist services. iv. Focus of quality measurement has been on diabetes, hypertension, hyperlipidemia, and adverse drug events. i. National Quality Forum (NQF) i. NQF was created in 1999 by a Presidential Commission to review health care quality and consumer protection. ii. Measure endorsement is the NQF’s primary role. iii. Criteria for measure endorsement are as follows: (a) Be in the public domain (b) Be fully tested for reliability and validity (c) Compare importance, scientific merit, feasibility, and usability with competing similar measures 3. Accreditation organizations a. National Committee for Quality Assurance (NCQA) i. Founded in 1979 by the managed care industry to review PPO (preferred provider organization) and HMO (health maintenance organization) plans ii. “Reestablished” itself in 1990 as a private, independent, nonprofit health care quality oversight organization iii. Develops the HEDIS measures for employers to evaluate the health plans they use for employee benefits (a) Providers who contract with these health plans are responsible for meeting the applicable measures. (b) HEDIS measures are updated yearly. (c) Many of the HEDIS measures are associated with medication use and the patient care work of pharmacists in the ambulatory care setting. (d) HEDIS measures are updated annually and available at www.ncqa.org/hedis/measures/. iv. Provides accreditation, certification, and recognition programs (a) ACO accreditation (b) PCMH recognition (c) Diabetes management recognition program b. Center for Pharmacy Practice Accreditation (CPPA)

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 690

Developing and Managing a Clinical Practice

i. Established in 2012 through the efforts of the American Pharmacists Association, the National Association of Boards of Pharmacy, and the American Society of Health-System Pharmacists ii. The initial accreditation program offered by CPPA is for community pharmacy practice. iii. Plans to cover the complete ambulatory practice arena c. Utilization Review Accreditation Commission (URAC) i. Originated in the health care use review industry ii. Provides a wide variety of accreditation programs (a) ACO accreditation (b) PCMH recognition (c) Drug therapy management accreditation (d) Mail service pharmacy accreditation (e) Pharmacy benefit management accreditation (f) Specialty pharmacy accreditation (g) Community pharmacy accreditation (h) Telehealth accreditation d. Joint Commission: Offers accreditation for medical practices and a certification for primary care medical homes 4. Professional organizations and collaboratives a. Institute for Healthcare Improvement b. Patient-Centered Primary Care Collaborative c. Physician Consortium for Performance Improvement 5. Payers a. Payers are currently the main drivers of determining quality measurement for most health care organizations. b. Payers are within either a government or a commercial sector. c. The commercial sector commonly uses the NCQA HEDIS measures because they directly pertain to the payer’s accreditation; however, the commercial sector can also use measures from other sources and select specific sets of measures in contractual agreements with your organization. d. Government payers may include state or federal payers or the health care exchanges. State provider payment program requirements for quality measures vary for each state. If you provide services to patients insured under state programs, you will need to investigate the quality measures within the particular state’s insurance programs. e. CMS quality programs are used by the Medicare system. CMS regularly reports on its quality strategy, setting goals, objectives, and expected outcomes on the basis of the national strategy for quality improvement in health care (Box 4). The current CMS quality programs are listed later in this chapter. Box 4. CMS Quality Strategy Goals

• Make care safer by reducing harm caused while care is delivered • Improve support for a culture of safety • Reduce inappropriate and unnecessary care • Prevent or minimize harm in all settings • Help patients and their families be involved as partners in their care • Promote effective communication and coordination of care • Promote effective prevention and treatment of chronic disease • Work with communities to help people live healthily • Make care affordable Centers for Medicare & Medicaid Services (CMS). CMS’ Quality Strategy. Available at www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/ Value-Based-Programs/CMS-Quality-Strategy.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 691

Developing and Managing a Clinical Practice

Practice Case 9. You practice within a medical group accountable for MIPS measure reporting for Medicare payment. The organization’s goal is to achieve a score in the calendar year that will result in bonus Medicare payments. In addition to clinical quality measures, which set of MIPS measures is best to focus on to successfully contribute to the group’s MIPS score? A. B. C. D.

Develop an opioid education program for patients and providers. Measure patient satisfaction with your services. Focus on decreasing hospitalizations for the patients within your service. Ensure that your data are included in the group’s quality registry.

6. Federal government a. Quality measurement and MACRA i. Quality measurement and payment on the basis of reported quality measures is the cornerstone of the MACRA law and the changes in reimbursement for Medicare Part B. The law went into effect in January 2017. ii. Eligible clinicians or groups have two avenues of participation: advanced APMs and MIPS. iii. MIPS eligible clinicians able to participate as of 2021 include physicians, osteopathic practitioners, chiropractors, physician assistants, nurse practitioners, clinical nurse specialists, certified registered nurse anesthetists, certified nurse-midwives, physical therapists, occupational therapists, clinical psychologists, qualified speech-language pathologists, qualified audiologists, and registered dietitians or nutrition professionals. iv. Guidance for the two tracks included in the program – advanced APMs and MIPS – is available at the Quality Payment Program (QPP) website (https://qpp.cms.gov/). v. The QPP goal is to support patients and clinicians in making their own decisions about health care using data-driven insights, increasingly aligned and meaningful quality measures, and innovative technology. The program emphasizes high-value care and patient outcomes while minimizing burden on eligible clinicians. vi. MIPS is a payment adjustment to all Medicare claims made on the basis of the performance data and performance information submitted by eligible providers. (a) Providers can review and select the quality measures that fit their practice. The QPP goal is for practices to choose quality measures that are meaningful to them and the patients they serve. Approved measure sets exist for many specialties, including family practice, cardiology, internal medicine, and geriatrics, and are available at https://qpp.cms.gov. (1) Participants must submit data for at least six measures for the 12-month performance period. (2) One of these measures should be an outcome measure; if there is no applicable outcome measure, a high-priority measure can be submitted instead. (3) Providers have more than 250 measures to choose from. See https://qpp.cms.gov/mips/ quality-requirements (4) A review of the 2018 measures revealed that pharmacist services affect 25%–30% of the measures available to providers. (5) A scoring guide is available on the QPP website under Resources/Library. (b) More than 100 options are available to meet the practice improvement measures. Several offer opportunities for pharmacists integration into the practice, such as coordinated anticoagulation management, glycemic management services, opioid written and verbal education, and drug cost transparency. The current list of improvement activities is available at https://qpp.cms.gov/ mips/improvement-activities. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 692

Developing and Managing a Clinical Practice

(c) In 2021, CMS proposed to transform MIPS to MIPS Value Pathways to improve quality of performance, improve meaningfulness of measures, and reduce clinician burden over the next 3–5 years. CMS will establish a framework to connect measures around three of the current payment categories and add measures across the three categories that focus on population health and interoperability (currently the fourth category). Eligible providers will choose measures from quality, improvement activities, and cost that are linked on the basis of clinician specialty or a medical condition. In time, CMS also plans to add patient-reported outcomes to the MIPS Value Pathways. b. Five-star quality rating programs: The CMS 2022 Star measures are available at www.cms.gov/files/ document/2022-announcement.pdf i. Mandatory program for Medicare Part C and D plans ii. The five-star quality ratings are intended to help beneficiaries choose the best plans and determine payment and participation in Medicare by plans. iii. Three medication-related Medicare Part D measures developed by the PQA on medication adherence continue in the 2022 Star quality measures weighted as a 3, or the highest level for scoring. iv. The PQA-developed “Statin Use in Persons with Diabetes” Medicare Part D measure is now weighted as a 3, increased from its weight of 1 in 2020. v. The PQA-developed “Medication Therapy Management (MTM) Program Completion Rate for Comprehensive Medication Reviews (CMR)” Medicare Part D measure continues with a weight of 1 for 2022. vi. Pharmacist-provided patient care services may affect the following Medicare Part C measures for 2022: (a) Annual flu vaccine (b) Monitoring physical activity (c) Care for older adults – medication review (d) Care for older adults – pain assessment (e) Osteoporosis management in women who have had a fracture (f) Diabetes care – eye examination (g) Diabetes care – kidney disease monitoring (h) Diabetes care – blood glucose controlled (i) Reducing the risk of falling (j) Medication reconciliation post-discharge (k) Getting appointments and care quickly (l) Statin therapy for patients with cardiovascular disease c. CMS HRRP (Hospital Readmissions Reduction Program): i. This is an important hospital-based quality program for ambulatory pharmacists to be aware of and is part of the Hospital Value-Based Purchasing Program started in 2012. ii. The program provides an opportunity for ambulatory pharmacists providing patient care services to help hospitals realize financial gains and avoid financial penalties. iii. The program provides financial incentives to reduce costly and unnecessary hospital readmissions. iv. A hospital readmission is defined as when a patient has an unplanned admission to any hospital within 30 days for the same specified diagnosis. v. Hospital payment for the diagnosis-related group is adjusted according to a calculated risk adjustment known as the excess readmission ratio (ERR) for each applicable condition. vi. Diagnosis-related groups currently affected by this quality program are as follows: (a) Acute myocardial infarction (b) Heart failure (c) Pneumonia

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 693

Developing and Managing a Clinical Practice

(d) Elective total hip arthroplasty and/or total knee arthroplasty (e) Chronic obstructive pulmonary disease (f) Coronary artery bypass grafting surgery H. Proposed Universal Core Measure Set 1. There has been great interest in developing a core measure set that would transcend all health care practice sites. 2. This core measure set was the initial plan by CMS for MACRA. However, because of feedback from providers, the MIPS program altered the core measure set plan to allow providers to select the quality measures that best fit their particular practice from the approved measure list. This approach allows specialties such as ophthalmology or rheumatology to select more appropriate measures for their populations. 3. For 2021, CMS identified 139 measures in the QPP that are considered high priority, such as controlling blood pressure, measures related to diabetes management, and several other measures around medication use. 4. In the 2020 Physician Fee Schedule (PFS), CMS published the quality measure list per specialty intended for 2022 and 2023. However, CMS was required by the Patient Protection and Affordable Care Act of 2010 (ACA), also known as Obamacare, to establish a core measure set for Medicaid. The 2021 set of measures (2021 Core Set of Adult Health Care Quality Measures for Medicaid [Adult Core Set]) is available at www. medicaid.gov/medicaid/quality-of-care/downloads/2021-adult-core-set.pdf. 5. Many measures within the Medicaid core set can be influenced by ambulatory pharmacist–provided patient care services. 6. However, states are not required to use the Adult Core Set. States can have their own set, found on the individual state Medicaid sites. 7. How best to use a high-priority or core measure set requires an understanding of how specific measures that apply to your patient population or service can be scaled to larger, more global measures. Figure 2 graphically describes this concept. 8. CMS measures can be accessed at www.cms.gov/medicare/quality-initiatives-patient-assessment-instruments/ qualitymeasures/cms-measures-inventory.html, which allows for filter selection to access meaningful measures, core measures, and other information.

Figure 2. Flow of granular measure to core measures. PBP = population-based payment.

Reprinted with permission from: Health Care Payment Learning & Action Network.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 694

Developing and Managing a Clinical Practice

VIII.  ENSURING THE CONTINUED COMPETENCY OF YOUR STAFF (Domain 3, Task 1, Items a, c, d; Domain 3, Task 3, Item c, d) A. Domains of Competency 1. General principles a. It is important to ensure that pharmacists in your practice have the knowledge, skills, attitudes, and behaviors to successfully provide the ambulatory services. b. A 2009 article introduced a taxonomy of professionalism that outlines domains of competency (Am J Pharm Educ 2009;73:1-10). 2. Information competency a. Baseline knowledge needed for your practice b. Self-directed learning; ability and drive to keep up with literature and new knowledge c. Ability to apply knowledge to patient care d. Willingness to seek out information when it is unknown e. Wisdom in decisions in unclear or challenging situations 3. Communication competency a. Compassion as a driver of patient care b. Empathy as a driver of patient care c. Self-control in challenging situations: kindness to patients, caregivers, and coworkers d. Influence on patients, other providers, and coworkers so that patients receive optimal care to produce optimal outcomes 4. Character competency a. Honesty, integrity, and humility b. Takes responsibility c. Motivated to provide the best service possible d. Moral courage to do what is right, even if it is difficult B. ACCP published a guideline on clinical pharmacist competencies in May 2017, which mirrors and expands on the competencies listed in the previous section. Table 2 summarizes the ACCP competencies. Table 2. ACCP Description of Clinical Pharmacist Competenciesa Competency Domain

Direct patient care

Elements of the Competencyb

Assess patients, including identifying and prioritizing patient problems and medication-related needs Evaluate drug therapy for appropriateness, effectiveness, safety, adherence, and affordability. Develop/initiate therapeutic plans and address medication-related problems Follow up on and monitor the outcomes of therapeutic plans Collaborate with other members of the health care team to achieve optimal patient outcomes across the continuum of care Apply knowledge of the roles and responsibilities of other health care team members to patient care

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 695

Developing and Managing a Clinical Practice

Table 2. ACCP Description of Clinical Pharmacist Competenciesa (continued) Competency Domain

Pharmacotherapy knowledge

Systems-based care and population health

Communication

Professionalism

Continuing professional development

Elements of the Competencyb

Demonstrate and apply in-depth knowledge of pharmacology, pharmacotherapy, pathophysiology, and the clinical signs, symptoms, and natural history of diseases and/or disorders Locate, evaluate, interpret, and assimilate scientific/clinical evidence and other relevant information from the biomedical, clinical, epidemiologic, and social-behavioral literature Use scientific/clinical evidence as the basis for therapeutic decision-making Possess the knowledge and experience commensurate with certification in one or more specialty areas of the BPS Maintain and enhance pharmacotherapy knowledge, including recertification or other appropriate methods of self-assessment and learning Use health care delivery systems and health informatics to optimize the care of individual patients and patient populations Participate in identifying systems-based errors and implementing solutions Resolve medication-related problems to improve patient/population health and quality metrics Apply knowledge of pharmacoeconomics and risk-benefit analysis to patient-specific and/or population-based care Participate in developing processes to improve transitions of care Design quality improvement processes to improve medication use

Communicate effectively with patients, caregivers, families, and laypersons of diverse backgrounds, in addition to health professionals and stakeholders Provide clear and concise consultations to other health professionals Develop professional written communications that are appropriate to the audience Use verbal communications tailored to varied clinical and patient-specific environments. Communicate with appropriate levels of assertiveness, confidence, empathy, and respect

Uphold the highest standards of integrity and honesty Commit to a fiduciary relationship with patients, always working in their best interests Serve as a credible role model/leader for students, trainees, and colleagues by exhibiting the values and behaviors of a professional Advance clinical pharmacy through professional stewardship, training of future clinical pharmacists, and active engagement in professional societies Commit to excellence and lifelong learning Demonstrate skills of self-awareness, self-assessment, and self-development Identify and implement strategies for personal improvement through continuing professional development Provide professional education to students, trainees, or other health professionals Maintain BPS certification to ensure that therapeutic knowledge is up to date

a These competencies are necessary to provide comprehensive medication management in team-based, direct patient care environments. Other competencies should be acquired as the clinical pharmacist progresses through his or her career and engages in additional professional activities.

These elements of competency help describe each competency but are not intended to be all-inclusive. Other and related elements may apply depending on the clinical pharmacist’s practice setting and activities.

b

BPS = Board of Pharmacy Specialties.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 696

Developing and Managing a Clinical Practice

C. Philosophy of Practice 1. Philosophy of practice is potentially the most important characteristic of the pharmacists and technicians practicing in your setting. 2. A philosophy of practice articulates pharmacists’ responsibilities in addition to why and how they deliver care. 3. A philosophy of practice guides practitioners’ behaviors, attitudes, and work. For pharmacists who provide patient care, this philosophy should reflect being fully responsible and accountable for patients’ medications. 4. A 2018 article (Pharmacotherapy 2018;38:69-79) proposes five tenets for a pharmacist philosophy of practice: a. Meeting a societal need b. Assuming responsibility for optimizing medications c. Embracing a patient-centered approach d. Caring through an ongoing pharmacist-patient relationship e. Working as a collaborative member of the health care team D. Processes to Ensure Competency 1. Determine the minimum or desired training needed to perform the current job. a. Level of base degree or licensure b. Level of postgraduate training, if desired c. Level of experience that may offset other requirements d. Certification required or desired – Many certifications are available; some have greater recognition than others in practice. Listed here are the certifications most commonly recognized: i. Board Certified Pharmacotherapy Specialist (BCPS) ii. Board Certified Ambulatory Care Pharmacist (BCACP) iii. Other Board of Pharmacy Specialties (BPS) certifications (a) Cardiology (b) Compounded Sterile Preparations (c) Critical Care (d) Emergency Medicine (e) Geriatrics (f) Infectious Diseases (g) Nuclear (h) Nutrition Support (i) Oncology (j) Pediatrics (k) Psychiatric (l) Solid Organ Transplantation iv. Certified Diabetes Care and Education Specialist (CDCES) v. Board Certified-Advanced Diabetes Management (BC-ADM) vi. Immunization certification vii. Other disease certifications, such as anticoagulation, asthma, pain management, and smoking cessation viii. Before deciding to obtain a particular certification, due diligence in ascertaining the quality and recognition of the certification should be performed. 2. Ensuring maintenance of competency a. Credentialing is a process to ensure or validate that the pharmacist (or health professional) has the credentials, clinical experience, and the professional license to be granted practice rights and responsibilities in an organization. b. Privileging is the granting of approval to perform a set of services within the provider’s scope of practice in the organization.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 697

Developing and Managing a Clinical Practice

c. Credentialing and privileging may be required by a payer or an organization. d. Methods for credentialing and privileging may occur at time intervals such as 90 days for newly credentialed and privileged providers and up to every 24 months for maintenance of privileges. i. Providers may be required to perform a certain number of services during a certain period for which they are credentialed and/or privileged in providing ii. The quality of services provided by a provider may be evaluated over a prespecified period determined by the organization iii. Optimal methods to ensure continued competency include peer review of a subset of the services provided at regular intervals iv. Continued education in areas that are credentialed and privileged may be required throughout the selected time period

IX.  REIMBURSEMENT FOR PHARMACIST SERVICES IN THE AMBULATORY SETTING (Domain 3, Task 1, Item a, b, c; Domain 3, Task 3, Item a, b, c, e) A. Potential Revenue Sources for Pharmacist Services 1. General principles a. Because pharmacists are not federally recognized providers, they cannot directly bill for most patient care services through federal and most state government entities, though with recent advances at the state level, several states now have exceptions. b. Exceptions are immunizations, diabetes education, and MTM in Medicare Part D through prescription drug plans (PDPs) that include this mechanism. c. However, revenue for pharmacist-provided patient care services can be captured through programs that currently exist at the federal level. d. This section will review the structure and language of CMS billing, which is critical to understanding how Medicare works and the rationale for the rules that are established. The opportunities for current and future opportunities for revenue generation for pharmacist-provided patient care services will follow. 2. Federal government and Medicare services. Medicare is a federal program that provides health coverage regardless of income for individuals 65 and older, those with a severe disability, and those with end stage renal disease. Government payers are not-for-profit, and unlike commercial payers who are risk-averse to patients with complex conditions, government payers must focus on managing care for high-risk patients. a. Medicare Part A i. Administers rules and payment for services from hospitals, health systems, long-term care facilities, hospice, and home health services ii. Benefit available for all eligible beneficiaries (who must have contributed to Social Security during their lives) b. Medicare Part B i. Administers rules and payments for medically necessary outpatient services ii. Regulated by rules set forth in the PFS iii. Covers services provided by those with Medicare Part B provider status iv. Those with Medicare Part B provider status are physicians and other nonphysician providers. CMS uses the terminology qualified health care professional (QHP) when referring to providers approved under Medicare Part B who are nonphysicians from the approved list that may be identified as eligible to participate in the various Medicare programs. The complete list is available at www.cms.gov/ Outreach-and-Education/Medicare-Learning-Network-MLN/MLNProducts/EnrollmentResources/ provider-resources/provider-enrolment/Med-Prov-Enroll-MLN9658742.html. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 698

Developing and Managing a Clinical Practice

v. Covers some preventive services (e.g., immunizations, durable medical equipment) and some home care services vi. Not available to those without Social Security benefits vii. Eligible beneficiaries can opt out of this benefit; therefore, not every Medicare patient has this coverage. c. Medicare Part C or Medicare Advantage i. Medicare health plan offered by a private company that contracts with Medicare to provide Part A and B benefits ii. Many plans also provide Part D benefits. iii. Medicare pays a fixed amount for each beneficiary each month to the contracted Part C companies. iv. Part C must provide benefits that are at least equivalent to those of traditional Parts A and B; however, more benefits may be offered as well. v. The percentage of beneficiaries choosing these contracted health plans may grow with the implementation of the new models of care. Medicare Part C has almost doubled over the past 10 years and now enrolls 39% of Medicare beneficiaries. vi. Beneficiaries opt in. d. Medicare Part D – Prescription benefits i. Administered by commercial payers or PDPs ii. Includes MTM services iii. Beneficiaries opt in. 3. Private organizations. Most of these organizations are for-profit and are therefore more focused on managing costs because they, unlike government entities, can build policies to minimize their financial risk of high-risk patients (e.g., low income, disability) that the government payers must cover by law. a. Commercial insurers b. Self-insured employers or employer groups 4. State-run programs a. Medicaid is a state and federal program that provides health coverage for very low-income patients. i. The federal government pays a specified percentage of the program costs, which averaged 64% of the costs per state in 2019. ii. Criteria for very low-income patients vary by state and may require patients to have non–incomebased factors to qualify. b. Patients eligible for both Medicare and Medicaid coverage are termed dual eligible. Medicare serves as the primary insurance and covers 80% of the cost of health services, whereas Medicaid serves as the secondary insurance and pays for the patient’s 20% copayment after Medicare. c. Insurance exchanges i. The ACA established the Health Care Exchange program in each state. ii. This legislation addressed the many individuals in the United States without health care insurance. iii. The exchanges provide individuals, families, and small businesses with the means and option to purchase health care coverage that meets the rules dictated in the act regarding affordability, benefits, and market standards. iv. Those with low or modest income have the opportunity to receive premium and cost-sharing subsidies. v. States can create their own exchanges, collaborate with other states, or participate in a federal nationwide exchange. 5. Self-pay, though possible, is uncommon and difficult to sustain.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 699

Developing and Managing a Clinical Practice

Practice Case 10. You have been instructed by your director to meet with your organization’s compliance officer to discuss the opportunity to use incident-to codes to directly generate revenue for the patient care services you provide to the clinic. In preparing for this meeting, you want to make sure you understand the terminology and rules for these codes. Which factor regarding the characteristics and considerations for using incident-to codes is most important to ensure the types of service you provide are eligible for reimbursement? A. B. C. D.

They fall under American Medical Association (AMA) CPT level 1 codes. They require documentation of E/M of a condition. They can only be used for established patients. They require direct supervision for you to provide the services.

B. Generating Revenue for Pharmacist-Provided Patient Care Services 1. Understanding reimbursement terminology and language a. Healthcare Common Procedural Coding System (HCPCS) codes, often called “Hic-Pic” codes, describe which service, product, or procedure the patient received from the billing health care provider. HCPCS has two levels. i. Level I – CPT codes (a) Set of medical nomenclature used to report medical procedures and services to public and private health insurance programs (b) These codes were developed and are currently maintained and owned by the AMA. (c) There are three categories of codes. For pharmacist-provided patient care services, only the first category of E/M codes and the last category where MTM codes reside are used to describe pharmacist-provided patient care services (Box 5). (1) E/M codes (A) Five-digit CPT codes that begin with 99; describe services related to physician visits in the ambulatory setting (B) Require that E/M services be performed and documented as defined by the E/M regulations (C) Documentation requirements for these codes are discussed in the text that follows. ii. Level II – Codes for product supplies and services not covered under CPT (e.g., ambulance, durable medical equipment) (a) Codes range from A to V alphanumeric codes. (b) Examples include G codes, which are classified as temporary procedures and professional services. These include diabetes education codes and J codes, which are codes for drugs administered other than by mouth that are commonly used in outpatient infusion clinics. iii. Resource-based relative value scale (RBRVS) (a) Standardized reimbursement model created to analyze the resources involved in providing health care services or procedures that allows for discrimination between the varied work of physicians (b) RBRVS considers the following factors: (1) Physician work or the complexity and difficulty of the procedure or visit using time, technical skill, effort expended, judgment, and stress level (2) Practice expense, such as rent and wages of staff (3) Professional liability insurance (c) A RVU is assigned to each CPT code, which determines the final payment a provider will receive for that code. (1) RVUs are determined yearly by an AMA committee. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 700

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(2) RVUs are adjusted according to geographic practice cost indexes, which are then multiplied by a conversion factor to determine the payment adjustment for the CPT code. The conversion factor formula is determined by statute and updated annually. (3) MTM codes do not have RVUs. Box 5. CPT Code Categories

Category 1 Evaluation and management (E/M): 99201–99499 Example: 99211 incident-to code Anesthesia: 00100–01999; 99100–99150 Surgery: 10000–69990 Radiology: 70000–79999 Pathology and laboratory: 80000–89398 Medicine: 90281–99099; 99151–99199; 99500–99607 Example: 99605–99607 medication therapy management services

Category 2 Supplementary tracking codes that can be used for performance measurement Category 3 Emerging technology codes CPT = Current Procedural Terminology.

b. International Statistical Classification of Diseases and Related Health Problems (ICD) is a medical classification system for disease and condition codes maintained by the World Health Organization under the direction and authority of the United Nations. i. Describes why the service being billed was provided ii. The next version (ICD-11) is expected to be implemented in January 2022. iii. ICD-10 code structure: (a) 69,000 code numbers are available in the current version. (b) All codes are alphanumeric and begin with a letter followed by a number; a mix of letters and numbers are used thereafter. (c) ICD-10 code lengths vary from four to seven alphanumeric characters. c. Medicare administrative contractors (MACs) i. In the past, MACs were also called fiscal intermediaries or Part B carriers. ii. MACs are private companies contracted with Medicare to administer Medicare funds to providers. iii. Moreover, MACs provide reimbursement services, medical coverage review, and audits; respond to provider inquiries; educate providers; establish local coverage determinations; and process claims. iv. Currently, there are 12 Medicare Part A and B MACs and 4 durable medical equipment MACs. v. Because MACs may add interpretation to CMS billing rules, it is important to regularly review your region’s MAC website for any additional rules and regulations pertaining to the billing codes being used for your service. vi. You can find more information regarding the role of MACs and determine your MAC at the following links: (a) www.cms.gov/medicare/medicare-contracting/medicare-administrative-contractors/what-is-amac (b) www.cms.gov/research-statistics-data-and-systems/monitoring-programs/medicare-ffscompliance-programs/review-contractor-directory-interactive-map/index

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d. Health Care Financing Administration 1500 form (HCFA-1500) and the electronic format, called the 837P i. The official standard form and electronic format used by individual health care providers (e.g., physicians, nurse practitioners) when submitting bills or claims to payers for reimbursement ii. Primarily a federal government form, but used universally e. The CMS-1450 (previously called UB-04 or UB-92) and its electronic format, called the 837I i. Form or electronic format used by facilities or institutions (e.g., hospitals, long-term care facilities) when submitting bills or claims for reimbursement ii. Some private payers may still use UB-04. f. National Provider Identifier (NPI) i. NPI is a 10-digit identification number available for issue to all health care providers, including pharmacists, and to all U.S. health care organizations. ii. NPI use is mandatory for electronic billing and for those who use electronic transactions of protected personal health information. g. Medical necessity i. The services you provide must be deemed medically necessary. ii. CMS defines medically necessary as “services or supplies that are proper and needed for the diagnosis or treatment of a medical condition and are provided for the diagnosis, direct care, and treatment of the medical condition, meet the standards of good medical practice in the local area, and are not mainly for the convenience of the patient or the provider” (this definition is available at www.medicare.gov/glossary/m.html). 2. Rules and regulations are constantly changing, with frequent updates. a. Staying abreast of these changes is generally the responsibility of the organization’s compliance officer and the billing and coding personnel. b. It may be difficult to keep up with them yourself. Instead, develop relationships with those responsible for billing in the organization so that you remain informed. c. Remember that the one source of truth is Medicare; other entities may not be current or may not correctly interpret the information. You can connect with the Medicare Learning Network and sign up for its e-newsletter and other resources (www.cms.gov/Outreach-and-Education/Outreach-and-Education. html). This resource is highly recommended because CMS has made significant effort through this forum to help providers understand the rules and regulations of its programs. d. Medicare documents yearly set the rules for benefits and billing. i. Outpatient prospective payment system (OPPS) or hospital outpatient prospective payment system (HOPPS) – Call for comment released in early summer (June) with final rules released in late fall (November) ii. PFS – Call for comment released in early summer (June) with final rules released in late fall (November) iii. CMS call letter – For Medicare Parts C and D, with call for comment released in early winter with final rules released in early spring C. Medicare Rules for Billing 1. By law, Medicare beneficiaries must be billed using usual and customary prices. 2. This approach to billing means that a provider cannot discriminate against Medicare patients in billing or give another group of patients a substantially cheaper rate for the same service. 3. Consequently, most organizations will follow Medicare rules for all patients (non-Medicare patients) unless specific state rules exist for state-run programs or unless a contractual relationship exists that dictates a different process with commercial payers.

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D. Institutional Revenue Generation Options for Pharmacists – Medicare Governed by HOPPS or OPPS 1. “Facility fee” billing a. Typically used for non–Medicare B-recognized providers who are employed, contracted, or leased by a hospital or health system b. Essentially pays the hospital the costs of using the facility to provide services to the beneficiary c. Uses Ambulatory Payment Classification (APC) system codes – a coding system housed under HCPCS level II d. APC was established as a way to pay for facility outpatient services; it is analogous to the way in which inpatient services or diagnosis-related groups are paid. e. When billing the facility fee, APC code 5012 is used together with the HCPCS level II G0463 code. 2. Requirements for facility fee billing: a. Medically necessary b. Sufficiently documented c. Established patient (seen within the past 3 years) d. Meet incident-to requirements (Table 3) e. Differences in requirements specific for HOPPS are as follows: i. The supervising provider must provide general supervision for hospital outpatient therapeutic services. General supervision requires the service to be furnished under the physician’s overall direction and management, but the physician’s presence is not required during the provision of the service. ii. Must have a financial relationship with the hospital as an employee, leased employee, or independent contractor iii. The hospital must make public and easily accessible the charges for “shoppable services,” which include facility fee billing for outpatient services. 3. Barriers to facility fee billing a. Copayment for the patient for use of the facility (what is being reimbursed by Medicare) together with the supervising provider bill with copayment. This creates several fees for the patient associated with one visit. b. Can be lumped into deductibles for commercial payers Table 3. Medicare Requirements for Incident-to Services and Billing Criteria for Billing Incident-to Services Physician Office Services

Hospital Outpatient Services

Established patient: Patient must be an established patient with the eligible provider and must have an initial faceto-face visit with the provider where the plan of care is established

Same

Service is provided under the direct supervision of an eligible physician or nonphysician practitioner, defined as within the suite or office space where the service is performed and immediately available to provide assistance

Service is an integral, though incidental, part of the eligible provider’s services

Services are commonly rendered without charge or are included as part of the eligible provider’s bill

Service is provided under the general supervision of an eligible physician or nonphysician practitioner, defined as the physician’s overall direction and management, but the physician’s presence is not required during provision of the service

Same Same

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Table 3. Medicare Requirements for Incident-to Services and Billing (continued) Criteria for Billing Incident-to Services Physician Office Services

Hospital Outpatient Services

Service must be medically necessary, authorized (authorized practitioner’s order), and documented

Same

A financial relationship must exist between the auxiliary personnel and the eligible provider

An employee relationship must exist with the hospital as an employee, leased employee, or independent contractor

Services are of a type that is commonly furnished and appropriate to be provided in a physician’s offices or clinic

Same

Authorized provider must provide subsequent services at a frequency that reflects active participation in treating the patient and plan of care

Same

Services provided are within the scope of practice for the auxiliary personnel as dictated by the state practice act

Same

E. Clinic or Physician Office Revenue Options for Pharmacists – Medicare Governed by the PFS 1. Incident-to billing definition and scope a. Incident-to billing is an indirect billing mechanism whereby auxiliary personnel under their state scope of practice can provide patient care services under the direct supervision of a physician or other approved Medicare Part B provider b. The service must be a necessary service that is under and integral to the service provided by the approved Medicare Part B provider. c. Medicare Part B pays for management for medical conditions or problems; it does not pay for medication therapy management (MTM), which CMS considers a Part D benefit. 2. Incident-to billing requirements a. Patient must be established with the practice (seen in the practice within the past 3 years). b. Must have a face-to-face visit with the Medicare Part B provider before the incident-to visit c. Service must be medically necessary. d. Service is an integral, though incidental, part of the approved Medicare Part B provider’s service. e. Service is commonly provided in the provider’s office. f. Service is part of the provider’s bill. g. Must be provided under the direct supervision (i.e., must be present in the office space or suite) of the approved Medicare Part B provider who is directing the patient’s care plan or a Medicare Part B provider within the same medical group. i. Per the 2021 PFS, for the duration of the COVID-19 public health emergency, CMS revised the definition of direct supervision to include virtual presence of the supervising physician or practitioner using interactive audio/video real-time communications technology (not audio only). h. The approved Medicare Part B provider must actively be involved by continuing to have face-to-face visits and E/M of the problem associated with the incident-to billing. There are no Medicare-established rules on frequency of the provider’s involvement, but the industry often suggests the “one-in-three” rule, meaning that the provider sees the patient every third visit. i. The service provided must be within the state scope of practice of the auxiliary personnel. j. Must meet all the requirements for incident-to services (see Table 3) 3. Levels of E/M incident-to billing a. Five billing levels (Table 4)

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b. Specifics of the required elements for incident-to billing are outlined in the Medicare E/M 1995 or 1997 regulations, which converted to the AMA/CPT E/M framework in 2021. The specific changes are available at www.ama-assn.org/system/files/2019-06/cpt-office-prolonged-svs-code-changes.pdf. c. CMS Medicare E/M documentation requirements for billing Medicare Part B (addressed later in this chapter) when using E/M codes: i. Documentation must state that the service is medically reasonable and necessary and describe the work the provider performed. ii. The requirements are physician focused; however, when pharmacists as auxiliary personnel are providing services that are billed incident-to physicians, they must follow the same E/M requirements, regardless of the site of service. iii. See Table 4 for a listing of the elements that must be in your documentation if you are using E/M CPT codes. iv. CMS has provided an excellent resource for E/M documentation in the Medical Learning Network (www.cms.gov/outreach-and-education/medicare-learning-network-mln/mlnproducts/downloads/ eval-mgmt-serv-guide-icn006764.pdf). v. Four levels of service are used in E/M rules, which denote that increasing complexity (and therefore reimbursement) should be evident in the documentation (Table 5). (a) Medical problem focused (b) Expanded medical problem focused (c) Detailed (d) Comprehensive vi. History component – Information provided should substantiate medical decision-making. (a) Chief concern (b) History of present illness (HPI) (c) Past, family, and social history (PFSH) (d) Review of systems (ROS) vii. Examination: Physical examination according to body area or organ system viii. Medical decision-making is evident by the assessment and plan of the documentation. (a) Assessment – Includes a list of diagnoses or potential diagnoses (b) Must address the chief concern (c) Plan – Must list orders ix. Four levels of complexity or risk with medical decision-making factor into payment for the service: (a) Minimal (b) Low (c) Moderate (d) High 4. Medicare changes in E/M incident-to billing a. To reduce documentation as part of the Patients over Paperwork initiative, CMS changed requirements for E/M documentation in the 2019 rules. i. When relevant information is already contained in the medical record, practitioners can focus their documentation on what has changed since the last visit, or on pertinent items that have not changed; they do need not to re-record the defined list of required elements if evidence shows they reviewed the previous information and updated it as needed. ii. In addition, practitioners need not re-document the patient’s chief concern and history if they have already been appropriately documented by ancillary staff or the beneficiary. iii. However, practitioners must document that the medical record was reviewed and the information verified.

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b. Beginning in 2021, CMS revised the rules for office or other outpatient E/M services to allow for selection of the appropriate code level for the services rendered according to the level of the medical decision-making or total time for E/M services performed on the date of the encounter. i. CMS specified that when time is used to select the appropriate level for E/M service codes, the E/M services for which these guidelines apply require a face-to-face encounter with the physician or other QHP. ii. However, if the physician’s or other QHP’s time is spent in the supervision of clinical staff who perform the face-to-face services of the encounter, 99211 should be used. c. Incident-to billing and pharmacist-specific rules and interpretations i. The changes outlined by CMS in the 2021 physician fee schedule included language to formally define pharmacists as auxiliary personnel and restrict pharmacists’ ability to bill incident-to E/M codes at levels higher than 99211. ii. Specifically, CMS noted that pharmacists are not among the nonphysician QHPs who can furnish and bill for office/outpatient E/M visit codes because 99212–99215 are, by definition, only performed and directly reported by physicians or nonphysician QHPs. (a) When time is used to select the appropriate visit level, only the time of the physician or nonphysician QHP can be considered. (b) Level 2–5 codes cannot be used to bill for time spent solely by a pharmacist working “incidentto” the services of a billing physician or nonphysician QHP. iii. CMS acknowledged and noted the value of specially trained pharmacists with broadened scopes of practice and suggested that new codes would be useful to identify and reimburse for these pharmacist-provided clinical services. d. MTM cannot be billed under incident-to rules because MTM is a Part D, not Part B, benefit. Table 4. Incident-to E/M Codes for Billing According to Levels of Service and Required Supporting Elements Established Patient E/M Codes 99211 Assessments of care N/A

99212

99214

99215

Straightforward Low

Moderate

High

Problem focused

99213

Expanded problem focused

Detailed

Comprehensive

Level of decision-making

N/A

Chief concern

N/A

Required

Required

Required

Required

HPI elements

N/A

Brief or 1–3 elements

Brief or 1–3 elements

Extended ≥ 4 elements (1995) > 4 elements or 3 from chronic conditions (1997)

ROS elements

N/A

N/A

Problem pertinent

Extended ≥ 4 elements (1995) > 4 elements or 3 from chronic conditions (1997) Extended 2–9 elements

Complete minimum of 10 elements

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Table 4. Incident-to E/M Codes for Billing According to Levels of Service and Required Supporting Elements (continued) Established Patient E/M Codes 99211 PFSH elements

N/A

PE elements

N/A

99212

99213

99214

99215

1–5 elements in ≥ 1 organ system

≥ 6 elements in ≥ 1 organ system

2 elements in ≥ 6 organ systems or 12 elements in ≥ 2 organ systems

Elements from 8 organ systems (1995) 2 elements from 9 organ systems (1997)

N/A

N/A

Pertinent or 1 item from any of the areas

Complete 1 element from 2 or 3 of the 3 categories

E/M = evaluation and management; HPI = history of present illness; N/A = not applicable; PE = physical examination; PFSH = past family and social history; ROS = review of systems.

Information from: Centers for Medicare & Medicaid Services (CMS). Evaluation and Management Services. Available at www.cms.gov/outreach-and-education/ medicare-learning-network-mln/mlnproducts/downloads/eval-mgmt-serv-guide-icn006764.pdf.

Table 5. Determinants of Complexity of MDM and Time-based Criteria for Selection of Office or Other Outpatient E/M Services Established Patient E/M Codes

Level of MDM

Number and Complexity of Problems Addressed

Straightforward

Minimal

99211

N/A

99213

Low

99212 99214

99215

Moderate High

Amount and/or Complexity of Data to Be Reviewed

Risk of Complications, Morbidity, and/or Mortality

Time-based (min)

Minimal or none

Minimal

10-19

N/A

N/A

Limited

Limited

Multiple

Extensive

Moderate

Extensive

N/A

Low

Moderate High

N/A

20-29 30-39

40-54a

For services ≥55 minutes, G2212 should be reported for each additional 15 minutes of time spent by the physician or QHP, as long as the level 5 office/outpatient E/M visit is exceeded by at least 15 minutes on the date of service. a

E/M = evaluation and management; MDM = medical decision-making

Practice Case 11. You recently completed a community residency practice and have been hired by an independent pharmacy that wants to start building services beyond MTM through Medicare Part D. Your practice is in a rural community where there is an older adult population and a high incidence of common chronic conditions such as hypertension, type 2 diabetes, chronic obstructive pulmonary disease, obesity, and smoking. You have a good relationship with the regional hospital and the family practice physician in town. The pharmacy owner has added a stipulation that there must be revenue to cover the expense of the service (e.g., staffing, promotion, and materials needed). Which service is best to initiate? A. B. C. D.

Medicare Diabetes Prevention Program (MDPP). Transitional care management (TCM). Chronic care management (CCM). Annual wellness visits (AWVs).

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F. Other Billing Opportunities Available for Pharmacists Under Medicare 1. Diabetes self-management training a. HCPCS level II codes, G codes i. G0108 – Individual visits (a) Individual training (b) Billable and paid in 30-minute increments (1 unit) ii. G0109 – Group visits (a) Group training (b) 2–20 participants (c) Do not all need to be Medicare beneficiaries (d) Billable and paid in 30-minute increments (1 unit) b. Requires a physician order that states the following: i. Initial and follow-up hours needed (a) Initial training (1) Beneficiary has not previously received initial or follow-up training under HCPCS G0108 or G0109. (2) Furnished within a continuous 12-month period (3) 10 hours or fewer of initial training spread over the 12-month period or less provided in any combination of ½-hour increments (4) Except for 1 hour of individual training, training is usually furnished in a group setting. The 1 hour of individual training can be used for any part of the training, including insulin training. (5) Medicare covers training on an individual basis if one of the following criteria are met: • No group session is available within 2 months of the date the training is ordered • The beneficiary’s Medicare Part B provider documents in the electronic medical record that the beneficiary has special needs because of conditions that would hinder effective participation in a group training (i.e., hearing or vision disabilities) • The physician orders additional insulin training (6) FQHC diabetes education programs operate differently and are reimbursed only for individual diabetes self-management training. (b) Follow-up training (1) 2 hours or fewer of individual or group training per year furnished in any combination of ½-hour increments (2) Furnished any time in a calendar year after the year in which the beneficiary completes the initial training ii. Topics to be covered iii. Whether patient should receive individual or group training c. To bill Medicare, must be accredited from the Association of Diabetes Care & Education Specialists, American Diabetes Association, or Indian Health Service program (other payers may not require certification) 2. CMS AWVs a. HCPCS level II codes, G codes i. G0402 (Initial Preventive Physical Examination [IPPE]). The IPPE or “Welcome to Medicare” preventive visit can only be done by a physician or nonphysician provider, not a pharmacist. ii. G0438 (initial AWV, once in lifetime) iii. G0439 (subsequent AWV) iv. G0468 (initial and subsequent AWV services provided in a FQHC)

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b. This service is only available under Medicare Part B. c. Will pay either the practitioner or the facility for furnishing the visit d. Who is eligible to provide AWVs? i. A physician ii. Nonphysician provider: Physician assistant, nurse practitioner, clinical nurse specialist iii. Medical professional – A health educator, registered dietitian, nutrition professional, other licensed practitioner, including pharmacists or a team of such medical professionals working under the direct supervision of a physician e. Initial AWV includes 10 required functions: i. Establishment of an individual’s medical/family history ii. Establishment of a list of current providers and suppliers regularly involved in providing medical care to the individual iii. Measurement of an individual’s height, weight, BMI (or waist circumference, if appropriate), blood pressure, and other routine measurements, as deemed appropriate on the basis of the beneficiary’s medical/family history iv. Detection of any cognitive impairment the individual may have, assessed through direct observation with consideration of information obtained by patient report and concerns raised by family members, friends, caretakers, or others v. Review of the individual’s potential (risk factors) for depression, including current or past experiences with depression or other mood disorders, using an appropriate screening instrument for individuals without a current diagnosis of depression, which the health professional can select from various available standardized screening tests designed for this purpose and which are recognized by national medical professional organizations vi. Review of the individual’s functional ability and level of safety, which may be performed by direct observation, use of appropriate screening questions, or a screening questionnaire selected by the health professional, who can select from various available screening questions or standardized questionnaires designed for this purpose and recognized by national professional medical organizations vii. Establishment of a written screening schedule for the individual, such as a checklist for the next 5–10 years, as appropriate, on the basis of recommendations of the U.S. Preventive Services Task Force and the Advisory Committee on Immunization Practices, as well as the individual’s health status, screening history, and age-appropriate preventive services covered by Medicare viii. Establishment of a list of risk factors and conditions for which primary, secondary, or tertiary interventions are recommended or are under way for the individual, including any mental health conditions or any such risk factors or conditions that have been identified through an IPPE, and a list of treatment options and their associated risks and benefits ix. Furnishing of personalized health advice to the individual and a referral, as appropriate, to health education or preventive counseling services or programs aimed at reducing identified risk factors and improving self-management, or community-based lifestyle interventions to reduce health risks and promote self-management and wellness, including weight loss, physical activity, smoking cessation, fall prevention, and nutrition x. Any other elements determined to be appropriate by the Secretary of Health and Human Services through the National Coverage Determination f. Subsequent AWVs: Depression and functional status screening are no longer required for the visit. g. As of 2016, CMS will pay a Part B practitioner or a facility for an AWV, thus allowing hospitals to provide this service under HOPPS.

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3. Transitional care management (TCM) a. HCPCS level I, CPT E/M codes i. 99496 (seen within 7 days of discharge): Medical decision-making of high complexity during the service period ii. 99495 (seen within 14 days of discharge): Medical decision-making of at least moderate complexity during the service period b. May be billed by physicians or qualified nonphysician providers of care management for discharges from the following: i. Inpatient hospital setting (including rehabilitation and psychiatric institutions) ii. Observational setting (less than a 48-hour inpatient stay) iii. Skilled nursing facility c. Must be discharged to a community setting (home or assisted living) d. Bundle face-to-face and non–face-to-face coordinated activities into one payment e. Face-to-face interview must be done by a Medicare-recognized qualified provider; the non–face-to-face interview can be done by or under the direction of a provider working within the scope of his or her practice. i. Pharmacists can do non–face-to-face interviews and coordination of activities and can assist the physician or other Medicare-recognized provider during the face-to-face visit. ii. Must follow incident-to rules; however, in 2015, CMS relaxed the rule of direct supervision to general supervision by the Medicare Part B provider for auxiliary personnel (includes pharmacists) for the non–face-to-face coordinated activities with transitions of care. The face-to-face services remain under direct supervision. General supervision requires the procedure or service to be furnished under the physician’s overall direction and control, but the physician’s presence in the suite or office space where the service is performed is not required during the procedure or service. iii. Before 2016, the practice had to bill at 30 days after discharge, not on the date of the visit(s). In 2016, the billing procedures changed so that the practice could bill on the date of service. However, if the patient is readmitted within 30 days and the practice has already billed TCM for that patient, the practice cannot bill for TCM when the patient is discharged the second time. If the patient is readmitted and the practice has not yet billed, the practice can wait until the patient is discharged the second time, track the patient for TCM, and bill after the second face-to-face visit. f. Required components for billing: i. Communication with patient or caregiver within 2 days of discharge ii. Face-to-face visit within either 7 or 14 days, depending on the complexity of medical decisionmaking iii. Required documentation: (a) Complexity of medical decision-making (moderate or high) (b) Date of discharge (c) Date of interactive contact with patient or caregiver (d) Date of face-to-face visit iv. Only one health care professional can submit the claim for TCM services in the 30 days after discharge. g. Components of service that can be furnished by physicians or other Medicare-recognized providers: i. Obtaining and reviewing discharge information ii. Reviewing the need for follow-up on pending diagnostic tests and treatment iii. Interacting with other health care providers (specialists) who will assume or reassume care of the beneficiary iv. Providing education v. Establishing or reestablishing referrals and arranging needed community resources vi. Assisting in scheduling any required follow-ups with community providers and services ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 710

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h. Components of service that can be furnished by non–Medicare-recognized health care practitioners: i. Communicating with agencies and community services used by the beneficiary ii. Providing education to support self-management, independent living, and activities of daily living iii. Assessing and supporting treatment regimen adherence and medication management iv. Identifying available community and health resources v. Helping the beneficiary and/or family access needed care and services. A change as of 2020 is that TCM codes can be billed with the following CPT codes: care plan oversight; CCM; end-stage renal services; prolonged services without direct patient contact; home and outpatient INR monitoring services; and data analysis codes. 4. Chronic care management a. HCPCS level I, CPT E/M codes i. 99490: CCM code ii. 99487 and 99489: Complex CCM codes b. Incident-to visits for CCM – To support primary care and recognize CCM as a critical component of primary care, CMS has created initiatives to improve payment for and encourage long-term investment in CCM. In 2017, CMS added additional codes with increased payment for patients with more complex conditions. c. Requirements for billing all available CCM codes: i. An initiating visit must be done by a Medicare Part B eligible provider for any new patient or patients not seen within 1 year before the provider billing for CCM services. (a) The eligible provider can use any of the following visit types: AWV, IPPE, or face-to-face E/M visit (level 4 or 5 visit not required). (b) In 2017, CMS also provided an add-on code (G0506) to the initiating visit, recognizing that establishing the plan of care may require extensive assessment and care planning beyond the usual effort as described by the separately billable CCM initiating visit. ii. Beneficiary or patient requirements: (a) Several (two or more) chronic conditions (b) Chronic conditions expected to last at least 12 months, or until the patient’s death (c) Chronic conditions place the patient at significant risk of death, acute exacerbation/ decompensation, or functional decline iii. A comprehensive care plan is established by the Medicare Part B eligible provider and is implemented, revised, or monitored by the health care team. iv. As noted with TCM, CMS provides an exception to incident-to rules of general versus direct supervision and states that the auxiliary personnel need not be direct employees. d. Additional rules: i. Copayment from beneficiary required (a) For dual-eligible patients, state Medicaid is required to pay the copayment. (b) For patients with private Medicare supplement insurance, the insurance is required to pay the copayment. (c) For patients with a secondary to Medicare full health care insurance plan (e.g., employer-based plan), the insurance is not required to pay the copayment. (d) New legislation, the Chronic Care Management Improvement Act, is being proposed to eliminate the cost-sharing component of CCM to increase its utilization by Medicare beneficiaries and improve reimbursement to providers. ii. Patient consent must be obtained before furnishing or billing for CCM services. This consent can be verbal or written, but it must be documented in the medical record and should inform the patient about: (a) Availability of CCM services and applicable cost sharing

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 711

Developing and Managing a Clinical Practice

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(b) That only one practitioner can furnish and be paid for CCM services during a calendar month (c) The right to stop CCM services at any time (effective at the end of the calendar month) Required scope-of-service elements: i. The patient must have access to the practice for urgent needs 24 hours/day, 7 days/week for CCM services. Patients must be provided with a means to make timely contact with health care providers in the practice to address their urgent care needs. The practice should use available enhanced opportunities for communication such as: (a) Secure messaging (b) Telephone access (c) Internet (d) Other asynchronous non–face-to-face consultation methods ii. Continuity of care with a designated practitioner or member of the care team with whom the patient can obtain successive routine appointments iii. Care is comprehensive and includes a systematic assessment of the following: (a) Patient medical, functional, and psychosocial needs (b) Timely receipt of all recommended preventive care services (c) Medication reconciliation with a review of adherence and potential interactions (d) Oversight of patient self-management of medications iv. An electronic patient-centered comprehensive care plan is created, revised, and/or monitored and shared electronically or by fax outside the practice, and a copy is given to the patient and/or caregiver. The following are the details suggested for the comprehensive care plan. The comprehensive care plan should contain the elements that are important for the patient and address all of the patient’s health issues. (a) Problem list (b) Expected outcome and prognosis (c) Measurable treatment goals (d) Cognitive and functional assessment (e) Symptom management (f) Planned interventions (g) Medical management (h) Environmental evaluation (i) Caregiver assessment (j) Interaction and coordination with outside resources and providers (k) Requirements for periodic review Electronic health record (EHR) requirements: i. Ability to fulfill the scope of service and other elements listed earlier ii. EHR certified to the edition of certification criteria that is acceptable for the EHR Incentive Programs as of December 31 of the calendar year before the PFS (PFS payment year) iii. Meet the final core EHR capabilities (structured recording of demographics, problems, medications, medication allergies, and creation of a structure clinical summary record) Can be billed under HOPPS. In this case, the patient must be informed that hospital personnel are providing this service. Requirements for the specific CCM codes: i. CCM code 99490 (a) At least 20 minutes of clinical staff time directed by a physician or other qualified health care provider per calendar month (b) Only code available to be used by FQHCs and rural health clinics

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 712

Developing and Managing a Clinical Practice

(c) As of 2020, CMS added G2058. The code is intended to be added to CCM code 99490 if an additional 20 minutes of clinical staff time is needed. G2058 can be reported no more than two times within a given service period for a given beneficiary. ii. Complex CCM codes 99487 and 99489 (a) Evidence of moderate- or high-complexity medical decision-making (see Table 5) (b) For 60 minutes of clinical staff time directed by a physician or other QHP per calendar month, use code 99487. (c) For each additional 30 minutes of clinical staff time directed by a physician or other QHP per calendar month, use 99489 as an add-on code to 99487 only. (d) Must meet the time elements to bill each code; cannot use the codes for less time (e.g., 45 minutes instead of 60 minutes) for 99487 or 20 minutes instead of 30 minutes for 99489 iii. Can use only CCM or complex CCM code for any given month; cannot use both codes in the same month 5. Principal care management (PCM) services a. CMS introduced PCM as new codes in 2020. b. PCM coding and payment for care management services for patients with one serious chronic condition expected to last 3 months to 1 year, or until the patient’s death, may have led to a recent hospitalization, and/or place the patient at significant risk of death, acute exacerbation/decompensation, or functional decline. c. The code is intended for when an exacerbation of the patient’s complex chronic condition or recent hospitalization occurs such that disease-specific care and management are warranted. d. The service code covers care management when a single condition is of such complexity that it cannot be managed as effectively in the primary care setting and instead requires management by another, more specialized, practitioner; however, CMS is placing no restrictions on which specialty can use the codes and acknowledges that primary care can use the code. e. The expected outcome of PCM is for the patient’s condition to be stabilized by the treating clinician so that overall care management for the patient’s condition can be returned to the patient’s primary care practitioner. f. PCM services include coordination of medical and/or psychosocial care related to the single complex chronic condition provided by a physician or clinical staff under the direction of a physician or other qualified health care provider. g. When using other clinical staff, services can be provided under general supervision. h. PCM services can simultaneously be provided by more than one clinician if the patient has an exacerbation of more than one complex chronic condition. i. The scope-of-service requirements for PCM are slightly different from those for CCM and include the following: i. Verbal consent from the patient must be obtained and documented in the medical record and should inform the patient about: (a) The availability of the service (b) That only one practitioner can bill per month (c) The patient’s right to stop services effective at the end of any service period (d) That cost sharing applies (if no supplemental insurance) ii. As with CCM, the eligible provider can initiate the service during another visit type that is separately paid. iii. Certified EHR use requirements are the same as for CCM. iv. Disease-specific care management includes the following, as applicable: (a) Systematic needs assessment (medical and psychosocial) (b) Ensures receipt of preventive services (c) Medication reconciliation, management, and oversight of self-management ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 713

Developing and Managing a Clinical Practice

v. A disease-specific electronic care plan versus general as in CCM, with consideration of the same elements as for CCM vi. Management of care transitions/referrals, such as discharges, ED visit follow-up, and referrals, as applicable, through creation and exchange of continuity of care documents in a timely manner (format not prescribed) vii. Home- and community-based care coordination with any home- and community-based clinical service providers and documentation of communication with them regarding psychosocial needs and functional deficits, as applicable viii. Enhanced communication opportunities through offering asynchronous non–face-to-face methods other than telephone, such as secure e-mail j. PCM cannot be billed by the same practitioner for the same patient concurrently with certain other care management services, such as CCM, behavioral health integration services, or monthly capitated payments for end-stage renal disease. k. Payment will be under four new billing codes defined by CMS. Only 99426 and 99427 can be used by the billing provider for pharmacist-provided patient care services. i. 99424: Comprehensive care management services for a single high-risk disease (i.e., PCM) with at least 30 minutes of physician or other nonphysician QHP time per calendar month with the following elements: (a) One complex chronic condition lasting at least 3 months, which is the focus of the care plan; (b) The condition is of sufficient severity to place the patient at risk of hospitalization or to have caused a recent hospitalization; (c) The condition requires development or revision of the disease-specific care plan; (d) The condition requires frequent adjustments in the medication regimen; and (e) Management of the condition is unusually complex because of comorbidities. ii. 99425: For each additional 30 minutes of PCM services for a single high-risk disease provided personally by a physician or other nonphysician QHP, per calendar month, as an add-on code to 99424 only. iii. 99426: Comprehensive care management for a single high-risk disease (i.e., PCM) with at least 30 minutes of clinical staff time directed by a physician or other nonphysician QHP, per calendar month with the following elements: (a) One complex chronic condition lasting at least 3 months, which is the focus of the care plan; (b) The condition is of sufficient severity to place the patient at risk of hospitalization or to have caused a recent hospitalization; (c) The condition requires development or revision of a disease-specific care plan; (d) The condition requires frequent adjustments in the medication regimen; and (e) Management of the condition is unusually complex because of comorbidities. iv. 99427: For each additional 30 minutes of clinical staff time directed by a physician or other nonphysician QHP to deliver PCM services for a single high-risk disease, per calendar month, as an add-on code to 99426 only. l. Reimbursement for G2065 is similar to that for CCM. m. CMS will monitor use of the PCM codes before considering creating an add-on code for additional time spent each month. n. Beginning in 2021, rural health clinics and FQHCs are able to bill for care management services (as HCPCS codes G0511 and G0512), including PCM, either alone or with other payable services. G. Medicare Diabetes Prevention Program 1. The MDPP is an evidence-based set of services aimed to help prevent the onset of type 2 diabetes among Medicare beneficiaries who have prediabetes.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 714

Developing and Managing a Clinical Practice

2. MDPP became available to Medicare beneficiaries in April 2018. 3. MDPP consists of the following: a. Structured sessions with a “coach” using a CDC-approved curriculum to provide training in dietary change, increased physical activity, and weight-loss strategies b. Twelve months of core sessions with an additional 12 months of ongoing maintenance sessions for participants who meet weight-loss and attendance goals 4. MDPP organization requirements: a. Many requirements exist for pharmacists and their organizations to be approved to provide this program. b. One of the requirements is for organizations to have full or preliminary recognition by the CDC’s Diabetes Prevention Recognition Program. More information is available at https://innovation.cms.gov/ initiatives/medicare-diabetes-prevention-program/. 5. Coach eligibility: a. Requirements for coaches are also available at the CMS website. b. Coaches must have an NPI number. 6. Documentation: a. Many documentation requirements exist and are outlined at the CMS website. b. In particular, accurate documentation of attendance at sessions and weight loss is required. 7. Payment: a. MDPP providers submit claims through the usual Medicare Part B processes. b. Payments are made on the basis of beneficiary attendance and weight loss of 5% from baseline for the first year and 9% from baseline for the second year. c. A series of G codes are available for the billing of the various steps and outcomes as they occur (G9873-G9879, G9880-G9885, G9890, G9891). H. Community Pharmacy – Part D MTM Services 1. MTM CPT codes a. 99605: New patient, face-to-face visit: Initial 15 minutes b. 99606: Established patient, face-to-face visit: Initial 15 minutes c. 99607: Face-to-face visit i. For each additional 15 minutes ii. Used only in addition to 99605 or 99606 iii. Listed separately d. Summary of current use i. Lack of universal reimbursement for codes ii. Used in some state Medicaid programs and some prescription drug benefit programs e. Potential to use in private contract reimbursement 2. As a result of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, Medicare contracts with PDPs to provide MTM services. a. PDPs then contract with pharmacists and/or pharmacies to provide these services or can provide these services with internal staff. b. The pharmacy may or may not use MTM codes. 3. Requirements are updated yearly in the CMS call letter, usually released in the spring before the year when the regulations are implemented. The following is a summary of the 2022 requirements for Medicare Part D MTM services: a. Eligible beneficiaries must have an annual comprehensive medication review. i. Interactive person-to-person visit or telehealth consultation ii. May result in a recommended medication action plan b. Eligible beneficiaries should have at least quarterly targeted medication reviews with follow-up interventions, when necessary. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 715

Developing and Managing a Clinical Practice

c. Eligible beneficiaries must be provided information about safe disposal of prescription drugs that are controlled substances. d. Opt-out only: i. All eligible beneficiaries are to receive these services unless they decline to participate. ii. Beneficiaries may request to permanently opt out of the program; however, if the beneficiary seeks enrollment into the MTM program at a later time (i.e., due to a level of care iii. change), the plan must allow the beneficiary to participate as long as they meet eligibility criteria. e. May be furnished by a pharmacist or other qualified provider f. May distinguish between services in ambulatory and institutional settings g. Must be developed in cooperation with licensed and practicing pharmacists and physicians h. Measure outcomes of MTM program i. Examples of drug therapy problem recommendations made as a result of MTM ii. Examples of drug therapy problem resolutions made as a result of MTM recommendations i. Interventions for both beneficiaries and prescriber 4. Eligibility for MTM services under Medicare Part D: a. Have several chronic diseases, with three being the most that a Part D plan sponsor can require for targeted enrollment b. Taking several Part D drugs, with eight being the most that a Part D plan sponsor can require for targeted enrollment c. Likely to incur Part D drug costs of $4696 or greater I. Reimbursement for Pharmacist-Provided Patient Care Services Under Non-Medicare Payers 1. Private payers a. Contractual relationships in which all aspects of the service are negotiated between the pharmacist and the payer b. Can be done with the following: i. Commercial payers ii. Self-insured employers iii. Health care organizations 2. State-based programs a. At least 14 states have reimbursement for pharmacist-provided patient care services under Medicaid. b. Pharmacists should review their state requirements to determine reimbursement opportunities. 3. Self-paying patients a. Depends on the fees established for services b. Depends on your customers’ ability to pay J. Reimbursement in APMs or Value-Based Payment Models 1. General principles a. The current U.S. FFS model, in which reimbursement is based on services provided as described earlier, places the United States as the highest-spending industrialized country on health care. b. That spending level, together with the United States being at the bottom of the list for quality of care compared with similar industrialized countries, has spurred a change in reimbursement to paying for value of services and not just quantity of services provided. c. The payment strategy to solve this problem is to pay for value, not quantity of services, or to use valuebased payment as described previously in the quality section of this chapter. d. Many pharmacists are currently working and receiving financial reimbursement under this model. 2. Value in this context is defined as the quality of health outcomes achieved per dollar spent. a. Outcomes should be specific to a medical condition. b. Outcomes should reflect what is important to patients. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 716

Developing and Managing a Clinical Practice

c. The goal is maximum health benefits achieved with minimal cost. d. One challenge is that only 7% of all measures are outcome measures. i. Current efforts are to minimize process measures for payment because these are measures of providers, not patient outcomes. ii. Process measures are better used to ensure that the necessary standardization in care delivery processes are occurring in order to achieve the desired patient outcomes. 3. Strategically select measures for accountability for the care provided when your services significantly contribute to the measure. a. Include patients and other stakeholders in determining the measures that matter to them. b. Ensure your workflow and documentation allow for collection and analysis of quality data as close to real time as possible. 4. Structure clinic operations to meet new payment flow. a. Adjust financial aspects of your model to meet the cash flow of new models, which may be a base payment with payment for performance at the end of a fiscal year. b. Standardize patient care processes when it makes sense for efficiency and establishing quality in the quality measurement. For sound measurement, the denominators of what you are measuring must be the same with minimal variability. c. Invest in your IT structure to meet the demands of new payment models. d. In summary, financial payment will go to providers who can successfully manage all or much of a patient’s care to produce the desired outcomes at the lowest cost. This success requires teamwork among all health care providers and most likely innovative approaches for delivery of care. 5. Attribution is a set of rules used to determine which provider or group of providers is responsible for a patient’s care from a quality, cost, or payment perspective. Attribution is the foundation for population health. Pharmacists need to understand how their work contributes to value-based metrics. a. More than 170 models are currently being tested to assign attribution, but no industry standard has emerged. b. Elements to consider in attribution: i. The level of attribution or responsibility for pharmacist’s services provided is often determined on the basis of a formula of majority or plurality, meaning how many times the service or interventions were provided by the pharmacist compared with other health care personnel providing their services that influenced the outcome. For example, a reduction in blood pressure may be attributed to the provider in a manner related to most contacts with certain interventions. A pharmacist who over time provided 80% of patient visits compared with other providers who achieved the desired outcomes may receive an 80% attribution to the payment for that outcome. ii. Granularity of the outcome and attribution to a provider: (a) Some organizations or health care teams may choose not to go to the granularity of individual providers and may instead use the quality payments to further support the team. (b) Pharmacists must demonstrate value to the team on the basis of the population’s need for medication management or measures that demonstrate medication problems within the population. iii. An understanding of expected contribution to outcomes, cost, and quality from a set of services: Pharmacists will need to clearly define services and articulate their responsibility and accountability for outcomes of these services. For example, in a transitional care service, rehospitalizations as the result of medications is an outcome that can be 100% attributed to the pharmacist-provided patient care services. iv. A patient or group of patients who are touched by the level of provider: (a) Responsibility may be “risk” adjusted on the basis of the level of provider. For example, the physician as head of the team may bear more accountability than a mid-level provider such as a pharmacist.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 717

Developing and Managing a Clinical Practice

(b) This accountability is akin to that of the chief executive officer assuming full responsibility for all activities of those who report to her or him. v. Duration of intervention: (a) A value to quality and quantity that results in an effect may be considered. (b) This value may be easier for episodic or acute care. (c) Unknowns for chronic care are as follows: What is an optimal intervention? and How often should it occur?

X.  SUSTAINING YOUR PRACTICE FOR THE FUTURE (Domain 3, Task 3, Item c, d) A. Planning for Growth 1. Use structure-related measures (remember the balanced scorecard), and monitor the growth of your service at least quarterly. a. Number of referrals b. Number of patients in your clinic c. Number of visits d. Complexity of patients e. Swing patterns of the measures just noted f. Non-patient care workload i. Quality assurance or pay-for-performance measurement ii. Research activities iii. Administrative tasks (a) Committee work and meetings (b) Teaching 2. At 90% capacity, have a plan for hiring additional staff. a. Know the timeline for hiring in your organization. b. Know the timeline and availability of qualified pharmacists and other staff in your community. 3. Managing growth a. Short-term solutions i. Review the processes, and shift any work that you can to ancillary staff; it may be easier to add ancillary staff, if needed, to your team. ii. Close your service to new referrals, or refer the patient back to the referring provider for continued treatment until you can secure the needed staffing for growth (least desirable). iii. Redistribute responsibilities in the non-patient care workload for the short term. b. Long-term solutions i. Consider cross-training other pharmacists in your organization to assist in coverage during highvolume periods. ii. Hire additional practitioners. B. Strategic Planning 1. Strategic planning is a management activity used to set priorities and direction for your clinic or organization so that you are constantly adapting to the environment and any changes foreseen. 2. Review your current situation and your business plan. Is this the direction you are going? Is it the direction you want to go? Change what must be changed. a. Mission and vision b. Environmental scan – What is occurring in health care that requires you to adapt or change? ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 718

Developing and Managing a Clinical Practice

c. SWOT analysis d. Quality program and balanced scorecard e. Identify what is needed to achieve excellence in your practice. f. Reset goals and objectives to achieve the desired level of practice. 3. Setting the time interval a. Many strategic plans use a timeline such as 5–10 years. b. Practice and health care are rapidly changing, so the strategic planning document may be ongoing and revisited regularly. Practice Points 1. Plan for your pharmacists to practice at “the top of their license” for efficient use of your most costly resource. They should be doing activities that only pharmacists are qualified to do for most of their working time. For example, do not have your pharmacists scheduling patients or managing social issues such as Meals on Wheels. Your pharmacists should be able to make the appropriate referrals when such problems are identified. 2. If you are concerned that support to approve your proposed service is not strong, it may be wise to consider proposing a pilot with specific outcome measures as an option. 3. Your success will be based on your ability to build and describe a high-quality pharmacy patient care program that provides a specific set of services and is based on sound business principles. 4. Reevaluating your service, including policies, CPAs, and practice standards, at least annually will keep your practice current. 5. Using evidence-based processes from research on optimal team performance that includes team leadership, mutual performance monitoring, backup behavior, adaptability, and team orientation will enable your service to optimally function within the health care team. 6. Using the principles of meaningfulness, feasibility, and actionability in addition to a balanced score card as the foundation of your quality program will allow you to achieve the desired quality demanded in the current health care environment. 7. Medicare reimbursement processes are the gold standard for reimbursement in the United States. Medicare is also the source of truth; therefore, final decisions regarding reimbursement processes should be made only on the basis of current Medicare rulings and interpretations. 8. APMs that use value-based purchasing on the basis of the quality of services are the health care payment models of the future. Ambulatory pharmacists should ensure their practices are sustainable in the new payment models.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 719

Developing and Managing a Clinical Practice

REFERENCES General Management 1. American College of Clinical Pharmacy (ACCP) Clinical Practice Affairs Committee. Practice guidelines for pharmacotherapy specialists: a position statement of the American College of Clinical Pharmacy. Pharmacotherapy 2000;20:487-90. 2. American College of Clinical Pharmacy (ACCP) Public and Professional Relations Committee. Should organized clinical pharmacy promote a consistent process of patient care provided by clinical pharmacists that can apply to any clinical practice setting: part IIIB: application of major practice models to sample cases. ACCP Rep 2012;31:2-18. 3. American College of Clinical Pharmacy (ACCP). ACCP standards of practice for clinical pharmacists. Pharmacotherapy 2014;34:794-7. 4. American College of Clinical Pharmacy (ACCP). Establishing and evaluating clinical pharmacy services in primary care. Pharmacotherapy 1994;4:743-58. 5. American Pharmacists Association and National Association of Chain Drug Stores Foundation. Medication Therapy Management in Pharmacy Practice: Core Elements of an MTM Service Model, version 2.0, 2008. Available at https://aphanet. pharmacist.com/sites/default/files/files/core_elements_of_an_mtm_practice.pdf. 6. American Society of Health-System Pharmacists (ASHP). ASHP guidelines on documenting pharmaceutical care in patient medical records. Am J Health Syst Pharm 2003;60:705-7. 7. American Society of Health-System Pharmacists (ASHP). ASHP guideline: minimum standard for pharmaceutical services in ambulatory care. Am J Health Syst Pharm 1999;56:1744-53. 8. Bates DW. Role of pharmacists in the medical home. Am J Health Syst Pharm 2009;66:1116-8. 9. Bleser WK, Miller-Day M, Naughton D, et al. Strategies for achieving whole-practice engagement and buy-in to the patient centered medical home. Ann Fam Med 2014;12:27-45. 10. Bodenheimer T. Anatomy and physiology of primary care teams. JAMA Intern Med 2019;179:61-2. 11. Bodenheimer T, Sinsky C. From triple to quadruple aim: care of the patient requires care of the provider. Ann Fam Med 2014;12:573-6.

12. Brummel A, Lustig A, Westrich K, et al. Best practices: improving patient outcomes and costs in an ACO through comprehensive medication therapy management. J Manag Care Pharm 2014;20:1152-8. 13. Brush JE, Handberg EM, Biga C, et al. 2015 ACC health policy statement on cardiovascular team-based care and the role of advanced practice providers. J Am Coll Cardiol 2015;65:2118-36. 14. CMM in Primary Care Research Team. The Patient Care Process for Delivering Comprehensive Medication Management (CMM): Optimizing Medication Use in Patient-Centered, Team-Based Care Settings. Lenexa, KS: American College of Clinical Pharmacy, 2018. Available at https://www. accp.com/docs/positions/misc/CMM_Care_Process. pdf. 15. Dombrowski SK, Bacci JL, Klatt PM, et al. Key factors for sustainable integration of pharmacists in team-based primary care physician practices. J Am Pharm Assoc (2003). 2019;59:439-48.e1. 16. Epplen K, Dusing-Wiest M, Freedlund J, et al. Stepwise approach to implementing ambulatory clinical pharmacy services. Am J Health Syst Pharm 2007;64:945-51. 17. Epplen KT. Patient care delivery and integration: stimulating advancement of ambulatory care pharmacy practice in an era of health care reform. Am J Health Syst Pharm 2014;71:1357-65. 18. Fabel PH, Wagner T, Ziegler, et al. A sustainable business model for comprehensive medication management in a patient-centered medical home. J Am Pharm Assoc (2003). 2019;59:285-90. 19. Farrell B, Ward N, Dore N, et al. Working in interprofessional primary health care teams: what do pharmacists do? Res Social Adm Pharm 2013;9:208-301. 20. Get the Medications Right Institute. Get the Medications Right Blueprint for Change Report. Available at https://gtmr.org/blueprint-full/. 21. Get the Medications Right Institute. The Outcomes of Implementing and Integrating Comprehensive Medication Management in Team-Based Care: A Review of the Evidence on Quality, Access and Costs, October 2020. Available at https://16bvl028dn7zhgp35k7rzh5c-wpengine. netdna-ssl.com /wp-content /uploads/2020/11/ The-Outcomes-of-Implementing-and-Integrating-

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 720

Developing and Managing a Clinical Practice

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33. McFarland MS, Buck ML, Crannage E, et al; writing on behalf of the Get the Medications Right Institute. Assessing the impact of comprehensive medication management on achievement of the Quadruple Aim. Am J Med 2021;134:456-61. 34. McInnis T, Capps K. Get the Medications Right: a nationwide snapshot of expert practices – comprehensive medication management in ambulatory/ community pharmacy. Health2 Resources, May 2016. 35. Meade M, Borchert J, Griffin B, et al. Impact of health disparities on staff workload in pharmacistmanaged anticoagulation clinics. Am J Health Syst Pharm 2011;68:1430-5. 36. Meyers D, LeRoy L, Bailit M, et al. Workforce configurations to provide high-quality, comprehensive primary care: a mixed-method exploration of staffing for four types of primary care practices. J Gen Intern Med 2019;33:1774-9. 37. Militello LG, Arbuckle NB, Saleem JJ, et al. Sources of variation in primary care clinical workflow: implications for the design of cognitive support. Health Inform J 2014;20:35-49. 38. NICE Guideline. Medicines Optimisation: The Safe and Effective Use of Medicines to Enable the Best Possible Outcomes. National Institute for Health and Care Excellence (NICE), 2015. Available at https:// nice.org.uk/guidance/ng5. 39. Nigro SC, Garwood CL, Berlie H, et al. Clinical pharmacists as key members of the patient-centered medical home: an opinion statement of the Ambulatory Care Practice and Research Network of the American College of Clinical Pharmacy. Pharmacotherapy 2014;34:96-108. 40. O’Daniel M, Rosenstein AH. Professional communication and team collaboration. In: Hughes RG, ed. Patient Safety and Quality: An Evidence-Based Handbook for Nurses. Publication No. 08-0043. Rockville, MD: Agency for Healthcare Research and Quality, 2008. Available at www.ncbi.nlm.nih.gov/ books/NBK2637/. 41. Patient-Centered Primary Care Collaborative (PCPCC). Integrating Comprehensive Medication Management to Optimize Patient Outcomes, 2nd ed. Resource Guide. Washington, DC: PCPCC, 2012. Available at www.pcpcc.org/sites/default/files/media/ medmanagement.pdf. 42. Patient-Centered Primary Care Collaborative (PCPCC). Guidelines for the Practice and Documentation of Comprehensive Medication

CMM-in-Team-Based- Care-A-Review-of-theEvidence-on-Quality-Access-and-Costs-11252020. pdf. Gillis KD. Policy Research Perspectives: Physicians’ Patient Mix – A Snapshot from the 2016 Benchmark Survey and Changes Associated with the ACA. Chicago: American Medical Association, 2017. Available at www.ama-assn.org/sites/ama-assn.org/ files/corp/media-browser/public/health-policy/PRP2017-physician-benchmark-survey-patient-mix.pdf. Hammond RW, Schwartz AH, Campbell MJ, et al. Collaborative drug therapy management by pharmacists – 2003. Pharmacotherapy 2003;23:1210-25. Helling DK, Johnson SG. Defining and advancing ambulatory care pharmacy practice: it is time to lengthen our stride. Am J Health Syst Pharm 2014;71:1348-56. Holman GT, Beasley JW, Karsh BT, et al. The myth of standardized workflow in primary care. J Am Med Inform Assoc 2016;23:29-37. Isasi F, Krofah E. The Expanding Role of Pharmacists in a Transformed Health Care System. Washington, DC: National Governors Association Center for Best Practices, 2015. Available at www.nga.org/wp-content/uploads/2020/08/1501TheExpandingRoleOfPha rmacists.pdf. Joint Commission of Pharmacy Practitioners (JCPP). Pharmacists’ Patient Care Process. 2014. Available at https://jcpp.net/wp-content/uploads/2016/03/ PatientCareProcess-with-supporting-organizations. pdf. Jorgenson D, Laubscher T, Lyons B, et al. Integrating pharmacists into primary care teams: barriers and facilitators. Int J Pharm Pract 2014;22:292-9. Kheirkhah P, Feng Q, Travis LM, et al. Prevalence, predictors and economic consequences of no shows. BMC Health Serv Res 2016;16:1-6. Kliethermes MA, Brown TR, eds. Building a Successful Ambulatory Care Practice: Advancing Patient Care, 2nd ed. Bethesda, MD: American Society of Health-System Pharmacists, 2019. Luder HR, Frede SM, Kirby JA, et al. Transition RX: impact of community pharmacy postdischarge medication therapy management on hospital readmission rate. J Am Pharm Assoc 2015;55:246-54. Maine LL, Knapp KK, Scheckelhof DJ. Pharmacists and technicians can enhance patient care even more once national policies, practices, and priorities are aligned. Health Aff 2013;32:1956-62.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 721

Developing and Managing a Clinical Practice

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56. Sorensen TD, Pestka D, Sorge LA, et al. A qualitative evaluation of medication management services in six Minnesota health systems. Am J Health Syst Pharm 2016;73:307-14. 57. Talon B, Perez A, Yan C, et al. Economic evaluations of clinical pharmacy services in the United States: 2011–2017. J Am Coll Clin Pharm 2020;3:793-806. 58. Tan ECK, Stewart K, Elliot RA, et al. Pharmacist services provided in general practice clinics: a systematic review and meta-analysis. Res Social Adm Pharm 2014;10:608-22. 59. Thomas-Henkel C, Turner S, Freda B; Center for Health Care Strategies. Opportunities to Enhance Community-Based Medication Management Strategies for People with Complex Health and Social Needs. Center for Health Care Strategies, 2018. Available at www.chcs.org/media/CMMC_Report_062918-1.pdf. 60. Touchette DR, Doloresco F, Suda KJ, et al. Economic evaluations of clinical pharmacy services: 2006– 2010. Pharmacotherapy 2014;34:771-93. 61. Touchette DR, Stubbings J, Schumock G. Improving Medication Safety in High Risk Medicare Beneficiaries Toolkit. Effective Healthcare Research Report No. 38. AHRQ Publication No. 12-EHC027-EF. Rockville, MD: Agency for Healthcare Research and Quality, July 2012. Available at https://effectivehealthcare. ahrq.gov/sites/default/files/pdf/medication-therapymanagement-1_research.pdf. 62. Umbreit A, Holm E, Gander K, et al. Developing a dashboard for benchmarking the productivity of a medication therapy management program. J Am Pharm Assoc (2003). 2017;57:95-101. 63. U.S. Burdens of Disease Collaborators. The state of US health: 1990–2010: burden of disease, injuries and risk factors. JAMA 2013;310:591-608. 64. U.S. Department of Health and Human Services. Primary care and care coordination. Fed Regist 2012;77:68978-94. 65. Weber AZ, Skelley J, Sachdev G, et al. Integration of pharmacists into team-based ambulatory care practice models. Am J Health Syst Pharm 2015;72:745-51. 66. Weller J, Boyd M, Cumin D. Teams, tribes and patient safety: overcoming barriers to effective teamwork in healthcare. Postgrad Med J 2014;90:149-54. 67. White S. Leading from a staff or clinical position. Am J Health Syst Pharm 2009;66:2092-3. 68. Woolf SH, Aron L, eds. U.S. Health in International Perspective: Shorter Lives, Poorer Health. Panel on Understanding Cross-National Health Differences

Management in the Patient-Centered Medical Home. Appendix A. Available at www.pcpcc.org/sites/ default/files/resources/Appendix_A_Guidelines_ for_the_Practice_and_Documentation.pdf. Perez A, Doloresco F, Hoffman JM, et al. Economic evaluations of clinical pharmacy services: 2001– 2005. Pharmacotherapy 2009;29:128-66. Pharmacy E-Health Information Technology Cooperative. The Roadmap for Pharmacy Health Information Technology Integration in U.S. Health Care. Available at www.pharmacyhit.org/pdfs/11392_RoadMapFinal_singlepages.pdf. Pharmacy HIT Collaborative Workgroup 3. Workflow of Pharmacist Clinical Documentation Process in Pharmacy Practice Settings, July 28, 2014. Available at www.pharmacyhit.org/pdfs/workshop-documents/ WG3-Post-2014-03.pdf. Provost SM, Lanhan HJ, Leykum LK, et al. Health care huddles: managing complexity to achieve high reliability. Health Care Mange Rev 2015;14:2-12. Rollinson R, Young E. Strategic planning for the 21st century: a practical strategic management process. Chicago: LookingGlass, 2010. Sachdev G. Sustainable business models: systematic approach toward successful ambulatory care pharmacy practice. Am J Health Syst Pharm 2014;71:1366-74. Scuderi CB, Lee KY, Bilello LA, et al. Team-based care – the “who” of the patient-centered medical home. Osteopath Fam Physician 2014;6:14-9. Sinsky CA, Willard-Grace R, Schutzbank AM, et al. In search of joy in practice: a report of 23 highfunctioning primary care practices. Ann Fam Med 2013;11:272-8. Smith M, Bates DW, Bodenheimer T, et al. Why pharmacists belong in the medical home. Health Aff (Millwood) 2010;29:906-13. Smith MA. Pharmacists and the primary care workforce. Ann Pharmacother 2012;46:1568-71. Smith MA. Primary care teams and pharmacist staffing ratios: is there a magic number. Ann Pharmacother 2018;52:290-4. Snella KA, Sachdev GP. A primer for developing pharmacist-managed clinics in the outpatient setting. Pharmacotherapy 2003;23:1153-66. Snyder ME, Earl TR, Gilchrist S, et al. Collaborative drug therapy management: case studies of three community-based models of care. Prev Chronic Dis 2015;12:140504.

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10. Ho PM, Lambert-Kerzner A, Carey EP, et al. Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge. JAMA Intern Med 2014;174:186-93. 11. Jun JK. Establishing clinical pharmacy services with prescribing privileges in a federally qualified health center primary care clinic. J Pharm Pract 2018;31:434-40. 12. Kripalani S, Roumie CL, Dalal AK, et al. Effect of a pharmacist intervention on clinically important medication errors after hospital discharge. Ann Intern Med 2012;157:1-10. 13. Lamb KD, Baker JW, McFarland MS. Implementation of a pharmacotherapy clinic into the patient centered medical home model by a second year pharmacy resident. Am J Health Syst Pharm 2015;72:S83-9. 14. Lauffenburger JC, Vu MG, Burkhart JL, et al. Design of a medication therapy management program for Medicare beneficiaries: qualitative findings from patients and physicians. Am J Geriatr Pharmacother 2012;10:129-38. 15. Lifer SM, Musser MR, Kier K. Evaluation of a pharmacist-run antiarrhythmic clinic in an ambulatory practice. J Am Pharm Assoc 2015;55:e381-6. 16. Martin P, Tamblyn R, Benedetti A, et al. Effect of a pharmacist-led educational intervention on inappropriate medication prescriptions in older adults: the D-PRESCRIBE randomized clinical trial. JAMA 2018;320:1889-98. 17. McConaha JL, Tedesco GW, Civitarese L, et al. A pharmacist’s contribution within a patient-centered medical home. J Am Pharm Assoc 2015;55:302-6. 18. Pherson EC, Shermock KM, Efird LE, et al. Development and implementation of a postdischarge home-based medication management service. Am J Health Syst Pharm 2014;71:1576-83. 19. Pringle JL, Boyer A, Conklin MH, et al. The Pennsylvania project: pharmacist intervention improved medication adherence and reduced health care costs. Health Aff 2014;33:1444-52. 20. Romanelli RJ, Leahy A, Jukes T, et al. Pharmacist-led medication management program within a patientcentered medical home. Am J Health Syst Pharm 2015;72:453-9. 21. Sanchita S, Bowen JF, Ganetsky VS et al. Pharmacists implementing transitions of care in inpatient, ambulatory and community practice settings. Pharm Pract 2014;12:4398.

Among High-Income Countries. Washington, DC: National Academies Press, 2013. 69. Yoon J, Rose DE, Canelo I, et al. Medical home features of VHA primary care clinics and avoidable hospitalizations. J Gen Intern Med 2013;28:1188-94. 70. Zieler-Brown (Haines) SL, Brown TR, Chen D, et al. Clinical documentation for patient care: models, concepts and liability considerations for pharmacists. Am J Health Syst Pharm 2007;64:1851-8. Clinical Service Descriptive Reports/Research 1. Arnold ME, Buys L, Fullas F. Impact of pharmacist intervention in conjunction with outpatient physician follow-up visits after hospital discharge on readmission rate. Am J Health Syst Pharm 2015;72:S36-42. 2. Carmichael JM, Alvarez A, Chaput R, et al. Establishment and outcomes of a model primary care pharmacy service system. Am J Health Syst Pharm 2004;61:472-82. 3. Choudhry NK, Isaac T, Lauffenburger JC, et al. Effect of a remotely delivered tailored multicomponent approach to enhance medication taking for patients with hyperlipidemia, hypertension, and diabetes: the STIC2IT cluster randomized clinical trial. JAMA Intern Med 2018;178:1182-9. 4. Cioffi ST, Caron MF, Kalus JS, et al. Glycosylated hemoglobin, cardiovascular, and renal outcomes in a pharmacist-managed clinic. Ann Pharmacother 2004;38:771-5. 5. Cone SM, Brown MC, Stambaugh RL. Characteristics of ambulatory care clinics and pharmacists in veterans’ affairs medical centers: an update. Am J Health Syst Pharm 2008;65:631-5. 6. Fabel PH, Wagner T, Ziegler, et al. A sustainable business model for comprehensive medication management in a patient-centered medical home. J Am Pharm Assoc 2019;59:285-90. 7. Fay AE, Ferreri SP, Shepherd G, et al. Care team perspectives on community pharmacy enhanced services. J Am Pharm Assoc 2018;58:S83-8. 8. Heilmann RM, Campbell SM, Kroner BA, et al. Evolution, current structure, and role of a primary care clinical pharmacy service in an integrated managed care organization. Ann Pharmacother 2013;47:124-31. 9. Hill RR, Herner SJ, Delate T, et al. Ambulatory clinical pharmacy specialty services: the Kaiser Permanente Colorado experience. J Manag Care Spec Pharm 2014;20:245-53.

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Action Guide for Community Pharmacists. Atlanta: CDC, 2019. 4. Chung N, Rascati K, Lopez D, et al. Impact of a clinical pharmacy program on changes in hemoglobin A1c, diabetes-related hospitalizations, and diabetesrelated emergency department visits for patient with diabetes in an underserved population. J Manag Care Pharm 2014;20:914-9. 5. Franklin BE, Farland MZ, Thomas J, et al. Pharmacoeconomic analysis of the diabetes initiative program: a pharmacist-physician collaborative care model. Ann Pharmacother 2013;47:1627-34. 6. Jacobs M, Sherry PS, Taylor LM, et al. Pharmacistassisted medication program enhancing the regulation of diabetes (PAMPERED) study. J Am Pharm Assoc 2012;52:613-21. 7. Shane-McWhorter L, Armor B, Johnson JT, et al. The Scope and Standards for the Practice of Diabetes Education by Pharmacists. Chicago: American Association of Diabetes Educators.2005 Available at www.diabeteseducator.org/docs/default-source/legacy-docs/_resources/pdf/PharmDScopeStandards. pdf. 8. Shane-McWhorter L, McAdam-Marx C, Lenert L, et al. Pharmacist-provided diabetes management and education via a telemonitoring program. J Am Pharm Assoc 2015;55:516-26. 9. Wallgren S, Berry-Cabán CS, Bowers L. Impact of clinical pharmacist intervention on diabetes-related outcomes in a military treatment facility. Ann Pharmacother 2012;46:353-7. 10. Wubben DP, Vivian EM. Effects of pharmacist outpatient interventions on adults with diabetes mellitus: a systematic review. Pharmacotherapy 2008;28:421-36. 11. Yu JY, Shah BM, Ip EJ, et al. A Markov model of the cost-effectiveness of pharmacist care for diabetes in prevention of cardiovascular diseases: evidence from Kaiser Permanente Northern California. J Manag Care Pharm 2013;19:102-14.

22. Ulrich IP, Patel S, Gilmer B. Evaluation of a pharmacist-physician co-visit model in a family medicine practice. J Am Pharm Assoc 2019;59:129-35. Clinical Services for Different Patient Populations Anticoagulation 1. Philip A, Green M, Hoffman T, et al. Expansion of clinical pharmacy through increased use of outpatient pharmacists for anticoagulation services. Am J Health Syst Pharm 2015;72:568-72. 2. Singh LG, Accursi M, Korch Black K. Implementation and outcomes of a pharmacist-managed clinical video telehealth anticoagulation clinic. Am J Health Syst Pharm 2015;72:70-3. Asthma 1. Gums TH, Carter BL, Milavetz, et al. Physician– pharmacist collaborative management of asthma in primary care. Pharmacotherapy 2014;34:1033-42. 2. Pett RG, Nye S. Evaluation of a pharmacist-managed asthma clinic in an Indian health service clinic. J Am Pharm Assoc 2016;56:237-41. Cardiology 1. Jackevicius CA, deLeon NK, Lu L. Impact of a multidisciplinary heart failure post-hospitalization program on heart failure readmission rates. Ann Pharmacother 2015;49:1189-96. 2. Ripley TL, Adamson PB, Hennebry TA, et al. Collaborative practice model between cardiologists and pharmacists for management of patients with cardiovascular disease in an outpatient clinic. Ann Pharmacother 2014;48:412-9. 3. Warden BA, Shapiro MD, Fazio S. The role of the clinical pharmacist in a preventive cardiology practice. Ann Pharmacother 2019;53:1214-9. Diabetes 1. Benedict AW, Spence MM, Sie JL, et al. Evaluation of a pharmacist-managed diabetes program in a primary care setting within an integrated health care system. J Manag Care Spec Pharm 2018;24:114-22. 2. Bluml BL, Watson LL, Skelton JB, et al. Improving outcomes for diverse populations disproportionally affected by diabetes: final results of Project IMPACT: Diabetes. J Am Pharm Assoc 2014;54:477-85. 3. Centers for Disease Control and Prevention (CDC). Rx for the National Diabetes Prevention Program:

Geriatrics 1. Davis RG, Hepfinger CA, Sauer KA, et al. Retrospective evaluation of medication appropriateness and clinical pharmacist drug therapy recommendations for home-based primary care veterans. Am J Geriatr Pharmacother 2007;5:40-7. 2. George J, Elliott RA, Stewart DC. A systematic review of interventions to improve medication taking

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3.

4.

in elderly patients prescribed multiple medications. Drugs Aging 2008;25:307-24. Rojas-Fernandez CH, Patel T, Lee L. An interdisciplinary memory clinic: a novel practice setting for pharmacists in primary care. Ann Pharmacother 2014;48:785-95. Roth MT, Ivey JL, Esserman DA, et al. Individualized medication assessment and planning: optimizing medication use in older adults in the primary care setting. Pharmacotherapy 2013;33:787-97.

5.

6.

Heart Failure 1. Koshman SL, Charrois TL, Simpson SH, et al. Pharmacist care of patients with heart failure: a systematic review of randomized trials. Arch Intern Med 2008;168:687-94. 2. Milfred-LaForest SK, Chow SL, DiDomenico RJ, et al. Clinical pharmacy services in heart failure: an opinion paper from the Heart Failure Society of America and American College of Clinical Pharmacy Cardiology Practice and Research Network. J Card Fail 2003;19:354-69. 3. Murray M, Young J, Hoke S, et al. Pharmacist intervention to improve medication adherence in heart failure: a randomized trial. Ann Intern Med 2007;146:714-25. 4. Schumacher C, Moaddab G, Colbert M, et al. The impact of the clinical pharmacist on readmission rates of heart failure patients in the accountable care environment. J Manag Care Spec Pharm 2018;24:795-9.

7.

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collaborative model for the management of hypertension. Pharmacotherapy 2016;36:374-84. Margolis KL, Asche SE, Bergdall AR, et al. Effect of home blood pressure telemonitoring and pharmacist management on blood pressure control: a cluster randomized clinical trial. JAMA 2013;310:46-56. Margolis KL, Asche SE, Dehmer SP, et al. Long-term outcomes of the effects of home blood pressure telemonitoring and pharmacist management on blood pressure among adults with uncontrolled hypertension: follow-up of a cluster randomized clinical trial. JAMA Netw Open 2018;1:e181617. O’Neill JL, Cunningham TL, Wiitala WL, et al. Collaborative hypertension case management by registered nurses and clinical pharmacy specialists within the Patient Aligned Care Teams (PACT) model. J Gen Intern Med 2014;29:S675-81. Ripley TL, Hennebry TA, Sanders TN, et al. Impact of a clinical pharmacist on a cardiovascular surrogate endpoint: a pilot study. Pharm Pract 2012;10:173-9. Zillich AJ, Jaynes HA. Bex SD, et al. Evaluation of pharmacist care for hypertension in the Veterans Affairs patient-centered medical home: a retrospective case-control study. Am J Med 2015;539:e1-539.e6.

Hyperlipidemia 1. Miller AE, Hansen LB, Saseen JJ. Switching statin therapy using a pharmacist-managed therapeutic conversion program versus usual care conversion among indigent patients. Pharmacotherapy 2008;28:553-6. 2. Olson KL, Potts LA. Role of the pharmacist in the management of dyslipidemia. J Pharm Pract 2006;19:94-102.

Hepatitis C 1. Smith JP, Dong MH, Kaunitz JD. Evaluation of a pharmacist-managed hepatitis C care clinic. Am J Health Syst Pharm 2007;64:632-6.

Oncology 1. Shah S, Dowell J, Greene S. Evaluation of clinical pharmacy services in a hematology/oncology outpatient setting. Ann Pharmacother 2006;40:1527-33. 2. Tuffaha HW, Abdelhadi O, Omar SA. Clinical pharmacy services in the outpatient pediatric oncology clinics at a comprehensive cancer center. Int J Clin Pharm 2012;34:27-31. 3. Watkins JL, Landgraf A, Barnett CM, et al. Evaluation of pharmacist-provided medication therapy management services in an oncology ambulatory setting. J Am Pharm Assoc 2012;52:170-4.

Hypertension 1. Carter BL, Ardery G, Dawson JD, et al. Physician and pharmacist collaboration to improve blood pressure control. Arch Intern Med 2009;169:1996-2002. 2. Carter BL, Coffey CS, Ardery G, et al. Clusterrandomized trial of a physician/pharmacist collaborative model to improve blood pressure control. Circulation 2015;132:93-100. 3. Carter BL, Rogers M, Daly J, et al. The potency of team-based care interventions for hypertension: a meta-analysis. Arch Intern Med 2009;169:1748-55. 4. Isetts BJ, Buffington DE, Carter BL, et al. Evaluation of pharmacists’ work in a physician-pharmacist

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Palliative Care 1. Atayee RS, Best BM, Daniels CE. Development of an ambulatory palliative care pharmacist practice. J Palliat Med 2008;11:1077-82.

4.

Psychiatry 1. Caballero J, Souffrant C, Heffernan E. Development and outcomes of a psychiatric pharmacy clinic for indigent patients. Am J Health Syst Pharm 2008;65:229-33.

5. 6.

Smoking Cessation 1. Bock BC, Hudmon KS, Christian J, et al. A tailored intervention to support pharmacy-based counseling for smoking cessation. Nicotine Tob Res 2010;12:217-25.

7.

Transplantation 1. Chient R, Coutsouvelis J, Poole S, et al. Improving the transition of highly complex patients into the community: impact of a pharmacist in an allogeneic stem cell transplant (SCT) outpatient clinic. Support Care Cancer 2013;21:3491-5. 2. Chisholm-Burns MA, Spivey CA, Garrett C, et al. Impact of clinical pharmacy services on renal transplant recipients’ adherence and outcomes. Patient Prefer Adherence 2008;2:287-92. 3. Wang HY, Chan AL, Chen MT, et al. Effects of pharmaceutical care intervention by clinical pharmacists in renal transplant clinics. Transplant Proc 2008;40:2319-23.

8.

9. 10.

11.

Developing a Service or Business Plan 1. Harris IM, Baker E, Berry TM, et al. Developing a business-practice model for pharmacy services in ambulatory settings. Pharmacotherapy 2008;28:7e-34e.

12.

Operations and Workflow 1. Centers for Disease Control and Prevention (CDC). CLIA Law and Regulations. CDC. Available at www. cdc.gov/clia/law-regulations.html 2. Health Insurance Portability and Accountability Act (HIPAA). Summary of the HIPAA Security Rule. HIPAA PHI Regulations. Available at www.hhs. gov/hipaa/for-professionals/privacy/laws-regulations/ index.html. 3. Hirsch JD, Metz KR, Hosokawa PW, et al. Validation of a patient-level medication regimen complexity index

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as a possible tool to identify patients for medication therapy management intervention. Pharmacotherapy 2014;34:826-35. Meyers D, LeRoy L, Bailit M, et al. Workforce configurations to provide high-quality, comprehensive primary care: a mixed-method exploration of staffing for four types of primary care practices. J Gen Intern Med 2019;33:1774-9. Moore CG, Wilson-Witherspoon P, Probst JC. Time and money: effects of no-shows at a family practice residency clinic. Fam Med 2001;33:522-7. Nguyen TT, Mehta BH, Rodis JL, et al. Evaluation of provider documentation of medication management in a patient-centered medical home. Innov Pharm 2014;5:1-7. Nuti LA, Lawley M, Turkcan A, et al. No-show to primary care appointments: subsequent acute care utilization among diabetic patients. BMC Health Serv Res 2012;12:304. Snella K, Trewn R, Hansen L, et al. Pharmacist compensation for cognitive services: focus on the physician office and community pharmacy. Pharmacotherapy 2004;24:372-8. Trong HA, Groves CN, Congdon HB, et al. Potential cost savings of medication therapy management in safety-net clinics. J Am Pharm Assoc 2015;55:269-72. Umbreit A, Holm E, Gander K, et al. Developing a dashboard for benchmarking the productivity of a medication therapy management program. J Am Pharm Assoc 2017;57:95-101. Unertl K, Weinger MB, Johnson KB, et al. Describing and modeling workflow and information flow in chronic care. J Med Inform Assoc 2009;16:826-36. U.S. Food and Drug Administration (FDA). Clinical Laboratory Improvement Amendments. Available at www.fda.gov/ m e d ic a l- d ev ic e s /ivd-r eg u lat or y-a ssi st a nc e / clinical-laboratory-improvement-amendments-clia. VandeGriend JP, Saseen JJ, Bislip D, et al. Prioritization of patients for comprehensive medication review by a clinical pharmacist in family medicine. J Am Board Fam Med 2015;28:418-24. Van Dril E, Schumacher C, Kliethermes MA, et al. Workload evaluation of clinical pharmacists in the ambulatory care setting. J Am Coll Clin Pharm 2020;3:1015-27. Xakellis GC, Bennett A. Improving clinic efficiency of a family medicine teaching clinic. Fam Med 2001;33:533-8.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 726

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Quality 1. Agency for Healthcare Research and Quality (AHRQ). 2019 National Healthcare Quality and Disparities Report. Content last reviewed June 2021. Rockville, MD: AHRQ. Available at www.ahrq.gov/ research/findings/nhqrdr/nhqdr19/index.html. 2. Barr MS. The patient-centered medical home: aligning payment to accelerate construction. Med Care Res Rev 2010;67:492-9. 3. Centers for Medicare & Medicaid Services. Blueprint for CMS Measures System, Version 16.0, September 2020. Available at www.cms.gov/Medicare/QualityInitiatives-Patient-Assessment-Instruments/MMS/ Downloads/Blueprint.pdf. 4. Centers for Medicare & Medicaid Services (CMS). CMS Quality Strategy 2016. Available at www. cms.gov/Medicare/Quality-Initiatives-PatientAssessment-Instruments/QualityInitiativesGenInfo/ Downloads/CMS-Quality-Strategy.pdf. 5. Centers for Medicare & Medicaid Services (CMS). CMS Quality Measure Development Plan: Supporting the Transition to the Merit-Based Incentive Payment System (MIPS) and Alternative Payment Models (APMs). Available at www.cms.gov/Medicare/ Quality-Initiatives-Patient-Assessment-Instruments/ Value-Based-Programs/MACRA-MIPS-and-APMs/ Final-MDP.pdf. 6. Centers for Medicare & Medicaid Services (CMS). Medicare Learning Network. Improving Quality of Care for Medicare Patients: Accountable Care Organizations. Available at www.cdc.gov/cliac/ docs/addenda/cliac0212/Tab_28_CLIAC_2012Feb_ Reference08_ACO_Factsheet.pdf. 7. Centers for Medicare & Medicaid Services (CMS). Quality Payment Program Resources. Available at https://qpp.cms.gov/about/resource-library. 8. Centers for Medicare & Medicaid Services (CMS). Trends in Part C & D Star Rating Measure Cut Points. Available at www.cms.gov/files/document/2021-cutpoint-trend.pdf. 9. Donabedian A. The quality of care: how can it be assessed? JAMA 1988;260:1743-8. 10. Glasgow JM, Scott-Caziewell JR, Kaboli PJ. Guiding inpatient quality improvement: a systematic review of Lean and Six Sigma. Jt Comm J Qual Patient Saf 2010;36:533-40. 11. Institute of Medicine (IOM). Medicare: A Strategy for Quality Assurance. Washington, DC: National Academies Press, 1990.

12. Institute of Medicine (IOM). Vital Signs: Core Metrics for Health and Health Care Progress. Washington, DC: National Academies Press, 2015. 13. Kaplan RS, Norton DP. Balanced Scorecard: Translating Strategy into Action. Boston: Harvard Business School, 1996. 14. Kirwin J, Canales AE, Bentley ML, et al. Process indicators of quality clinical pharmacy services during transitions of care. Pharmacotherapy 2012;32:e338-e347. 15. Kleinman LC, Dougherty D. Assessing quality improvement in health care: theory for practice. Pediatrics 2013;131:S110. 16. Kliethermes MA. Outcomes evaluation: striving for excellence in ambulatory care pharmacy practice. Am J Health Syst Pharm 2014;71:1375-86. 17. Kohn LT, Corrigan JM, Donaldson MS. To Err Is Human: Building a Safer Health System. Committee on Quality in America. Washington, DC: Institute of Medicine, National Academy Press, 1999. 18. Levine DM, Linder JA, Landon BE. The quality of outpatient care delivered to adults in the United States, 2002-2013. JAMA Intern Med 2016;176:1778-90. 19. McKesson Health Solutions. The State of ValueBased Reimbursement and the Transition from Volume to Value in 2014. Available at www. statecoverage.org/files/McKesson_State_of_ValueBased_Reimbursement.pdf. 20. Porter M. What is value in health care? N Engl J Med 2010;363:2477-81. 21. Schneider EC, Sarnak DO, Squires D, et al. Mirror, Mirror 2017: International Comparison Reflects Flaws and Opportunities for Better U.S. Health Care. New York: Commonwealth Fund, 2017. Available at interactives.commonwealthfund.org/2017/july/ mirror-mirror/. 22. Varkey P, Reller MK, Resar RK. Basics of quality improvement in health care. Mayo Clin Proc 2007;82:735-9. 23. World Health Organization (WHO). The World Health Report 2000: Health Systems: Improving Performance. Geneva: WHO, 2000. Available at who. int/whr/2000/en/whr00_en.pdf. Competency 1. Blair MM, Carmichael J, Young E, et al. Pharmacist privileging in a health system: report of the Qualified Provider Model Ad Hoc Committee. Am J Health Syst Pharm 2007;64:2373-81.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 727

Developing and Managing a Clinical Practice

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medicare-learning-network-mln/mlnproducts/downloads/chroniccaremanagement.pdf. 5. Centers for Medicare & Medicaid Services (CMS). Contract Year 2022 Part D Medication Therapy Management Program Guidance and Submission Instructions. Available at www.cms. gov/files/document/memo-contract-year-2022-medication-therapy-management-mtm-program-submission-v-043021.pdf. 6. Centers for Medicare & Medicaid Services (CMS). Evaluation and Management Services Guide. Available at www.cms.gov/outreach-and-education/ medicare-learning-network-mln/mlnproducts/downloads/eval-mgmt-serv-guide-icn006764.pdf. 7. Centers for Medicare & Medicaid Services (CMS). Transitional Care Management Services. Available at www.cms.gov/outreach-and-education/medicarelearning-network-mln/mlnproducts/downloads/ transitional-care-management-services-fact-sheeticn908628.pdf. 8. Centers for Medicare & Medicaid Services (CMS). Medicare Preventive Services. Available at www. cms.gov/Medicare/Prevention/PrevntionGenInfo/ medicare-preventive-ser vices/ MPSQuickReferenceChart-1.html 9. Medicare Program; CY 2022 Payment Policies Under the Physician Fee Schedule and Other Changes to Part B Payment Policies; Medicare Shared Savings Program Requirements; Provider Enrollment Regulation Updates; Provider and Supplier Prepayment and Post-Payment Medical Review Requirements [Final Rule]. Federal Register 2021;86:64996-6031. 10. Centers for Medicare & Medicaid Services. Medicare Program: Hospital Outpatient Prospective Payment and Ambulatory Surgical Center Payment Systems and Quality Reporting Programs; Price Transparency of Hospital Standard Charges; Radiation Oncology Model; Request for Information on Rural Emergency Hospitals [Proposed rule]. Federal Register. 2021;86(147): 42018-360. 11. Centers for Medicare & Medicaid Services (CMS). Overview [of the PFS Look Up]. Available at www. cms.gov/apps/physician-fee-schedule/overview.aspx. 12. Centers for Medicare & Medicaid Services (CMS). Annual Wellness Visit. Available at www.cms.gov/outreach-and-education/medicare-learning-network-mln/ mlnproducts/downloads/awv_chart_icn905706.pdf.

Brown D, Ferrill MJ. The taxonomy of professionalism: reframing the pursuit of academic professional development. Am J Pharm Educ 2009;73:1-10. Burke JM, Miller WA, Spencer AP, et al. ACCP white paper: clinical pharmacist competencies. Pharmacotherapy 2008;28:806-15. Claxton KL, Woital P. Design and implementation of a credentialing and privileging model for ambulatory care pharmacists. Am J Health Syst Pharm 2006;63:1627-32. Galt KA. Credentialing and privileging for pharmacists. Am J Health Syst Pharm 2004;61:661-70. Pestka DL, Sorge LA, McClurg MR, et al. The philosophy of practice for comprehensive medication management: evaluating its meaning and application by practitioners. Pharmacotherapy 2018;38:69-79. Rouse MJ, Vlasses PH, Webb CE; Council on Credentialing in Pharmacy. Credentialing and privileging of pharmacists: a resource paper from the Council on Credentialing in Pharmacy. Am J Health Syst Pharm 2014;71:1891-900. Saseen JJ, Ripley TL, Bondi D, et al. ACCP clinical pharmacist competencies. Pharmacotherapy 2017;37:630-6.

Reimbursement 1. American Medical Association (AMA). CPT® Evaluation and Management (E/M) Office or Other Outpatient (99202-99215) and Prolonged Services (99354, 99355, 99356, 99417) Code and Guideline Changes. AMA, 2021. Available at www.ama-assn. org/system/files/2019-06/cpt-office-prolonged-svscode-changes.pdf. 2. Centers for Disease Control and Prevention (CDC). Rx for the National Diabetes Prevention Program: Action Guide for Community Pharmacists. Atlanta: CDC, 2019. Available at www.cdc.gov/diabetes/prevention/pdf/pharmacists-guide.pdf. 3. Centers for Medicare & Medicaid Services (CMS). Care Management Services in Rural Health Clinics (RHCs) and Federally Qualified Health Centers (FQHCs) Frequently Asked Questions. CMS, 2019. Available at https://www.cms.gov/Medicare/ Medicare-Fee-for-Service-Payment/FQHCPPS/ Downloads/FQHC-RHC-FAQs.pdf. 4. Centers for Medicare & Medicaid Services (CMS). Chronic Care Management Services. Available at www.cms.gov/outreach-and-education/

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 728

Developing and Managing a Clinical Practice

13. Centers for Medicare & Medicaid Services (CMS). Evaluation and Management Services. Available at https://www.cms.gov/Outreach-and-Education/ Medicare-Learning-Network-MLN/MLNProducts/ Downloads/eval-mgmt-serv-guide-ICN006764.pdf. 14. Centers for Medicare and Medicaid Services. Medicare Benefit Policy Manual, Chapter 6: Hospital Services Covered Under Part B. Available from www.cms.gov/Regulations-and-Guidance/Guidance/ Manuals/Downloads/bp102c06.pdf. 15. Centers for Medicare and Medicaid Services. Medicare Benefit Policy Manual, Chapter 15: Covered Medical and Other Health Services. Available from www.cms.gov/Regulations-and-Guidance/Guidance/ Manuals/Downloads/bp102c15.pdf. 16. Centers for Medicare and Medicaid Services. Medicare Claims Processing Manual, Chapter 12: Physicians/Nonphysician Practitioners. Available from www.cms.gov/Regulations-and-Guidance/ Guidance/Manuals/Downloads/clm104c12.pdf. 17. Centers for Medicare and Medicaid Services. MLN Matters SE0441. “Incident to” Services. Available from www.cms.gov/Outreach-andEducation/Medicare-Learning-Network-MLN/ MLNMattersArticles/downloads/se0441.pdf 18. Kliethermes MA. Value-based payment: preparing for changes in payment for services. Pharmacy Today 2019;25:4453. 19. Kliethermes MA. Understanding health care billing basics. Pharmacy Times 2017;23:57-68. 20. Kuo GM, Buckley TE, Fitzsimmons DS, et al. Collaborative drug therapeutic management services and reimbursement in a family medicine clinic. Am J Health Syst Pharm 2004;61:343-54. 21. Robert Wood Johnson Foundation (RWJF). Payment Matters: The ROI for Payment Reform. 2013. Available at www.rwjf.org/en/library/research/2013/02/payment-matters--the-roi-for-payment-reform.html. 22. Snella KA, Trewyn RR, Hansen LB, et al. Pharmacist compensation for cognitive services: focus on the physician office and community pharmacy. Pharmacotherapy 2004;24:372-8. 23. Warshany K, Sherrill CH, Cavanaugh J, et al. Medicare annual wellness visits conducted by a pharmacist in an internal medicine clinic. Am J Health Syst Pharm 2014;71:44-9.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 729

Developing and Managing a Clinical Practice

ANSWERS AND EXPLANATIONS TO PRACTICE CASES 1. Answer: D The best first step is to use the skills you gained during residency to collect the necessary information to determine what is most needed by your organization and what can be resolved with pharmacist services (Answer D is correct). Performing this gap analysis and developing your service while keeping your organization’s needs in mind provide the best chance for your program to be approved and continue to be successful. Review of the literature is an important step; however, it would be a second step after the optimal service is determined on the basis of need and resources (Answer A is incorrect). Your residency training should provide you with the critical thinking skills and understanding of how to start a new service, and although it would be convenient to perform a service with which you have experience, that service may not meet the organization’s needs (Answer B is incorrect). Although managing high-cost specialty medications is needed by many organizations, it may not be needed by your organization (Answer C is incorrect).

are not familiar or for a reason they may not understand can be problematic (Answer C is incorrect). It is difficult for any organization to treat one payer population by providing services different from other payer organizations. This approach is also problematic with Medicare if the Medicare population is not receiving the same service as other populations for financial reasons; therefore, this process is not recommended (Answer D is incorrect). 4. Answer: C A standard in Medicare billing, especially in the FFS billing that eligible providers use for delegated services such as pharmacist-provided patient care services, is the concept of medical necessity. It requires the billing provider to document a statement of medical necessity or the reason why the patient must see the provider to whom he or she was referred. Although this can be documented in the assessment and plan of the note of the referring provider, its inclusion in a referral form ensures that this step is documented. Payers such as Medicare will audit billed services. Not having this information may constitute fraud and usually results in any payment for the referred service being returned to the payer. This consideration makes the reason for referral the most important item that is nonnegotiable when creating your referral template or process (Answer C is correct). The points in Answers A, B, and D are also important for optimal coordination and communication.

2. Answer: A The most important information to obtain from an external environmental scan is supportive literature because evidence is strong for positive outcomes and the value of using pharmacists in blood pressure management (Answer A is correct). Answers B, C, and D might provide information that would support your expansion of services; however, with the strength of evidence, Answer A would best justify the expansion of pharmacy services.

5. Answer: B Although reasonable timelines will vary depending on when investment revenue is available or whether any construction is required, in general, you will want to take enough time to make sure you have addressed all considerations so that, when your clinic opens, it can focus primarily on patients and less on management issues. You also do not want to have excessive delays because, to administrators, “time is money.” The ideal time is 6 months (Answer B is correct). Three months is likely too short to address all the items required in developing and operating a service (Answer A is incorrect). Going beyond 12 months is likely too long and may discourage your stakeholders from supporting your clinic (Answers C and D are incorrect).

3. Answer: B It is best to have a group of patients identified and scheduled when the doors of your service open. This approach accomplishes several goals, including efficiency with no excessive downtime, whereas use of other approaches may cause other employees in the service to question what you are doing. In addition, this approach allows you to begin generating outcomes sooner that sufficiently demonstrate your value (Answer B is correct). Waiting for referrals by a physician is problematic, primarily because of the following: in their busy schedule, physicians may not often think about referring their patients; they may have incentives not to refer, depending on the billing incentives in the ACO; and they may not initially trust in the pharmacist’s skill set (Answer A is incorrect). Asking patients to make another appointment with a provider with whom they

6. Answer: B Answer B is correct. An initial CPA is often narrow in scope. It often requires time to build trust in your competency and skill with your team and supervising providers.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 730

Developing and Managing a Clinical Practice

of the risk-sharing model is to share the risk and losses for not achieving quality measures or cost goals, Answer C is incorrect.

As that trust progresses, your team will refer more patients with a broader range of conditions. Expanding your scope of practice in a CPA is the quickest and simplest fix. Adjusting your schedule is an option if you have an endocrinologist’s supervision to manage diabetes; however, many of the patients you see routinely may be treated by primary care and not need that level of specialist care or cost (Answer A is incorrect). Hiring an additional pharmacist is an option, though costly and unnecessary if you can handle the workload (Answer C is incorrect). Establishing an electronic-based communication system is not the root cause of the problem you are facing (Answer D is incorrect).

9. Answer: C In MIPS, four categories contribute to the total score: clinical quality measures, practice improvement activities, advancing care information, and cost. Cost of care is increasing in importance, which currently accounts for 20% of the total score and will increase to 30% in 2024. Cost is determined on the basis of the total per capita cost, which includes total Medicare Part A and B costs for a beneficiary; thus, total per capita costs include costs from hospitalizations. Pharmacist-provided patient care services have clearly decreased hospitalizations; therefore, this strategy would best assist the practice with its MIPS score (Answer C is correct). Developing an opioid education program is included in improvement activities; however, improvement activities contribute to only 15% of the total score and are not as effective as decreasing costs and contributing to the cost of the MIPS score (Answer A is incorrect). Measuring patient satisfaction has received increased CMS attention; however, practice CAHPS (Consumer Assessment of Healthcare Providers and Systems) scores do not directly include pharmacist services and would not be as effective as reducing hospitalization costs (Answer B is incorrect). Although use of a registry is associated with collecting data on clinical quality measures, a registry cannot discern attribution of your work as a clinical pharmacist; nevertheless, you would want your data to be included in the quality registry (Answer D is incorrect).

7. Answer: C Answer C is correct. As new therapies and updated guidelines are available, it is important to review your CPAs to ensure the allowed practices are current and fully reflect the pharmacist’s services. If CPAs are not reviewed at least yearly, they may quickly become outdated. Because Medicare billing requirements include that services provided by auxiliary staff must be within their scope of practice, a CPA that does not cover a provided service results in that service not being within the scope of practice (i.e., a state pharmacy practice act allows such services only under a CPA). In such situations under a Medicare audit, CMS may require that all payments for such services be returned. Answer A is incorrect because if sodium-glucose cotransporter-2 inhibitors were part of the CPA, it would be within the state scope of practice. Answer B is currently incorrect because Medicare allows reimbursement for auxiliary services if they are within the pharmacist’s scope of practice. Medicare can change the rules at any time, which stresses the importance of staying current on billing rules and regulations. Answer D is incorrect because billing rules and regulations are not governed by organizational policy and procedures.

10. Answer: B Answer B is correct. The most important aspects for which you are fully responsible are documenting your visit and ensuring that it meets the requirements of E/M of a medical condition, which is what is paid for under Medicare Part B. You must follow the E/M guidance as set forth by CMS. Although incident-to codes fall under AMA CPT level 1 codes and you should know the terminology, it is less important for you to understand the CPT level for effective use of the codes (Answer A is incorrect). In addition, incident-to codes can only be used for established patients, meaning you cannot see a patient before the patient sees the eligible Part B provider. Eligible Part B providers must establish the plan of care and the medical necessity for your service incident-to their services. Although this is important for you to know, it is most important for the clinic and other providers to know this progression before a patient

8. Answer: D Answer D is correct. In global payment, the provider receives a set fee per member for a designated time and then earns additional revenue on the basis of quality performance. In the FFS model, there is no standard payment per beneficiary (Answer A is incorrect). In the FFS model, a reimbursement for service is provided, with the potential for additional reimbursement on the basis of quality measures. Bundled payments are a set payment for a particular service or diagnosis for a member (e.g., pregnancy, hip replacement). Bundled payments are not per-member per-time period (Answer B is incorrect). Because the basis

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 731

Developing and Managing a Clinical Practice

is referred to you or placed on your schedule (Answer C is incorrect). Incident-to requires immediate supervision, which is also important for you to know but is more important for whoever manages the clinic operations to know to ensure a supervising provider is present when you are providing your services (Answer D is incorrect). 11. Answer: A The MDPP is not a large undertaking, and it would allow you to better understand how best to incorporate a clinical program into the pharmacy workflow. The program can also be created and billed directly by the pharmacy. Starting this program would give you experience in managing revenue for a clinical program (Answer A is correct). Although TCM and CCM are also good choices, they are complex (Answers B and C are incorrect). In addition to their complexity, the rules for these programs require contracting with either the hospital or the physicians in the area because only eligible Medicare Part B providers can bill for the services. It may be best to start with a smaller self-sustaining and manageable program. Depending on which services the hospital has and its readmission rates, TCM may be a reasonable alternative. Because AWVs require direct supervision, they can only be performed in a physician’s office (Answer D is incorrect). Although community pharmacists are assisting physicians by staffing this program in a physician office, this approach does pull that resource away from the pharmacy for a shift and may not be optimal in an independent pharmacy.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 732

Developing and Managing a Clinical Practice

ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS 1. Answer: B The first step in planning any service is determining your organization’s needs. The optimal method is to perform what is termed an internal environmental scan, which is the collection of needed internal data that will identify important needs of the organization (Answer B is correct). Once these are identified, you can use other strategies to develop your proposal such that it becomes viable solution for the organization’s needs. Such strategies include the external environmental scan. To build the case for your services, you can use what is reported in the literature or provide examples of competitive organizations in your community that are already providing such services. You can also use your literature search to learn best practices and design your service to avoid barriers that others have identified and that may affect your services (Answer A is incorrect). Determining payer mix and reimbursement potential is crucial but is a secondary step after organizational needs are identified (Answer C is incorrect). Although you may be proud of your training and expertise, it may not mesh with the needs of the current job you are undertaking. Be confident that your training provides you with sufficient knowledge and self-directed learning skills to gain the necessary knowledge to develop services outside your comfort zone. If this development is well beyond your scope of knowledge, you may need to include hiring personnel with the desired training in your proposal. Never start a service that is not needed; it will be doomed to failure (Answer D is incorrect).

Rigid scheduling, an approach that health care has used for many years, is not optimal because it is not patient centered (Answer C is incorrect). Allowing flexibility in scheduling (e.g., building 10-minute catch-up slots or saving spots for daily unexpected needs) improves patient satisfaction and may even improve efficiency. Establishing a separate referral process is not a good choice because trying to create a new process only for your clinic requires your referral sources to learn and remember something different from what they are used to performing. This change in usual process would ultimately negatively affect your referrals (Answer D is incorrect). 3. Answer: C Opportunities are situations and information that are external to your business or service that will support your initiative. That the population your pharmacy serves is primarily that for which data show is the fasting-growing population with diabetes suggests a need for and sustainability of your service (Answer C is correct). A strength of your proposed program is hiring a pharmacist with interest and competency in the prevention program. Strengths are internal criteria that support the program (Answer A is incorrect). The same is true for Answer B; it is a strength of your pharmacy that you have existing appropriate space (Answer B is incorrect). The availability of billing codes is a benefit but a questionable opportunity if costs are not fully covered (Answer D is incorrect). 4. Answer: A Ensuring the providers are trained in correct blood pressure technique is a measure of your clinic structure, ensuring that blood pressure is documented at each visit is a process measure, achieving a blood pressure goal is an outcome, and knowing how that outcome influences the organization’s financial status is an important financial measure, thus meeting the four key elements of the balanced scorecard: structure, process, outcomes, and financial measurement (Answer A is correct). Answer B is lacking a structure measurement. The computerized provider order entry system would be a structure measure that could be used in this case to meet a balanced scorecard with the other measures listed. Answer C does not have a financial measure component, and Answer D does not have an outcome measure component.

2. Answer: B A common mistake made by pharmacists is to undertake duties that less-qualified support personnel can perform. Although it may seem reasonable to perform these duties when starting your clinic, it will be difficult to pass this work back to others as your practice becomes increasingly busy. It is wise to develop your workflow from the planning stages so that the work provided by the pharmacist is work that only you or another provider with similar skills can perform. Plan and negotiate using existing staff such as a medical assistants, schedulers, and front desk staff to perform functions and support they are already doing for others that you also will need. Provide them with guidelines and expectations for your services. They can make sure no patients are lost to follow-up if the expectation and process are clear (Answer A is incorrect; Answer B is correct).

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 733

Developing and Managing a Clinical Practice

5. Answer: D The MSSP was established by CMS under the ACA as a new approach to health care delivery to facilitate coordination and cooperation among providers to improve the quality of care for Medicare beneficiaries and reduce unnecessary costs. To participate in the MSSP, providers should either be an ACO or participate in an ACO. Participants must report on the ACO quality measures established by CMS (Answer D is correct). The MIPS measurement of interoperability is for Medicare Part B, which is a FFS model (Answers B and C are incorrect). The HEDIS measure set is for commercial plans (Answer A is incorrect).

they require direct supervision (Answers C and D are incorrect). Medication therapy management is not a recognized billing code under Medicare Part B (Answer A is incorrect).

6. Answer: C Although BCACP status, PGY2 training, and MTM certification may all be desired credentials, they within themselves will not guarantee that the new hire meets the needs of your organization or be at the same skill level as you, the organization’s current patient care pharmacist (Answers A, B, and D are incorrect). The necessary degree of trust for that individual will develop on the basis of his or her performance, thus making peer review of services the best option for building the needed trust and confidence (Answer C is correct). 7. Answer: C Under HOPPS, all mid-level practitioners who are employees of the hospital and meet incident-to rules bill the same facility fee code. The current revenue for that code is a reasonable reimbursement (Answer C is correct). Codes for MTM are not currently recognized or payable under Medicare Part B (Answer A is incorrect), nor are the incident-to E/M codes submitted by pharmacists currently recognized under HOPPS (Answer B is incorrect). The CCM codes can only be used for patients who meet the criteria established by CMS (Answer D is incorrect). In addition, the reimbursement for CCM codes is currently less than that for the facility fee code. 8. Answer: B Medicare relaxed the incident-to rules of direct supervision for CCM and TCM services that can be performed by auxiliary personnel within their scope of practice (includes pharmacists) to bill these particular codes. General supervision is thought to be sufficient because the Medicare-approved provider in these cases would be setting, sharing, and reviewing patients’ plans of care, thus providing general supervision (Answer B is correct). Incident-to E/M codes and AWVs are incorrect because ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 734

Psychiatric Disorders Melissa C. Palmer, Pharm.D., BCPS, BCPP Alaska VA Healthcare System Anchorage, Alaska

William A. Kehoe, Pharm.D., M.A., FCCP, BCPS University of the Pacific Stockton, California

Psychiatric Disorders

Psychiatric Disorders Melissa C. Palmer, Pharm.D., BCPS, BCPP Alaska VA Healthcare System Anchorage, Alaska

William A. Kehoe, Pharm.D., M.A., FCCP, BCPS University of the Pacific Stockton, California

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 737

Psychiatric Disorders

Learning Objectives 1. Analyze the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria and disease course for anxiety disorders, sleep disorders, major depression, bipolar disorder, attention-deficit/hyperactivity disorder, schizophrenia, and substance use disorders. 2. Apply a working knowledge of common drug and nondrug therapies for psychiatric disorders, including drug, dose, frequency, adverse effects, drug interactions, and monitoring values. 3. Recommend appropriate treatments, including both lifestyle modification and specific drug therapy (medication dose, schedule, and delivery system), on the basis of relevant patient factors (pharmacodynamic, physiologic, pharmacokinetic, and socioeconomic parameters). 4. Monitor for adverse drug effects, drug-drug and drug-disease interactions, and appropriateness of therapy, including polytherapy.

Abbreviations in This Chapter

Baseline Knowledge Statements

ADHD Attention-deficit/hyperactivity disorder AIMS Abnormal Involuntary Movement Disorder Scale ANC Absolute neutrophil count BD Bipolar disorder CBT Cognitive behavioral therapy CPAP Continuous positive airway pressure DSM-5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition EPS Extrapyramidal symptoms FGA First-generation antipsychotic GAD Generalized anxiety disorder GI Gastrointestinal LAIA Long-acting injectable antipsychotic MAOI Monoamine oxidase inhibitor OCD Obsessive-compulsive disorder PHQ-9 Patient Health Questionnaire-9 PTSD Posttraumatic stress disorder RLS Restless legs syndrome SGA Second-generation antipsychotic SNRI Serotonin-norepinephrine reuptake inhibitor SSRI Selective serotonin reuptake inhibitor TCA Tricyclic antidepressant TD Tardive dyskinesia

Readers of this chapter are presumed to be familiar with the following: • Cause and pathophysiology of common psychiatric conditions • Pharmacology of anxiolytics, hypnotics, antidepressants, mood stabilizers, antipsychotics, and stimulants • Concepts related to the importance of adherence

Self-Assessment Questions Answers and explanations to these questions can be found at the end of the chapter. 1. M.P. is a 33-year-old woman who comes to the clinic for a follow-up of her first episode of major depression. She has taken citalopram 20 mg orally daily for 8 weeks with partial symptom relief. She takes no other medications, and her laboratory values are all normal. M.P. states that she still feels sad and is uninterested in many activities but that she is sleeping better and has returned to work. She is tolerating the medication well. Which intervention is most appropriate for M.P.? A. B. C. D.

Continue citalopram 20 mg/day. Increase citalopram. Add amitriptyline at bedtime. Change to mirtazapine at bedtime.

2. M.H. is a 28-year-old man who presents to the clinic with newly diagnosed generalized anxiety disorder (GAD). He has not previously been treated, and

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 738

Psychiatric Disorders

he mentions that he has problems with weight gain. Which is most appropriate for his initial treatment? A. B. C. D.

6. C.B. is a 9-year-old boy with attention-deficit/hyperactivity disorder (ADHD), combined type. He has been taking methylphenidate immediate release (IR) 10 mg orally in the morning and after school. His appetite is unchanged, though he has difficulty falling asleep at night. His teachers state that C.B. is disruptive during his afternoon classes. C.B. has comorbid asthma and eczema. Which is best for C.B.?

Escitalopram. Alprazolam. Paroxetine. Pregabalin.

3. R.R. is a 23-year-old woman who arrives at the clinic for a follow-up after her first episode of schizophrenia. She has taken risperidone 3 mg orally twice daily for 6 weeks with an overall decrease in hallucinations, but ongoing auditory hallucinations are affecting her ability to concentrate on tasks. She has stiffness in her joints, and psychomotor retardation is present. Which treatment is most appropriate? A. B. C. D.

A. Increase methylphenidate IR dose. B. Change to methylphenidate transdermal patch. C. Move his methylphenidate IR afternoon dose to noon. D. Discontinue methylphenidate IR and initiate methylphenidate extended release (ER) (Concerta).

7. K.K. is a 35-year-old man with a diagnosis of schizophrenia who has taken several antipsychotics during his 15 years of illness. He now takes olanzapine 20 mg orally at bedtime. To ensure the safety and tolerability of olanzapine, which monitoring value or group of monitoring values is best to obtain routinely?

Increase risperidone. Increase risperidone and add benztropine. Decrease risperidone and add olanzapine. Change to olanzapine.

4. J.D. is a 62-year-old man who recently lost his job and is having insomnia. He has a history of poor sleep, which has been exacerbated by his current stressful work situation. J.D. has obesity (body mass index 35 kg/m2), hypertension, and hyperlipidemia, for which he takes lisinopril 20 mg orally daily and atorvastatin 20 mg orally daily. J.D. reports drinking two or three beers each night. Which intervention, in addition to a further assessment of alcohol use, is best for J.D.? A. B. C. D.

A. B. C. D.

Questions 8–10 pertain to the following case. J.Y. is a 33-year-old man who comes to the ambulatory care clinic for a follow-up of migraine headaches. During the interview, he says he has feelings of failure and worthlessness, no interest in his usual activities, and depressed mood. He denies thoughts of suicide. He recently lost his job and is having difficulty finding another. A medical workup has been completed and medical conditions appear stable. His other problems include focal seizures treated with carbamazepine ER 400 mg twice daily and migraine headaches treated with sumatriptan 6 mg subcutaneously as needed for acute headache and propranolol long-acting 80 mg once daily. He smokes 2 packs/day and drinks four or five beers per day. His Patient Health Questionnaire-9 (PHQ-9) score is 12.

Administration of temazepam at bedtime. Assessment for obstructive sleep apnea. Evaluation for restless legs syndrome (RLS). Administration of ramelteon at bedtime.

5. D.L. is a 45-year-old woman who has been increasingly tearful lately; she is sleeping more and feels drowsy most of the day. She has not attended book club meetings for several weeks, which she normally enjoys. She had a depressive episode as a teenager, which, she reports, “never really went totally away.” She denies suicidal ideation. She does not smoke tobacco, denies using recreational drugs, and takes no prescription medications. Which medication is the best initial choice for D.L.? A. B. C. D.

Thyroid-stimulating hormone. Serum creatinine and blood urea nitrogen. Fasting blood glucose and total lipid profile. Prolactin concentration.

8. Which best indicates J.Y.’s level of depression, given his PHQ-9 score? A. B. C. D.

Sertraline. Paroxetine. Amitriptyline. Mirtazapine.

Mild. Moderate. Moderately severe. Severe.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 739

Psychiatric Disorders

9. Which antidepressant should be avoided when developing J.Y.’s treatment plan?

13. Which feature in T.R.’s history would best indicate that he has bipolar I disorder, not bipolar II disorder?

10. Which constellation of symptoms is most suggestive of serotonin syndrome?

14. M.N. is a 24-year-old man who comes to the ambulatory care clinic today for possible treatment of opioid use disorder in the buprenorphine program. He has used hydrocodone/acetaminophen 5/325 mg nonmedically for at least 3 years. He currently orally ingests up to 20 tablets/day. He has used heroin sporadically, with last use 1 week ago. He has had two arrests for selling narcotics. He comes to the clinic today because of a family intervention, with the contingency that if he is not enrolled in a treatment or maintenance program, he will be told to leave home. In the clinic today, M.N. appears calm, and his physical examination is unremarkable. Which would be the best recommendation for M.N. today?

A. B. C. D.

A. B. C. D.

A. B. C. D.

Bupropion. Venlafaxine. Sertraline. Levomilnacipran.

Nausea, vertigo, and chest pain. Confusion, hyperreflexia, and restlessness. Dry mouth, constipation, and dry eyes. Headache, chest pain, and flushing.

Questions 11–13 pertain to the following case. T.R. is a 59-year-old man seen in the ambulatory care clinic for a follow-up of hypertension, heart failure, and atrial fibrillation. Five years ago, he had a myocardial infarction. His blood pressure is stable and in goal range with lisinopril, metoprolol, and furosemide. He has maintained a normal sinus rhythm with amiodarone. He has a long history of bipolar I disorder, for which he takes lithium and divalproex. His most recent mood episode was depression 6 months ago. Today in the clinic, he is hyperactive and hyperverbal; he reports not sleeping for the past few nights and has racing thoughts. A psychiatric consult is obtained. During his interview, he states that he cannot control his thoughts, and he appears agitated and restless. He has elated and grandiose thoughts but is not delusional. He reports no suicidal thoughts. He is found to be in the initial stages of an acute bipolar I episode.

His current mood is manic. He has a history of a major depressive episode. He is not delusional. He does not have suicidal thoughts.

A. Buprenorphine/naloxone the clinic today. B. Buprenorphine/naloxone given. C. Buprenorphine/naloxone given. D. Buprenorphine/naloxone given.

should not be given in

2 mg/0.5 mg should be 4 mg/1 mg should be 8 mg/2 mg should be

11. Which type of acute episode is T.R. most likely experiencing? A. B. C. D.

Mania. Mixed episode. Depression. Rapid cycling.

12. T.R.’s physician wants to initiate a second-generation antipsychotic (SGA). Which antipsychotic should be avoided in this patient? A. B. C. D.

Aripiprazole. Brexpiprazole. Ziprasidone. Risperidone.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 740

Psychiatric Disorders

I.  ROLE OF THE CLINICAL PHARMACIST IN THE CARE OF PATIENTS WITH PSYCHIATRIC CONDITIONS Introduction (Domain 1) 1. Patients with psychiatric conditions are generally followed by practitioners in both psychiatric and medical disciplines. Drug-drug and drug-disease interactions can occur between the medications used for medical and psychiatric conditions. The clinical pharmacist is in an opportune position to assess these. 2. Nonadherence is common among patients taking psychotropic medications, just as with non-psychotropic medications. Adverse effects of pharmacotherapy may range from sleepiness and sexual dysfunction to more serious adverse effects such as hyponatremia or diabetes. Risks associated with medications will be discussed throughout the text. Patients with psychiatric conditions often lack insight into the mental health problem, termed anosognosia, which may result in not taking their medications. This is a common risk factor for hospital readmission. Clinical pharmacists can use scales to assess attitudes toward medications and target specific attitudes for educational interventions. Two examples are the Medication Adherence Rating Scale and the ASK12 adherence barrier survey (available at www.easacommunity.org/files/Medication%20Adherence%20Scale.pdf and https://eprovide.mapi-trust.org/instruments/adherence-starts-with-knowledge-12). 3. Medication education for patients with mental health conditions can be a challenge, depending on the state of the patient. Those admitted to acute inpatient units may be unable to meaningfully process new information. In these situations, providing basic drug information and encouragement may be best. If the patients can comprehend new information, or if they are in the outpatient setting receiving maintenance therapy, more in-depth education should be provided. Key components include building a therapeutic alliance, having a collaborative communication style, using shared decision-making, and providing details of treatment and its effects (BMC Psychiatry 2012;12:2-12). 4. Providing informational materials to patients and caregivers can also improve patient understanding. One source of information is the National Alliance on Mental Illness (www.nami.org). NAMI is geared toward patients and those who support them. Other reliable sources of information for patients and clinicians alike include the National Institute of Mental Health (www.nimh.nih.gov) and Mental Health America (https://mhanational.org/).

II.  ANXIETY DISORDERS A. Introduction (Domain 1) 1. Psychotherapy is effective for anxiety disorders, though underused because of factors such as cost, time commitment, insurance coverage, and lack of readily available trained providers. 2. Antidepressants, specifically selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs), are typically first-line pharmacologic agents. 3. Table 1 lists diagnostic features.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 741

Psychiatric Disorders

Table 1. Clinical Presentation of Anxiety, Trauma/Stress, and OCD – Highlights from DSM-5

Generalized Anxiety Disorder Excessive anxiety and uncontrolled worry Feeling on edge, poor concentration Restlessness, fatigue, muscle tension Difficulty sleeping, irritability Impairment in social or occupational functioning

Obsessive-Compulsive Disordera Obsessions: Recurrent thoughts, images, or impulses Compulsions: Repetitive activities or mental acts that reduce the anxiety caused by the obsessions

Panic Disorder Recurrent panic attacks manifested by these symptoms: Physical symptoms: Chest pain, dizziness, shortness of breath, tachycardia, tremor, nausea, palpitations, sweating Psychological: Fear of losing control or dying

Agoraphobia Fear or anxiety in ≥ 2 of the following situations: Public transportation, open spaces, enclosed places, standing in line or being in a crowd, being away from home alone. The person fears or avoids these situations because of thoughts that escape will be difficult or help will not be available; these fears are out of proportion to the situation

Posttraumatic Stress Disorderb Symptom complexes as follows: Intrusion: Frequent upsetting memories/dream of the trauma, flashbacks, or dissociative reactions Avoidance: Avoiding thoughts, feelings, conversations, people, or activities related to the event; inability to recall the event; avoiding others (isolating); sense of a foreshortened future Cognition/mood: Excessively negative worldly viewpoints, assigning self-blame, feelings of shame, anger, or fear, anhedonia Reactivity: Increased irritability, rash behavior, hypervigilance, sleep alterations Social Anxiety Disorder Fear of being embarrassed, humiliated, or evaluated by others Fear of situations: Speaking, eating, or interacting in a group of people or with authority figures; public speaking; talking with strangers Physical symptoms: GI upset, diarrhea, sweating, flushing, tachycardia, tremor OCD is now considered an obsessive-compulsive and related disorder in DSM-5, not an anxiety disorder.

a

b

PTSD is now considered a trauma- and stressor-related disorder in DSM-5, not an anxiety disorder.

DSM = Diagnostic and Statistical Manual of Mental Disorders; GI = gastrointestinal; OCD = obsessive-compulsive disorder; PTSD = posttraumatic stress disorder.

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Psychiatric Disorders

Patient Case 1. M.P. is a 34-year-old woman who presents to the clinic with difficulty sleeping and feeling tired. She has felt this way for some time, but her symptoms worsened recently after her husband lost his job and they began having financial difficulties. When questioned, she endorses difficulty concentrating and being unable to control her worry about life situations. She states that she has always been a “worrier” but that it is now affecting her ability to perform her job functions. M.P. drinks alcohol only socially and does not smoke tobacco. Laboratory results include sodium 140 mEq/L, serum creatinine (SCr) 0.9 mg/dL, blood urea nitrogen 10 mg/dL, alanine aminotransferase 75 IU/L, and aspartate aminotransferase 90 IU/L. Blood pressure in the clinic is 140/88 mm Hg. Since her husband lost his job, they have been without health insurance. Which drug is the best initial treatment for M.P.? A. B. C. D.

Duloxetine. Escitalopram. Lorazepam. Hydroxyzine.

B. Examples of Common Rating Scales (Domain 1) 1. The Hamilton Anxiety Scale (HAM-A) is the gold standard rating scale for anxiety disorders used in clinical trials and requires a trained rater. In clinical trials, a treatment response is denoted by a 50% decrease in the HAM-A score; remittance is indicated by a score less than 7. 2. The Generalized Anxiety Disorder 7-Item Scale (GAD-7) is a useful screening tool. An online version can be found at https://www.mdcalc.com/gad-7-general-anxiety-disorder-7. This is an easy-to-use tool in the primary care setting. Scores indicate the following symptom severity: 0–4 minimal, 5–9 mild, 10–14 moderate, and 15 or greater severe anxiety. Subsequent evaluation is recommended for those with a score of 10 or greater. C. Nonpharmacologic Treatment of Anxiety Disorders: Psychotherapy is commonly used in all anxiety disorders. (Domain 1) 1. Cognitive behavioral therapy (CBT) a. CBT has been used with or without drug therapy in clinical trials. CBT is considered first line for most anxiety disorders. b. CBT identifies negative thoughts or behaviors that lead to anxiety symptoms with subsequent reframing. 2. EMDR (eye movement desensitization and reprocessing) a. Evidence-based treatment for posttraumatic stress disorder (PTSD) b. Consists of focusing on the traumatic event while focusing attention on a back-and-forth movement or sound 3. Exposure therapy a. Helpful for anxiety disorders, PTSD, and obsessive-compulsive disorder (OCD) b. Involves exposing patients to fears to reduce distress and decrease avoidance behaviors 4. Supportive therapy includes breathing techniques, mindfulness, relaxation therapy, and meditation. D. Pharmacologic Treatment of Anxiety Disorders (Domains 1, 2) 1. Antidepressants (see Depression section for information on specific drug information) a. SSRIs i. Considered first line for all anxiety disorders and PTSD ii. Onset of effect within the first 2–4 weeks, but may take 8–12 weeks for full effect. For OCD, an adequate trial is considered 6 weeks or more at the maximum tolerated dose. iii. Initially, agitation and irritability are common, and patients may think anxiety symptoms are worsening.

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Psychiatric Disorders

iv. Initial doses of antianxiety medications may be lower than doses used for depression to improve patient tolerability. Table 2 lists dosing information. v. Antidepressants with differing mechanisms of action may be used adjunctively. Table 2. SSRI Dosing in Anxiety Disorders and PTSD Agent

Citalopram

Indication

GAD

Panic disorder PTSD OCD

Escitalopram

Initial Dosing

10 mg PO daily

Increase as tolerated at ≥ 10 mg PO daily × 3–7 weekly intervals to max days; then 20 mg daily of 40 mg daily 20 mg PO daily

SAD

10–20 mg PO daily

GAD

10 mg PO daily

SAD

5–10 mg PO daily

Panic disorder PTSD

10 mg PO daily

GAD

10–20 mg PO daily

Panic disorder

5–10 mg PO daily × 3–7 days; then increase by 5–10 mg

PTSD

OCD SAD

Increase as tolerated to max of 40 mg daily after 6 wk

Clinical Pearls

Age > 60 yr: Max 20 mg/day for all indications Consider ECG at baseline and as clinically indicated in patients with cardiac disease or QTc prolongation risk factors

Increase as tolerated at ≥ weekly intervals to max 5 mg PO daily × 3–7 days; then 10 mg daily of 20 mg daily

OCD

Fluoxetine

Titration

10–20 mg PO daily

Increase as tolerated at ≥ weekly intervals to max of 40 mg daily

Increase dosing in intervals of 1–4 wk for PTSD

Increase as tolerated at ≥ weekly intervals to max of 60 mg daily

Does not require taper for discontinuation because of long half-life; however, if patient is taking higher dose, monitor for withdrawal symptoms

Increase as tolerated at ≥ weekly intervals to max of 60 mg daily (usual dose 20–40 mg daily) Increase as tolerated at ≥ weekly intervals to max of 80 mg daily (usual dose 40–60 mg daily)

Higher doses of up to 60 mg/day have been evaluated for patients with refractory disease; however, there was an associated increase in adverse effects

OCD: Some patients may require up to 120 mg/day for clinical response; however, adverse effects may increase

Increase as tolerated at ≥ weekly intervals to max of 80 mg daily Increase as tolerated after 6 wk; max 60 mg daily

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Psychiatric Disorders

Table 2. SSRI Dosing in Anxiety Disorders and PTSD (continued) Agent

Paroxetine

Sertraline

Indication

Initial Dosing

Titration

GAD

IR: 10 mg PO daily

Panic disorder

IR: 10 mg PO daily × 3–7 days; then increase to 20 mg daily ER: 12.5 mg PO daily

PTSD

IR: 20 mg PO daily

OCD

IR: 20 mg PO daily

SAD

IR: 10 mg PO daily ER: 12.5 mg PO daily

GAD

25 mg PO daily

Panic disorder PTSD

25 mg PO daily × 3–7 Increase as tolerated at ≥ days; then 50 mg daily weekly intervals to max of 200 mg daily 25–50 mg PO daily

SAD

25–50 mg PO daily

OCD

50 mg PO daily

Increase as tolerated at ≥ weekly intervals to max of 50 mg daily

Clinical Pearls

Increase as tolerated at ≥ weekly intervals to max of 60 mg daily (IR) or 75 mg daily (ER); usual dose 20–40 mg daily (IR) Increase as tolerated at ≥ weekly intervals to max of 60 mg daily Increase as tolerated at ≥ weekly intervals to max of 60 mg daily; usual range 40–60 mg daily Increase as tolerated at ≥ weekly intervals to max of 60 mg daily (IR) or 37.5 mg daily (ER)

Increase as tolerated at ≥ weekly intervals to max of 200 mg daily (usual dose 50–150 mg daily)

Increase after 6 wk as tolerated to max of 200 mg daily

SAD: ER formulation may require dosing of up to 75 mg/day for optimal response OCD: Doses should be increased weekly, as tolerated; some patients had a modest clinical benefit at 400 mg/day, but there is an increased risk of adverse effects PTSD and SAD: Doses of up to 250 mg/day have been used in clinical practice and can provide further benefit

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Psychiatric Disorders

Table 2. SSRI Dosing in Anxiety Disorders and PTSD (continued) Agent

Fluvoxamine

Indication

Initial Dosing

Titration

Clinical Pearls

Panic disorder

IR: 25–50 mg PO daily

Titrate as tolerated to 100–200 mg daily

PTSD

IR: 75 mg PO BID

Increase as tolerated to 300 mg daily

OCD

IR: 50 mg PO bedtime Increase as tolerated IR: When dosing > 100 mg daily, ER: 100 mg PO at every 4–7 days to max of give in BID dosing (may give bedtime 300 mg daily larger dose at bedtime)

SAD

IR: 50 mg PO daily ER: 100 mg PO daily at bedtime

Fluvoxamine is a strong CYP1A2 inhibitor. Concentrations may be lower in patients who smoke Evidence is mainly limited to open-label trials. VA/DoD PTSD guidelines indicate insufficient evidence to recommend for or against

Increase by 50 mg daily each week to target dose of 100–300 mg daily

BID = twice daily; CYP = cytochrome P450; EX = extended release; GAD = generalized anxiety disorder; IR = immediate release; PO = oral(ly); SAD = social anxiety disorder; SSRI = selective serotonin reuptake inhibitor.

b. SNRIs i. SNRIs are useful alternatives to SSRI therapy and are recommended as first line together with SSRIs by some guidelines. Table 3 lists dosing information. Table 3. SNRI Dosing in Anxiety Disorders and PTSD Agent

Duloxetine

Indication

Initial Dosing

Titration

Clinical Pearls

Panic disorder

20–30 mg PO daily

Increase as tolerated to 60–120 mg PO daily

PTSD

30 mg PO daily

Use only supported by a small openlabel trial that used flexible dosing of up to 120 mg/day

OCD

30 mg PO daily

SAD

30 mg PO daily Increase as tolerated to 60 mg PO daily

GAD

30–60 mg PO daily

If starting at 30 mg, increase to 60 mg PO daily after 1 wk

Additional benefit at doses ≥ 60 mg/ day not robust

Evidence limited to an open-label trial and case reports Evidence limited to an open-label trial (dosing 60–120 mg/day) and an RCT (dosing 20–60 mg/day)

Evidence limited to one RCT (which found no difference in patients increased to 120 mg/day vs. 60 mg/ day) and case reports (which have used dosing of up to 120 mg/day)

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Psychiatric Disorders

Table 3. SNRI Dosing in Anxiety Disorders and PTSD (continued) Agent

Venlafaxine

Indication

Initial Dosing

Titration

Panic disorder

ER: 37.5 mg daily

Increase to 75 mg daily after 1 wk; increase thereafter weekly up to 225 mg daily

GAD

ER: 37.5–75 mg Increase after ≥ 4 days as daily tolerated to max of 75–225 mg PO daily

PTSD

ER: 37.5 mg daily

OCD

IR: 25 mg PO TID ER: 75 mg PO daily

SAD

ER: 37.5 mg PO daily

Clinical Pearls

Only ER formulation is FDA approved for GAD and panic disorder. ER is generally preferred because of ease of daily dosing. Low dose (37.5 mg/day) acts as an SSRI

Increase after ≥ 4 days as tolerated to 300 mg PO daily

Increase every 2 wk to 225 mg daily (may increase to 350 mg daily, if necessary) Increase to 75 mg PO daily after 1–2 wk; then increase up to max of 225 mg daily

Doses > 75 mg have more adverse effects with no accompanying increase in efficacy

RCT = randomized controlled trial; SNRI = serotonin-norepinephrine reuptake inhibitor; TID = three times daily.

c. Tricyclic antidepressants (TCAs) i. Imipramine and clomipramine are effective for anxiety disorders, specifically panic disorder and OCD, respectively. Table 4 lists dosing information. Table 4. TCA Dosing in Anxiety Disorders and PTSD Agent

Imipramine

Indication

Initial Dosing

Titration

Panic disorder

10 mg PO daily

Increase over 3–5 wk to target dose of 100–300 mg daily

GAD

PTSD Clomipramine

Panic disorder

25–50 mg PO daily at bedtime

25–50 mg PO daily at bedtime 10–25 mg PO daily

OCD

25 mg PO daily

SAD

25 mg PO daily

Titrate as tolerated to target dose of 150 mg daily

Titrate as tolerated to target dose of 200–300 mg daily Increase by 10–25 mg every 2 or 3 days as tolerated to target dose of 50–150 mg daily in one to three doses (max dose 250 mg daily)

Increase over 2 wk to 100 mg daily in divided doses. Maintenance dose may be as high as 250 mg daily given once daily at bedtime Titrate as tolerated to 200–250 mg daily

Clinical Pearls

TCA use tends to limited by anticholinergic effects, particularly in older adults. Avoid use in older patients, if possible. May see patients taking TCAs for other conditions such as neuropathic pain, insomnia, and migraines. Toxic in overdose

Evidence limited to two open-label trials

TCA = tricyclic antidepressant.

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Psychiatric Disorders

d. Monoamine oxidase inhibitors (MAOIs) and other antidepressants i. Phenelzine can be used in treatment-resistant cases for several indications. ii. Agents such as mirtazapine, bupropion, vortioxetine, and vilazodone have been used for various anxiety conditions. Evidence is not as robust for some of these agents. Table 5 lists indications and dosing information. Table 5. MAOI and Other Antidepressant Dosing in Anxiety Disorders and PTSD Agent

Phenelzine

Indication

Panic disorder OCD

Initial Dosing

15 mg PO at bedtime

PTSD SAD

Mirtazapine

GAD Panic disorder

GAD Panic disorder

Vortioxetine

GAD

Vilazodone

GAD SAD

Clinical Pearls

Titrate as tolerated to target dose of Requires dietary tyramine 45–90 mg daily restrictions PTSD: Titrate as tolerated to target dose of 60–90 mg daily

Cannot be used with other serotonergic agents

Requires washout period if 15 mg PO daily Titrate to 45 mg total daily by week changing from antidepressant × 3 days; then 2 and 60 mg total daily by week 3, increase to 30 up to 75–90 mg daily mg daily 15 mg PO daily Titrate as tolerated to 30–45 mg at bedtime daily Increase weekly by 15 mg up to 45 or 60 mg daily at bedtime

PTSD

Bupropion

Titration

Titrate as tolerated to 30–60 mg daily XL 150 mg PO daily in the morning

Titrate as tolerated to target dose range 150–300 mg daily

5 mg PO daily

Titrate as tolerated to max dose of 20 mg PO daily

SR/XL 150 mg PO daily in the morning

Titrate as tolerated to max dose of 400 mg daily (SR 200 mg BID if using SR formulation)

Evidence is more supportive of use as an adjunctive agent than as monotherapy PTSD: Worsening anxiety is possible. Startle response may also be increased

Administer in morning. Some patients may not tolerate because of “activating” features

Higher doses may be effective for agoraphobia Data are conflicting regarding benefit. Nausea very prevalent. Benefit of higher doses in GAD unclear. 5 mg/day is the most commonly studied dose

Titration based off labeling 10 mg PO daily After additional week at 20 mg, may increase to max dose of 40 mg for depression. Recent meta× 7 days; then daily analysis concluded that 40 mg/ 20 mg daily day was likely effective for GAD, though effect size was small and long-term studies are needed. Administer with food

MAOI = monoamine oxidase inhibitor; SR = sustained release; XL = extended release.

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Psychiatric Disorders

2. Anticonvulsants (see Bipolar Disorder section for specific drug therapy information). Anticonvulsants, though not approved for these indications, are sometimes used. See Table 6 for dosing information. Table 6. Anticonvulsants in Anxiety Disorders Agent

Gabapentin

Pregabalin

Indication

Panic disorder SAD

GAD

Initial Dosing

300 mg PO BID (100 mg PO TID in patients with respiratory concerns) 150 mg PO daily in two or three doses

OCD

75 mg daily

SAD

100 mg PO TID

Titration

Increase by 300 mg/ day up to max 3.6 g/ day divided in TID dosing

Clinical Pearls

Only recommended in refractory cases Potential for misuse

Titrate as tolerated to May be used as monotherapy 300 mg daily or adjunctively. Evidence > 300 mg daily uncertain Increase as tolerated to 600 mg daily

Controlled substance

Recommended only as adjunctive treatment

May be used as monotherapy or adjunctively

3. Atypical antipsychotics (see Schizophrenia section for specific drug information): Are not approved for these indications but are sometimes used. a. Risperidone, quetiapine, and olanzapine have limited evidence of efficacy as augmenting agents in GAD. b. Newer evidence generally does not support their use in PTSD. c. May be used adjunctively for OCD (specifically aripiprazole, risperidone, quetiapine, and olanzapine in relative order of level of evidence). 4. Buspirone a. Buspirone is FDA approved for the treatment of GAD only. b. Clinical trials do not show consistent efficacy in other anxiety disorders. c. Onset of effect is 2–4 weeks; patients who have previously tried benzodiazepines may not respond. Buspirone should not be used on an as-needed basis. d. Adverse effects include nausea, headache, and dizziness. e. Usual initial dose is 5–7.5 mg orally twice daily, with a maintenance range of 15–60 mg/day. 5. Hydroxyzine a. FDA approved for anxiety; however, considered less effective than first- and second-line agents. The pamoate form is preferred to hydrochloride for anxiety symptoms. b. Usual initial dose is 25 mg orally twice daily, which can be titrated to a maximum recommended dose of 400 mg/day. c. Hydroxyzine should be avoided in conditions that could worsen secondary to anticholinergic adverse effects. 6. β-Blockers a. May be useful in performance-related social anxiety disorders such as public speaking. b. Propranolol is most commonly used (10–80 mg per dose) or atenolol (25–50 mg per dose) taken 1–2 hours before the performance. c. β-Blockers decrease the physiologic effects of anxiety.

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Psychiatric Disorders

7. Prazosin a. May be used to treat PTSD-associated nightmares. b. Initial dose of 1 mg orally at bedtime titrated as tolerated to 16 mg. Prazosin is not indicated for global symptoms of PTSD. A recent study evaluated prazosin use in patients with chronic combat-related PTSD and frequent nightmares (n=152). There were no significant changes at 26 weeks (N Engl J Med 2018;378:507-17). The 2017 Veterans Administration/Department of Defense (VA/DoD) clinical practice guidelines for managing PTSD downgraded their support for prazosin use, now having “no recommendation for or against” use for PTSD-associated nightmares. c. Blood pressure and orthostatic changes should be monitored. Prazosin can cause first-dose syncope. 8. Benzodiazepines (C–IV substances) a. Most are effective for GAD, though they do not treat psychological underpinnings. In general, these medications are used short term because of concerns for dependence and tolerance (i.e., 2–3 weeks while initiating and titrating a first-line treatment). b. Limited use for panic disorder because of oral onset of action, which is typically longer than the duration of the panic attack c. Benzodiazepines should be avoided in PTSD. Benzodiazepines can interfere with the efficacy of traumabased psychotherapy. Early administration after trauma has also been associated with higher rates of progression to PTSD. d. Benzodiazepines have limited efficacy in OCD. e. Use should be avoided in patients with a history of, or current, substance use. Benzodiazepines may also worsen depression. f. Avoid use in older adults. When other alternatives are ineffective and a benzodiazepine is required for severe anxiety, consider lorazepam or oxazepam because of lack of active metabolites (see Table 7). g. Central nervous system (CNS) adverse effects include drowsiness, sedation, ataxia, confusion, irritability, paradoxical excitement, decreased concentration, anterograde amnesia, and memory impairment. h. Benzodiazepine therapy should be tapered slowly to avoid rebound anxiety and withdrawal. i. In general, reduce the dose by 25% per week until the dose is halved. Then reduce the dose by oneeighth every 4–7 days until off. This can be done more quickly or more slowly, depending on length of treatment. ii. If therapy lasts more than 1 year, taper over 2–4 months or longer. There is no one agreed-on plan for tapering, and the amount of dose reduction and timings of dose reductions vary. Available dosage strengths is a practical concern. iii. In the past, changing patient to a long-acting agent and then starting the taper was suggested to reduce the likelihood of withdrawal symptoms. However, this is not considered necessary. The more critical elements of the taper are decreasing the dose in small increments over an appropriate time interval (JAMA Intern Med 2014;174:890-8). Table 7. Commonly Used BZDs Brand Name

Generic Name

Onset of Effect

Elimination Half-Life, hr

Active Metabolite

Xanax

Alprazolam

Intermediate

12–15

Not significant

Klonopin

Clonazepam

Intermediate

20–50

Not significant

Ativan

Valium Serax

Librium

Lorazepam Diazepam

Oxazepam

Chlordiazepoxide

Intermediate

10–20

Rapid

> 100

Slow

5–14

Intermediate

> 100

None

N-DMDZ None

N-DMDZ

BZD = benzodiazepine; N-DMDZ = N-desmethyldiazepam.

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Psychiatric Disorders

9. Alternative therapies – Long-term effects are unknown. a. Kava i. Two reviews of kava for anxiety were published in 2018. One review focused on GAD and reported on two placebo-controlled trials that found efficacy. Conclusions were that although kava may be promising, current literature is insufficient to promote use. The second review found support in three of seven trials and concluded that it may be beneficial for short-term treatment of anxiety (Complement Ther Clin Pract 2018;33:107-17). ii. Standardized dietary extracts (most commonly WS 1490) are used at a dose of 100 mg orally three times daily. iii. Hepatotoxicity and liver failure have been reported. iv. May aggravate symptoms of Parkinson disease, inhibit platelet aggregation, or cause kava dermopathy (scaly eruption). b. Valerian i. Scant controlled evidence of efficacy. ii. Use in pregnancy should be avoided. iii. There have been reports of liver toxicity, including life-threatening liver damage, though direct causation is questionable. c. Lavender oil i. A lavender oil preparation named Silexan has been compared with paroxetine for GAD and found similar on the basis of HAM-A scores. Dosing is 80 or 160 mg orally once daily. May cause GI upset. ii. No clinically significant drug-drug interactions have been found with cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, or 3A4. E. Approaches to Pharmacotherapy for Anxiety Disorders: These suggested pharmacotherapeutic approaches are based on the guidelines referenced at the end of this section. They represent general steps and are an attempt to capture similarities between the different guidelines. In addition, guidelines may recommend some but not all agents in a class. Psychotherapeutic and other nonmedication approaches are recommended for most, if not all, patients with anxiety disorders.

Start SSRI or SNRI and/or CBT. May consider BZD short term Change to second SSRI/SNRI Pregabalin or new SSRI/SNRI TCA or buspirone Augment with/trial hydroxyzine, SGA, gabapentin, or antidepresssant with differing mechanism of action

Figure 1. General approach to GAD.

BZD = benzodiazepine; CBT = cognitive behavioral therapy; GAD = generalized anxiety disorder; SGA = second-generation antipsychotic; SNRI = serotoninnorepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

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Psychiatric Disorders

Start CBT or SSRI Switch SSRIs or initiate venlafaxine Augment buspirone or trial gabapentin, buspirone, SGA Phenelzine

Figure 2. General approach to SAD. SAD = social anxiety disorder.

CBT or SSRI or venlafaxine. Consider BZDs when prompt symptom control neededa Switch to second SSRI or venlafaxine TCA Augment with SGA, BZD, CBT Phenelzine

Figure 3. General approach to panic disorder.

a BZDs may be of little use for treatment of an acute panic attack, given the delayed onset of action with oral administration compared with the relatively short length of a panic attack.

CBT ± SSRI SSRI or venlafaxine Clomipramine Augment with antipsychotic

Figure 4. General approach to OCD. XR = extended release.

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Psychiatric Disorders

Trauma-focused psychotherapy ± SSRI/SNRI Add psychotherapy or switch SSRI/SNRI Change to TCA Change to mirtazapine, SGA, or phenelzine

Figure 5. An approach to PTSD.

*Sleep problems may not respond adequately to first-line agents and may require additional/separate treatment. OCD = obsessive-compulsive disorder; PTSD = posttraumatic stress disorder.

F. Monitoring 1. Patients should be monitored every 2–4 weeks during drug titration, then periodically to symptom remission. 2. Therapy duration is typically at least 1 year after achieving remission. G. Therapy Summary and Patient Counseling (Domain 1) 1. Somatic disorders are often the reason for the clinic visit; evaluate for underlying anxiety as part of the treatment plan. 2. Serotonergic agents are first line for anxiety disorders. 3. Can take several weeks before full effects of pharmacologic intervention realized. 4. Withdrawal effects are common with abrupt discontinuation; counsel patient on the need to adhere to therapy. 5. Counsel patient to avoid other CNS depressants in combination with benzodiazepines, including alcohol. 6. Take a complete substance use history. 7. Encourage patients to seek psychotherapeutic treatment. H. Resources (Domain 2) 1. Treatment guidelines a. Canadian Clinical Practice Guidelines (panic disorder, agoraphobia, specific phobia, social anxiety disorder, OCD, PTSD): https://bmcpsychiatry.biomedcentral.com/articles/10.1186/1471-244X-14-S1S1#citeas b. American Psychiatric Association: www.psychiatryonline.com (OCD, panic disorder, PTSD) c. National Institute for Clinical Excellence (NICE) UK: www.nice.org.uk (GAD, panic disorder, social anxiety disorder, PTSD) d. U.S. Department of Veterans Affairs: www.healthquality.va.gov (PTSD) e. International Psychopharmacology Algorithm Project: www.ipap.org (PTSD, GAD) f. Harvard Psychopharmacology Algorithm Project (GAD, PTSD, social anxiety disorder) 2. Patient resources a. Anxiety and Depression Association of America: www.adaa.org b. National Alliance on Mental Illness: www.nami.org c. National Institute of Mental Health: www.nimh.nih.gov d. Obsessive-Compulsive Foundation: www.ocfoundation.org e. PTSD Association: www.ptsdassociation.com f. Mental Health America: www.mentalhealthamerica.net/

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Psychiatric Disorders

III.  SLEEP DISORDERS A. Insomnia: Evaluation of Sleep Disorders (Domains 1, 2) 1. Questions to ask: a. What is your usual sleep pattern? b. What do you do before you go to sleep? c. How long have you had this problem? d. Was there an event that precipitated this problem? e. How long does it take you to fall asleep? f. Do you awaken during the night? g. Do you use any substances (tobacco, caffeine, alcohol)? h. Do you take naps in the daytime? i. Do you feel sleepy during the day? j. Do you snore? k. Does anything help you sleep? 2. Evaluate medical, psychiatric, and medication history (Table 8). Treatment of insomnia includes addressing underlying causes. 3. Determining the type of sleep problem will direct pharmacotherapy (see Table 9). Use a combination of the patient’s answers to questions and historical evaluation to develop a treatment plan with patient. a. The VA/DoD released the Management of Chronic Insomnia Disorder and Obstructive Sleep Apnea guideline in 2019. The pocket card with treatment algorithm can be found at https://www.healthquality. va.gov/guidelines/CD/insomnia/VADoDSleepCPGPocketCardFinal508.pdf. i. Recommended: Low-dose doxepin, benzodiazepine-1 receptor agonists ii. Not recommended: Diphenhydramine, melatonin, chamomile, valerian, kava b. The American Academy of Sleep Medicine published a clinical practice guideline for insomnia that recommends against the use of diphenhydramine, melatonin, tiagabine, trazodone, l-tryptophan, and valerian (J Clin Sleep Med 2017;13:307-49). Table 8. Possible Contributors to Sleep Disorders Medical Illnesses

Anemia Angina Arthritis or chronic pain Asthma COPD GERD or peptic ulcer disease Head injury Hepatic or renal failure Hypoglycemia Malignancy Parkinson disease Seizure disorders Sleep apnea

Psychiatric Disorders

Anxiety disorders Depression Manic episodes Mood disorders Psychotic disorders Substance use disorder(s)

Drugs

Alcohol Amphetamines Antipsychotics β-Blockers Bupropion Caffeine Cocaine Decongestants Diuretics

Levodopa Nicotine SNRIs SSRIs Theophylline Thyroid supplementation TCAs

COPD = chronic obstructive pulmonary disease; GERD = gastroesophageal reflux disease.

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Psychiatric Disorders

Table 9. Pharmacotherapy Selection According to Type of Insomnia Medication

Sleep Latency

Temazepam Doxepin

Sleep Maintenance x

Eszopiclone

Lemborexant

Both x x x

Suvorexant Ramelteon

x

Zaleplon

x

Trazodone

x

x

Zolpidem IR

x

Zolpidem CR

x

CR = controlled release

4. Epworth Sleepiness Scale a. Patient-rated scale that assesses the risk of a patient dozing off in several different situations. b. Scale range is from 0 (no risk of falling asleep) to 3 (high risk of falling asleep). c. Total score of greater than 10 indicates further assessment by a specialist should be considered. 5. Nonpharmacologic treatment of insomnia: Studies have shown that they are effective and should be considered as part of the initial treatment of insomnia in all patients. a. Stimulus control i. Go to bed and wake up at the same time every day (including weekends). ii. Go to bed only when sleepy. iii. Get out of bed if not asleep within 30 minutes. iv. Use the bedroom for sleep and intimacy only. v. Avoid daytime naps. vi. Schedule “worry time.” b. Sleep hygiene i. Exercise routinely, but not directly before bedtime. ii. Avoid the use of electronic devices immediately before bedtime. iii. Discontinue or reduce the use of caffeine, nicotine, and alcohol, if possible. iv. Have a comfortable sleeping environment: comfortable room temperature, decreased noise, darkened room. v. Do something relaxing to wind down before bed. vi. Try relaxation therapy. c. Cognitive behavioral therapy for insomnia (CBT-I) i. In clinical trials, CBT-I is more effective in the long term than drugs alone. Short-term medication treatment with CBT-I can improve initial outcomes. ii. CBT-I is used to decrease negative connotations related to sleep and to ascertain and address psychological concerns. iii. Although CBT-I is advocated by sleep experts as the gold standard treatment of primary insomnia, trained providers are lacking. 6. Pharmacologic treatment of insomnia a. Benzodiazepine sedative-hypnotics (see Table 10) i. Can induce and maintain sleep, though delta sleep and REM (rapid eye movement) sleep can be suppressed ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 755

Psychiatric Disorders

ii. Benzodiazepine hypnotics include flurazepam, triazolam, temazepam, estazolam, and quazepam. Temazepam is the most commonly prescribed. iii. Tolerance can develop, which limits use to the short term. iv. Rebound insomnia and life-threatening withdrawal have been reported with abrupt discontinuation. v. These drugs are generally CYP3A4 substrates. Drug interactions are possible with strong 3A4 inhibitors or inducers. vi. Avoid use in older adults (listed as potentially inappropriate medications for use according to the 2019 Beers Criteria). vii. Avoid use with other CNS depressants. b. Benzodiazepine-1 receptor agonists (BZD-1 RAs, Z-hypnotics) i. Zolpidem, zaleplon, eszopiclone (see Table 10) ii. Thought to be less disruptive to normal sleep parameters than benzodiazepines. iii. All three agents can be used for difficulties with sleep onset. For problems with sleep maintenance, select zolpidem controlled release (CR) and eszopiclone. iv. Adverse effects include amnesia, dizziness, headache, and GI effects. Eszopiclone can cause a metallic taste. v. Sleep-eating and sleep-driving have sometimes been reported with the Z-hypnotics. In April 2019, the FDA added a boxed warning indicating reports of serious injury and death as the result of complex sleep behaviors. vi. Z-hypnotics are CYP3A4 substrates, though zaleplon to a lesser extent. vii. Clinical trials have shown efficacy for eszopiclone and zolpidem CR up to 6 months. viii. Rebound insomnia and tolerance are less likely with zaleplon. ix. All Z-hypnotics are schedule IV controlled substances. x. Avoid use with other CNS depressants and in older adults (listed as potentially inappropriate medications for use by the 2019 Beers Criteria). Table 10. BZD and Z-Hypnotic Medications Brand Name

Generic Name

Dose, mg

Formulation(s)

Restoril

Temazepam

7.5–30

Capsules

Prosom

Estazolam

0.5–2

Tablets

Halcion Doral

Dalmane Lunesta

Ambien

Ambien CR

Edluar

Intermezzo Zolpimist Sonata

Triazolam

Quazepam

Flurazepam

Eszopiclone Zolpidem Zolpidem

Zolpidem Zolpidem Zolpidem Zaleplon

0.125–0.25

Tablets

7.5–15

Tablets

15–30

Capsules

1–3

5–10

Tablets

Tablets

a

6.25–12.5

Extended-release tablets

1.75–3.5

Sublingual tablets

a

5, 10

Sublingual tablets

b

5 mg/actuationa 5–10

Oral spray Capsules

The lower dose of zolpidem IR, zolpidem CR, and zolpidem sublingual tablets (5 mg, 6.25 mg, and 1.75 mg orally at bedtime, respectively) is the initial dose for women and older adults. a

Zolpidem sublingual tablets are indicated for insomnia when the patient experiences middle-of-the-night awakenings with difficulty returning to sleep. There must be at least 4 hr of sleep remaining.

b

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 756

Psychiatric Disorders

c. Ramelteon i. Ramelteon is not associated with dependence or tolerance and can be used for chronic insomnia. ii. Improves sleep latency but may not affect sleep duration iii. Benefit may not be clear until 3 weeks of use. Table 11 lists dosing of this agent and others. iv. Adverse effects include daytime sleepiness, dizziness, and stomach upset. v. Ramelteon is a CYP1A2 substrate; use with 1A2 inhibitors (e.g., fluvoxamine) can increase ramelteon serum concentrations. d. Trazodone i. A serotonergic antidepressant commonly used for sleep induction in patients with comorbid depression ii. The American Academy of Sleep Medicine recommends against trazodone for sleep onset/sleep maintenance insomnia on the basis of 50-mg dosing at bedtime. A 2018 meta-analysis evaluating seven trials (n=429) showed that patient-perceived sleep quality improved, though sleep efficiency did not improve significantly (Sleep Med 2018;45:25-32). iii. A longer duration of action can result in daytime hangover. iv. Priapism is possible, with onset more common in the first month of therapy with doses of 50–150 mg daily. Incidence is 0.01%–0.1%. Orthostatic hypotension and dizziness are quite common. e. Doxepin i. FDA approved under the brand name Silenor. ii. Warnings for Silenor include suicidal thinking (warning for all antidepressant agents) and sleepdriving (warning for sedative-hypnotic drugs). iii. Monitor for anticholinergic effects. f. Antihistamines i. Diphenhydramine and other antihistamines (e.g., doxylamine) are in over-the-counter sleep agents. ii. Tachyphylaxis to sedative effects is common, and the drug is usually effective for a few weeks and then wears off. A drug holiday is needed for continued effect. iii. Anticholinergic adverse effects limit its usefulness. These drugs should be avoided in older adults. g. Suvorexant (Belsomra) and lemborexant (DayVigo) i. Both are orexin receptor antagonists indicated for insomnia characterized by problems with sleep onset or maintenance. ii. There should be at least 7 hours between taking the dose and having to wake up. Reduce suvorexant dose to 5 mg with moderate CYP3A4 inhibitors. iii. Both are controlled substances (C–IV). iv. The most common adverse effect is drowsiness. v. A diagnosis of narcolepsy constitutes a contraindication to use. Table 11. Non-BZD and Z-Hypnotic Medications Brand Name

Generic Name

Dose, mg

Administration

Oleptro

Trazodone

50–150

Food increases absorption; take at bedtime

Rozerem Silenor

Belsomra DayVigo

Ramelteon Doxepin

Suvorexant

Lemborexant

8

3–6

10–20 5–10

Do not take with or after high-fat meal; take 30 min before bedtime Take on empty stomach 30 min before bedtime Take 30 min before bedtime

Take on empty stomach at bedtime

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 757

Psychiatric Disorders

7. Alternative therapies a. Melatonin i. Can be useful for jet lag and in older adults who should not take other agents. b. Chamomile i. Theorized to affect the benzodiazepine receptor. Robust clinical studies are lacking. ii. Many teas and extracts contain chamomile. Roman chamomile (Chamaemelum nobilis) is preferred to German chamomile (Matricaria recutita) (Psychother Res 2019;33:1604-15). iii. May be cross-reactive with ragweed allergy. iv. Can increase the risk of bleeding, especially in patients taking anticoagulants. c. Valerian i. Thought to inhibit the breakdown of GABA or increase GABA release. ii. Efficacy has not been shown consistently in clinical trials. iii. There have been several reports of liver toxicity, most of which resolved with discontinuation of valerian. Drug-drug interactions have historically been of concern, though a 2014 review concluded that possible interactions were not clinically relevant (Evid Based Complement Alternat Med 2014;2014). 8. Therapy summary and patient counseling a. Evaluate patients for underlying causes of insomnia and address these in treatment. b. Sedative-hypnotic therapy is recommended for short-term use only; zolpidem CR, eszopiclone, and ramelteon are FDA approved for treatment up to 6 months. c. Nonpharmacologic interventions are often preferred for first-line therapy in the treatment guidelines, given that the actual benefits of pharmacotherapy are limited to a decrease in sleep latency and increase in sleep maintenance by only minutes. d. Rebound insomnia and withdrawal are possible with abrupt discontinuation of drug therapy. e. A taper to discontinuation after long-term use is necessary. f. Monitoring of pharmacotherapy should include improved sleep, adherence to prescribed dosing, daytime hangover, changes in mood, and adverse effects. B. Sleep Apnea (Domains 1, 2) 1. Overview a. In sleep apnea, respiration ceases during sleep for brief periods. b. Sleep becomes fragmented because these brief periods can take place several hundred times a night. c. Excessive daytime sleepiness and snoring are common symptoms. Other risk factors include BMI greater than 30 kg/m2, age older than 50, menopausal status, neck circumference, family history, and crowded oropharynx. d. Obstructive sleep apnea is the most common type and is characterized by an anatomic obstruction in the airway. e. These patients may also have primary insomnia and should be evaluated for this as well. f. The STOP questionnaire is recommended for risk stratification by the VA/DoD clinical practice guidelines. The STOP consists of four questions, with a patient determined to be at “high risk” if more than two items are answered “yes.” 2. Treatment of obstructive sleep apnea a. Weight loss may significantly improve symptoms. b. Suggest sleeping on the side. c. Surgical correction of obstruction can also be attempted. d. Avoid alcohol and CNS depressants, which can relax the airway muscles.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 758

Psychiatric Disorders

e. When treating comorbid insomnia that persists after appropriate treatment of sleep apnea, avoid benzodiazepines because they decrease upper airway tone and the ventilatory response to hypoxia. Nonbenzodiazepine hypnotics do not significantly affect respiratory measures and are a safer alternative. Suvorexant and ramelteon are also reasonable options. f. Continuous positive airway pressure (CPAP) is very effective, but adherence is a barrier. BiPAP (bilevel positive airway pressure) can be recommended in patients who cannot tolerate CPAP. g. Modafinil is FDA approved as adjunctive therapy for excessive daytime sleepiness (EDS) despite use of CPAP or other interventions. i. Modafinil is a C–IV controlled substance. ii. Modafinil is a major CYP3A4 substrate as well as a strong CYP2C19 inhibitor and a moderate inducer of CYP3A4. iii. Dose is 200 mg in the morning. Higher doses are not consistently more effective. h. Armodafinil (R-enantiomer of modafinil) is FDA approved for EDS in patients with obstructive sleep apnea (OSA), narcolepsy, and shift work disorder. Armodafinil is a C–IV controlled substance and a major substrate for CYP3A4. Dose is 150–250 mg once daily in the morning, though doses greater than 150 mg have no shown increased benefit. i. Solriamfetol is FDA approved for EDS secondary to OSA (C–IV controlled substance). i. Does not treat underlying airway obstruction. This needs to be treated for at least 1 month before medication initiation. ii. Initial dosing is 37.5 mg once daily, titrated as tolerated to effect to max dose of 150 mg/day. Requires renal dose adjustment iii. Adverse effects include headache, decreased appetite, and psychiatric effects (anxiety, insomnia, and irritability). C. Resources (Domain 1) 1. Sleep disorder information and resources: www.talkaboutsleep.com 2. Sleep disorders: www.nlm.nih.gov/medlineplus/sleepdisorders.html 3. Restless legs syndrome: www.rls.org 4. American Sleep Apnea Association: www.sleepapnea.org 5. VA/DoD guidelines: https://www.healthquality.va.gov/guidelines/CD/insomnia/index.asp Patient Case 2. B.G. is a 46-year-old woman who presents to the primary clinic with a 2-week history of difficulty sleeping. She has difficulty falling asleep, often lying in bed for up to 2 hours before onset of sleep. She states that she has always been a “light sleeper,” but her current difficulties are new. She is a single mother of two teenage boys and works as an office secretary. B.G. has limited prescription drug coverage through her employer. Her medical history includes migraine headaches, hypercholesterolemia, and obesity. Her current weight is 101 kg (225 lb), blood pressure 140/86 mm Hg, and heart rate 84 beats/minute. Her current medications include ibuprofen 400 mg orally every 6 hours as needed for headache, simvastatin 40 mg orally daily, and sumatriptan 50 mg orally as needed for headache (she has taken two doses in the past 7 days). B.G. does not currently have headache pain. She states that she has tried to sleep in a calm environment, goes to bed at the same time each night, and has tried over-the-counter remedies with no effect. She does not drink alcohol and smokes ½ pack of cigarettes per day. B.G. has to be awake by 5:30 a.m. daily to get her children to school and go to work. Which drug therapy is the best initial choice for B.G.’s treatment? A. B. C. D.

Trazodone. Zolpidem. Flurazepam. Ramelteon.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 759

Psychiatric Disorders

IV.  MAJOR DEPRESSION A. Introduction (Domain 1) 1. Although individual patients may respond differently to antidepressants, at the population level, these drugs have similar rates of responses or remissions. 2. Drug therapy should be based on the adverse effect profile, adherence factors, and cost. 3. Patient should be counseled about the time to onset of action (weeks), significant adverse effects, and treatment duration. 4. All antidepressants carry a boxed warning for increased suicidal thinking and behavior in patients younger than 24 years. 5. Many patients need more than one treatment trial, and some require augmentation strategies. B. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Diagnostic Criteria for Major Depression (Domains 1, 2): Five or more of the following symptoms present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either depressed mood or loss of interest or pleasure. (Note: Do not include symptoms that are clearly the result of a general medical condition.) 1. Depressed mood 2. Markedly diminished interest or pleasure in activities 3. Appetite alterations 4. Insomnia or hypersomnia 5. Observable psychomotor agitation or retardation 6. Fatigue or loss of energy 7. Feelings of worthlessness or excessive or inappropriate guilt 8. Diminished ability to think or concentrate 9. Recurrent thoughts of death (not just fear of dying); recurrent suicidal ideation C. Clinical Course and Treatment Goals (Domains 1, 2) 1. Symptoms develop in days to weeks; in mild cases, symptoms can be present for weeks to months before they progress such that patient might seek treatment. 2. Prognostic factors that increase the risk of recurrence include residual symptoms, childhood abuse, prior depressive episodes, and comorbid anxiety. 3. The self-administered Patient Health Questionnaire-9 (PHQ-9) may be useful in the primary care setting, both to identify patients with depression and to monitor response. 4. Scores on the PHQ-9 of 0–4 indicate none to minimal depression, 5–9 mild, 10–14 moderate, 15–19 moderately severe, and 20–27 severe. 5. An important treatment goal is a return to premorbid baseline functioning. 6. Other goals include improved quality of life, decreased symptoms, achievement of response and remission, and prevention of relapse. 7. Mixed depression is an episode meeting the criteria for a major depressive disorder, but also includes subsyndromal mania or hypomania. Current opinion suggests that second-generation antipsychotics (SGAs) play an important role in treating this disorder (see CNS Spectr 2017;22:203-19 for a more complete discussion).

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Psychiatric Disorders

Patient Case 3. G.B. is a 45-year-old woman who presents to the primary care clinic with nonspecific feelings of pain, fatigue, sadness, and irritability as well as difficulty sleeping. Her medical history includes allergies, for which she takes cetirizine 10 mg orally daily. Her score on a PHQ-9 is 15. On questioning, you learn that she recently decreased the time she spends gardening and reading, saying she cannot concentrate. She is going to work but has difficulty getting out of bed in the morning. She cannot identify any recent traumatic events in her life. Which is the best first-line drug therapy for G.B.? A. B. C. D.

Sertraline. Selegiline patch. Aripiprazole. Amitriptyline.

D. Nonpharmacologic Treatment of Major Depression (Domain 1) 1. Psychotherapy plays an important role in the treatment of mood disorders. 2. Dynamic psychotherapy, interpersonal psychotherapy, and CBT are all useful in treatment. 3. Psychotherapy focuses on self-esteem, conflict resolution, the role of relationships in illness, identification of avoidance, fostering of engagement, and the patient’s treatment goals and strategies to achieve wellness. 4. Medications in combination with psychotherapy may provide the best initial and long-term treatment outcomes. E. Pharmacologic Treatment (Domains 1, 2) Psychotherapy (monotherapy if mild to moderate) ± medication (SSRI/SNRI, bupropion, mirtazapine, vortioxetine) Change medication or add psychotherapy Third medication trial with different MOA or augmentation (bupropion, mirtazapine, lithium, selected SGAs, lithyronine, methylphenidate)a Esketamine Monoamine oxidase inhibitor or ECT

Figure 6. General Approach to Treatment of Depression

When to change and when to augment: If patient has not had > 50% reduction in symptoms, considering changing over augmentation.

a

ECT = electroconvulsive therapy; MOA = mechanism of action.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 761

Psychiatric Disorders

F. Selective Serotonin Reuptake Inhibitors (Domain 1) Table 12. SSRI Antidepressants Brand Name

Prozac

Generic Name

Fluoxetine

Initial Dose

Max Dosage, mg/day

10 mg PO daily

80

Prozac Weekly

Fluoxetine

90 mg PO weekly

Paxil CR

Paroxetine

25 mg PO daily

62.5

20 mg PO daily

40

Paxil

Zoloft

Celexa

Lexapro

Paroxetine Sertraline

Citalopram

Escitalopram

90

10 mg PO daily

50

50 mg PO daily

200

10 mg PO daily

20

1. Adverse effects common to all SSRI antidepressants include anxiety, irritability, sedation, insomnia, sexual dysfunction, headache, sweating, abnormal bleeding, and GI effects. 2. Low initial dosing with slow titration may minimize or eliminate some of these adverse effects. See Tables 12 and 13. 3. Sexual dysfunction is a common adverse effect and often a reason for nonadherence. This can be treated by lowering the dose of the antidepressant, adding or changing to bupropion or mirtazapine, or adding a phosphodiesterase-5 inhibitor. 4. FDA revisions to the safety labeling for some SSRI antidepressants: a. Sertraline – Can cause a false-positive finding for benzodiazepines in urine drug screens. b. Citalopram – Not recommended for patients with congenital long QT syndrome; citalopram can cause dose-dependent QT prolongation and should not be dosed greater than 40 mg/day; hypokalemia and hypomagnesemia should be corrected before citalopram therapy is initiated; electrocardiogram (ECG) monitoring is recommended with concomitant medications that can also prolong the QT interval. Use lower doses of 20 mg/day for patients older than 60 or with hepatic impairment and 2C19-inhibiting drugs and for those who are CYP2C19 poor metabolizers. c. All SSRIs now have a warning to avoid concomitant use with linezolid or intravenous methylene blue. Table 13. SSRI Antidepressant Adverse Effects and CYP Interactions Generic Name

Adverse Effect Profile

CYP Inhibitory Potential

Fluoxetine

Insomnia, headache, nausea, anorexia, weakness, anxiety/nervousness, and sexual dysfunction

Paroxetine

Insomnia, headache, nausea, constipation or Inhibitor: 2D6 (high) diarrhea, decreased appetite, delayed ejaculation and other sexual dysfunction, asthenia

Sertraline

Insomnia, diarrhea, nausea, dizziness, sexual dysfunction, and fatigue

Inhibitor: 2D6 (high), 2C19 (high), 2C (low), 3A4 (low)

Inhibitor: 2C (low), 2D6 (V low), 3A4 (V low)

Half-Life

Parent compound: 4–6 days (chronic) Norfluoxetine: Average 9.3 days IR: 21 hr CR: 15–20 hr

Average 26 hr

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 762

Psychiatric Disorders

Table 13. SSRI Antidepressant Adverse Effects and CYP Interactions (continued) Generic Name

CYP Inhibitory Potential

Adverse Effect Profile

Citalopram

Nausea, diarrhea, drowsiness, insomnia, diaphoresis, sexual dysfunction

Escitalopram Diarrhea, nausea, sexual dysfunction, drowsiness, headache, dizziness, and insomnia

Half-Life

Inhibitor: 2D6 (V low)

Average 35 hr

Inhibitor: 2D6 (V low)

27–32 hr

V low = very low.

5. Important drug interactions a. Fluoxetine and paroxetine are strong CYP2D6 inhibitors that can increase the serum concentrations of metoprolol, haloperidol, and risperidone. Fluoxetine and paroxetine can also inhibit the conversion of tramadol and hydrocodone to active metabolites and reduce their efficacy in pain management. b. Use of tramadol in combination with serotonergic antidepressants can increase the risk of serotonin syndrome and the seizure-potentiating effect of tramadol. Other medications that can increase the risk of serotonin syndrome can be found in Table 20. c. Intensity of the drug interaction varies between patients. In general, doses of the interacting drugs are modified to account for the drug interaction, and patient outcomes are monitored, including laboratory values, adverse effects, and treatment response. 6. Monitoring values a. Assess response to therapy, suicidal thinking, and adverse effects at each visit. Response to therapy can be assessed using the PHQ-9. b. Baseline assessments of thyroid function, renal and hepatic function, electrolytes, pregnancy test, and urine drug screen should be considered. c. Hyponatremia is a possible adverse effect of the SSRIs – Periodic measurements of serum sodium concentrations should be considered, especially in older adults and those at risk of water intoxication, dehydration, or syndrome of inappropriate secretion of antidiuretic hormone. d. Use in combination with nonsteroidal anti-inflammatory drugs may increase the risk of bleeding. G. Serotonin-Norepinephrine Reuptake Inhibitors (Domain 1) Table 14. SNRI Antidepressants Brand Name

Generic Name

Initial Dose

Max Dosage

Effexor

Venlafaxine

25 mg PO TID

375 mg/day

Pristiq

Desvenlafaxine

50 mg PO daily

100 mg/day; no greater efficacy > 50 mg

Effexor XR Cymbalta Fetzima Savella

Venlafaxine Duloxetine

Levomilnacipran Milnacipran

37.5 mg PO daily 30 mg PO daily

20 mg PO daily 50 mg PO BID

225 mg/day 120 mg/day

120 mg/day; clinical trials lacked increased benefit > 60 mg 200 mg/day; only FDA approved for fibromyalgia

XR = extended release.

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Psychiatric Disorders

1. At doses lower than 150 mg, venlafaxine primarily inhibits serotonin reuptake. See Table 14 for dosing information on venlafaxine and other SNRIs. 2. SNRIs have the same serotonergic adverse effects as the SSRIs. See Table 15. 3. Duloxetine carries a warning for hepatotoxicity; baseline and periodic monitoring of liver function tests is suggested. 4. SNRIs can elevate blood pressure; use with caution in those with uncontrolled hypertension. This is typically dose related. 5. Duloxetine is metabolized by CYP 1A2 and 2D6. Inhibitors of these enzymes can increase duloxetine serum concentrations. 6. Venlafaxine is an inhibitor and substrate of CYP2D6. 7. Desvenlafaxine has no significant drug interactions. 8. Duloxetine is FDA approved for pain syndromes, including chronic musculoskeletal pain, fibromyalgia, and diabetic peripheral neuropathic pain. These agents should be considered first line for patients with considerable pain and depression. 9. SSRIs and SNRIs should not be used routinely as combination therapy because of overlapping mechanisms of action and increased risk of serotonin syndrome. 10. Monitoring values are similar to those listed for the SSRI antidepressants. 11. Like other antidepressants, SNRIs must be tapered when being withdrawn. Table 15. Common SNRI Adverse Effects Generic Name

Adverse Effects

Duloxetine

GI upset, xerostomia, drowsiness, headache, sexual dysfunction

Desvenlafaxine

Dizziness, insomnia, nausea, xerostomia, sexual dysfunction

Venlafaxine

Levomilnacipran Milnaciprana

Diaphoresis, anorexia, nausea, xerostomia, dizziness, drowsiness, insomnia, sexual dysfunction Orthostatic hypotension, nausea, constipation, tachycardia, sexual dysfunction

Headache, insomnia, hot flashes, nausea, constipation, dizziness, palpitations, sexual dysfunction

Milnacipran is only FDA approved for fibromyalgia.

a

H. Tricyclic Antidepressants (Domain 1) Table 16. Dosing of TCAs Brand Name

Generic Name

Initial Dose

Max Dosage, mg/day

Elavil

Amitriptyline

25–75 mg PO dailya

300

Sinequan

Doxepin

25–75 mg PO daily

300

Tofranil

Anafranil Pamelor

Norpramin Vivactil

Asendin

Ludiomil

Imipramine

Clomipramine Nortriptyline Desipramine Protriptyline Amoxapine

Maprotiline

25–75 mg PO dailya a

25–75 mg PO daily

a

25–50 mg PO daily

a

25–75 mg PO daily

a

15 mg PO daily

a

50 mg PO BID 25 mg PO TID

300 250 150

300 60

400 225

Usually given at bedtime when dosed once daily.

a

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Psychiatric Disorders

1. In addition to their use in depression, TCAs are commonly used for insomnia, neuropathic pain, and fibromyalgia (see Table 16 for dosing). 2. TCAs should be used with caution in older adults, if at all, because of cognitive effects and increased fall risk. 3. TCAs can be lethal in overdose secondary to cardiovascular effects including severe hypotension, seizures, and cardiac arrhythmias. TCAs should be used with extreme caution in patients with active suicidal ideation. Use of other serotonergic agents and CNS depressants Drug-drug interactions (specifically, CYP2D6) Periodic ECG, if warranted

Adverse effects: Sedation, anticholingergic effects, weight gain, sexual dsyfunction Figure 7. TCA monitoring. CNS = central nervous system.

I. Monoamine Oxidase Inhibitors (Domain 1) Table 17. MAOIs – Dosing Brand Name

Marplan

Nardil

Parnate

EMSAM

Generic Name

Isocarboxazid

Phenelzine

Tranylcypromine

Selegiline

MAOI Activity

A and B

A and B

Initial Dose

10 mg PO BID

15 mg PO BID

A and B

A (A and B at doses > 6 mg)

10 mg PO BID

6-mg/24-hr patch

Max Dosage

60 mg/day

90 mg/day

60 mg/day

12 mg/24 hr

1. MAOIs should not be used in combination with other antidepressants or serotonergic agents because of the significant risk of serotonin syndrome (see Table 17 for dosing). 2. The washout period before and after MAOI use is 2 weeks (exception: changing from fluoxetine to an MAOI requires a 5-week fluoxetine washout). 3. Adverse effects include orthostatic hypotension, headache, GI effects, dry mouth, sexual dysfunction, and hypertensive crisis. 4. Risk of hypertensive crisis is generally low but can be increased by ingesting foods containing tyramine, necessitating the use of a “tyramine diet.” Tyramine-containing foods to be avoided include the following: a. Aged cheeses, meat, beer, wine (red) b. Pickled meat, vegetables, and fish c. Smoked meat, sausage, salami, pepperoni, and fish d. Yeast extracts e. Caffeine and chocolate (can be ingested in moderation) 5. Drugs to avoid a. Amphetamines and methylphenidate b. Decongestants c. Dextromethorphan d. Ephedrine and epinephrine e. Meperidine f. Carbamazepine, oxcarbazepine g. Other antidepressants

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 765

Psychiatric Disorders

6. Dosing information: Selegiline patch a. Available as a capsule and an orally disintegrating tablet, but these formulations are only used for Parkinson disease b. Initial dose of 6 mg/24 hours does not require the tyramine diet; dose escalation to the 9- or 12-mg patch will require the low-tyramine diet. 7. Monitoring values are similar to those for other antidepressant agents, with the inclusion of reminders about the tyramine diet and the concomitant drug therapy to avoid. 8. MAOI therapy should be considered after failure of several other antidepressants. J. Bupropion (Domain 1) 1. Bupropion is considered to have no effect on serotonin reuptake at clinically useful doses. Table 18 lists bupropion dosing, among others 2. Adverse effects include insomnia, headache, agitation, dizziness, weight loss, xerostomia, tremor, and GI upset. 3. Bupropion is contraindicated for use in patients with seizure disorders and eating disorders. 4. For patients with somnolence or vegetative symptoms of depression, bupropion can be particularly beneficial. The sustained-release (SR) formulation is dosed twice daily, the IR two or three times daily, and the extended release (ER) once daily in the morning. If insomnia occurs, moving split daily dosing earlier in the day may help. 5. Bupropion is also available for smoking cessation and obesity; evaluate patient’s current medication regimen carefully to avoid duplicate therapy. 6. Bupropion can inhibit CYP2D6. Although the risk may be low, substrates such as venlafaxine, TCAs, paroxetine, fluoxetine, sertraline, haloperidol, risperidone, and metoprolol may be affected. Bupropion can also decrease plasma concentrations of digoxin. 7. Although not FDA approved, bupropion can be used in patients with attention-deficit/hyperactivity disorder (ADHD), though the evidence is of low quality (Cochrane Database Syst Rev 2017;10:CD009504). 8. Bupropion is associated with a low incidence of sexual dysfunction. Often added to SSRIs to combat SSRIinduced sexual dysfunction. Can also replace SSRIs if sexual dysfunction occurs. K. Mirtazapine (Domain 1) 1. Lower doses are more likely to cause sedation than higher doses. 2. Increased appetite and weight gain are common. 3. Mirtazapine is associated with a lower risk of sexual dysfunction. 4. Other adverse effects include increased cholesterol values, constipation, dry mouth, peripheral edema, and dizziness. 5. Rarely, mirtazapine can cause neutropenia or agranulocytosis. 6. Significant drug interactions are rare. 7. Combination therapy with other antidepressants is common. Because of the effects of mirtazapine on serotonin, the risk of serotonin syndrome, though rare, should be considered. L. Trazodone (Domain 1) 1. Usual antidepressant dose is 200–600 mg/day. 2. Trazodone is a substrate of CYP3A4 and possibly a clinically significant inhibitor of CYP2D6. 3. Priapism is a rare but urgent adverse effect of trazodone at higher doses. Medical attention should be sought immediately if this occurs.

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Psychiatric Disorders

M. Vilazodone (Domain 1) 1. Adverse effects: Similar to those for other serotonergic antidepressants, including GI effects, dizziness, and insomnia. Abnormal dreams were noted more often than in placebo groups in clinical trials. Phase III studies showed a minimal impact on sexual functioning, but this remains to be seen with increased use in the clinical treatment setting. 2. Vilazodone is a major substrate of CYP3A4. N. Vortioxetine (Domain 1) 1. Given once daily without regard to meals. Usual initial dose is 10 mg, and dose can be increased, depending on tolerability, to 20 mg daily, if necessary. A dose of 5 mg can be used if higher doses are not tolerated. 2. Package label states that tapering should be considered for doses greater than 10 mg. 3. The most common adverse effects are nausea, constipation, and vomiting. Vortioxetine does not appear to affect body weight. Sexual dysfunction may also be lower. 4. CYP2D6 is the main route of elimination. Poor metabolizers can have higher serum concentrations. O. Brexanolone 1. FDA approved in March 2019 for postpartum depression. 2. Administered as a 60-hour continuous infusion with a stepwise titration and taper (0-4 hours: 30 mcg/kg/ hour; 4-24 hours: 60 mcg/kg/hour; 24-52 hours: 90 mcg/kg/hour; 52-56 hours: 60 mcg/kg/hour; 56-60 hours: 30 mcg/kg/hour). 3. Brexanolone carries a black box warning for excessive sedation and sudden loss of consciousness which necessitates continuous pulse oximetry monitoring during infusion. Brexanolone is only available through Zulresso REMS. Table 18. Novel Antidepressant Dosing Brand Name

Generic Name

Initial Dosing

Wellbutrin

Bupropion

Remeron

Mirtazapine 15 mg once daily

Trintellix

Vortioxetine 10 mg once daily

Viibryd

Vilazodone

IR: 100 mg PO BID SR/XL: 150 mg daily

10 mg once daily for 7 days, then 20 mg once daily for 7 days

Max Dose, mg Notes 450 45

40 20

For maintenance, the IR form is dosed TID, the SR forms are dosed BID, the XL forms are dosed once daily Give at bedtime because of possible sedation Dose titration because of GI adverse effects

No need to taper off for 10-mg dose, but taper for doses of 15–20 mg

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Psychiatric Disorders

P. Augmentation Therapies and Approach to Nonresponses or Partial Responses (Domain 1) Table 19. Depression Augmentation Medications Brand Name

Generic Name

Dosing

Clinical Pearls

Spravato

Esketamine

Induction: 56 mg intranasally BID (can increase to 84 mg twice weekly) Maintenance (weeks 5+): Dose decreased to once weekly or every 2 wk

Seroquel IR/ ER

Quetiapine

Approved for treatment-resistant depression. C-III substance. Use is restricted under Spravato REMS, which requires administration under provider’s supervision with subsequent 2-hr monitoring

Abilify

Aripiprazole

Rexulti

Brexpiprazole

Symbyax

Olanzapine/ fluoxetine

Lithobid

Wellbutrin

Lithium carbonate

Bupropion

Initial dose 300–600 mg PO daily in one or two doses; target dose 900 mg/ day

50 mg PO daily on days 1 and 2; increase to 150 mg on day 3 (typical range 150–300 mg daily)

Target concentration 0.6–1 mEq/L in BD; lower end usually targeted for MDD. Reduces suicidal thinking

Typically dosed at bedtime because of sedation. Monitor for metabolic effects

2–5 mg PO daily; may increase as tolerated to 15–20 mg daily

Monitor for akathisia and metabolic effects (though has lower risk of metabolic changes than quetiapine)

6/25 mg PO daily in evening. Usual dose range 6/25 to 12/50 mg daily

Approved for treatment-resistant depression. Monitor for metabolic effects

25 mcg PO daily; increase to 50 mcg daily on the basis of response and tolerability

Typically well tolerated

0.5–1 mg PO daily; may increase as tolerated to 3 mg daily

See Table 18

Can also be used monotherapy. Contraindicated in seizure disorders

Cytomel, Triostat

Liothyronine

Ritalin

Methylphenidate 2.5–5 mg PO once or twice daily. May Good choice for patients with vegetative IR increase as needed up to total of 40 mg symptoms such as extreme fatigue daily

BD = bipolar disorder; MDD = major depressive disorder; REMS = Risk Evaluation and Mitigation Strategies.

Q. Stages of Treatment in Depression (Domains 1, 2) 1. Acute: Initial goals are to achieve symptom control and attain remission. 2. Continuation: Sustained use of antidepressant treatment to prevent relapse of depressive symptoms. Treatment should continue in this phase for at least 4–9 months. 3. Maintenance: Patients at high risk of recurrent episodes (more than two prior episodes, chronic symptoms lasting more than 1 year, strong suicidal ideation) should continue pharmacotherapy for 1 year or potentially indefinitely. 4. No firm recommendation for how long maintenance therapy will last. Individualized to the patient, though in general, length of maintenance treatment should increase with each depressive recurrence. R. Suicidal Thinking and Behavior: Black Box Warning (Domain 2) 1. Antidepressant medications, aripiprazole, quetiapine, lurasidone, anticonvulsant drugs, and atomoxetine carry warnings for increased suicidal thinking and behaviors in patients 24 years and younger. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 768

Psychiatric Disorders

2. Increased suicidal thinking and behaviors have not translated to an actual increase in completed suicides related to the use of these medications. A risk of suicide is inherent in mood disorders, so suicide risk should be evaluated at each visit. 3. Patients and caregivers or parents should be educated about this risk and counseled on the need for awareness of new-onset or worsening thoughts of suicide. S. Switch Strategies for Antidepressant Therapy (Domain 1) 1. Only about one-third of patients respond adequately to the first antidepressant used. 2. If initial therapy fails, the medication can be changed to another antidepressant, either within the same class or within another class of antidepressants. 3. If patient does not tolerate serotonergic adverse effects (i.e., sexual dysfunction), a trial of bupropion, mirtazapine, or other traditional augmenting agents is appropriate. 4. Changing to another antidepressant can be done either as a slow cross-taper or as an immediate change (see CNS Drugs 2009;23:627-47). Receptor pharmacology should be considered, as should half-life, to ensure patient does not experience withdrawal symptoms. T. Combination Therapy (Domain 1) 1. Use of two antidepressant therapies may be warranted. 2. Rational combination therapy considers the receptor pharmacology and mechanisms of action of the proposed combination. U. Antidepressant Withdrawal Syndrome (Domain 1) 1. SSRI/SNRI withdrawal symptoms include increased anxiety, depression, irritability, feeling of mild electric shocks, flu-like symptoms, and GI symptoms. 2. Antidepressant withdrawal syndrome can occur when the drug is abruptly discontinued. Syndrome is more common with medications with shorter half-life. Symptoms are usually self-limiting and improve if the taper is slowed. V. Serotonin Syndrome (Domain 1) 1. Serotonin syndrome is a potentially life-threatening condition characterized by autonomic instability (labile blood pressure, tachycardia, hyperthermia), mental status changes (agitation, hallucinations), neuromuscular symptoms (hyperreflexia, incoordination), and GI concerns (nausea, vomiting, diarrhea). 2. This syndrome is the result of excessive serotonergic activity, usually caused from using several serotonergic drugs. 3. Most cases of serotonin syndrome are mild and can be treated by withdrawing the offending agents. More severe cases can be treated with benzodiazepines and cyproheptadine (a serotonin antagonist). 4. Use of serotonergic antidepressants in combination with the drugs listed in Table 20 can precipitate serotonin syndrome. Table 20. Medications That Increase Risk of Serotonin Syndrome Linezolid

Lithium

Cyclobenzaprine

Dextromethorphan

Amphetamines Methadone

St. John’s wort

Tramadol

Meperidine

Metoclopramide

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Psychiatric Disorders

W. Complementary and Alternative Treatments: Use of nondrug treatments is often warranted in treatment-resistant depression. (Domain 1) 1. Electroconvulsive therapy is more effective than pharmacotherapy. Contraindications to use include a recent myocardial infarction and high risk of bleeding or hemorrhage. Retrograde and anterograde amnesia and cognitive dysfunction can be adverse effects. Maintenance therapy can include continued periodic electroconvulsive therapy or pharmacotherapy. 2. Vagus nerve stimulation is reserved for adults with depression lasting more than 2 years that has not adequately responded to at least four antidepressants. 3. Transcranial magnetic stimulation can be useful for patients not benefiting from medication therapy and is the least invasive of the alternative nondrug therapies. 4. Bright light therapy is useful for depression with a seasonal pattern. Patient should be exposed to artificial light of at least 2500 lux. 5. St. John’s wort is recommended as a first-line agent for mild depression for those who prefer herbal options according to the VA/DoD clinical practice guidelines. St. John’s wort can induce several CYP isoenzymes, including 2C9, 3A4, and 1A2, necessitating evaluation of the drug therapy regimen. Usual dose is 300 mg of the standardized extract (hyperforin 2%–5%) orally three times daily. Patients taking St. John’s wort should be cautioned that it can cause photosensitivity. 6. Folic acid supplementation in the form of folic acid 400 mcg or l-methylfolate 7.5 mg orally daily has been studied as an adjunctive treatment in major depression. The theoretical usefulness of folate for depression comes from the need for folate in the synthesis of monoamine neurotransmitters. Those with MTHFR gene mutations have limited ability to create l-methylfolate and thus may be more likely to respond to treatment. Clinical literature supporting the efficacy of folic acid supplementation in the general population is limited. 7. S-adenosylmethionine (SAMe) has been studied for use as an adjunctive to antidepressants in treating depression. A recent study noted an increased response and remission rate when SAMe 400 mg orally twice daily was added to a current serotonergic antidepressant regimen. Use of SAMe with serotonergic antidepressants has been associated with the development of serotonin syndrome; therefore, monitor closely. 8. Omega-3 fatty acids received recent attention after the release of guidelines for their use in major depressive disorder (International Society for Nutritional Psychiatry Research practice guidelines located at https:// www.karger.com/Article/FullText/502652). Recommendations are to consider omega-3 fatty acids (products with an eicosapentaenoic acid/docosahexaenoic acid ratio greater than 2:1) adjunctively for acute episodes at a dose of 1–2 g of total eicosapentaenoic acid per day. Maintenance therapy can be considered. X. Use of Antidepressants in Pregnancy and Lactation (Domain 1) 1. Untreated maternal depression can result in premature birth, low birth weight, and postnatal complications, as well as negative psychiatric outcomes for the child. The FDA further states that antidepressants should be used for pregnant women as clinically indicated. 2. No evidence supports an increased risk of major malformations with SSRI use (N Engl J Med 2014;370:2397407) or an increased risk of autism (JAMA 2017;317:1553-62). 3. Paroxetine should be avoided during pregnancy. 4. Use of monotherapy at higher doses is suggested over the use of more than one antidepressant medications. 5. If a woman discovers she is pregnant while taking an antidepressant, it is recommended to continue that antidepressant rather than change to another to limit fetal drug exposure. 6. Most antidepressants have limited data related to breast milk concentrations. Sertraline, paroxetine, and some TCAs have minimal concentrations. Long half-life of fluoxetine can cause accumulations in breast milk and thus is not preferred.

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Psychiatric Disorders

Y. Treatment Guidelines (Domain 1) 1. Psychopharmacology algorithm project, Harvard Medical School (psychotic depression) 2. American Psychiatric Association: www.psychiatryonline.org/guidelines.aspx 3. National Institute for Health and Care Excellence (NICE) UK: www.nice.org.uk 4. U.S. Department of Veterans Affairs: www.healthquality.va.gov 5. Canadian Network for Mood and Anxiety Treatments (CANMAT): https://www.canmat.org/2019/03/17/2016depression-guidelines/ Z. Patient Resources (Domain 1) 1. National Alliance on Mental Illness: www.nami.org 2. Mental Health America: www.mentalhealthamerica.net/

V.  BIPOLAR DISORDER A. Introduction (Domain 1) 1. Mood-stabilizing drug therapies such as lithium, anticonvulsant mood stabilizers, and atypical antipsychotics are considered the mainstay of maintenance therapy for BD. 2. Although the predominant mood pole in BD is depression for most patients, use of antidepressant therapy in this condition is controversial, given both questionable effectiveness and the risk of inducing mania. 3. Pregnancy is a risk factor for a mood episode in BD, which can complicate treatment. B. Clinical Presentation of BD (Domains 1, 2) 1. Bipolar I disorder: Manic or mixed episodes and depressive episodes 2. Bipolar II disorder: Hypomanic or mixed episodes and depressive episodes 3. Manic episode a. Mood is elevated, expansive, or irritable for at least 1 week. b. Symptoms include grandiosity, irritability, decreased need for sleep, flight of ideas or racing thoughts, pressured speech, distractibility, increased activity, poor judgment/involvement in pleasurable activities with potentially negative consequences. Patient needs three of these symptoms to diagnose a manic episode (four symptoms if mood is only described as irritable). c. If severe, patient may have psychotic symptoms. d. Marked impairment in social or occupational functioning. 4. Mixed episode a. Features of both mania and depression (depressive symptoms similar for major depressive disorder) b. There is a higher risk of comorbid substance use and suicidality. 5. Depressive episode (see Depression section): Psychotic symptoms are more common than in unipolar depressive episodes. 6. Hypomanic episode a. Less severe form of mania. b. Mood episode that is expansive, irritable, or elevated, lasting at least 4 days. c. Symptoms are similar to those of a manic episode but not severe enough to affect social or occupational functioning; hospitalization not needed. Changes in mood and functioning are still noticeable by others. 7. Rapid cycling: This specifier is used with four or more mood episodes in 1 year. Rapid cycling can make the disorder more difficult to manage. Valproate is often preferred to lithium for rapid cyclers. These patients can also be at higher risk of mood destabilization with antidepressants.

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Psychiatric Disorders

8. Risk factors for BD a. Family history/genetics: One of the strongest predictors b. Environmental or psychosocial stressors c. Sleep dysregulation d. Separated or divorced, higher socioeconomic level C. Clinical Course (Domains 1, 2) 1. BD often goes unrecognized for years because of misdiagnosis. 2. BD is a recurrent illness, with more than 90% of patients having multiple episodes. 3. Suicide attempts occur in more than 50% of patients with BD, with up to 20% of patients with bipolar I disorder dying by suicide. 4. Rating scales a. The Young Mania Rating Scale is the gold standard scale used to rate manic symptoms. Often used in clinical trials but rarely in clinical practice. Consists of 11 items, with a maximum score of 60. Scores greater than 25 indicate severe mania; scores less than 11 indicate euthymia. Patient Case 4. G.G. is a 34-year-old woman who presents to the primary clinic with symptoms of depression, including decreased energy, lack of interest in activities, and poor sleep. She has missed some days of work in the past few weeks because of her inability to get out of bed in the morning. She has no other medical conditions and currently takes no routine medications. Her laboratory values, including thyroid function, are within normal limits. Her past antidepressant treatment has been ineffective, including citalopram and fluoxetine use. On questioning, G.G. reports having an elevated mood in the past, with a decreased need for sleep and an increase in goal-directed activities, and she was told she may have bipolar disorder. Mood episodes have been generally depressed. Which is best for initial medication treatment of G.G.? A. B. C. D.

Divalproex. Venlafaxine. Aripiprazole. Quetiapine.

D. Nonpharmacologic Treatment of BD (Domain 1) 1. Adequate sleep and regulation of circadian rhythm 2. Individual or group psychotherapy, supportive therapy, and counseling 3. CBT 4. Stress reduction a. Improved nutrition b. Exercise c. Relaxation 5. Electroconvulsive therapy – Can be useful, especially in the context of treatment-resistant depressive episodes E. Pharmacologic Treatment of BD (Domain 1) 1. When a treatment plan for an acute episode is developed, maintenance treatment should be a factor in decision-making. 2. General guidelines for treatment a. Assess for secondary causes, including thyroid function, substance use, and medication-induced episodes. b. Optimize doses of mood-stabilizing medications. Some may involve therapeutic drug monitoring. c. Consider tolerability in choosing the medication regimen. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 772

Psychiatric Disorders

d. Consider the type of BD and the efficacy of the individual medication. See evidence-based guidelines in choosing from lithium, mood-stabilizing anticonvulsants, and SGAs. e. The time in which medications begin to affect symptoms should also be considered. Lithium can take longer than other therapies to improve symptoms (typically at least 1 week). 3. First-line approaches to BD by type a. Acute manic episode: Lithium, divalproex, or an SGA. If severe, can consider using a combination of lithium or valproate plus an antipsychotic, or combination lithium and valproic acid. b. Acute bipolar depression: Consider quetiapine, lurasidone, olanzapine/fluoxetine, or cariprazine. Lithium and lamotrigine can also be used. c. Acute mixed episode: Valproate plus an antipsychotic. d. Maintenance: Lithium, divalproex, or an SGA. Combination therapy may be necessary. 4. Lithium a. Can be used alone or in combination with other agents for both mania and depression. Is considered more effective than other anticonvulsants for bipolar depression. Combination with an SGA may be more effective than either agent alone. b. Therapeutic serum concentration: 0.6–1.2 mEq/L i. Acute treatment: 1.0–1.2 mEq/L ii. Maintenance treatment: 0.6–1.0 mEq/L c. Toxicity concentration: This can be highly variable. Some patients begin to have adverse effects within the therapeutic range, but serious toxicity (e.g., arrhythmias, seizures, renal toxicity) is rare at concentrations less than 2.0 mEq/L. Treatment of toxicity will depend on the severity of clinical presentation. Neurologic adverse effects are concentration-dependent. Treatment can range from holding the lithium dose until symptoms subside to undergoing hemodialysis. d. Monitor serum concentrations 4–5 days after initiation. e. Usual adult dose: 900 mg orally daily (can be divided in doses twice daily or given once daily at bedtime). Individualize the dose on the basis of serum concentration monitoring. f. Adverse effects include GI upset, tremor, diabetes insipidus, weight gain, acne, alopecia, leukocytosis, and hypothyroidism. Renal toxicity has also occurred with lithium. Renal toxicity is a slow decrease in estimated glomerular filtration rate (eGFR) that appears to be related to both the serum concentration and the therapy duration. Elevated lithium concentrations, either acute or chronic, increase the risk of renal toxicity. End-stage renal disease occurs in a small patient subset. Risk is minimized by monitoring SCr and eGFR regularly and keeping the maintenance lithium concentration at the low end of the range. g. Some adverse effects can be treated pharmacologically. i. Tremor – Propranolol ii. Hypothyroidism – Levothyroxine

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Psychiatric Disorders

Table 21. Lithium Monitoring Values Lithium

Renal function

Pregnancy test Electrolytes

Thyroid function

CBC with differential ECG

Weight

Serum concentration

Baseline x x

Every 6–12 mo x

x

x

x

x

x

As Clinically Indicated x

x

x

a

x

x

xb

x x

If ≥ 40 yr of age.

a

b

Once clinically stable.

h. Drug interactions i. Increased lithium concentration: Nonsteroidal anti-inflammatory drugs, thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, sodium depletion. ii. Decreased lithium concentration: Caffeine, theophylline, high dietary sodium, acetazolamide. iii. Clinician’s response to drug interactions with lithium is generally to monitor lithium serum concentrations more closely when an interacting drug is added or discontinued. Table 21 lists additional monitoring. i. Important patient counseling points i. Maintain salt intake – No significant fluctuations ii. Maintain fluid intake and avoid dehydration. iii. Expected adverse effects iv. Adherence 5. Divalproex or valproic acid a. May be more useful for mixed episodes and rapid cyclers. Onset of action occurs within days with loading. b. Initial dose of divalproex delayed release (DR) is 750 mg/day in divided doses. A loading strategy such as 20-mg/kg dosing per day can be used. Maximum dose is 60 mg/kg/day. Valproic acid IR can also be used at the same total daily dosage, dosed three or four times daily. Target serum concentration is 50–125 mcg/mL. c. The ER dosage form should be given once daily at bedtime if patient can tolerate it; doses greater than 2000 mg/day should be divided. d. Bioavailability of the ER tablet is 90% relative to the DR tablet. The package label suggests starting the ER dosage form at 8%–20% greater than the DR amount. If this calculation does not fit with available strengths, increasing to the next available DR strength before converting can be considered. e. Adverse effects include GI upset, weight gain, thrombocytopenia, hyperammonemia, alopecia, tremor, hepatotoxicity, pancreatitis, polycystic ovary syndrome, amenorrhea, leukopenia, osteoporosis, and sedation. Table 22 lists additional monitoring. f. Boxed warnings for valproic acid i. Hepatic failure ii. Life-threatening pancreatitis has been reported in children and adults. Patient should be counseled to seek medical attention for abdominal pain, nausea, vomiting, or loss of appetite. Valproic acid and derivatives should be discontinued if patient develops pancreatitis.

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Psychiatric Disorders

Table 22. Divalproex Monitoring Values Divalproex

Pregnancy test

CBC with differential Weight

Serum concentration

Liver function tests Ammonia

Baseline

Every 6–12 mo

x

x

x

x

As Clinically Indicated x

x

x

x

x xa

If patient has altered mental status.

a

g. Drug interactions i. Carbapenems – Reduced valproic acid concentrations ii. Phenytoin – Valproic acid clearance increased iii. Warfarin – May prolong bleeding time iv. Lamotrigine – Increased lamotrigine concentration. If this drug combination is used, clinician should pay special attention to the dose escalation of lamotrigine (lower doses used). v. Ritonavir – Decreased valproate concentration 6. Carbamazepine a. Generally tried after failure of other mood stabilizers b. Initial dose of both the IR and the XR formulations is 200 mg orally twice daily, which can be titrated to a maximum of 1600 mg/day. IR can be given in two to four daily doses, and XR is dosed twice daily. c. Metabolism: Carbamazepine is an autoinducer; will need to increase dose after 4–6 weeks d. No correlation with therapeutic serum concentration for use in BD; however, same range of 4–12 mcg/ mL for seizures is generally used for toxicity purposes. e. Carbamazepine is a potent inducer of CYP 1A2, 2C, and 3A4. f. Adverse effects include rash, sedation, anticholinergic effects, weight gain, cardiac conduction abnormalities, hyponatremia, agranulocytosis, osteoporosis, and hepatotoxicity. g. Boxed warnings for carbamazepine i. Potentially fatal blood cell abnormalities, including aplastic anemia and agranulocytosis/severe neutropenia, have been reported. Use with caution in patients with a history of cardiac disease, ECG abnormalities, and hepatic or renal disease. ii. Use caution and screen for genetic susceptibility in patients of Asian race. A patient who is positive for the HLA-B*1502 allele should not receive carbamazepine. There is a significantly greater risk of adverse effects, including Stevens-Johnson syndrome.

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Psychiatric Disorders

Table 23. Carbamazepine Monitoring Values Carbamazepine

Pregnancy test

CBC with differential Electrolytes ECG

a

Serum concentration Renal function

Liver function tests

Baseline

Every 6–12 mo

x

x

x x

x x x

As Clinically Indicated x x

x

x

x

x

If cardiac disease is present.

a

h. Routine monitoring i. Hyponatremia is common, often secondary to syndrome of inappropriate antidiuretic hormone secretion. Reported incidence varies but, in patients with epilepsy, has been reported in up to 50% of patients. ii. Check serum concentration if toxicity or nonadherence is suspected. Table 23 lists additional monitoring. iii. Watch for signs and symptoms of infection that do not resolve or flu-like symptoms. i. Drug interactions i. Oral contraceptives – Can lead to contraceptive failure. Patient should be informed of this interaction, provide informed consent, and receive patient counseling to avoid unwanted pregnancy (see Appendix A). Use of alternative forms of birth control is recommended. ii. Any 1A2 or 3A4 substrate – Decreased serum concentration of substrate iii. Lamotrigine – Decreased serum concentration of lamotrigine iv. Ketoconazole – Increased carbamazepine serum concentration 7. Oxcarbazepine a. This is the 10-keto analog of carbamazepine. Evidence for use is not overly compelling. b. Usual adult dose: 300 mg orally twice daily c. Fewer blood cell abnormalities but more instances of hyponatremia than with carbamazepine d. Does not autoinduce its own metabolism e. A CYP3A4 enzyme inducer at higher doses (greater than 1200 mg total daily) f. Oxcarbazepine is generally reserved for those whose carbamazepine or other mood stabilizers have failed. g. As with carbamazepine, oral contraceptives may not be as effective when used concomitantly with higher doses of oxcarbazepine (specifically doses greater than 1200 mg total daily). h. Monitor serum sodium concentrations. 8. Lamotrigine a. Considered first line for the maintenance treatment of bipolar depression. However, it may not be effective in preventing manic episodes. The titration process limits its usefulness for acute depressive episodes. b. There is a long titration schedule to therapeutic dose (in general, 6–8 weeks until the target dose is reached). c. There is a boxed warning for Stevens-Johnson syndrome, which is minimized with slow-dose titration. i. If used as monotherapy: 25 mg orally daily for 2 weeks, 50 mg/day for 2 weeks, then adjust over weeks 5–7 to 200 mg/day, if needed. ii. If used in combination with valproic acid: 25 mg orally every other day for 2 weeks, 25 mg/day for 2 weeks, and then increase over weeks 5–7 to 100 mg/day, if needed. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 776

Psychiatric Disorders

iii. If used in combination with carbamazepine (or enzyme inducer): 50 mg orally daily for 2 weeks, 50 mg twice daily for 2 weeks, and then increase over weeks 5–7 to 400 mg/day, divided twice daily if needed. d. For patients taking divalproex and lamotrigine, dose adjustment is necessary when discontinuing either agent. e. Adverse effects include rash, Stevens-Johnson syndrome, sedation, headache, GI effects, increased risk of arrhythmias, and blurred vision. f. Baseline monitoring i. CBC with differential ii. Liver function tests iii. Assess for structural or functional heart disorders, including arrhythmias. Avoid use with sodium channel blockers, if possible. g. Routine monitoring: Liver function tests annually h. Drug interactions i. Valproic acid decreases the elimination of lamotrigine. Initial dose of lamotrigine must be reduced if used with valproic acid. ii. Carbamazepine can induce the metabolism of lamotrigine and reduce its effectiveness. iii. Estrogen-containing oral contraceptives can reduce lamotrigine serum concentrations (significantly, by 40%–60%). 9. Atypical antipsychotics (see Schizophrenia section for specific drug information) a. Most atypical antipsychotics are FDA approved for the acute and maintenance treatment of mixed or manic episodes in BD, either as monotherapy or in combination (adjunctive) with lithium or valproic acid (except for clozapine). See Table 24. Table 24. Indications of SGAs in BD Aripiprazole

Acute Mixed

Maintenance for Mania

x

x

x

x

Asenapine

Brexpiprazole

x

Bipolar Depression

a

Cariprazine

Clozapine

Acute Manic

x

x

x

a

Iloperidonea

Lumateperonea Lurasidonea

Olanzapine

x

x

Olanzapine/samidorphan

x

x

Olanzapine/fluoxetine Quetiapine

Paliperidone

x

x

x

x x

a

Risperidone

x

Ziprasidone

x

x

x

No FDA-approved indications for BD. Clozapine, in particular, can be used off-label for resistant BD.

a

SGA = second-generation antipsychotic.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 777

x x

Psychiatric Disorders

b. Long-acting injections (risperidone, paliperidone, olanzapine, aripiprazole) may be useful for BD on the basis of patient preference or for adherence concerns. c. Conventional antipsychotics (or first-generation antipsychotics [FGAs]) are considered useful for acute agitation in bipolar mania but less so for maintenance treatment or affective symptoms. 10. Antidepressants (see Depression section for specific drug information) a. Use is controversial because of questionable efficacy and the risk of switching to a manic episode. Sertraline and fluoxetine are effective in patients with type II BD with lack of rapid cycling and nonmixed depressive episodes with no recent hypomania. b. If used, monitor closely for both efficacy and manic or hypomanic symptoms. c. Antidepressant therapy should generally be used in combination with a mood stabilizer and only when necessary. TCAs and venlafaxine may be associated with a greater risk of affective switching. F. Treatment of BD in Pregnancy and Lactation (Domain 1) 1. Risk of a bipolar episode was increased by 2-fold in pregnant patients who discontinued mood stabilizer therapy during pregnancy. Continued mood stabilizer therapy significantly reduces the risk of recurrence. 2. Teratogenic effects associated with the mood stabilizers include Ebstein anomaly (lithium) and neural tube defects (valproic acid, carbamazepine). Valproic acid includes a boxed warning for major congenital malformations such as spina bifida. Use of lithium in the first trimester should be avoided, when possible. 3. Recent evidence suggests that use of valproic acid during pregnancy in any trimester affects the offspring’s IQ, with as much as a 10-point difference in offspring and maternal IQ. 4. Atypical antipsychotics have limited evidence for teratogenicity in pregnancy but may be a better treatment option. 5. Treatment should be individualized and the risk of recurrence weighed against the risks. 6. Most mood stabilizers are excreted in breast milk at a significant percentage of the mother’s serum concentration. Carbamazepine and divalproex are preferred mood stabilizers for breastfeeding women compared with lithium. G. An Approach to Treatment (Domain 1): A general approach is shown in Figure 8. This figure summarizes common recommendations from the guidelines referenced in the text that follows.

• • • •

Mania

Lithium VPA SGA Combination if severe presentation • D/C antidepressant

Mixed

• SGA (aripiprazole, asenapine, cariprazine, olanzapine, quetiapine) • VPA

• • • • • •

Depression

Quetiapine Lurasidone Olanzapine/fluoxetine Cariprazine Lithium Lamotriginea

Figure 8. Approach to bipolar disorder.

Lamotrigine takes several weeks to reach an effective dose, which decreases usefulness for acute depression.

a

D/C = discontinue; VPA = valproic acid.

H. Treatment Guidelines (Domain 1) 1. American Psychiatric Association: www.psychiatryonline.org/guidelines.aspx 2. British Association for Psychopharmacology: https://www.bap.org.uk/pdfs/BAP_Guidelines-Bipolar.pdf 3. Psychopharmacology Algorithm Project, Harvard Medical School: www.psychopharm.mobi/ 4. Canadian Network for Mood and Anxiety Treatments (CANMAT): www.canmat.org

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Psychiatric Disorders

5. National Institute for Health and Care Excellence (NICE): www.nice.org.uk 6. World Federation of Societies of Biological Psychiatry (WFSBP): https://www.wfsbp.org/educationalactivities/wfsbp-treatment-guidelines-and-consensus-papers/ I. Patient Resources (Domain 1) 1. Depression and Bipolar Support Alliance: www.dbsalliance.org 2. National Alliance on Mental Illness: www.nami.org 3. Mental Health America: www.mentalhealthamerica.net/

VI.  SCHIZOPHRENIA A. Introduction (Domain 1) 1. Antipsychotic medications remain the treatment mainstay, though they are not a cure. 2. Other psychotic disorders include schizophreniform disorder, schizoaffective disorder, and other schizophrenia spectrum and psychotic disorders. Psychotic symptoms can also be present in major depression, BD, Parkinson disease, and dementia. B. Antipsychotic polytherapy, though clinically common, has not routinely resulted in added benefit; also increases the risk of serious adverse effects 1. Clinical Presentation, Signs and Symptoms (Domains 1, 2) 2. The features of schizophrenia can be divided into five main areas. a. Hallucinations – Can be visual, auditory, sensory, or olfactory b. Delusions – Fixed false beliefs that are outside the societal norm c. Disorganized speech d. Disorganized or abnormal motor behavior e. Negative symptoms: Blunted affect, poverty of speech, alogia, avolition, anhedonia, and psychomotor retardation 3. Clinical course a. Schizophrenia is an episodic, chronic illness whose onset can be abrupt or insidious. b. Many patients have a prodromal phase characterized by negative or cognitive symptoms. c. Most patients have relapses over time; antipsychotic drug therapy lengthens time to relapse and reduces relapse severity. C. Treatment Goals and Expectations (Domain 1) 1. Treatment goal is remission to baseline level of functioning. This may not be possible with some patients. 2. In reality, antipsychotic medications treat the positive symptoms of the illness but are often not fully effective for negative or cognitive symptoms. 3. The degree of residual symptoms can predict a higher number and severity of future episodes, with baseline functional level worsening after each episode. 4. Full engagement of the patient in treatment improves medication adherence. 5. Encouraging family and social support is important. 6. Rating scales can be used to monitor symptoms. a. The Positive and Negative Syndrome Scale (PANSS) is the gold standard rating scale used in clinical trials to assess patient response to treatment. PANSS is a 30-item scale with each item rated on a scale from 1 (not present) to 7 (extremely severe), for a possible score of 210 (indicating extremely severe disease). ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 779

Psychiatric Disorders

b. The Brief Psychiatric Rating Scale (BPRS) is a rater-administered, 18-item scale derived from the PANSS, with subscales in thinking disturbance, anxiousness and depression, hostility and suspiciousness, withdrawal, and activation. The BPRS is also used in clinical trials. c. The Abnormal Involuntary Movement Scale (AIMS) is rater administered and commonly used to assess for tardive dyskinesia (TD). Periodic use of the AIMS is recommended for all patients receiving longterm antipsychotics. Many training programs are available. d. The Extrapyramidal Symptom Rating Scale (ESRS) is a comprehensive scale for assessing drug-induced effects, including akathisia, pseudoparkinsonism, dystonias, and dyskinesias. The ESRS is also rater administered. 7. Other psychotic disorders: a. Brief psychotic disorder is the presence of psychotic symptoms lasting less than 1 month. b. Schizophreniform disorder uses the same diagnostic criteria as schizophrenia, but the period from illness onset is less than 6 months. After 6 months, patient diagnosis should be revised to schizophrenia if symptoms continue. c. Schizoaffective disorder is thought to be a combination of schizophrenia and mood disorder symptoms occurring at the same time. An episode of psychosis must occur in the absence of mood symptoms to meet diagnostic criteria for schizoaffective disorder. Can be very difficult to differentiate schizoaffective disorder from BD or depression with psychotic features d. Substance-induced psychotic disorder is psychosis that occurs solely during periods of substance use. No psychotic symptoms are present during periods of nonuse. D. Treatment of First-Episode Schizophrenia (Domain 1) 1. Recognition of schizophrenia early in the disease course, either during the prodromal period or during the first episode of psychosis, confers a better functional outcome. 2. The doses of antipsychotic medications needed for first-episode schizophrenia are often lower than those for chronic schizophrenia. Adherence to antipsychotic drugs can be improved through education about the medications, adverse effects, and expected outcomes. Several long-acting injectable antipsychotics (LAIAs) are now available. Some manufacturers offer outpatient assistance to reduce costs. Many pharmacists are now administering LAIAs in community pharmacy settings. E. Nonpharmacologic Treatment of Schizophrenia (Domain 1) 1. Cognitive remediation is a program using goal-directed activities to improve and maintain cognitive functioning. These programs often include software that the patient can use independently. 2. Psychosocial therapy, including group therapy, can help people with schizophrenia develop and maintain social skills and gain an understanding of their illness.

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Psychiatric Disorders

F. Pharmacologic Treatment of Schizophrenia (Domain 1) 1. Typical (conventional antipsychotics, FGAs)

Orthostasis

CYP Isoenzyme Substrate (major)

Perphenazine

EPS

Trilafon

Fluphenazine

ACH Effects

Haloperidol

Prolixin

Sedation

Haldol

Usual Dose Range, mg/day

Chlorpromazine

Chlorpromazine Equivalents, mg

Thorazine

Generic Name

Brand Name

Table 25. Typical (Conventional) Antipsychotic Agents

100

200–800

High

High

Low

High

2D6

2

1–40

Low

2

8

5–20

Low

V low

8–32

Low-Mod

Low

2–20

Low

Low

6–30

Mod-High

10

20–100

Mod

Adasuve

Loxapine

2–10

1A2

High

4

2

Low

Low

Thiothixene Pimozide

2D6

High

Navane Orap

Low

Low

300–800

a

High

High

100 5

2D6, 3A4

High

Thioridazine

Trifluoperazine

V low

V high

Mellaril

Stelazine

V high

Low

Low

Low

High

Low

High

Mod

Mod

Low

V low Mod

2D6

2D6 1A2 3A4

Unknown

a

Pimozide is indicated only for the treatment of tics associated with Tourette disorder not effectively treated with other agents. Pimozide is rarely used for other indications.

ACH = anticholinergic; EPS = extrapyramidal symptoms; Mod = moderate; V high = very high.

Information from: Saklad SR. Antipsychotic adverse effects comparison. Presented at: CPNP 2021 Annual Meeting; April 16-23, 2021; Virtual. Available at https://cpnp. org/ed/meeting/2021/session/schizophrenia.

a. All typical antipsychotics are equally effective in treating positive symptoms in schizophrenia. The choice of drug is based on adverse effect profile, patient tolerability, and history of adverse effects (especially EPS). See Table 25 for further information. b. Although QTc prolongation is a known effect of antipsychotics, thioridazine, pimozide, and haloperidol (intravenously) may have greater risk. The recently published APA resource document on QTc prolongation and psychotropic medications provides a summary on considerations for the clinician in the decision-making process (Am J Psychiatry 2020;177:273-4). c. Boxed warnings for conventional antipsychotics i. Older adults with dementia-related psychosis treated with antipsychotics are at a higher risk of death than placebo groups. This warning also exists for atypical antipsychotics. ii. All antipsychotics carry a risk of cardiovascular adverse effects, including arrhythmia. Use with caution in patients with a cardiac risk history; avoid the use of thioridazine if patient has a history of arrhythmia. 2. Atypical (second-generation) antipsychotics: The term atypical as it pertains to these drugs comes from the added effects on serotonergic neurotransmission. See Tables 26 and 27 for additional information.

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Psychiatric Disorders

Brexpiprazole

1–4

Brand Name Vraylar

Clozaril Fanapt

Caplyta Latuda

Zyprexa Invega

Seroquel

Risperdal Geodon

Asenapine

Cariprazine Clozapine

Lumateperone

Low

Low

Mod

2D6, 3A4

V low

Mod

2D6, 3A4

High

High

1A2

V low

Low

10–20

Mod

V low

1.5–6

Low-Mod

V low

6–12

Mod

V low

Mod

V low

300–900

Iloperidone

CYP Isoenzyme Substrate (major)

Rexulti

Saphris

Orthostasis

10–30

ACH Effects

Aripiprazole

Sedation

Abilify

Generic Name

Usual Maintenance Dose Range, mg/ day

Table 26. Atypical Antipsychotic Agents

Low

High

Low

Low

High

42

High

5–30

High

Quetiapine

150–800

High

Mod

Mod

Ziprasidone

80–160

Mod

Low-Mod

Low

Lurasidone

40–160

Paliperidone

3–12

Olanzapine

Risperidone

2–6

Low

Mod

Mod Low

Low

1A2 3A4

2D6, 3A4 3A4

Low

3A4

Low

1A2

Mod

Renal

Mod

2D6

3A4

Aldehyde oxidase

Information from: Saklad SR. Antipsychotic adverse effects comparison. Presented at: CPNP 2021 Annual Meeting; April 16-23, 2021; Virtual. Available at https://cpnp. org/ed/meeting/2021/session/schizophrenia.

Table 27. Atypical Antipsychotic Caveats

Aripiprazole (Abilify, Abilify Maintena, Abilify MyCite, Aristada [generic is aripiprazole lauroxil])

• • • • •

Asenapine (Saphris, Secuado)

• Sublingual tablet (black cherry flavor) and topical patch only • Nothing by mouth, including smoking, for 10 min after sublingual administration

Brexpiprazole (Rexulti)

Cariprazine (Vraylar)

Partial dopamine receptor agonist, though this is lost at doses > 45 mg/day Lower rates of EPS, orthostasis, sedation, or anticholinergic effects Higher rates of akathisia and risk of compulsive behavior Does not increase prolactin concentrations Abilify MyCite available, which is a tablet within a digital ingestion tracking system • Long-acting injectable formulation available

• Dose reductions for severe hepatic or renal insufficiency • Partial dopamine agonist • Dose-related akathisia should be monitored for, together with compulsive behaviors • • • •

Binding profile similar to brexpiprazole Long-half life Reduce dose with strong CYP3A4 inhibitors Monitor compulsive behaviors

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Psychiatric Disorders

Table 27. Atypical Antipsychotic Caveats (continued)

Clozapine (Clozaril, Versacloz, FazaClo)

Iloperidone (Fanapt, Fanapt Titration Pack) Lumateperone (Caplyta) Lurasidone (Latuda)

Olanzapine (Zyprexa, Zyprexa Relprevv, Zyprexa Zydis) Olanzapine/samidorphan (Lybalvi) Paliperidone (Invega, Invega Sustenna, Invega Trinza) Quetiapine (Seroquel, Seroquel XR) Risperidone (Risperdal, Risperdal Consta, Perseris, Risperdal M-TAB) Ziprasidone (Geodon)

• Although antipsychotics are thought to have similar efficacy, exception is clozapine, which has shown increased efficacy • REMS program requires ANC monitoring • Highest metabolic burden. Also associated with myocarditis • Dose titration required • Smoking tobacco can decrease clozapine concentrations through CYP1A2. Caffeine can increase concentrations • Orthostasis common and requires slow dose titration • Dose adjustments provided for CYP2D6 poor metabolizers • Administer with food • Drowsiness is the most common adverse reaction • Initial and maintenance dosing are the same • • • •

Lower risk of metabolic effects, orthostasis, and QTc prolongation Akathisia more common CYP3A4 substrate Give with 350 kcal

• • • •

FDA approved in June 2021 for type I BD and schizophrenia Samidorphan component is to counteract weight gain associated with olanzapine Contraindicated in patients taking opioids (samidorphan is an opioid antagonist) Efficacy similar to olanzapine monoproduct

• • • •

Lower rates of sedation with XR Higher rates of metabolic effects Lower rates of EPS May need higher doses if taken with a strong CYP3A4 inducer

• • • •

Also available as short-acting injectable (max 40 mg/24 hr) Of the atypical antipsychotics, highest risk of QTc prolongation Low risk of EPS, weight gain, and metabolic effect Dosed BID and should be taken with 500 kcal

• Sedation and weight gain significant • Additional formulations to tablets include short-acting intramuscular injection, long-acting injection, and PO-ODT

• Metabolite of risperidone • Educate on presence of ghost tablet in stool • Long-acting injectables available

• Available as long-acting injectable, solution, tablet, and PO-ODT • Greater risk of EPS and hyperprolactinemia • 2D6 substrate

ANC = absolute neutrophil count; REMS = Risk Evaluation and Mitigation Strategies.

G. Clozapine Monitoring Guidelines (Domains 1, 2): Clozapine is associated with a risk of neutropenia. The risk is greatest during the first 18 weeks of therapy. The Clozapine REMS requires patient, prescriber, and pharmacy enrollment. Information can be obtained and enrollment completed at www.clozapinerems.com. Only the absolute neutrophil count (ANC) is reported. For clozapine therapy, ANC is calculated as white blood cells × % neutrophils, depending on the differential. Patients with benign ethnic neutropenia have different ANC monitoring values. Monitoring for ANC during initiation and maintenance of clozapine therapy is described in Table 28.

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Psychiatric Disorders

Table 28. Clozapine Monitoring According to the 2015 REMS Guideline (see www.clozapinerems.com) Measured ANC

Treatment

Monitoring

New patient enrollment: ANC ≥ 1500/mm3 Patients with BEN: ANC ≥ 1000 cells/mm3 in ≥ 2 measurements before starting therapy

Treatment can be initiated after enrollment in the registry If treatment is interrupted for < 30 days, monitoring can be continued as before; if > 1 mo, monitor as if newly enrolled

Monitor ANC weekly and report for the first 6 mo of treatment After 6 mo, frequency of monitoring can be reduced to every 2 wk After 1 yr of therapy, frequency can be reduced to monthly

ANC values of 500– 999 cells/mm3 are considered moderate neutropenia

For the general population, a hematology consult should be considered; treatment should be discontinued if the neutropenia is thought to be caused by clozapine; treatment can be reinitiated when ANC ≥ 1000 cells/mm3 For patients with BEN, a hematology consult should be considered; treatment can be continued

For the general population, ANC is monitored daily until ≥ 1000 cells/mm3 and then three times weekly until ANC ≥ 1500 cells/mm3; after that, ANC should be monitored weekly for 4 more weeks; then patient can resume the last normal monitoring interval For patients with BEN, ANC is monitored three times weekly until ANC ≥ 1000 cells/mm3 or to the patient’s known baseline value; after that, ANC is monitored weekly for 4 wk; then patient can resume the last normal monitoring interval

ANC values of 1000–1499 cells/mm3 are considered mild neutropenia

ANC values of < 500 cells/mm3 are considered severe neutropenia

For the general population, treatment can be continued, but ANC monitoring changes For patients with BEN, this ANC range is normal, and treatment can be continued; values in this range should be confirmed with ≥ 2 baseline measurements; if treatment is interrupted for < 30 days, continue to monitor as before; if ≥ 30 days, monitor as if a new patient

For the general population, ANC monitoring should be done three times weekly until ANC ≥ 1500 cells/mm3, at which time resume the patient’s last monitoring interval For patients with BEN, ANC should be monitored weekly for 6 mo, then every 2 wk until 12 mo, and then monthly thereafter

For the general population and patients For the general population, monitor ANC daily with BEN, consider a hematology until ≥ 1000 cells/mm3; then monitor three consult; interrupt treatment if the times weekly until ≥ 1500 cells/mm3; if patient neutropenia is thought to be caused by is given clozapine again, start treatment as if clozapine; patients should not receive newly initiated as described earlier when ANC a rechallenge unless benefits are ≥ 1500 cells/mm3 thought to outweigh risks For patients with BEN, monitor ANC daily until ≥ 500 cells/mm3; then monitor three times weekly until ANC reaches the patient’s prior baseline value; if patient is given clozapine again, start treatment as if newly initiated as described earlier when ANC ≥ 1000 cells/mm3 or at the patient’s baseline value

BEN = benign ethnic neutropenia.

If clozapine is discontinued because of neutropenia, patients should be monitored as follows. Moderate neutropenia (500–999 cells/mm3). General population: monitor ANC daily until ≥ 1000 cells/mm3; then three times weekly until ≥ 1500 cells/mm3. Severe neutropenia (≥ 500 cells/mm3). General population: monitor ANC daily until ≥ 1000 cells/mm3; then three times weekly until ≥ 1500 cells/mm3. Patients with BEN: Monitor ANC daily until ≥ 500 cells/mm3; then three times weekly until ANC reaches the patient’s established baseline value.

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H. Adverse Effect Management 1. Extrapyramidal symptoms (Domain 1) a. Acute dystonic reactions usually involve the muscles of the neck and face, though the back, legs, and arms can also be affected. i. Dystonic reactions occur most often during initiation of an antipsychotic drug or after a dose increase. ii. Treat dystonic reactions with an intramuscular or intravenous anticholinergic drug such as benztropine or diphenhydramine. b. Pseudoparkinsonism usually appears within the first 3 months of treatment. Symptoms include cogwheel rigidity, tremor at rest, reduced arm movement, akinesia, masked face, and shuffling walk. i. Oral anticholinergic medications can be used to treat pseudoparkinsonism, including benztropine, diphenhydramine, and trihexyphenidyl. Routine oral dosing twice daily is generally effective. These drugs can worsen cognition and dementia and must be used with caution in older adults. ii. Monitor closely for effectiveness of treatment and for decreased cognition. c. Akathisia is described as a feeling of inner restlessness or an inability to sit still. Akathisia is an underrecognized adverse effect and one that patients generally do not identify unless questioned specifically about these symptoms. Akathisia is associated with an increased risk of suicide. First-line treatment is low-dose propranolol, followed by lorazepam. d. Tardive dyskinesia (TD) is characterized by involuntary, repetitive movements, most often in the orofacial area though other muscle groups can be involved. i. Risk factors include older age, female sex, high-dose antipsychotic exposure, and long-term antipsychotic exposure. TD is potentially irreversible. The risk of TD is higher with typical antipsychotics. Rates of TD in patients treated with clozapine are similar to placebo. ii. Anticholinergic medications are not effective for TD and may worsen the symptoms. Treatment of choice is to withdraw the offending antipsychotic; if this is not possible, use the lowest effective dose and consider additional pharmacologic treatment. iii. Valbenazine (Ingrezza) is approved for the treatment of TD. The dose is 40 mg/day for 1 week, which is then increased to 80 mg/day. Deutetrabenazine (Austedo) is also approved for TD. Deutetrabenazine is initiated at 6 mg twice daily and then titrated over several weeks, as tolerated, to a maximum of 48 mg/day given twice daily. 2. Hyperprolactinemia (Domain 1) a. Antipsychotics such as haloperidol, fluphenazine, risperidone, and paliperidone are more likely to cause this. b. Symptoms include breast tenderness, galactorrhea, and altered menstrual cycles. Elevated prolactin values are common in asymptomatic patients. Only check a prolactin concentration in symptomatic patients. c. Adding aripiprazole to the regimen can reduce prolactin concentrations (Schizophr Res 2020;222:8896). However, to avoid dual antipsychotic therapy, this should not be done routinely unless changing to a less potent dopamine antagonist drug does not resolve the problem. 3. Sedation (Domain 1) a. Somnolence is a common adverse effect with antipsychotic agents, particularly with chlorpromazine, olanzapine, clozapine, and quetiapine. b. Tolerance to somnolence can occur over time with continued use of the agent. c. Somnolence itself should not be the sole reason to use a particular antipsychotic agent. Quetiapine use for insomnia should be discouraged. 4. Weight gain (Domain 1) a. Although weight gain is associated with many antipsychotic agents, clozapine, olanzapine, quetiapine, risperidone, and chlorpromazine are more likely to cause weight gain. b. Nutrition and exercise counseling should begin with initiation of the agent, if possible.

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Psychiatric Disorders

5. Metabolic adverse effects (Domains 1, 2) a. Both typical and atypical antipsychotics have been associated with an increased risk of developing metabolic syndrome. b. People with serious mental illness are at risk of acquiring this condition without the use of drug therapy. c. The American Diabetes Association and the American Psychiatric Association published a consensus conference statement in February 2004 to provide guidance for monitoring (see Table 29). Table 29. Suggested Metabolic Monitoring Recommendationsa Personal or family history Weight (BMI)

Baseline

4 Wk

8 Wk

12 Wk

x

x

x

x

x

Waist circumference

x

Fasting plasma glucose

x

Blood pressure

Fasting lipid profile

x

x

x

x

x

Quarterly Annually x

x

Every 5 Yr

x x x

x

Some clinicians and health care systems also suggest that hemoglobin A1C be monitored.

a

BMI = body mass index.

d. Of the atypical antipsychotics, clozapine and olanzapine carry the greatest risk, followed by quetiapine, risperidone, paliperidone, and then iloperidone, asenapine, brexpiprazole, and cariprazine. Lumateperone, lurasidone, and ziprasidone carry the lowest risk. e. If metabolic syndrome develops, consider changing to a lower-risk antipsychotic, especially if patients have gained more than 5% of their baseline weight during therapy. Consider risks of loss of symptom control versus metabolic effects. 6. QTc prolongation and cardiovascular effects (Domain 1) a. All antipsychotics have been associated with cardiovascular adverse effects. b. Thioridazine and haloperidol have boxed warnings regarding QTc prolongation, though torsades de pointes is rare. c. Most antipsychotics have warnings in their labeling about QTc prolongation. Some of the higher increases are for thioridazine (33–41 milliseconds), ziprasidone (16–21 milliseconds), haloperidol (7–15 milliseconds), quetiapine (14 milliseconds), clozapine (10 milliseconds), and iloperidone (9 milliseconds). Risk factors such as drug-drug interactions and underlying cardiovascular disease can influence whether these increases lead to arrhythmias. d. Monitor drug regimen, as well as medical history, for risk factors for QTc prolongation. e. Many antipsychotics can block α-adrenergic receptors, which can result in orthostatic hypotension. This is especially common in older adults. 7. Neuroleptic malignant syndrome (NMS) (Domain 1) a. NMS is a potentially life-threatening condition related to the blockade of dopamine receptors. b. Risk factors include higher doses of antipsychotic agents, rapid escalation of dose increases, and intramuscular injections. c. NMS symptoms include hyperthermia, altered mental status, muscular rigidity, and autonomic dysfunction. This can be difficult to distinguish from serotonin syndrome. Symptoms of serotonin syndrome such as hyperreflexia, myoclonus, and ataxia are uncommon in NMS and can assist in differentiation. d. Treatment includes immediate discontinuation of the offending agent and supportive care, generally in the hospital setting.

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Psychiatric Disorders

8. Boxed warnings for atypical antipsychotics (Domain 1) a. All antipsychotics – Older adults with dementia-related behavioral disorders treated with atypical antipsychotics are at greater risk of death than those taking a placebo. b. Clozapine – Significant risk of neutropenia, potentially life threatening (less than 1% worldwide) c. Clozapine – Seizures have been associated with clozapine use in a dose-dependent manner. Clinically, use the lowest dose that is effective for treatment; use with extreme caution in patients with seizure disorders or those at risk of seizures, including those with head trauma. d. Clozapine – Fatalities caused by myocarditis have been reported. The highest risk occurs in the first month of therapy. Cardiomyopathy or myocarditis should be suspected for patients who present with symptoms of heart failure, chest pain, ECG abnormalities, or unexplained fever. e. Clozapine – Can cause orthostatic hypotension (with or without syncope). Orthostasis risk can be minimized using a very slow dose titration and an initial dose of 12.5 mg once or twice daily. f. Aripiprazole, brexpiprazole, cariprazine, lurasidone, and quetiapine also have boxed warnings about suicidal ideation and behaviors in children, adolescents, and young adults. Monitor for suicidal ideation with all antipsychotics. 9. Antipsychotic polytherapy (Domains 1, 2) a. Polytherapy with two or more antipsychotic agents is clinically common but not supported by the clinical literature. b. According to most guidelines, rational polytherapy for antipsychotics should be reserved for patients with several failures of both FGA and SGAs and clozapine monotherapy. c. Polytherapy can result in the additive risk of adverse effects and medication nonadherence. 10. LAIAs (Domain 1) a. Nine LAIA formulations are available (see Table 30). b. Before administration, tolerability of the oral agent should be established. Table 30. LAIA Formulations LAIA Formulation

Initial Dose

PO Overlap

Maintenance Dose

Haloperidol decanoate (IM)

10–20 x PO dose (if > 100 mg given, 2 injections separated by 3–7 days)

Taper over 2–3 mo

10–15 x PO dose q4wk

Fluphenazine decanoate (IM)

6.25–25 mg every 2 wk

Decrease PO dose by 50% after first injection and D/C after second

Aripiprazole (IM)a (Abilify Maintena)

400 mg monthly

2 wk per package insert (3 wk clinically)

Titrate cautiously to 100 mg. Effects can last 4–6 wk, and frequency of administration can be increased

Aripiprazole lauroxil (IM) (Aristada)

1-day overlap: Give aripiprazole 30 mg PO + aripiprazole lauroxil (Aristada Initio) 675 mg IM + aripiprazole lauroxil (Aristada) within 10 days: 10 mg PO = 441 mg monthly; 15 mg PO = 662 mg monthly OR 882 mg q6wk OR 1064 mg q2mo; ≥ 20 mg PO = 882 mg monthly

3 wk if Aristada Initio not administered

400 mg monthly (can reduce to 300 mg for tolerability) Depends on response

21-day overlap: Give aripiprazole lauroxil dose according to conversion earlier + 3-wk PO overlap ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 787

Psychiatric Disorders

Table 30. LAIA Formulations (continued) LAIA Formulation

Initial Dose

PO Overlap

Maintenance Dose

Risperidone (IM) (Risperdal Consta)

25 mg q2wk

3 wk

25–50 mg q2wk

None

90 or 120 mg monthly

Paliperidone palmitate (IM) (Invega Sustenna)

3 mg PO = 90 mg 4 mg PO = 120 mg

234 mg on day 1; then 156 mg on day 8

None

Monthly injection. Adjust as needed

None

Administered every 3 mo. Adjust dose as needed

None

Administered every 6 mo at either 1092 mg or 1560 mg

None

If received 210 mg q2wk x 4 doses OR 405 mg q4wk x 2 doses, then 150 mg q2wk OR 300 mg q4wk

Risperidone (SC) (Perseris)

Paliperidone palmitate (IM) (Invega Trinza)

Paliperidone palmitate (Hafyera)

Olanzapine (IM)b (Relprevv)

3 mg PO = 39 or 78 mg 6 mg PO = 117 mg 9 mg PO = 156 mg 12 mg PO = 234 mg

Must be on Invega Sustenna for 4 mo. The following conversion can be used as a guide: 78 mg = 273 mg 117 mg = 410 mg 156 mg = 546 mg 234 mg = 819 mg

Must be on Invega Sustenna for 4 mo OR Trinza x 1 dose. The following conversion can be used: 156 mg monthly or 546 mg q3mo = 1092 mg q6mo 234 mg monthly or 819 mg q3mo = 1560 mg q6mo 10 mg PO = 210 mg q2wk x 4 doses OR 405 mg q4wk x 2 doses 15 mg PO = 300 mg q2wk x 4 doses 20 mg PO = 300 mg q2wk

If received 300 mg q2wk x 4 doses, then 210 mg q2wk or 405 mg q4wk If received 300 mg q2wk, continue 300 mg q2wk

Not recommended to use strong CYP3A4 inducers for more than 14 days.

a

Zyprexa Relprevv (olanzapine) requires a REMS because of postdose delirium/sedation syndrome. Patient must wait in the clinic for at least 3 hr after injection to monitor for this adverse effect.

b

LAIA = long-acting injectable antipsychotic; SC = subcutaneous(ly).

11. Schizophrenia guidelines and choice of therapy (Domain 1) a. Choice of drug therapy should be based on the adverse effect profile, personal and familial antipsychotic history, and patient preference. b. Most guidelines recommend an SGA over an FGA. Second-line options can be either a different SGA or an FGA. Consider clozapine after the failure of two antipsychotics. c. Psychosis can take 4–6 weeks to show a complete response. Early nonresponse has been associated with lack of response with continued use of the chosen agent.

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Psychiatric Disorders

12. Treatment of schizophrenia in pregnancy and lactation (Domain 1) a. In general, use of antipsychotics in pregnancy slightly increases the risk of major malformations, heart defects, preterm delivery, and decreased birth weight. b. Use of antipsychotics in the third trimester can lead to EPS and possible withdrawal symptoms in the newborn. 13. Substance use – Focus on tobacco (Domain 1) a. More than 75% of people with schizophrenia are estimated to use tobacco products. b. Clinicians often believe that tobacco use is “the least of the patient’s problems” and that working with patients to recover from tobacco dependence will not be successful. c. Assess tobacco and other substance use at each visit; tobacco cessation pharmacotherapy and/or substance use treatment should be offered, if appropriate. d. Varenicline can be used successfully in people with schizophrenia. Package label includes warnings related to behavioral changes, suicidal thinking, and psychosis. Current studies evaluating varenicline use in the serious mental illness population with stable symptoms have not shown an increase in neuropsychiatric adverse events. If varenicline is used in patients with psychiatric conditions, monitor for changes in mood. 14. Strategies to improve treatment adherence (Domain 1) a. Patient-centered care is imperative to treatment success. Patients should be involved in treatment planning as much as possible. b. Offer LAIAs as convenience therapy, if appropriate. c. Counseling and education regarding adverse effects and expectations of treatment can improve adherence. 15. Treatment guidelines (Domain 2) a. Psychopharmacology Algorithm Project, Harvard Medical School: www.psychopharm.mobi b. International Psychopharmacology Algorithm Project: www.ipap.org/algorithms.php c. National Institute for Health and Care Excellence (NICE) UK: https://www.nice.org.uk/guidance/CG82 d. American Psychiatric Association: www.psychiatryonline.org/guidelines.aspx e. PORT Schizophrenia Treatment Recommendations: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2800150/pdf/sbp130.pdf f. Canadian Guidelines for Schizophrenia. Can J Psychiatry 2017;62:604-16. 16. Patient resources (Domain 1) a. National Alliance on Mental Illness: www.nami.org b. Mental Health America: www.mentalhealthamerica.net/ c. Psych Central: https://psychcentral.com/schizophrenia/schizophrenia-overview

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Psychiatric Disorders

Patient Case Questions 5 and 6 pertain to the following case. D.B. is a 22-year-old white man who presents to the clinic 10 days after discharge from the hospital after a first-episode schizophrenia. He has no other chronic medical conditions and takes no routine medications except for risperidone. His dose was titrated over 2 weeks to 6 mg orally at bedtime for command hallucinations and persecutory delusions. He has a history of opioid use and does not use tobacco; he drinks alcohol only occasionally. He is a full-time college student studying computer science. His auditory hallucinations are well controlled, but he had feelings of inner restlessness that worsened when the risperidone dose was increased from 4 mg to 6 mg. 5. Which is the best initial treatment? A. B. C. D.

Change to olanzapine 10 mg orally at bedtime. Consider risperidone (Risperdal Consta) 50 mg intramuscularly every 2 weeks. Decrease risperidone to 4 mg orally at bedtime. Change to clozapine 25 mg orally at bedtime.

6. When D.B. returns to the clinic 2 weeks later, he continues to endorse feelings of inner restlessness. He cannot sit through his 2-hour lectures, and his friends have commented on how “antsy” he appears all the time. He is concerned about adverse effects, but he has been adherent. He is wary of changing medications because of complete resolution of his hallucinations. To address his concerns, which medication is most appropriate? A. B. C. D.

Diphenhydramine. Propranolol. Lorazepam. Benztropine.

VII.  ATTENTION-DEFICIT/HYPERACTIVITY DISORDER A. Introduction (Domain 1) 1. Stimulant medications have been used for decades to treat ADHD. 2. Alternative drug therapy includes atomoxetine, clonidine, and guanfacine. Bupropion and TCAs have been studied, though neither have as much clinical evidence. 3. Modified diets and dietary supplementation have not been shown effective in controlled trials. B. Clinical Presentation, Signs and Symptoms, and DSM-5 Criteria for ADHD (Domains 1, 2) 1. Symptoms may present in early childhood but are usually recognized when the child begins preschool or school. 2. Symptom onset, regardless of the age at diagnosis, must occur before age 12 years and be present in two or more settings for at least 6 months. 3. Children with ADHD must have at least six of the following signs of inattention (for patients older than 17 years at diagnosis, the requirement is five symptoms): a. Often fails to give close attention to details or makes careless mistakes b. Often has difficulty sustaining attention in tasks or play activities c. Often does not seem to listen when spoken directly to d. Often does not follow through on instructions e. Often has difficulty organizing tasks and activities

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Psychiatric Disorders

f. Often avoids, dislikes, or is reluctant to engage in activities requiring sustained mental effort g. Often loses things necessary for tasks or activities h. Is often easily distracted by external stimuli i. Is often forgetful in daily activities 4. Children with ADHD must have at least six of the following symptoms of hyperactivity or impulsivity (for patients older than 17 years at diagnosis, the requirement is five symptoms): a. Often fidgets with hands or feet or squirms in seat b. Often leaves seat in classroom c. Often runs about or climbs excessively when it is inappropriate to do so. Adolescents or adults may simply feel restless. d. Often has difficulty playing or engaging in leisure activities quietly e. Often is “on the go” or acts as if “driven by a motor” f. Often talks excessively g. Often blurts out answers before questions have been completed h. Often has difficulty awaiting his or her turn i. Often interrupts or intrudes on others 5. Three types of ADHD diagnoses: a. ADHD, combined presentation (meets criteria for inattention and hyperactivity or impulsivity) b. ADHD predominantly inattentive presentation c. ADHD predominantly hyperactive-impulsive presentation C. Therapy Goals and Expectations (Domain 1) 1. Treatment goal for ADHD is to reduce or eliminate symptoms such that the patient can engage and be functional in all environments. 2. Because ADHD is a chronic disorder, treatment should be considered across the life continuum. 3. Hyperactivity tends to dominate symptoms in childhood; these symptoms can diminish as the child ages into adulthood and inattentions predominates. 4. Reevaluate stimulant medication dosing periodically to ensure the lowest effective dose is used. 5. Stimulants can improve attention in any person who takes them, so improvement in attention with medication use is not diagnostic for ADHD. D. Rating Scales (Domains 1, 2) 1. Rating scales should be performed in all environmental settings, to include parents and teachers. 2. The most commonly used rating scale is the Conners Parent and Teacher Rating Scale. This is a 27- or 28item scale done by the parents and teacher. 3. The ADHD Rating Scale-IV is an 18-item scale that is rated by parents, teachers, and adolescent self-report. E. Nonpharmacologic Treatment (Domain 1) 1. Many behavioral approaches can be used with children with ADHD, including contingency/reinforcement plans (behavioral modification), classroom behavioral strategies, and patient/family education. 2. CBT has been shown beneficial in adults only, though the effect size is less than stimulant medication treatment. Evidence in children is insufficient. 3. EndeavorRx, a prescription-only game-based device, was approved in 2020 for patients 8–12 years of age with inattentive or combined-type ADHD.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 791

Psychiatric Disorders

F. Pharmacologic Treatment of ADHD (Domain 1) 1. Stimulant dosing recommendations and special considerations (Tables 31 and 32 contain formulation and dosing information). Table 31. Amphetamine-Based Stimulants: Drugs and Dosage Forms Generic Name

Methylphenidate

Brand Name

Ritalin

Methylin Metadate Concerta

Daytrana Aptensio

Adhansia

Contempla Relexxii

Quillivant

QuilliChew Dexmethylphenidate Dextroamphetamine

Jornay PM Focalin

Dexedrine Zenzedi

Mixed amphetamine salts (amphetamine/ dextroamphetamine)

ProCentra Adderall Mydayis

Lisdexamfetamine

Vyvanse

Amphetamine sulfate

Evekeo Dyanavel XR Adzenys

Methamphetamine

Desoxyn

Available Dosage Forms, mg

Tablet: 5, 10, 20; LA capsule: 10, 20, 30, 40 mg SR tablet: 20 mg Tablet: 5, 10, 20; ER tablet: 10, 20 mg Chewable tablet: 2.5, 5, 10 Solution: 5 mg/5 mL, 10 mg/5 mL CD capsule: 10, 20, 30, 40, 50, 60 mg ER tablet: 10, 20 mg ER tablet: 18, 27, 36, 54 mg

Transdermal patch: 10, 15, 20, 30 mg/9 hr XR capsule: 10, 15, 20, 30, 40, 50, 60 mg XR capsule: 25, 35, 45, 55, 70, 85 mg XR-ODT: 8.6, 17.3, 25.9 mg CR capsule: 72 mg

XR suspension: 25 mg/5 mL

ER chewable tablet: 20, 30, 40 mg

Delayed/ER capsule: 20, 40, 60, 80, 100 mg

Tablet: 2.5, 5, 10; XR capsule: 5, 10, 15, 20, 25, 30, 35, 40 mg ER capsule: 5, 10, 15 mg Tablet: 5, 10 mg

Tablet: 2.5, 5, 7.5, 10, 15, 20, 30 mg Solution: 5 mg/5 mL

Tablet: 5, 7.5, 10, 12.5, 15, 20, 30 mg XR capsule: 5, 10, 15, 20, 25, 30 mg ER capsule: 12.5, 25, 37.5, 50 mg

Chewable tablet: 10, 20, 30, 40, 50, 60 mg Capsule: 10, 20, 30, 40, 50, 60, 70 mg Tablet: 5, 10 mg ODT-IR tablets 5, 10, 15, 20 mg ER PO suspension 2.5 mg/mL

ER PO suspension 1.25 mg/mL ODT-ER tablets 3.1, 6.3, 9.4, 12.5, 15.7, 18.8 mg Tablet: 5 mg

CD = controlled delivery; ER = extended release; LA = long-acting; ODT = orally disintegrating tablet.

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Psychiatric Disorders

Table 32. Stimulant Dosing Recommendations Stimulant Medication

Methylphenidate: IR FDA indicated for those ≥ 6 yr IR (Ritalin, Methylin)

Methylphenidate: ER (Metadate)

Methylphenidate: LA: Ritalin LA, 50% IR beads, 50% ER beads

Methylphenidate: ER: Concerta, ER inner tablet coated with IR methylphenidate

Methylphenidate: LA, Daytrana, transdermal patch

Duration of Effect, hr

Initial Dose, Usual Range, Max Dose

Special Considerations

3–6

5 mg BID; increase by 5–10 mg/day at weekly intervals; max dose 60 mg/day

Fast acting, short duration

3–8

Metadate CD: 20 mg/day; increase by 10–20 mg/day weekly; max dose 60 mg/day Metadate ER: See IR dosing earlier

Can be dosed once or twice daily. Metadate CD is ~30% IR beads and ~70% ER beads. CD capsule contents can be sprinkled on applesauce. ER must be swallowed whole

8

10-20 mg in the morning; range 20–60 Can use once-daily dosing. mg/day; max dose 60 mg/day LA capsule contents can be sprinkled on applesauce

10–12

18 mg in the morning; range 27–72 mg/day; max dose 72 mg/day

12 (when worn for 9 hr)

10 mg applied to hip each morning; remove after 9 hr; dose range 10–30 mg

90% bioavailability of IR coating; must counsel about caplet “ghost” found in stool; cannot crush Risk of rash at site of patch placement (rotate placement). Symptoms can rebound in evening as plasma concentrations decrease

Methylphenidate: ER (Ritalin SR, Aptensio XR)

8

SR/Aptensio XR: 10 mg PO daily; increase by 10 mg/day weekly to max 60 mg/day

Methylphenidate: ER (Contempla XR-ODT, Quillivant XR, QuilliChew ER)

12

MPH: ER (Jornay PM)

Peaks at 14 hr; then decrease for remainder of day

Grape flavored ODT: 17.3 mg PO in the morning; increase by 8.6–17.3 mg/day weekly to max 51.8 mg/day XR/ER: 20 mg PO in the morning; increase by 10–20 mg/day weekly to max 60 mg

Methylphenidate: CR (Relexxii)

12

20 mg PO at around 8 p.m.; increased by 20 mg/day weekly to max 100 mg/ day Can be initiated in patients taking previous methylphenidate dose of 20 mg PO BID or TID

Aptensio can last up to 12 hr, and its capsule contents can be sprinkled on applesauce

Designed for administration in the evening and then lasting throughout the next day Administered once daily. Must be swallowed whole

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Psychiatric Disorders

Table 32. Stimulant Dosing Recommendations (continued) Stimulant Medication

Methylphenidate: ER (Adhansia XR)

Dexmethylphenidate: FDA indicated for those ≥ 6 yr IR

Duration of Effect, hr 13–16

Initial Dose, Usual Range, Max Dose

25 mg PO in the morning; increase by 10–15 mg/day every ≥ 5 days to a max 100 mg/day

Special Considerations

Doses > 85 mg were associated with increased adverse effects in adults; similar response with > 70 mg in children

3–5

2.5 mg in the morning or BID; dose range 5–10 mg/day BID, max daily dose 20 mg

No greater effectiveness than methylphenidate

Dexmethylphenidate: LA; Focalin XR, 50% IR beads, 50% ER beads

8–12

5 mg in the morning; range 5–10 mg/ day; max dose 30 mg/day

Mixed amphetamine salts; Adderall, FDA indicated for those ≥ 3 yr IR

4–6

2.5–5 mg in the morning or BID, usually BID; range 10–40 mg/day; max dose 40 mg/day

Once-daily dosing. XR capsule contents can be sprinkled on applesauce

Mixed amphetamine salts: ER FDA indicated for those ≥ 6 yr Adderall XR: 50% IR beads, 50% ER beads

9

5–10 mg in the morning; range 10–30 mg/day; max dose 30 mg/day

Can be opened and sprinkled on applesauce

Mixed amphetamine salts: ER (Mydayis)

Up to 16 hr

12.5 mg PO in the morning; increased by 12.5 mg/day weekly up to 25 mg/ day

Can sprinkle capsule contents on applesauce

Dextroamphetamine: IR (Zenzedi, ProCentra, Dexedrine) FDA indicated for those ≥ 3 yr IR

Dextroamphetamine: ER (Dexedrine Spansule, Dexedrine SR)

3–5

6–9

2.5–5 mg in the morning; range 10–40 Higher abuse potential mg/day BID than spansule or lisdexamfetamine

5–10 mg in the morning or BID; range Once-daily dosing possible 5–30 mg/day or 5–15 mg BID; max dose 40 mg/day

Lisdexamfetamine: (Vyvanse) FDA indicated for those ≥ 6 yr

10–12

30 mg in the morning; increase by 10–20 mg/day weekly up to max dose 70 mg/day

Methamphetamine (Desoxyn) FDA indicated for those ≥ 6 yr

3–5

Initiate 5 mg once or twice daily; can increase to a total of 20–25 mg/day in two doses; avoid evening dosing

Prodrug of dextroamphetamine; theoretically reduces abuse potential. Chewable is strawberry flavored Rarely used

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Psychiatric Disorders

Table 32. Stimulant Dosing Recommendations (continued) Stimulant Medication

Amphetamine ER: (Dyanavel XR, Adzenys XR-ODT, Adzenys ER)

Amphetamine (Evekeo, Evekeo ODT)

Duration of Effect, hr

Dyanavel: 13 Adzenys: 10–12

Evekeo: 4-6

Initial Dose, Usual Range, Max Dose

Dyanavel: 2.5 mg PO in the morning; increase by 2.5–10 mg/day every 4–7 days up to 20 mg/day Adzenys ODT/ER: 6.3 mg PO in the morning; increase by 3.1–6.3 mg/ day up to 18.8 mg/day (12.5 mg/day for those ≥ 13 yr for ER suspension)

Special Considerations

Dyanavel is bubble gum flavored. Shake bottle before use. Adzenys ODT is orange flavored

Evekeo: 3-5 yr old: Initiate 2.5 mg Do not chew or crush ODT daily in the morning; can increase tablet. weekly by 2.5 mg/day to response; can give doses BID ≥ 6 yr: Initiate 5 mg once or twice daily; can increase weekly by 5 mg/ day; doses should not exceed 40 mg/ day Evekeo ODT: 6-17 yr old: Initiate 5 mg once or twice daily; can increase weekly by 5 mg/day; doses should not exceed 40 mg/day

2. Principles of stimulant medication therapy a. First-line treatment of ADHD: The American Academy of Pediatrics recommends methylphenidate or amphetamine products as first line for those age 6–18. In children age 4–5, behavioral therapy alone is recommended first line (methylphenidate second line for this age group). If both stimulant derivatives are tried and have failed, second-line options are atomoxetine, guanfacine ER, or clonidine ER (see text that follows). b. Start with a low morning dose and evaluate the response. Response to dose occurs within the first 1–2 days of administration. Increase dose on a weekly basis relative to response. c. If there is no response to the first agent, change to another (i.e., methylphenidate to mixed amphetamine salts or dextroamphetamine); 75% of patients will respond. d. If using IR and ER dosage forms together, use the same chemical (i.e., use methylphenidate, not methylphenidate plus mixed amphetamine salts). e. Combination therapy with atomoxetine has been studied, but combination does not consistently improve response and can increase adverse effects. f. Common adverse effects include decreased appetite, insomnia, anxiety, stomach upset, irritability, increased heart rate and blood pressure, and growth suppression. Table 33 outlines management strategies. g. Rare adverse effects include arrhythmias, psychotic symptoms, priapism, and Raynaud-like syndrome. Stimulants can also precipitate mania if used in patients with BD. h. Growth suppression is possible; evidence suggests about 2 cm loss in height and 2.7 kg loss in weight per 3 years, but the child will catch up over time. Closely monitor growth. i. Monitor for substance use as well; question the child about his or her doses and the way in which he or she takes them. Unfortunately, diversion of stimulants by parents and caregivers is possible. Many believe that illicit drug use reflects an impulse control problem and will treat ADHD symptoms with a stimulant if patient is not actively using other substances. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 795

Psychiatric Disorders

j.

Stimulants can worsen preexisting tic disorders or promote the emergence of tics. In comorbid Tourette disorder, stimulants can be used with close monitoring for worsening of symptoms. k. Periodic evaluation of the drug and dose for each patient is necessary. The decision about trying a drug holiday should consider the severity of symptoms and the impact on psychosocial functioning. l. Drug interactions include additive stimulant adverse effects when used in combination with other stimulants. MAOIs should not be given with stimulants, and a washout period of 14 days is necessary before using MAOIs. Methylphenidate can increase serum concentrations of TCAs. Using methylphenidate in combination with clonidine can increase cardiovascular effects. m. Boxed warnings for stimulant medications i. Potential for drug dependency exists. Avoid abrupt discontinuation in patients. ii. Use has been associated with serious cardiovascular events, including sudden death in patients with preexisting structural cardiac abnormalities or other serious heart problems. Assess the patient for a personal or family history of cardiac disease. Any patient thought to be at risk should be referred for a cardiovascular workup before the stimulant is initiated. Table 33. Stimulant Adverse Effects and Management Adverse Effect

Management

GI upset

Give with or after food; consider lower dose

Insomnia

Give as early as possible; D/C afternoon or evening dose; consider melatonin at bedtime

Dysphoria

Reduce dose; consider alternative stimulant

Anorexia (lack of appetite High-calorie meal when stimulant effects are low; consider cyproheptadine at bedtime or desire for food) Growth delay, reduced growth velocity Irritability

Consider drug holiday

Trial dose reduction

“Zombie” state ↑ BP, HR Tics

Hallucinations

Reduce dose; consider alternative stimulant Monitor

Reduce dose, consider alternative stimulant D/C stimulant

BP = blood pressure; HR = heart rate.

3. Atomoxetine a. May not be as effective as stimulant medications and is generally a second-line therapy after stimulant treatment fails. b. Onset of effect can be up to 4 weeks. Parents and patients must be counseled about this if they have experience with stimulant medications. c. Dosage adjustments must be made if used with a strong CYP2D6 inhibitor. d. Adverse effects are dose related and include stomach upset, insomnia, and dizziness. These can be minimized by giving the dose with food or dividing dosing twice daily. e. Atomoxetine carries a warning for hepatotoxicity. Perform liver function tests at baseline and periodically. f. A boxed warning is also included for increased suicidal thinking in pediatric patients taking atomoxetine. 4. Clonidine and guanfacine a. These agents may be more effective for impulsivity and hyperactivity than for attentional deficits. Because of this, they are generally not used as monotherapy. b. Only the ER formulations are approved, though the IR formulation is used off-label.

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Psychiatric Disorders

c. Adverse effects include sedation, dizziness, and hypotension. A slow-dose titration should minimize these effects. d. Use with caution with other CNS depressants or with drugs having hypotensive effects. e. Clonidine and guanfacine may be particularly useful for patients who have insomnia secondary to stimulant medications or for those with comorbid tic disorders (see Table 34). 5. Viloxazine a. Approved for use in those younger than 18 years b. Adverse effects include increases in diastolic blood pressure, increased heart rate, drowsiness, headache, and GI upset. c. Strong CYP1A2 inhibitor Table 34. Non-stimulant Formulations and Dosing Non-Stimulants Brand Name Atomoxetine

Strattera

Formulations

Guanfacine ER

Intuniv

Guanfacine

Tenex

1-, 2-, 3-, 4-mg tablets

Clonidine

Catapres Catapres TTS

Clonidine ER

Kapvay

Viloxazine ER

Qelbree

10-, 18-, 25-, 40-, 60-, 80-, 100-mg capsules

Initial Daily Dosing

Weekly Titration

Max Dose

1 mg q AM

1 mg

6–12: 4 mg; 13–17: 7 mg

≤ 70 kg: 0.5 mg/ ≤ 70 kg: Increase to ~1.2 kg/day; > 70 kg: mg/kg/day after 3 days; 40 mg > 70 kg: Increase to 80 mg after 3 days

1-, 2-mg tablets 0.5 mg once daily or twice daily

Increase as tolerated to 1–4 mg/day

0.1-, 0.2-, 0.3mg tablets 0.1-, 0.2-, 0.3mg/day patches

Tablets: ≤ 45 kg: 0.05 mg HS; > 45 kg: 0.1 mg HS

0.1-, 0.2-mg tablets

0.1 mg HS

0.1 mg/day (in one or two divided doses)

100-, 150-, 200-mg capsules

6-11 yr old: Initiate 100 mg once daily 12-17 yr old: Initiate 200 mg once daily

Tablets: ≤ 45 kg: 0.05 mg/day q3–7 days (in one to four divided doses); > 45 kg: 0.1 mg/ day q3–7 days (in one to four divided doses)

≤ 70 kg: 1.4 mg/kg/ day, NTE 100 mg; > 70 kg: 100 mg

6–12: 4 mg

Tablets: ≤ 45 kg: Weight based; > 45 kg: 0.4 mg

0.4 mg

6-11 yr old: Can increase 400 mg by 100 mg weekly up to max dose of 400 mg/day 12-17 yr old: Can increase to 400 mg/day after one week

AM = morning; HS = at bedtime; NTE = not to exceed; q = every.

6. Bupropion a. Use for ADHD is off-label. A 2017 Cochrane review examined six studies (n=438) and concluded possible benefit with low-quality evidence (Cochrane Database Syst Rev 2017;10:CD009504). Bupropion has been used in both children and adults. b. An example dosing strategy in adults is bupropion SR: Start at 100 mg daily and then titrate to twicedaily dosing over 4 weeks to 200 mg twice daily. Few clinical trials in children. However, doses of 3–6 mg/kg/day have been used (see BMJ Clin Evid 2011. pii:0312; and J ADHD Relat Disord 2010;1:25-35). c. Up to 6 weeks may be needed to see the effect. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 797

Psychiatric Disorders

7. TCAs a. Have been studied for ADHD, with studies suggesting efficacy b. TCAs most commonly used: Imipramine, desipramine, and nortriptyline c. Onset of effect for ADHD may be 6 weeks; the most common use clinically is for sedation to treat insomnia secondary to stimulant medications. d. TCAs may be most useful in children with comorbid conditions, including anxiety, depression, enuresis, and tic disorders. e. Because of the risk of sudden cardiac death in children taking TCAs, evaluate for cardiac risk factors and use the lowest effective dose, especially if a TCA is used in combination with a stimulant. 8. Atypical antipsychotics a. Clinical trial data are very limited regarding this use. Use for ADHD is not currently recommended. b. A child with significant behavior problems should be referred for a mental health evaluation to assess for comorbid psychiatric disorders. G. Treatment of Adults with ADHD (Domain 1) a. Stimulant medications, as well as atomoxetine and TCAs, have clinical trial support for effectiveness in the treatment of adults with ADHD. b. Doses of stimulant medications needed to treat adults are often larger than those used to treat children. As-needed dosing may be effective for adult patients who can ascertain their need for stimulant drugs on the basis of particular environmental needs. H. Alternative Treatments (Domain 2): Omega-3 fatty acids have been evaluated in several psychiatric disorders, including ADHD. Although evidence may support their use in early psychosis and depression, clinical trials are limited in ADHD and results are inconsistent. Further clinical trials are needed. I. Treatment Guidelines (Domain 2) 1. British Association for Psychopharmacology 2014: https://www.bap.org.uk/pdfs/BAP_GuidelinesAdultADHD.pdf 2. National Institute for Health and Care Excellence (NICE) UK: www.nice.org.uk 3. American Academy of Pediatrics: https://pediatrics.aappublications.org/content/128/5/1007 4. Canadian ADHD Resource Alliance (CADDRA): https://www.caddra.ca/canadian-adhd-practice-guidelines/ J. Patient and Family Resources (Domain 1) 1. Children and Adults with ADHD: www.chadd.org 2. Centers for Disease Control and Prevention: www.cdc.gov/ncbddd/adhd/ 3. National Alliance on Mental Illness: https://www.nami.org/Learn-More/Mental-Health-Conditions/ADHD

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Psychiatric Disorders

Patient Case Questions 7 and 8 pertain to the following case. J.S. is a 7-year-old boy brought to his pediatrician’s office by his mother. His teacher has noted that J.S. cannot sit still in his seat and constantly fidgets, blurts out answers, and does not finish homework. He is not easily redirected in class and often does not turn in his homework. His mother states that he is constantly climbing on things at home and has angry outbursts. J.S. has no chronic medical conditions and takes no routine medications. He has difficulty swallowing whole capsules/tablets, and his mother hopes for a medication with limited daily dosing. 7. Which medication is best for J.S.’s initial treatment? A. B. C. D.

Methylphenidate immediate release (Methylin). Methylphenidate extended release (Concerta). Mixed amphetamine salts ER (Adderall XR). Atomoxetine.

8. J.S. returns to the pediatrician’s office 3 weeks later. He is doing well with his current drug therapy, but it is not lasting through the day. J.S. continues to have problems after school, at home during dinnertime, and while working on homework. Which intervention is best for J.S.? A. B. C. D.

Change to lisdexamfetamine. Increase dose of mixed amphetamine salts ER to twice daily. Add clonidine XR at bedtime. Add bupropion SR in the morning.

VIII.  SUBSTANCE USE DISORDERS A. Introduction (Domain 1) 1. Pharmacotherapy (where available) and psychotherapy are often needed in combination to successfully treat substance use disorders. 2. FDA-approved pharmacologic treatments of tobacco, alcohol, and opioid use disorders are available (for opioid and alcohol use disorders, see Appendix B1 and B2, respectively). Research continues into treatment options for other substances, including marijuana, cocaine, and amphetamines. 3. Withdrawal from a substance after discontinuing use is not life threatening for most substances (except for alcohol, benzodiazepines, and barbiturates), but the patient can feel significant discomfort. Supportive care should be used. B. DSM-5 Criteria for Substance-Related Disorders (Domain 1) 1. 10 classes of drugs are addressed in DSM-5: alcohol, caffeine, hallucinogens (phencyclidine is separate), inhalants, opioids, sedatives/hypnotics/anxiolytics, stimulants, tobacco, and other. Alcohol, cannabis, opioids, stimulants, and tobacco will be briefly reviewed. 2. Severity is determined by the number of criteria present over 12 months (see Table 35). In general, mild substance use disorder will have two or three symptoms; moderate will have four or five symptoms, and severe will have six or more symptoms.

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Psychiatric Disorders

Table 35. DSM-5 Behavior Domains of Substance Use Disorders and Accompanying Criteria Impaired Control

Social Impairment

Risky Use

Using substance in larger amounts or for longer than anticipated

Ongoing substance use resulting in inability to complete obligations

A lot of time spent acquiring/using the substance

Withdrawing from activities in life secondary to substance use

Unable to lower or discontinue use

Cravings

Ongoing use despite problems, both socially and interpersonally, caused by use

Pharmacologic Criteria

Using substance despite potential for physical harm

Tolerance to substance

Continuing to use substance even though it may be causing mental or physical problems

Withdrawal symptoms after a decrease or discontinuation of use

C. Tobacco Use (Domain 1) 1. Behavioral interventions and pharmacotherapy remain the treatment mainstay for tobacco dependence. 2. Length of FDA-approved treatment for tobacco cessation is usually 3–6 months. Individualized treatment regimens that allow a longer period of pharmacotherapeutic treatment may result in more successful cessation of use. 3. Symptoms of nicotine withdrawal include anxiety, craving, difficulty concentrating, and an increased appetite. 4. Nicotine replacement therapy a. Nicotine gum, patches, lozenges, nasal spray, and oral inhalers are available. b. Combination treatment with more than one of the dosage forms is more effective than use of one modality. For instance, combining a long-acting nicotine patch with a short-acting product such as the gum or a lozenge is more effective than monotherapy. c. Fourteen states have created, or are in the process of creating, avenues for independent pharmacist prescriptive authority of tobacco cessation products (https://naspa.us/resource/tobacco-cessation/). 5. Bupropion a. Bupropion is available as a generic or under the brand name Zyban for smoking cessation. b. Initial dose is the SR dosage form, 150 mg orally daily for 3 days, and then a maintenance dose of SR 150 mg twice daily. c. Can be initiated 1–2 weeks before the quit date and continued for up to 6 months, though longer duration of use may be considered in those who identify continued benefit d. Adverse effects and cautions are the same as for the use of bupropion for depression. e. Bupropion can be used successfully in combination with nicotine replacement therapy products to further support abstinence. 6. Varenicline a. Varenicline can minimize withdrawal symptoms from nicotine while blocking the satisfaction obtained from using tobacco. b. In clinical trials, varenicline is more effective than bupropion and nicotine replacement therapy. c. Dosing (starting 1 week before the quit date): Days 1–3: 0.5 mg orally every morning; days 4–7: 0.5 mg orally twice daily; day 8 to week 12: 1 mg orally twice daily. If unsuccessful in stopping tobacco use after varenicline use for 12 weeks, patient can continue for another 12 weeks. Alternative quitting strategies can be used, including setting quit date for day 8 or gradually reducing smoking with goal of cessation by week 12. d. Dose should be reduced in renal impairment with a creatinine clearance less than 30 mL/minute/1.73 m2. e. In patients with stable psychiatric conditions, the risk of neuropsychiatric events is no higher than with other smoking cessation treatments. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 800

Psychiatric Disorders

D. Alcohol Use Disorder (Domain 1) 1. Alcohol withdrawal a. The stages of alcohol withdrawal begin within 6–8 hours of alcohol intake cessation and continue for around 3–5 days. b. The final stage (stage 4) is delirium tremens, which can occur in about 5% of patients who have alcohol withdrawal. Symptoms of delirium tremens include confusion, hallucinations, agitation, tachycardia, and hyperthermia. These can progress to arrhythmias, seizures, shock, and aspiration. Mortality rate of untreated delirium tremens is 5%–15%. Risk factors include a history of delirium tremens, heavy and long-term use of alcohol, and age older than 30. c. Benzodiazepines are the treatment mainstay for alcohol withdrawal. Long- and intermediate-acting benzodiazepines (chlordiazepoxide, diazepam, lorazepam, oxazepam) are typically preferred to provide a smoother withdrawal. Lorazepam and oxazepam are preferred in patients with liver dysfunction because these agents have no active metabolites. Choice of a specific agent should depend on patient-specific values. Dosing of benzodiazepines can be fixed according to a tapering schedule or individualized to the patient’s symptoms. i. The Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) scale is commonly used in the inpatient treatment setting to assess withdrawal symptoms and to guide individualized symptom-driven benzodiazepine therapy as well as evaluate the possibility of dose reduction of the benzodiazepine in fixed-dose therapy. The CIWA-Ar consists of 10 symptom domains rated on a scale of 0–7. The highest possible score is 67. Patients who score more than 9 or 10 may benefit from medication intervention. d. Outpatient management of withdrawal can be completed if patients can tolerate oral medications, are having only mild to moderate withdrawal symptoms, and can be seen for follow-ups in a timely manner. For additional information, see Am Fam Physician 2013;88:589-95. i. Chlordiazepoxide 25–50 mg per dose is often used on an outpatient basis. An example fixed schedule taper is as follows. Day 1: 25–50 mg orally every 6 hours. Day 2: Decrease to every 8 hours. Day 3: Decrease to every 12 hours. Day 4: Decrease to at bedtime. Day 5: Discontinue or continue one more day of bedtime dosing. ii. Anticonvulsants (gabapentin, carbamazepine, divalproex) can be considered in patients with mild withdrawal symptoms and low risk of complications. The ideal dosing strategy for gabapentin is unknown, though recent studies have used dosing such as 1200 mg/day in divided doses tapered over 4–6 days or a 900-mg loading dose and a 3-day taper; however, the 900-mg loading dose and 3-day taper strategy did not improve outcomes in a recent publication (Am J Drug Alcohol Abuse 2019 Sep 6:1-9). Carbamazepine can be dosed at 800 mg/day orally in divided doses tapered over 5–9 days and divalproex at 500 mg orally three times daily for 1 week. e. Wernicke encephalopathy is caused by thiamine deficiency. Encephalopathy can be precipitated by administering dextrose-containing fluids to the patient without replacing thiamine. In the outpatient setting, oral thiamine 100 mg/day may be given for 1–2 weeks to replace thiamine. Intravenous or intramuscular administration is used in the inpatient setting if encephalopathy is present. f. Korsakoff psychosis is a chronic and irreversible condition caused by long-term alcohol use. 2. Medications to aid in abstinence from alcohol a. Disulfiram i. This is considered aversion therapy because alcohol use while taking disulfiram causes significant adverse effects, including flushing, nausea, vomiting, and tachycardia. ii. Usual dose is 500 mg orally daily for 1–2 weeks; then dose is reduced to 250 mg once daily. The “disulfiram reaction” may continue for up to 14 days after disulfiram is discontinued. iii. Liver function testing should be done at baseline and routinely during therapy.

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Psychiatric Disorders

b. Naltrexone i. Clinical trials have shown that naltrexone reduces cravings, the number of binge-drinking days, and the number of drinks during binge drinking. ii. Oral dose is 50 mg once daily; select patients may benefit from 100 mg daily. iii. Hepatotoxicity has been noted; avoid use in patients with acute hepatitis or hepatic failure. iv. Vivitrol is an intramuscular depot formulation of naltrexone given as a once-monthly injection of 380 mg. An oral test dose of naltrexone should be given before the initial injection to ensure tolerability. The FDA has received reports of injection site reactions, including tissue necrosis. c. Acamprosate i. Acamprosate can help maintain abstinence in patients who have stopped drinking. Not as effective as naltrexone in reducing binge drinking. ii. Dose is 666 mg orally three times daily. Medication adherence can be a barrier. iii. Usually well tolerated; diarrhea is the most common adverse effect. iv. Acamprosate carries a warning for suicidal thinking; patients should be educated about this effect and appropriately monitored. v. Renal dosing is required for a creatinine clearance of 50 mL/minute/1.73 m2 or less. d. Other interventions i. Topiramate: Clinical trials have shown that it reduces reducing heavy drinking days and increases the number of abstinent days. Recommended as a first-line agent by the VA/DoD guidelines. May be most useful in comorbid PTSD ii. Gabapentin may be of particular use in patients with comorbid sleep disturbances. iii. Baclofen may beneficial in patients with end-stage liver disease. iv. Combination therapy with acamprosate and naltrexone theoretically could improve outcomes, though clinical trial results have been mixed.

First-line therapies include naltrexone and acamprosate Second-line therapies include disulfiram,a topiramate,b and gabapentin

Figure 9. American Psychiatry Association practice guidelines for the pharmacologic treatment of patients with alcohol use disorder. Disulfiram should only be used if the goal of therapy is complete alcohol cessation.

a

b

Topiramate is listed as a first-line agent in the VA/DoD guidelines.

E. Opioid Use Disorder (Domain 1) 1. Opioid withdrawal symptoms include GI effects (nausea, vomiting, and diarrhea), anxiety, headache, muscle pain, fever, elevated blood pressure and heart rate, mydriasis, rhinorrhea, and lacrimation. 2. Medications to alleviate these withdrawal symptoms include clonidine, loperamide, nonsteroidal antiinflammatory drugs, antinausea drugs (ondansetron), and dicyclomine. In general, these drugs are used on an as-needed basis for both outpatient and inpatient withdrawal symptoms. 3. The Clinical Opiate Withdrawal Scale (COWS) is commonly used to evaluate the severity of withdrawal symptoms. The COWS contains 11 symptom complexes rated either from 0 to 4 or from 0 to 5, with a maximum score of 48. A score of 25 is considered moderately severe; a score of greater than 36 is considered severe withdrawal.

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Psychiatric Disorders

4. Withdrawal symptoms may continue for up to 2 weeks, with symptoms peaking after a few days. Outpatient treatment of opioid withdrawal should include patient education about the use of as-needed medication. a. Lofexidine (Lucemyra) i. Approved for opioid withdrawal symptoms ii. Initiated at 0.54 mg orally four times daily during peak withdrawal symptoms. This is usually within 5–7 days after the last opiate dose. Administer every 5–6 hours. Lofexidine is then continued for up to 14 days, with the dose adjusted according to symptoms. Lofexidine should then gradually be tapered off over the next 2–4 days. iii. Is only intended to reduce the symptoms of opiate withdrawal and not as a long-term maintenance therapy to reduce relapses. iv. Dose should be reduced with hepatic or renal insufficiency. v. Lofexidine can increase the QTc interval, so if it is used for patients receiving methadone, ECG should be monitored. vi. Clonidine is available as a less expensive alternative for opioid withdrawal. Clonidine is often administered on the basis of COWS scores (similar to lorazepam with the CIWA). 5. Methadone a. Methadone maintenance has been shown in clinical trials to decrease opioid use compared with placebo, with an improved length of time in treatment. Methadone maintenance programs require the patient to attend therapy programming, provide urine drug screens as requested, and appear daily, at least initially, for observed methadone dosing. b. Methadone is currently the only FDA-approved treatment option for opioid dependence for pregnant women. The criteria for admission to the treatment program are relaxed for pregnant women because of the risk to the fetus with continued opioid use. c. Usual initial dose of methadone to reduce craving and withdrawal symptoms is 10–30 mg orally once daily. Optimal dose range is 80–120 mg once daily. d. The long half-life of methadone (24–36 hours) allows once-daily dosing for opioid maintenance treatment. e. Methadone is metabolized through the CYP3A4 isoenzyme; medications that are moderate or strong inhibitors will increase serum concentrations of methadone and increase the risk of significant adverse effects. Methadone can be fatal in overdose. f. Methadone can prolong the QTc interval; it is recommended that a baseline ECG be obtained before initiating therapy and regularly throughout treatment, especially if dose changes are made. 6. Buprenorphine detoxification and maintenance a. Buprenorphine is available in several formulations, including buprenorphine sublingual tablet (Subutex – no longer manufactured as brand name), subcutaneous monthly injection (Sublocade), subdermal implant (Probuphine); and buprenorphine/naloxone sublingual film (Suboxone), tablet (Zubsolv), and buccal film (Bunavail). b. Induction and maintenance treatment is initiated once patient develops moderate withdrawal symptoms. This ensures that buprenorphine will not precipitate serious withdrawal symptoms. Buprenorphine induction begins with 2–4 mg of buprenorphine or combination buprenorphine/naloxone up to 8 mg of buprenorphine on day 1 and 16 mg on day 2. The dose is adjusted in 2- to 4-mg increments every 5–7 days (target dose 16 mg). Combination product is not recommended for patients with severe hepatic impairment. c. Buprenorphine has a ceiling effect, with limited efficacy over 24 mg/day. d. Patients treated with buprenorphine for opioid dependence should carry a card that informs emergency treatment providers they are receiving this therapy. e. The Drug Addiction Treatment Act of 2000 (DATA 2000) requires that providers who prescribe buprenorphine or buprenorphine/naloxone for opioid maintenance complete a specialized training program and obtain a waiver from the U.S. Department of Health & Human Services. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 803

Psychiatric Disorders

7. Naltrexone maintenance a. Naltrexone intramuscular depot formulation (Vivitrol) is FDA approved for the treatment of opioid dependence to prevent relapse to opioid use after detoxification. Patient must be opioid free for at least 7–10 days. b. Dose is the same as for treatment of alcohol dependence, with the same warnings, adverse effects, and laboratory monitoring recommendations (see Alcohol Use Disorders earlier). c. Induction should begin with a test dose, followed by administration of the 25-mg oral tablet. If no withdrawal symptoms or allergic symptoms are present, the long-acting injectable can be administered monthly. d. Treatment with oral naltrexone can be considered only in patients who cannot afford the long-acting injectable and/or who are in an environment with high levels of monitoring. F. Stimulant Use Disorder (Domain 1) 1. Symptoms of cocaine and stimulant withdrawal are similar and may begin soon after use, including cravings, dysphoria, depression, desire for sleep, and agitation. A few days after last use of the drug, patient may continue to have hypersomnia and may develop an increased appetite. 2. Although the actual withdrawal from cocaine or stimulants is rarely life threatening, significant depression and suicidal thinking are common problems. Resolution of this depression can take several months to 1 year. 3. There are no FDA-approved medications for stimulant use disorder. Bupropion and methylphenidate may improve outcomes in patients with lower levels of methamphetamine use. The combination of bupropion and naltrexone long-acting injectable resulted in an 11% treatment effect in a recent trial (N Engl J Med 2021;384:140-53). Mirtazapine has resulted in a 30%–40% reduction in methamphetamine use and may decrease associated high-risk sexual behaviors. 4. Patients with stimulant use disorder will benefit from referral to and engagement in substance use treatment programs that incorporate psychotherapy and other therapy modalities such as contingency management. G. Cannabis Use Disorder (Domain 1) 1. Use of marijuana is increasing after legal status changes at the state level. 2. Acute effects of cannabis use can include euphoria, altered sensory perception, anxiety, paranoia, increased appetite, and increased heart rate. Cannabis has also been associated with psychotic reactions and hallucinations. 3. Withdrawal symptoms are minor for most patients; heavy cannabis use can cause a withdrawal syndrome beginning about 24 hours after the last use and continuing for 1–2 weeks. 4. Symptoms of withdrawal include irritability, insomnia, loss of appetite, sweating, diarrhea, and mild increases in heart rate and blood pressure. 5. There are no FDA-approved drug treatments for cannabis use disorder. H. Treatment Guidelines 1. U.S. Department of Veterans Affairs: www.healthquality.va.gov (several substances are included, and this is an in-depth set of guidelines) 2. American Psychiatric Association: https://psychiatryonline.org/guidelines 3. Substance Abuse and Mental Health Services Administration (SAMHSA): https://store.samhsa.gov/ product/TIP-63-Medications-for-Opioid-Use-Disorder-Full-Document-Including-Executive-Summary-andParts-1-5-/SMA19-5063FULLDOC

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 804

Psychiatric Disorders

Patient Case 9. B.R. is a 28-year-old man with a diagnosis of BD and alcohol use disorder. He also occasionally misuses opioids and smokes cigarettes. He has successfully been treated for his mood disorder with divalproex ER 1500 mg orally at bedtime and risperidone 2 mg orally at bedtime. He has weight gain and GI upset related to his drug therapy, but he has no other adverse effects and remains adherent to treatment. Although he has had suicidal thoughts in the past, he has none currently. B.R. continues to use tobacco, alcohol, and nonmedical hydrocodone, when he can obtain it. He is interested in treatment for his substance use disorders. Although nicotine replacement therapy (nicotine gum) has failed in the past, he is motivated for treatment. He has been attending group therapy for substance use. He uses alcohol and tobacco daily; his last use of hydrocodone was 8 days ago. Which is the best initial medication regimen for B.R.? A. B. C. D.

Disulfiram, nicotine patch, nicotine gum. Naltrexone oral, bupropion XL. Acamprosate, varenicline. Naltrexone long-acting injectable, nicotine patch, nicotine gum.

Key Takeaways/Practice Points • First-line pharmacologic agents for anxiety disorders generally include SSRIs and SNRIs. Psychotherapy is also effective. Many other agents can be used, selection of which depends on the indication and patient-specific factors. Options can include pregabalin, gabapentin, TCAs, buspirone, and atypical antipsychotics. • Selection of pharmacotherapy for insomnia depends on the type of sleep difficulty. For problems related to sleep latency, ramelteon, trazodone, zaleplon, and zolpidem IR can be considered. In patients with only sleep maintenance issues, doxepin and suvorexant can be used. For patients with both latency and maintenance problems, temazepam, eszopiclone, and zolpidem CR are viable options. • Major depressive disorder can be treated with several first-line agents, including SSRIs, SNRIs, bupropion, mirtazapine, and vortioxetine. Augmentation can occur with select atypical antipsychotics, lithium, triiodothyronine, or an antidepressant with a differing mechanism of action. Psychotherapy should also be considered during treatment. • Pharmacotherapy for bipolar disorder is guided by the presenting polarity. Bipolar depression is treated with specific atypical antipsychotics (quetiapine, lurasidone, cariprazine, olanzapine/fluoxetine), lithium, or lamotrigine. Mania can be treated with mood stabilizers and antipsychotics, alone or in combination. • Antipsychotics are used for the treatment of schizophrenia. Typical antipsychotics carry a higher risk of EPS, whereas atypical antipsychotics generally have higher rates of metabolic effects. Some atypical drugs are considered more metabolically neutral. Agent selection is typically guided by the adverse effect profile. • Stimulants are the treatment mainstay for ADHD, though second-line therapies include atomoxetine, guanfacine, and clonidine.

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Psychiatric Disorders

REFERENCES Depression 1. Ables AZ, Nagabilli R. Prevention, diagnosis, and management of serotonin syndrome. Am Fam Physician 2010;81:1139-42. 2. Freeman MP, Fava M, Lake J, et al. Complementary and alternative medicine in major depressive disorder: the American Psychiatric Association Task Force report. J Clin Psychiatry 2010;71:669-81. 3. Manning J, Jackson C. Treating depression in primary care: initial and follow-up treatment strategies. J Clin Psychiatry 2015;76:e05. 4. Mulsant B, Blumberger D, Ismail Z, et al. A systematic approach to the pharmacotherapy of geriatric major depression. Clin Geriatr Med 2014;30:517-34. 5. Rush AJ, Warden D, Wisneiwski SR, et al. STAR*D: revising conventional wisdom. CNS Drugs 2009;23:627-47. 6. Schwartz J, Murrough J, Losifescu D. Ketamine for treatment-resistant depression: recent developments and clinical applications. Evid Based Mental Health 2016;19:35-8. 7. Stahl S, Morrisette D, Faedda G, et al. Guidelines for the recognition and management of mixed depression. CNS Spectr 2017;22:203-19. 8. Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;114:703-13.

Anxiety Disorders 1. Doroshyenko O, Rokitta D, Zadoyan G, et al. Drug cocktail interaction study on the effect of the orally administered lavender oil preparation Silexan on cytochrome P450 enzymes in healthy volunteers. Drug Metab Dispos 2013;41:987-93. 2. Katzman M, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. MBC Psychiatry 2014;14(suppl 1):1-83. 3. Koran L, Simpson H. Guideline Watch (March 2013): Practice Guideline for the Treatment of Patients with Obsessive-Compulsive Disorder. American Psychiatric Association Practice Guideline Series. 2013. Available at www.psychiatryonline.org. 4. Krystal J, Rosenheck R, Cramer J, et al. Adjunctive risperidone treatment for antidepressant-related symptoms of chronic military service-related PTSD. JAMA 2011;306:493-502. 5. Pottie K, Thompson W, Davies S, et al. Deprescribing benzodiazepine receptor agonists. Evidence-based clinical practice guideline. Can Fam Physician 2018;64:339-51. Sleep Disorders 1. Buysse D. Insomnia. JAMA 2013;309:706-16. 2. Department of Veterans Affairs and Department of Defense (VA/DoD). VA/DoD Clinical Practice Guideline for the Management of Chronic Insomnia Disorder and Obstructive Sleep Apnea. 2019. Available at https://www.healthquality.va.gov/guidelines/CD/insomnia/VADoDSleepCPGFinal508.pdf. Accessed October 16, 2020. 3. Mukherjee S, Patel S, Kales S, et al. An official American Thoracic Society statement: The importance of healthy sleep: recommendations and future priorities. Am J Respir Crit Care Med 2015;191:1450-8. 4. Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine practice guideline. J Clin Sleep Med 2017;13:307-49.

Bipolar Disorder 1. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet 2011;378:1306-15. 2. Ketter TA. Acute and maintenance treatments for bipolar depression. J Clin Psychiatry 2014;75:e10. 3. Mohammad O, Osser D. The psychopharmacology algorithm project at the Harvard South Shore Program: an algorithm for acute mania. Harv Rev Psychiatry 2014;22:274-94. 4. Viguera AC, Whitfield T, Baldessarini RJ, et al. Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry 2007;164:1817-24.

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Psychiatric Disorders

Schizophrenia 1. Dixon L, Goldman H, Bennett M, et al. Implementing coordinated specialty care for early psychosis: the RAISE Connection Program. Psychiatr Serv 2015;66:691-8. 2. Funk MC, Beach SR, Bostwick JR, et al. QTc prolongation and psychotropic medications. Am J Psychiatry 2020;177:273-4. 3. Jones PB, Barnes TRE, Davies L, et al. Randomized controlled trial of the effect of quality of life on second- vs first-generation antipsychotic drugs in schizophrenia (CUtLASS 1). Arch Gen Psychiatry 2006;63:1079-87. 4. Kreyenbuhl J, Buchanan RW, Dickerson FB, et al. The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009. Schizophr Bull 2010;36:94-103. 5. Labad J, Montalvo I, González-Rodríguez A, et al. Pharmacological treatment strategies for lowering prolactin in people with a psychotic disorder and hyperprolactinaemia: a systematic review and metaanalysis. Schizophr Res 2020;222:88-96. 6. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013;382:951-62. 7. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009;360:225-35. 8. Remington G, Addington D, Honer W, et al. Guidelines for the pharmacotherapy of schizophrenia in adults. Can J Psychiatry 2017;62:604-16. 9. Sethuram K, Gedzior J. Akathisia: case presentation and review of the newer treatment agents. Psychiatr Ann 2014;44:391-6. 10. Tiihonen J, Lonnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009;374:620-7.

3. 4.

5. 6. 7.

8.

9.

Feldman H, Reiff M. Attention deficit-hyperactivity disorder in children and adolescents. N Engl J Med 2014;370:838-46. Gibson AP, Bettinger TL, Patel NC, et al. Atomoxetine versus stimulants for treatment of attention deficit/hyperactivity disorder. Ann Pharmacother 2006;40:1134-42. Gould MS, Walsh BT, Munfakh JC, et al. Sudden death and use of stimulants in youths. Am J Psychiatry 2009;166:992-1001. Keen D, Hadijikoumi I. ADHD in children and adolescents. BMJ Clin Evid 2011. pii:0312. Sharma A, Couture J. A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother 2014;48:209-25. Silva RR, Skimming JW, Muniz R. Cardiovascular safety of stimulant medications for pediatric attention-deficit hyperactivity disorder. Clin Pediatr 2010;49:840-51. Wilens T, Prince J, Waxmonsky J, et al. An open trial of sustained-release bupropion for attentiondeficit/hyperactivity disorder in adults with ADHD plus substance use disorders. J ADHD Relat Disord 2010;1:25-35.

Substance Use Disorders 1. Andaluz A, DeMoss D, Claassen C, et al. Fixed-dose gabapentin augmentation in the treatment of alcohol withdrawal syndrome: a retrospective, open-label study. Am J Drug Alcohol Abuse 2019 Sep 6:1-9. 2. Ciccarone D. Stimulant abuse: pharmacology, cocaine, methamphetamine, treatment, attempts at pharmacotherapy. Prim Care Clin Office Pract 2011;38:41-58. 3. Muncie HL Jr, Yasinian Y, Oge’ L. Outpatient management of alcohol withdrawal syndrome. Am Fam Physician 2013;88:589-95. 4. Raupach T, van Schayck CP. Pharmacotherapy for smoking cessation: current advances and research topics. CNS Drugs 2011;25:371-82. 5. Ross S, Peselow E. The neurobiology of addictive disorders. Clin Neuropharm 2009;32:269-76. 6. Siefried KJ, Acheson LS, Lintzeris N, et al. Pharmacological treatment of methamphetamine/ amphetamine dependence: a systematic review. CNS Drugs 2020;34:337-65.

Attention-Deficit/Hyperactivity Disorder 1. Dopheide JA, Pliszka SR. Attention-deficithyperactivity disorder: an update. Pharmacotherapy 2009;29:656-79. 2. Faraone SV, Glatt SJ. A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry 2010;71:754-63.

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Psychiatric Disorders

7.

Trivedi MH, Walker R, Ling W, et al. Bupropion and naltrexone in methamphetamine use disorder. N Engl J Med 2021;384:140-53.

Medication Adherence 1. Thompson L, McCabe R. The effect of clinicianpatient alliance and communication on treatment adherence: a systematic review. BMC Psychiatry 2012;12:2-12.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 808

Psychiatric Disorders

ANSWERS AND EXPLANATIONS TO PATIENT CASES 1. Answer: B Lorazepam can be considered short term if bridging therapy is needed for anxiety symptoms before the onset of efficacy of a first-line agent, but it should not be used as monotherapy for this patient, making Answer C incorrect. Hydroxyzine is not a first-line agent for anxiety, making Answer D incorrect. Both SSRIs and SNRIs are firstline agents for GAD (Answers A and B). When selecting between escitalopram and duloxetine, comorbidities should be considered. This patient’s blood pressure and hepatic enzymes were elevated in the clinic, and SNRIs can elevate blood pressure. Duloxetine also has a higher risk of hepatoxicity than escitalopram. Given both of these concerns, escitalopram would be best, making Answer B correct and Answer A incorrect.

making Answer A incorrect. Venlafaxine is an SSRI that has been suggested to carry a higher risk of inducing manic symptoms. Antidepressants should not be used as monotherapy in BD and are not thought to be overly effective, making Answer B incorrect. Aripiprazole lacks evidence to support its use for bipolar depression, making Answer C incorrect. Quetiapine is FDA approved for bipolar depression and is listed as a first-line agent by several guidelines, making Answer D correct. 5. Answer: C This patient has responded well to risperidone and has had no adverse effects while taking risperidone 4 mg orally at bedtime. It is most reasonable to try reducing the risperidone dose back to 4 mg (Answer C is correct) because it appears the dose increase precipitated the patient’s akathisia. Given his good response to risperidone, a dose decrease should be tried before changing to a different antipsychotic (Answers A and D are incorrect). Changing to risperidone long-acting injectable should not be initiated while the patient has akathisia (Answer B is incorrect).

2. Answer: B Answer B is correct. Zolpidem is recommended for problems with sleep latency and is fairly inexpensive. Ramelteon, though available as a generic and also indicated for problems with sleep latency, is more expensive, which could be problematic for this patient, making Answer D incorrect. Trazodone is not generally recommended outside comorbid depression and insomnia, making Answer A incorrect. Flurazepam is not the best choice because the primary active metabolite has an extended half-life, which increases the risk of morning grogginess. The patient has a fairly early awakening time (Answer C is incorrect).

6. Answer: B Diphenhydramine and benztropine (Answers A and D) are typically used for dystonic reactions and pseudoparkinsonism, which this patient does not appear to have, making these incorrect. Lorazepam (Answer C) could be considered for akathisia, though only after the failure of propranolol (Answer B), which is a first-line agent. In addition, the patient has a history of substance use, which would warrant careful consideration before prescribing a benzodiazepine. Propranolol is the best choice. Although an additional dose decrease of risperidone was not presented as an option, it would be prudent and of best practice to ensure this patient is taking the lowest effective dose for his symptoms.

3. Answer: A A PHQ-9 score of 15 indicates moderate to severe symptoms of depression. Sertraline is first line to treat the first episode of major depression (Answer A is correct). The selegiline patch is an MAOI that is usually reserved for treatment-resistant depression (Answer B is incorrect). Aripiprazole is FDA approved for the treatment of major depressive disorder in combination with an antidepressive agent, which this patient is not yet taking, making Answer C incorrect. Because TCAs are not first-line agents, Answer D is incorrect.

7. Answer: C Methylphenidate IR (Methylin) is available as a chewable tablet, but it will necessitate twice-daily dosing secondary to a duration of action of 3–6 hours. This patient’s mother would prefer limited daily dosing, making Answer A incorrect. Methylphenidate ER (Concerta) must be swallowed whole. This patient has difficulty swallowing whole capsules, making Answer B incorrect. Atomoxetine is second line after the failure or intolerability of stimulants; it also must be swallowed whole, making Answer D incorrect.

4. Answer: D This patient presents with symptoms of depression and endorses a possible past hypomanic or manic episode, indicating BD. Divalproex is not preferred in bipolar depression. Although divalproex could be considered in a mixed episode, this patient has no symptoms of mania,

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 809

Psychiatric Disorders

Mixed amphetamine salts ER (Adderall XR) have a longer duration of action (around 9 hours), and the capsule contents can be sprinkled on applesauce, making Answer C correct. 8. Answer: A Amphetamine salts ER are only dosed once daily, and if changed to twice daily, the patient would likely experience problems with sleep, making Answer B incorrect. Stimulant therapy should be maximized before considering the addition of other agents such as clonidine (Answer C is incorrect). In addition, administration of clonidine at bedtime will not help the patient’s return of symptoms after school. Adding bupropion should be reserved for patients after stimulant failure (Answer D is incorrect). In addition, these medications cannot be crushed, and the patient may have difficulty swallowing them whole. Lisdexamfetamine is available as a chewable tablet, and its duration of action is around 10–12 hours, which is longer than that of mixed amphetamine salts ER. This would provide once-daily dosing and avoid the need to swallow a tablet or capsule, making Answer A correct. 9. Answer: D This patient has both substance use and a mental health diagnosis, which can be treated at the same time. Answer A addresses only nicotine and alcohol use. In addition, disulfiram is not a first-line agent. Answer B addresses nicotine use with bupropion and alcohol and opioid use with naltrexone. However, oral naltrexone should only be used for opioid use disorder in patients who cannot afford or tolerate the long-acting injectable, or who can be closely monitored for adherence (Answer B is incorrect). Answer C addresses only alcohol and nicotine with acamprosate and varenicline; it does not address opioid addiction. Answer D is best for this patient right now because it is the only option that addresses all three substances of concern (opioids, nicotine, and alcohol) in an evidence-based manner. The patient should establish oral tolerability to naltrexone before receiving the long-acting injectable.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 810

Psychiatric Disorders

ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS 4. Answer: B Although ramelteon or temazepam may improve this patient’s insomnia, he has a body mass index of 35 kg/ m2, drinks alcohol, and has hypertension, all of which contribute to sleep apnea. Therefore, the patient should be evaluated prior to any additional pharmacological treatment (Answer B). Drug therapy should not be used in sleep apnea without the concurrent use of positive airway pressure during sleep (Answers A and D are incorrect). The patient endorses no symptoms consistent with RLS (Answer C is incorrect).

1. Answer: B This patient’s depressive symptoms have partially responded to citalopram, thus, she may derive benefit from an increase in dose. The most appropriate intervention at this point is increasing citalopram to 40 mg/day (Answer B). Continuing her current dose after 8 weeks of treatment is unlikely to further improve symptoms (Answer A is incorrect). There is currently no need to change her drug therapy to another agent as she has not failed a higher dose of citalopram (Answers C and D are incorrect). If the patient does not achieve remission after 8 weeks of therapy with citalopram 40mg/day, a switch in medication and addition of adjunctive therapy could be considered.

5. Answer: A Both SSRIs and SNRIs are first-line agents for depression, including sertraline and paroxetine (Answers A and B). As the patient is already experiencing excess sleep and drowsiness, paroxetine (Answer B) is not preferred. Mirtazapine can also cause sedation (Answer D is incorrect). Amitriptyline is a TCA, and TCAs are generally second- or third-line agents because of adverse effects such as sedation and anticholinergic effects (Answer C is incorrect). Sertraline is the best choice (answer A).

2. Answer: A The SSRI agents escitalopram and paroxetine are both considered first line for GAD, however, as this patient has concerns about weight, paroxetine would not be an ideal initial choice (Answer C is incorrect). Escitalopram is less likely to affect weight (Answer A is correct). Treatment with alprazolam should be initiated only for anxiety symptoms causing significant functional impairment while the SSRI becomes effective; however, there is no indication that the patient’s GAD is severe enough to warrant this (Answer B is incorrect). Pregabalin could also cause weight gain and is not a clear first-line agent in all guidelines (Answer D is incorrect).

6. Answer: C Methylphenidate IR is only partly effective for this patient, and its effect does not last throughout the school day. A dose increase will not lengthen the time of symptom response (Answer A in incorrect). The patient has eczema, and there is a risk of skin irritation/rash at the site of application with the transdermal patch. Other options should be maximized before considering use of the patch (Answer B is incorrect). Changing to methylphenidate ER (Concerta) can exacerbate the patient’s insomnia because of its 12- to 18-hour duration of action, thus Answer D is incorrect. Because the patient has afternoon symptoms after the wearing-off of the morning methylphenidate IR dose, moving the afternoon dose from after school to around noon can provide more afternoon symptom coverage and improve insomnia (Answer C is correct)

3. Answer: D This patient’s symptoms have partially improved after 6 weeks of treatment, but auditory hallucinations continue to cause functional impairment. In addition, the patient is exhibiting EPS. Increasing risperidone might address the residual psychosis but worsen the preexisting EPS, making Answer A incorrect. Increasing risperidone and adding benztropine (Answer B) would not be ideal because benztropine has its own adverse effect profile. Adequate control of schizophrenia symptoms with one antipsychotic devoid of significant adverse effects is preferable to adding medications to treat these adverse effects, which adds to pill burden and contributes to polypharmacy (Answer B is incorrect). Adding olanzapine might further complicate adverse effects; moreover, duplicate therapy with two or more antipsychotics is not supported by the current evidence (Answer C is incorrect). The best choice for this patient is a change to olanzapine (Answer D).

7. Answer: C Olanzapine is associated with a higher risk of metabolic syndrome than the other atypical antipsychotics, except clozapine. A fasting blood glucose test and total lipid profile should be obtained at baseline, 4 weeks, 12 weeks, and annually (Answer C is correct). Although thyroidstimulating hormone concentrations, prolactin serum

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 811

Psychiatric Disorders

12. Answer: C The biggest concern with using an SGA with amiodarone is the added increase in the QTc interval. Among these agents, ziprasidone has the highest risk (Answer C is correct). Aripiprazole, brexpiprazole, and risperidone can increase QTc, but not to the same extent as ziprasidone, thus Answers A, B, and D are incorrect.

concentrations, and renal function testing can be obtained at baseline, they are not required routine monitoring values for olanzapine (Answers A, B, and D are incorrect). A prolactin concentration is only obtained if the patient has signs of hyperprolactinemia. 8. Answer: B Symptom scores on the PHQ-9 are categorized into mild, moderate, moderate-severe, and severe. A score of 12 is in the moderate range (Answer B is correct). Mild depression would be indicated by a total score of 5-9 (Answer A is incorrect), moderate depression by a score of 10–14, moderately severe depression by a score of 15–19, and severe depression by a score of 20–27. Given the patient’s score of 12, Answers A, C, and D are incorrect.

13. Answer: A Major depressive episodes are not unique to bipolar I disorder and may be present in type II BD (Answer B is incorrect). Similarly, suicidal thoughts can occur in both bipolar I and II disorder (Answer D is incorrect). Bipolar I disorder requires a manic episode, which describes the patient’s current presentation. Psychosis and/or delusions can be a feature of mania but do not occur with hypomania (Answer C is incorrect). Answer A is correct.

9. Answer: A Bupropion increases seizure risk and should be avoided in patients with a history of seizures; Answer A is correct. Although other antidepressants (such as venlafaxine, sertraline, and levomilnacipran) may reduce seizure threshold, the impact on seizure risk is less, and they are often used (Answers B, C, and D are incorrect).

14. Answer: A This patient currently has no symptoms of withdrawal. Buprenorphine is a partial opioid agonist and when given to patients currently using full opioid agonists such as hydrocodone can displace these agents and precipitate withdrawal. Buprenorphine/naloxone therapy can be initiated once the patient begins to exhibit opioid withdrawal symptoms because buprenorphine/naloxone will then relieve these symptoms (Answers B, C, and D are incorrect). In addition, naloxone has poor oral bioavailability, and negligible amounts are absorbed through the transmucosal route. Naloxone in the buprenorphine/naloxone combination product acts as an abuse deterrent to avoid manipulation of the product and subsequent snorting or intravenous injection. When used by these routes, naloxone can exert its opioid antagonist effects. Once the patient begins to exhibit withdrawal signs and symptoms, 2-4 mg of buprenorphine can be administered on day 1.

10. Answer: B Hallmark signs of serotonin syndrome are muscular rigidity or hyperreflexia, autonomic dysregulation, restlessness, and mental status changes such as confusion (Answer B is correct). Although there may be GI concerns, they are not hallmark signs of the syndrome (Answer A is incorrect). Dry mouth, constipation, and dry eyes could be associated with anticholinergic effects, but are not associated with serotonin syndrome (Answer C is incorrect). Although patients may experience a headache, chest pain and flushing are not likewise associated (Answer D is incorrect). 11. Answer: A This patient does not appear to have signs of depression (Answer C is incorrect). Rather, his symptoms of grandiosity, elated mood, lack of sleep, racing thoughts, hyperverbal speech, and agitation are all classic signs and symptoms of mania (Answer A is correct). Without signs of depression, this episode would be considered mania instead of a mixed episode (Answer B is incorrect). Rapid cycling is four or more mood episodes in a year. Given the provided information, this patient does not meet these criteria (Answer D is incorrect).

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 812

Psychiatric Disorders

Appendix A.

INFORMED CONSENT FOR PSYCHOACTIVE MEDICATIONS (Domain 1)

The issue of informed consent for medication therapy in general has received more attention recently as the patient’s role in treatment has become more active. With the increased use of psychoactive medications for off-label uses, as well as the significant adverse effects of these medications, there is a renewed focus on informed consent. A 2008 article sought to define the essential components of informed consent.a The patient’s ability for decision-making must be ascertained by the clinician. Elements include communication of the agent, reason for use, adverse effects, and expectations of treatment; documentation of the informed consent process; warnings for use in pregnancy; black box warnings; off-label use of medications; drug interactions, including alcohol; adverse effects, including cognitive impairment; and the risk of causing or exacerbating medical conditions, including cardiovascular, metabolic, and movement adverse effects. The patient should sign an informed consent document that is maintained in the patient’s medical record. Frank B, Gupta S, McGlynn DJ. Psychotropic medications and informed consent: a review. Ann Clin Psychiatry 2008;20:87-95. a

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 813

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Buprenorphine (Probuphine)

Buprenorphine (generic; Subutex brand name no longer manufactured)

Methadone

Medication

Subdermal implant

Sublingual tablet

PO concentrate, PO solution, tablet, soluble tablets

Formulations

Appendix B1. Treatment of OUD

Maintenance treatment of opioid dependence in patients whose disease is stable on ≤ 8 mg of Suboxone or equivalent for at least 3 mo

Opioid dependence

Medically supervised withdrawal, maintenance treatment

Indications

Implanted for 6 mo; then removed and second product may be implanted (4 rods, each containing 80 mg)

Target: 16 mg/ day Range: 4–24 mg

Varies by indication and patient

Dosing

Can consider supplementation if patients report inadequate symptom control

Mono-product recommended in treatment of pregnant women

No or low opioid tolerance: 5–10 mg

Dosing Notes

See buprenorphine sublingual tablet mono-product earlier. Additional adverse effects of implant include implant site pain, itching, and swelling. Migration rare but possible

Oral numbness, constipation, glossodynia, vomiting, intoxication, insomnia, opioid withdrawal, diaphoresis, blurred vision

Constipation, nausea, sweating, sexual dysfunction, drowsiness, weight gain

Adverse Effects

State PDMP, physical examination, urine drug screen, liver function, pregnancy test, hepatitis and HIV status

State PDMP, physical examination, urine drug screen, liver function, pregnancy test, hepatitis and HIV status, ECG if high risk

Baseline Assessments

Above + wound healing 1 wk after insertion

Blood pressure (initiation and titration), liver enzymes periodically, sedation

ECG if indicated, blood pressure, sedation

Safety Monitoring

Psychiatric Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

815

Buprenorphine ER injection (Sublocade)

Subcutaneous injection

Buprenorphine/ Buccal film naloxone (Bunavail)

Moderate-severe OUD in patient initiated on transmucosal buprenorphine for ≥ 7 days

Opioid dependence

Opioid dependence

Buprenorphine/ Sublingual naloxone tablet (generic; brand name Zubsolv)

Indications

Opioid dependence

Formulations

Buprenorphine/ Sublingual film naloxone (Suboxone)

Medication

Appendix B1. Treatment of OUD (continued)

300 mg/1.5 mL monthly for 2 mo; then 100 mg maintenance dose

Target: 8.4 mg/1.4 mg daily Range: 2.1 mg/0.3 mg to 12.6 mg/2.1 mg daily

Target: Generic 16 mg/4 mg daily Zubsolv 11.4 mg/2.9 mg daily Range: Generic 4 mg/1 mg to 24 mg/6 mg; Zubsolv 2.9 mg/0.71 mg to 17.2 mg/4.2 mg

Target: 16 mg/4 mg/day Range: 4 mg/1 mg to 24 mg/6 mg

Dosing

Reports of fetal adverse reactions in animals; IV injection can result in death

Bunavail has greater bioavailability than Suboxone; thus, 4.2 mg/0.7 mg Bunavail = 8 mg/2 mg of Suboxone

Zubsolv has greater bioavailability than Suboxone; thus, 5.7 mg/1.4 mg of Zubsolv = 8 mg/2 mg of Suboxone

Do not use combination products in patients with severe hepatic impairment (Child-Pugh 10–15)

Dosing Notes

See buprenorphine sublingual tablet mono-product earlier. Additional adverse effects include injection site reactions

Baseline Assessments

See buprenorphine State PDMP, sublingual tablet mono- physical product earlier examination, urine drug screen, liver function, pregnancy test, hepatitis and HIV status

Adverse Effects

Above + monthly liver enzymes

Blood pressure (initiation and titration), liver enzymes periodically, sedation

Safety Monitoring

Psychiatric Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Naltrexone XR (Vivitrol)

Naltrexone (Revia)

Medication

IM injection

PO tablet

Formulations

Opioid dependence

Opioid dependence

Indications

Appendix B1. Treatment of OUD (continued)

380 mg monthly in gluteal (alternate each month)

25 mg test dose; then 50 mg PO once daily thereafter. Can consider alternative maintenance regimens

Dosing

See earlier and establish PO tolerability before administration

Opioid antagonism can be overridden with high-dose opioids

Dosing Notes

Injection site reaction, insomnia, hepatic enzyme increases, nasopharyngitis, depression

Headache, insomnia, dizziness, anxiety, nausea, vomiting, diarrhea, depression, hepatic enzyme increases

Adverse Effects

Above + presence of coagulation disorder

Depression, suicidal ideation, liver enzymes periodically

Safety Monitoring

PDMP, recent Depression, opioid use, liver enzymes physical examination, urine drug screen, pregnancy test, liver and kidney function, hepatitis and HIV status

Baseline Assessments

Psychiatric Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

816

817

PO capsules, PO solution, PO tablets

PO tablet

Disulfiram (Antabuse)

Gabapentin (Neurontin)

Delayed release tablet

Formulations

Acamprosate (Campral)

Medication

Appendix B2. Treatment of AUD

AUD off-label

AUD

AUD

Indications

300 mg PO daily and titrate by 300 mg every 1 or 2 days to target dose 600 mg PO three times daily

Initial: 500 mg PO daily for 1–2 wk Maintenance: 125–500 mg PO daily (average is 250 mg)

666 mg PO three times daily

Dosing

Linear dose response when evaluating abstinence and reduced drinking

Patient must be alcohol free ≥ 12 hr

Lower dose (333 mg PO three times daily) may be effective in some patients. Efficacy of promoting abstinence unclear. Initiate after patient has achieved cessation. Maintain medication administration if patient resumes alcohol use

Dosing Notes

Liver function test, CBC, serum chemistry

Renal function

Baseline Assessments

Limited adverse Substance use, renal effects in studies function using gabapentin in alcohol use. General gabapentin adverse effects include dizziness, drowsiness, edema, mood changes, weight gain, nausea

Drowsiness, headache, rash, metallic taste, hepatitis

Diarrhea, insomnia, anxiety, depression

Adverse Effects

Renal function, edema, suicidal ideation

Use of medications that can trigger disulfiram reaction such as metronidazole or tonics, liver function test 10–14 days after initiation

Renal function (333 mg PO three times daily for CrCl 30–50 mL/ min/1.73 m2, contraindicated < 30 mL/min/1.73 m2), suicidal ideation

Safety Monitoring

Psychiatric Disorders

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

818

IM injection

Naltrexone XR (Vivitrol)

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Off-label AUD

AUD

AUD

AUD off-label

Indications

5 mg PO three times daily – increase every 3–5 days, depending on patient tolerance

380 mg IM monthly

50 mg PO daily

75–300 mg PO daily in divided doses

Dosing

Studies conflicting on optimal dose. France uses off-label to max 80 mg/day; however, other studies have looked at dosing > 270 mg/day. Do not discontinue abruptly

Establish PO tolerability before administration

Some patients may require 100 mg/day

No alcohol within 6 hr on either side of Trokendi XR administration

Dosing Notes

Drowsiness, nausea, vomiting, confusion, headache

Injection site reaction, insomnia, hepatic enzyme changes, nasopharyngitis

Renal function (initial dosing reduced for CrCl ≤ 80 mL/min/1.73 m2)

PDMP, recent opioid use, physical examination, urine drug screen, pregnancy test, liver and kidney function, hepatitis and HIV status, presence of coagulation disorder

Nausea, vomiting, Opioid use, pregheadache, insom- nancy test, liver and nia, daytime kidney function sleepiness, dizziness, abdominal pain

Baseline Assessments

Cognitive impair- Renal function, ment, dizziness, weight, serum taste changes, bicarbonate weight loss

Adverse Effects

Cognition and alertness

Depression, suicidal ideation, liver enzymes periodically

Depression, liver enzymes

Renal function (half dose for CrCl < 70 mL/ min/1.73 m2), suicidal ideation, eating habits

Safety Monitoring

Sources: Lexicomp®. Wolters Kluwer Clinical Drug Information; American Psychiatric Association. Practice Guideline for the Pharmacological Treatment of Patients with Alcohol Use Disorder, 2018; Sinclair JM, Chambers SE, Shiles CJ, et al. Safety and tolerability of pharmacological treatment of alcohol dependence: comprehensive review of evidence. Drug Saf 2016;39:627-45; U.S. Department of Veterans Affairs. VA PBM Academic Detailing Service. Alcohol Use Disorder: Leading the Charge in the Treatment of Alcohol Use Disorder, 2017. Available at https://www.pbm.va.gov/PBM/AcademicDetailingService/Documents/Academic_ Detailing_Educational_Material_Catalog/04_AUD_ProviderAD_Educational_Guide.pdf?t=tab2. Accessed January 20, 2020.

AUD = alcohol use disorder; CrCl = creatinine clearance; IM = intramuscular(ly); IV = intravenous(ly); OUD = opioid use disorder; PDMP = prescription drug monitoring program.

PO tablet

PO tablet

Naltrexone (Revia)

Baclofen (Lioresal)

PO extendedrelease capsule, PO tablet

Formulations

Topiramate (Topamax, Trokendi XR, Qudexy XR)

Medication

Appendix B2. Treatment of AUD (continued)

Psychiatric Disorders

Neurology Nicole Hahn, Pharm.D., BCACP Kaiser Permanente Denver, Colorado

Neurology

Neurology Nicole Hahn, Pharm.D., BCACP Kaiser Permanente Denver, Colorado

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 821

Neurology

Learning Objectives 1. Given a patient case, select an appropriate antiepileptic drug (AED) regimen for a patient with epilepsy on the basis of seizure type and AED mechanism of action, common adverse effects, and drug interactions. 2. Recommend an appropriate pharmacologic therapy for a patient with episodic or chronic migraine headache. 3. Recommend and manage appropriate disease-modifying therapy for a patient with multiple sclerosis (MS) on the basis of MS subtype and other patient-specific factors. 4. Recommend an appropriate pharmacologic therapy for a patient with Parkinson disease, neuropathic pain, or Alzheimer disease.

Abbreviations in This Chapter

PPMS REMS RRMS SNRI SPMS SSRI TCA UPDRS WHO

AAN American Academy of Neurology ACh Acetylcholine AD Alzheimer disease AE Adverse effect AED Antiepileptic drug CBD Cannabidiol CGRP Calcitonin gene-related peptide CIS Clinically isolated syndrome CNS Central nervous system COMT Catechol-O-methyl transferase CYP Cytochrome P450 DBS Deep brain stimulation DDI Drug–drug interaction DMT Disease-modifying therapy DRESS Drug reaction with eosinophilia and systemic symptoms ER Extended release ET Essential tremor FDA U.S. Food and Drug Administration GI Gastrointestinal HTN Hypertension IR Immediate release mAb Monoclonal antibody MAO Monoamine oxidase MCI Mild cognitive impairment MEDD Morphine equivalent daily dose MG Myasthenia gravis MMSE Mini-Mental State Examination MOH Medication-overuse headache MRI Magnetic resonance imaging MS Multiple sclerosis NMDA N-methyl-d-aspartate NSAID Nonsteroidal anti-inflammatory drug PD Parkinson disease

Primary progressive multiple sclerosis Risk Evaluation and Mitigation Strategies Relapsing remitting multiple sclerosis Serotonin norepinephrine reuptake inhibitor Secondary progressive multiple sclerosis Selective serotonin reuptake inhibitor Tricyclic antidepressant United Parkinson Disease Rating Scale World Health Organization

Baseline Knowledge Statements Readers of this chapter are presumed to be familiar with the following: • Basic understanding of epidemiology, etiology, pathophysiology and clinical presentation of included neurological disease states • General drug knowledge of pharmacologic therapies used for epilepsy, headache, pain, multiple sclerosis, Parkinson disease, and Alzheimer disease • Basic knowledge of pharmacokinetics and drug– drug interactions Additional Readings The following resources have additional background information on the topics included in this chapter: • Schmidt D, Schachter SC. Drug treatment of epilepsy in adults. BMJ 2014;348:g254. • Dodick DW. Migraine. Lancet 2018;391:1315-30. • Klotz L, Havla J, Schwab N, et al. Risks and risk management in modern multiple sclerosis immunotherapeutic treatment. Ther Adv Neurol Disord 2019;12:1-31. • Kalia LV, Lang AE. Parkinson’s disease. Lancet 2015;386:896-912.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 822

Neurology

Self-Assessment Questions Answers and explanations to these questions can be found at the end of the chapter.

with her dry mouth. She also reports drinking red wine regularly in the evening to calm down after a difficult day. Because of her stressful job, her sleep schedule is sporadic.

1. A physician would like help in choosing an antiepileptic drug (AED) that will not interfere with cyclosporine therapy for a transplant recipient. Assuming that all of the following AEDs will provide adequate seizure control, which AED is most appropriate to use in this patient?

4. Which is the most appropriate nonpharmacologic therapy to recommend for this patient?

A. B. C. D.

A. B. C. D.

Carbamazepine Lacosamide Oxcarbazepine Phenytoin

5. Which is the best option for preventing migraines in this patient?

A. Continue nortriptyline at 75 mg/day. B. Increase nortriptyline to 150 mg/day. C. Discontinue nortriptyline; start propranolol 80 mg/day. D. Discontinue nortriptyline; start candesartan 16 mg/day.

2. Your patient will be admitted for a cholecystectomy. She takes carbamazepine 400 mg orally three times daily. She will be unable to take any oral medications for 3 days after surgery and requires an AED available as an injectable formulation. Assuming that all of the following AEDs will provide adequate seizure control, which is the best AED treatment to recommend during this time? A. B. C. D.

6. Based on duration of action, which is the best option for abortive treatment of this patient’s migraines? A. B. C. D.

Carbamazepine Levetiracetam Topiramate Lamotrigine

Sumatriptan 50 mg Frovatriptan 2.5 mg Rizatriptan 5 mg Almotriptan 6.25 mg

7. A 50-year-old man comes to the clinic seeking abortive treatment for his migraine headaches. The patient has a history of benign prostatic hyperplasia, depression, and hypercholesterolemia. His home medications include tamsulosin 0.4 mg/day, selegiline 9 mg/24hour patch, and simvastatin 20 mg/day. Considering potential drug interactions, which is the best abortive treatment option for his migraine headache?

3. Carbamazepine is typically initiated at a low dose. Which is the best reason for starting at a low dose? A. B. C. D.

Change to diet soda. Limit red wine consumption. Begin taking naps during the day. Subscribe to a weight management program.

Precipitation of absence seizures Dizziness caused by initial dose Reduction in risk of rash Reduction in risk of hyponatremia

Questions 4–6 pertain to the following case. L.P. is a 46-year-old overweight woman who presents to the clinic with a severe migraine attack. She was given a diagnosis of migraine headaches when she was age 16 years. The patient says her headaches were mostly controlled until about 6 months ago, when they began occurring more often. She says her migraines usually last 24 hours and occur around the start of her menstrual cycle. She currently has severe pain, nausea, and vomiting. Her home medications include nortriptyline 75 mg orally daily and an oral contraceptive. The patient has a very stressful job and often misses meals. She hydrates with three 32-ounce caffeinated soft drinks throughout the day to “keep her going” and help

A. B. C. D.

Eletriptan Rizatriptan Sumatriptan Zolmitriptan

8. A 68-year-old man has localized neuropathic pain for whom antidepressant and AED therapies have failed (because of sedation). He had a fall while taking nortriptyline. He has hypertension (HTN) on lisinopril and a history of a gastrointestinal (GI) bleed. Which would be the best recommendation to treat his pain?

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 823

Neurology

A. B. C. D.

12. A 28-year-old female patient with multiple sclerosis (MS) is having relapses more often and has been treated with interferon β-1a for the past 3 years. She prefers an oral agent to address her relapses, and she wants to start a family in 5 years. Which is the best DMT to recommend now?

Topical lidocaine patch Naproxen Oxycodone/acetaminophen Lamotrigine

9. A patient requires appropriate therapy for his mild to moderate pain. He currently takes no medications for chronic pain. In conjunction with education on nonpharmacologic methods, which would be the most appropriate first step in therapy for a duration of 5 days?

A. B. C. D.

13. A 71-year-old woman is seen in the clinic for a routine annual visit. As part of the evaluation, a Mini-Mental State Examination (MMSE) is performed, on which she scores 23/30. Her score 1 year ago was 26/30. Her medical conditions include HTN, osteoporosis, hypothyroidism, and overactive bladder. Her current medication list includes hydrochlorothiazide 12.5 mg/ day, lisinopril 10 mg/day, alendronate 70 mg once weekly, calcium/vitamin D 500 mg/400 international units twice daily, levothyroxine 100 mcg/day, and tolterodine 4 mg/day. Her blood pressure is controlled at 132/84 mm Hg, and examination results are otherwise unremarkable. A thyroid-stimulating hormone measurement 2 months ago was 2.2 mIU/L. Which factor is most likely contributing to this patient’s cognitive changes?

A. Ibuprofen 400 mg three times daily B. Acetaminophen/hydrocodone 500 mg/10 mg as 1 tablet every 4–6 hours as needed C. Tramadol 50 mg three times daily D. Celecoxib 200 mg daily

10. A 40-year-old man presents with newly diagnosed myasthenia gravis (MG). He has bilateral upper extremity muscle weakness, sagging of the right side of his face, drooping of his right eyelid, and fatigue. He is given a new prescription for pyridostigmine today at his neurology office visit. Which is the most appropriate information to provide the patient regarding his medication? A. Pyridostigmine is indicated to help prevent the further progression of MG. B. Pyridostigmine should be taken only on an asneeded basis to prevent the development of tolerance. C. The most common adverse effects include abdominal cramping, diarrhea, nausea, and vomiting. D. The effect of the drug can be seen only 1–2 weeks after treatment initiation.

A. B. C. D.

Hypothyroidism Alzheimer disease Tolterodine Levothyroxine

14. A 77-year-old man with recently diagnosed probable Alzheimer disease (AD) (MMSE 22/30) began treatment with galantamine ER 8 mg/day 3 months ago. After taking this dose for 1 month, his dose was titrated to galantamine ER 16 mg/day, but he experienced intolerance because of nausea; therefore, the dose was decreased to the original dose of 8 mg/day. He continued this dose for 6 more weeks without adverse effects (AEs), so his dose was again titrated to 16 mg/day about 1 week ago. The patient’s wife calls the clinic today to report that her husband’s symptoms have not improved, he has been having nausea, and he has not eaten well since the dose increase. Which is the best treatment strategy for this patient?

11. A 24-year-old woman was recently given a diagnosis of relapsing-remitting multiple sclerosis (RRMS). She currently describes minimal disability. Magnetic resonance imaging (MRI) reveals one white matter brain lesion; no demyelinating lesions are seen on her spinal cord. She is severely depressed, and she is not taking an antidepressant. Taking a risk-stratified approach, which disease-modifying therapy (DMT) is most appropriate to use for this patient? A. B. C. D.

Mitoxantrone Teriflunomide Dimethyl fumarate Glatiramer acetate

Interferon β-1a Interferon β-1b Glatiramer acetate Fingolimod

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 824

Neurology

A. Discontinue galantamine; initiate donepezil 5 mg/ day. B. Decrease the galantamine ER dose to 8 mg/day. C. Discontinue galantamine; initiate memantine 5 mg/day. D. Discontinue galantamine; initiate rivastigmine 6 mg twice daily.

and affect his functioning. Which is the best initial recommendation for addressing this patient’s symptoms? A. Add levodopa/carbidopa 100/25 mg three times daily. B. Add ropinirole 0.25 mg twice daily. C. Discontinue metoclopramide 10 mg four times daily. D. Discontinue amlodipine 5 mg once daily.

15. A 72-year-old woman will begin treatment with the rivastigmine patch for moderate AD. Which is the best information to provide the patient and caregiver?

18. A 72-year-old man presents to the clinic with a 6-month history of intermittent tremor in his hands and difficulty with his gait. He states that his symptoms have worsened since his last visit 3 months earlier. Laboratory test results and a computed tomography scan at his previous visit were normal. Physical examination reveals a resting hand tremor, greater in the left hand than in the right, which ceases with purposeful movement. It also shows mild cogwheel rigidity in both elbows, left greater than right. Postural reflexes and balance assessments are mildly abnormal. A gait assessment reveals reduced arm swing while walking. He states that the symptoms are affecting his daily life and that he is concerned about his ability to continue working. From his medical history and physical examination, he is given a diagnosis of Parkinson disease (PD). Which is the most appropriate initial therapy for this patient?

A. Liver function tests will be required during the first 12 weeks. B. The drug will significantly improve the symptoms of the disease. C. Adding vitamin E to rivastigmine will improve the efficacy of the drug. D. Medications such as diphenhydramine or chlorpheniramine should be avoided while taking this drug.

16. A 76-year-old woman has taken donepezil 10 mg/day for 11 months and has tolerated it well, except for mild to moderate nausea on rare occasions. She is in the clinic today with her daughter, who is concerned about her mother’s worsening memory and daily functioning. The patient’s MMSE score today is 15/30 compared with 19/30 1 year ago. No evidence of acute medical problems is found during the examination, and a depression screen is negative. Which is the most appropriate recommendation now to address the daughter’s concerns? A. B. C. D.

A. B. C. D.

Benztropine 0.5 mg twice daily Coenzyme Q10 900 mg daily Levodopa/carbidopa 100/25 mg three times daily Pramipexole 1 mg three times daily

19. A 68-year-old woman with a recent diagnosis of PD began treatment with levodopa/carbidopa 100/10 mg three times daily 5 days ago. She calls the clinic to report symptoms, including nausea and light-headedness. She states that her PD symptoms are improved and that her ability to move around and function is better, but the AEs are difficult to tolerate. Which is the best recommendation for this patient?

Increase donepezil to 23 mg/day. Decrease donepezil to 5 mg/day. Continue donepezil; add memantine therapy. Discontinue donepezil and monitor.

17. A 64-year-old man with HTN, osteoarthritis, type 2 diabetes, renal insufficiency (estimated creatinine clearance 25 mL/minute/1.73 m2), and gastroesophageal reflux disease presents to the clinic with symptoms of rigidity in the upper extremities, mild hand tremors, and gait changes. He takes hydrochlorothiazide 25 mg once daily and amlodipine 5 mg once daily for HTN; ibuprofen 400 mg twice daily as needed for osteoarthritis; glipizide 5 mg twice daily for type 2 diabetes; and metoclopramide 10 mg four times daily and omeprazole 20 mg once daily for gastroesophageal reflux. He states that the symptoms are difficult for him to tolerate

A. Continue levodopa/carbidopa; add rasagiline 0.5 mg/day. B. Decrease levodopa/carbidopa dose to 100/10 mg twice daily. C. Discontinue levodopa/carbidopa; add ropinirole 0.25 mg three times daily. D. Change levodopa/carbidopa dose to 100/25 mg three times daily.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 825

Neurology

20. A 72-year-old woman with PD has taken levodopa/ carbidopa for more than 6 years. Her current dose is 100/25 mg, 2 tablets in the morning and 1 tablet at noon, 4 p.m., and 8 p.m. She has motor complications (on/off symptoms, wearing-off) related to chronic levodopa therapy, so her physician added rasagiline 1 mg once daily in the morning to her regimen 1 week ago. She is in the clinic today and reports having AEs since the new medication was added, including nausea and involuntary movements, which are identified on examination as dyskinesias. Which is the best recommendation for this patient? A. Discontinue rasagiline; add selegiline 5 mg twice daily. B. Decrease levodopa/carbidopa dose to 100/25 mg 1 tablet in the morning and at noon, 4 p.m., and 8 p.m. C. Discontinue rasagiline; add ropinirole 0.25 mg twice daily. D. Continue levodopa/carbidopa and rasagiline; add amantadine.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 826

Neurology

I.  EPILEPSY A. Etiology 1. Provoked seizure: Differentiated from the diagnosis of epilepsy, a provoked seizure is an isolated seizure with a known cause. a. Withdrawal of illicit drugs or alcohol b. Drugs that can lower the seizure threshold or precipitate a seizure (Box 1) c. Metabolic disturbances such as hypoglycemia or severe hyponatremia d. Central nervous system (CNS) infections, febrile illness Box 1. Drugs That May Precipitate Seizures Agents or Class of Drugs

Acetylcholinesterase inhibitors Alcohol withdrawal Amphetamines Anticholinergics Antidepressants Antiemetics Antihistamines Antipsychotics Baclofen (abruptly withdrawn) β-Blockers Bupropion

Cephalosporin Cocaine Cyclosporine Dalfampridine Estrogen (can worsen epilepsy) Imipenem Iodinated contrast dyes (angiography) Isoniazid Lithium Local anesthetics Methotrexate

Methylphenidate Metronidazole Narcotics Penicillins Pyrimethamine Quinolones Sympathomimetics Tacrolimus Theophylline Tramadol

2. Epilepsy a. Propensity to have unprovoked seizures repeatedly b. Diagnosis made after two unprovoked seizures more than 24 hours apart c. Diagnosis can be made after one episode for high-risk populations, such as older adults or patients postcerebrovascular accident. d. Causes i. Idiopathic: 68% ii. Cerebrovascular disease: 8%–12% iii. Developmental disabilities: 6% iv. CNS trauma: 4% v. CNS tumors: 4% vi. CNS infections: 3% vii. Degenerative diseases: 2% viii. Other: 1% B. Pathophysiology 1. Epileptic seizures are the result of excessive excitation of neurons. 2. Clinical symptoms of a seizure depend on the site of seizure onset, amount of brain tissue irritability and spread, and degree of the impulse. 3. Seizures may form by several mechanisms; however, most drug therapy is targeted toward inhibitory neurotransmitters (γ-aminobutyric acid [GABA]), excitatory neurotransmitters (glutamate), sodium and calcium ion channels, and neuromodulators such as norepinephrine, serotonin, and acetylcholine (ACh).

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 827

Neurology

C. Clinical Presentation 1. International Classification of Epileptic Seizures provides a detailed description of the individual seizure types (Box 2). 2. International Classification of Epilepsy Etiologies identifies the etiologic classification that can help guide treatment and determine prognosis. a. More than one etiology can be present. b. Examples are structural, genetic, infectious, metabolic, immune or unknown etiologies. Box 2. International Classification of Epileptic Seizures

A. Focal seizures begin focally in one hemisphere of the brain and are further classified as aware vs. impaired awareness and motor onset vs. nonmotor onset. a. Focal aware b. Focal impaired awareness c. Focal motor (atonic, clonic) d. Focal nonmotor (sensory) e. Focal to bilateral tonic–clonic B. Generalized seizures involve bilateral hemispheres and are further classified as motor onset vs. nonmotor onset. a. Absence (blanking/staring spells) b. Atonic (lack of muscle tone) c. Clonic (sustained jerking movements) d. Myoclonic (brief, shock-like jerks) e. Tonic (increased muscle tone/stiffening) f. Tonic–clonic (jerking followed by stiffening) g. Infantile spasms

C. Combined generalized seizures and focal seizures

D. Unknown: Unable to distinguish between focal seizures and generalized seizures because insufficient information is available. E. Status epilepticus a. Prolonged seizure ≥30 min b. Can be life-threatening c. Medical emergency

F. Notable changes with the 2017 update: a. Term focal has replaced partial b. Term unknown has replaced idiopathic c. Terms no longer used: complex partial, simple partial, partial, secondarily generalized tonic–clonic

G. Note on classifications a. Despite the update in classifications, the FDA has not updated the epilepsy classifications used for package inserts b. Package inserts and approved indications still use the older terminology such as simple partial and complex partial, which would correlate to focal aware and focal impaired awareness, respectively, with the new terminology c. It is currently unknown if and when the FDA will adopt these new classifications and update package inserts accordingly. Information from Scheffer IG, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58:512-21.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 828

Neurology

D. Prognosis 1. Seizure freedom can be achieved with antiepileptic drugs (AEDs) appropriate for seizure type. 2. Around 50% of patients will respond—become seizure free—to the first AED trial. 3. 66% will respond by their second or third AED trial. 4. 30% will continue to have seizures with all treatment attempts a. Pharmacoresistant or refractory epilepsy is the diagnosis for these patients. b. Most will require a polytherapy approach for epilepsy treatment. 5. Mortality a. Life expectancy is shortened for patients with epilepsy. b. Epilepsy-related causes of death i. Suicide ii. Seizure-related trauma: drowning, falling from ladders, burns iii. Status epilepticus: 20% mortality rate for each incidence iv. SUDEP (Sudden unexplained or unexpected death in epilepsy): 2%–18% of all deaths in patients with epilepsy E. Pharmacologic Therapy (Tables 1–4) 1. AEDs (may be termed anti-seizure medication) can be considered narrow-spectrum or broad-spectrum drugs, depending on their efficacy against focal and generalized seizures (i.e., broad-spectrum AEDs have efficacy for both focal and generalized epilepsies). 2. Choice of AED should be based on seizure type, AED tolerability, potential adverse effects (AEs), and cost, together with the patient’s age, sex, concurrent medical conditions, organ function, and concomitant drugs. a. Treatment guidelines for new-onset epilepsy and treatment-resistant epilepsy were updated in 2018 from the previous guideline in 2004 (Tables 5–6). b. Recommendations in these guidelines are limited because of the lack of high-quality studies for newer AEDs, lack of studies of certain patient demographic groups, and/or lack of head-to-head trials between AEDs. Tables 5 and 6 summarize these recommendations. c. Guidelines state that in selecting AEDs, several patient- and drug-specific factors should be considered, as described previously in the choice of AED. 3. First-generation or traditional AEDs (year of U.S. Food and Drug Administration [FDA] label approval) a. Phenobarbital (1912) b. Primidone (1938) c. Phenytoin (1938) d. Ethosuximide (1960) e. Carbamazepine (1974) f. Valproate (1978) 4. Second- and third-generation AEDs (year of FDA label approval for epilepsy indication) a. Felbamate (1993) b. Lamotrigine (1993) c. Gabapentin (1994) d. Topiramate (1996) e. Tiagabine (1997) f. Oxcarbazepine (1999) g. Levetiracetam (2000) h. Zonisamide (2000) i. Pregabalin (2006) j. Lacosamide (2009) k. Rufinamide (2009)

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 829

Neurology

l. m. n. o. p. q. r.

Vigabatrin (2009) Ezogabine (2011)—permanently discontinued by manufacturer in 2017 Clobazam (2011) Perampanel (2012) Eslicarbazepine (2013) Brivaracetam (2016) Cannabidiol (2018) – Schedule V controlled substance when initially approved, but controlled designation was removed 4/2020 s. Stiripentol (2018) t. Everolimus (2018) u. Cenobamate (2019) 5. Certain AEDs are approved for very specific epilepsy syndromes/diagnosis, thus more detailed information on these medications is not included or is limited in this chapter given its general ambulatory care focus. The drug name and approved indications for which these AEDS are predominantly used are as follows: a. Vigabatrin: infantile spasms b. Cannabidiol: Lennox-Gastaut or Dravet syndrome in patients age 2 years or older and tuberous sclerosis complex in patients 1 year and older c. Stiripentol: Dravet syndrome in patients age 2 years or older taking clobazam d. Everolimus: tuberous sclerosis complex with subependymal giant cell astrocytoma that cannot be resected e. Fenfluramine: Dravet syndrome in patients 2 years and older; available only through a Risk Evaluation and Mitigation Strategies (REMS) program 6. Monitoring a. Bone disorders i. Consider dual-energy x-ray absorptiometry every 5 years depending on patient risks, such as being postmenopausal, taking an enzyme-inducing AED, and having risk factors for fracture ii. Supplementation: calcium (1200 mg mainly from dietary sources) and vitamin D (800 international units) b. Serum concentrations i. Use the concentration as a guide to therapy; treat the patient, not the concentration. ii. Trough concentration is most useful because it negates the variation in absorption. iii. Measure concentrations when trying to determine a drug–drug interaction (DDI), if seizures are not well controlled, if the patient is experiencing AEs, or if nonadherence is suspected. It is also useful to obtain a concentration measurement when the patient is doing well and to use this concentration as a historical control. iv. When obtaining a serum concentration measurement of a highly bound drug such as phenytoin or valproic acid, consider obtaining a free drug concentration or unbound serum concentration in certain situations: (a) If the patient has altered plasma protein binding, such as in malnutrition, pregnancy, and chronic hepatic or renal failure, or for burn survivors (b) If assessing the clinical effects of a DDI c. Driving restrictions i. Every state has different driving restrictions. ii. Most states require patients to be seizure free for a specific period, confirmed by their physician. d. Monitor for life-threatening rash i. Stevens-Johnson syndrome ii. Toxic epidermal necrolysis e. Potential cross-sensitivity between agents with an aromatic ring

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 830

Neurology

i. Phenytoin ii. Carbamazepine iii. Phenobarbital iv. Primidone v. Oxcarbazepine vi. Lamotrigine vii. Lacosamide (theoretical based on aromatic ring) viii. Rufinamide (theoretical based on aromatic ring) ix. Perampanel (based on aromatic ring) f. Discontinuing AEDs in the seizure-free patient i. Consider when seizure free for 2–5 years with a normal electroencephalogram finding while receiving treatment ii. Single seizure type, normal IQ, normal neurologic examination findings Table 1. Antiepileptic Drug Properties Drug Formulations

Brivaracetam (Briviact) 10-, 25-, 50-, 75-, 100-mg tablets; 10-mg/1-mL oral solution; 50-mg/5-mL IV solution as a single-dose vial

Indicationsa

Mechanism of Action

No current data

Synaptic vessel protein SV2A binding in the brain; mechanism for seizures is unknown

Lennox-Gastaut or Dravet syndrome at age ≥2 yr

No current data

Unknown

Cenobamate (Xcopri) 12.5-, 25-, 50-, 100-, 150-, 200-mg tablets

Eslicarbazepine acetate (Aptiom) 200-, 400-, 600-, 800-mg tablets

PS (adjunctive or monotherapy)

Cannabidiol (Epidiolex) 100-mg/1-mL oral solution

PS (adjunctive or monotherapy for age >16 yr); monotherapy approval added in 9/2017

Nonepileptic Indications

Carbamazepine (Tegretol) CPS; GTCS; mixed Chewable tablet 100 mg; tablet 200 seizure patterns mg; oral suspension 100 mg/5 mL; XR (Tegretol XR): 100-, 200-, and 400-mg tablets; XR (Carbatrol): 100-, 200-, and 300-mg capsules

Trigeminal neuralgia, Fast sodium channel blockade bipolar I

PS (adults)

No current data

Clobazam (Onfi) 5-, 10-, 20-mg tablets

LGS

Anxiety, alcohol Improves attraction of GABA to withdrawal syndrome its receptor site

Ethosuximide (Zarontin) 250-mg capsule; 250-mg/5-mL oral solution

Absence epilepsy

No current data

GTCS; PS; LGS (adjunctive)

No current data

Felbamate (Felbatol) 600-mg tablets; 650-mg/5-mL oral suspension

No current data

Sodium channel blocker; enhances GABA

Enhances sodium channel slow inactivation

Inhibits T-type calcium channels Fast sodium channel blockade; interacts with glutamate; enhances GABA

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 831

Neurology

Table 1. Antiepileptic Drug Properties (continued) Drug Formulations

Indicationsa

Nonepileptic Indications

Fosphenytoin (Cerebyx) phenytoin equivalents 50 mg/mL IV solution

GTCS; PS; SE

Lacosamide (Vimpat) 50-, 100-, 150-, 200-mg tablets; 200-mg/20-mL IV solution; 10-mg/mL oral solution

PS (adjunctive or No current data monotherapy for age ≥4 yr); pediatric approval added in 2017

Gabapentin (Neurontin) PS (adjunctive) 100-, 300-, 400-, 600-, and 800-mg tablets; 250-mg/5-mL oral solution

Lamotrigine (Lamictal) 25-, 100-, 150-, and 200-mg tablets; 2-, 5-, 25-mg chewable; 25-, 50-, 100-, 200-mg ODT; 25-, 50-, 100-, and 200-mg XR

Mechanism of Action

No current data

Fast sodium channel blockade

Pain, Postherpetic neuralgia

Interacts with the presynaptic voltage-gated calcium channels of the α-2-δ-1 subunit, modulates the release of excitatory neurotransmitters (glutamate, norepinephrine, substance P) Enhances sodium channel slow inactivation

GTCS; PS (adjunctive or monotherapy); LGS (adjunctive)

Trigeminal neuralgia, Fast sodium channel blockade; bipolar I inhibits glutamate

Levetiracetam (Keppra) 250-, 500-, 750-, and 1000-mg tablets; 100-mg/mL IV solution; 100-mg/mL oral solution; 500-mg XR

PS (adjunctive); myoclonic GTCS; primary GTCS

No current data

Synaptic vessel protein SV2A binding in the brain; mechanism for seizures is unknown

PS (adjunctive or monotherapy)

Bipolar I, trigeminal neuralgia

Fast sodium channel blockade

Perampanel (Fycompa) 2-, 4-, 6-, 8-, 10-, 12-mg tablets

PS (adjunctive for age ≥12 yr); GTCS (adjunctive)

No current data

AMPA glutamate receptor blocker

Insomnia

Enhances GABA

GTCS; PS; SE

Trigeminal neuralgia

Fast sodium channel blockade

PS (adjunctive)

Diabetic peripheral neuropathic pain, postherpetic neuralgia, fibromyalgia

Interacts with the presynaptic voltage-gated calcium channels of the α-2-δ-1 subunit, modulates the release of excitatory neurotransmitters (glutamate, norepinephrine, substance P)

Oxcarbazepine (Trileptal/Oxtellar XR) 150-, 300-, 600-mg tablets; 300-mg/5-mL oral suspension

GTCS; PS; SE; Phenobarbital (Luminal) myoclonic 15- (16.2), 30- (32.4), 60- (64.8), 97.2- (100) mg tablets; 20-mg/5-mL oral elixir Phenytoin (Dilantin) 30-, 100-, 200-, 300-mg XR; 125-mg/5-mL oral suspension; 50-mg chewable Pregabalin (Lyrica) 25-, 50-, 75-, 100-, 150-, 200-, 225-, 300-mg capsules

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 832

Neurology

Table 1. Antiepileptic Drug Properties (continued) Drug Formulations

Indicationsa

Primidone (Mysoline) 50-, 250-mg tablets

GTCS; PS

Stiripentol (Diacomit) 250-, 500mg capsules 250-, 500-mg powder for oral suspension

Nonepileptic Indications

Mechanism of Action

Essential tremor

Enhances GABA

Rufinamide (Banzel) 200-, 400-mg LGS (adjunctive); tablets PSa

No current data

Dravet syndrome for age ≥2 yr with clobazam

No current data

Prolongs sodium channel inactive state

Tiagabine (Gabitril) 2-, 4-, 12-, 16-mg tablets

PS (adjunctive)

No current data

Topiramate (Topamax, Trokendi XR, Qudexy XR) 15-, 25-mg sprinkle; 25-, 50-, 100-, 200-mg tablets; 25-, 50-, 100-, 150-, 200-mg ER tablets

Age ≥2 yr: LGS (adjunctive); PS (adjunctive or monotherapy), GTCS (adjunctive or monotherapy)

Migraine prophylaxis (monotherapy), neuropathic pain, essential tremor, weight loss

Fast sodium channel blockade; attenuates glutamate; enhances GABA; weak carbonic anhydrase inhibitor

Valproate (Depakene, Depakote, GTCS; PS; absence Depacon) seizures 250-mg capsules; 250-mg/5-mL oral syrup; 125-, 250-, 500-mg DR; 250-, 500-mg ER tablets

Migraine prophylaxis, trigeminal neuralgia, bipolar

Increases GABA; fast sodium channel blockade; inhibits T-type calcium channels

Vigabatrin (Sabril) 500-mg powder/solution; 500-mg tablet

No current data

GABA-transaminase inhibitor

Zonisamide (Zonegran) 25-, 50-, 100-mg capsules

Refractory CPS (adjunctive) Infantile spasm

No current data

Fast sodium channel blockade; inhibits T-type calcium channels; carbonic anhydrase inhibitor

PS (adjunctive)

Possibly by direct effects through GABA and indirect effects involving CYP inhibition (increases clobazam concentration) Enhances GABA

a Indications listed reflect approved indications per package inserts; however, for most antiepileptic drugs, seizure classifications and nomenclature have since been updated (see Box 2).

AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic; CYP = cytochrome P450; CPS = complex partial seizure; DR = delayed release; GABA = γ-aminobutyric acid; GTCS = generalized tonic–clonic seizure; LGS = Lennox-Gastaut syndrome; ODT = orally disintegrating tablets; PS = partial seizures; SE = status epilepticus; XR = extended release.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 833

Neurology

Table 2. Antiepileptic Drug Dosing and Metabolism/Elimination

Drug

Initial Dose, mg

Maintenance Dose, mg

Maximum Dose/Day

Typical Therapeutic Range

Metabolism/ Elimination

Brivaracetam

50 mg BID; may lower to 25 mg BID for hepatic impairment

50 mg BID; titrate based on clinical response from 25 mg to 100 mg BID

100 mg BID

Not established

Cannabidiol

2.5 mg/kg BID

5–10 mg/kg BID

20 mg/kg

Not established

Carbamazepine

200 mg BID IR: 800–1200 (suspension 100 mg divided 3–4 mg 4 times daily) times daily XR: 800–1200 mg divided BID

1200 mg

4–12 mcg/mL (carbamazepine10,11-epoxide active metabolite)

Cenobamate

12.5 mg daily

200 mg daily

400 mg

Not established

Clobazam

≤30 kg: 2.5 mg BID >30 kg: 5 mg BID

≤30 kg: 10 mg BID >30 kg: 20 mg BID

≤30 kg: 20 mg >30 kg: 40 mg

100–300 mcg/L

Hepatic CYP3A4 (weak inducer) Highly protein bound

1200 mg once daily

Not established

Hydrolysis to eslicarbazepine (major active metabolite) Glucuronidation Renal (90%)

Eslicarbazepine 400 mg once acetate daily

800 mg once daily

Hydrolysis by hepatic and extrahepatic amidase Hydroxylation mediated primarily by CYP2C19 CYP2C9 for hydroxylation of the propyl side chain Inhibitor of epoxide hydrolase Hepatic by CYP2C19, CYP3A4, UGT1A7, UGT1A9, UGT2B7 Hepatic (inducer/autoinducer) CYP3A4-S, CYP2C8

(minor)-S CYP1A2 ↑ CYP2B6 ↑ CYP2C8 ↑ CYP2C9 ↑ CYP2C19 ↑ CYP3A4 ↑ P-glycoprotein ↑

UGT2B7, UBT2B4, CYP2E1, CYP2A6, CYP2B6; lesser extent CYP2C19 and CYP3A4/5 Inhibits: CYP2B6, CYP2C19, CYP3A4 Induces: CYP2B6, CYP2C8, CYP3A4

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 834

Neurology

Table 2. Antiepileptic Drug Dosing and Metabolism/Elimination (continued)

Drug

Initial Dose, mg

Maintenance Dose, mg

Ethosuximide

3–6 yr: 250 mg/ day ≥6 yr: 500 mg/ day

Felbamate

1200 mg divided three or four times daily

Fosphenytoin (prodrug)

15–20 mg PE/kg 4–6 mg PE/kg/ IV loading dose, day IV/IM infusion up to a maximum rate of 150 mg PE/min; also can be given as IM

Gabapentin

≥12 yr: 300 mg TID 3–12 yr: 10–15 mg/kg/day divided TID

≥17 yr: 50 mg BID

Lacosamide

Lamotrigine

≥12 yr: 25 mg/day

Levetiracetam

IR ≥16 yr: 500 mg BID XR: 1000 mg/ day

Children: 20 mg/kg/day Adults: 500– 1000 mg divided BID

1200–3600 mg divided 3–4 times daily

900–3600 mg divided 3–4 times daily 3–12 yr: 10–15 mg/kg/day

200–400 mg/day

Maximum Dose/Day

Metabolism/ Elimination

1.5 g

Not established

Hepatic CYP3A4-S CYP2E1 (minor)-S

3600 mg divided 3–4 times daily

30–60 mcg/mL

Individualize dosing

10–20 mcg/mL

50% hepatic (inducer/ inhibitor) 50% renal CYP3A4-S CYP2E1 (minor)-S CYP2C19 ↓ CYP3A4 ↑

≥12 yr: 3600 mg

2–12 mcg/mL

Renal >95%

Not established

Renal (40%) CYP2C19 (30%)

3–12 yr: 15 mg/kg/day

400 mg

Individualize 225–375 mg/ day in 2 divided dosing doses (dose dependent on presence of other enzyme inducers/ inhibitions)

1000–3000 mg divided BID

Typical Therapeutic Range

3000 mg

Hepatic (inducer) CYP2C9-S CYP2C19-S CYP3A4 (minor)-S CYP2B6 ↑ CYP2C8 ↑ CYP2C9 ↑ CYP2C19 ↑ CYP3A4 ↑ Highly protein bound

2.5–15 mcg/mL

Hepatic UDPGT (weak inducer) Glucuronidation

8–26 mcg/mL

Renal (66%) Extrahepatic hydrolysis (24%)

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 835

Neurology

Table 2. Antiepileptic Drug Dosing and Metabolism/Elimination (continued)

Drug

Initial Dose, mg

Maintenance Dose, mg

Maximum Dose/Day

Typical Therapeutic Range

Oxcarbazepine

300 mg BID

1200 mg divided BID

2400 mg

Perampanel

2 mg once daily

8–12 mg once daily

12 mg once daily

Not established

Phenobarbital

0.25–0.5 mg/kg/ day divided BID or TID

1–3 mg/kg/day divided once or BID

200 mg

20–40 mcg/mL

Phenytoin

100 mg TID; 5–7 mg/kg/day Individualize phenytoin can be divided 1–3 daily dosing given as a loading dose

10–20 mcg/mL

Pregabalin

150 mg divided BID or TID

600 mg

Not established

Renal 90%

2000 mg

Not established

Hepatic (inducer)–phenobarbital component) CYP2C19-S CYP2E1 (minor)-S CYP2C9 (minor)-S CYP1A2-↑ CYP2B6 ↑ CYP2C8 ↑ CYP2C9 ↑ CYP3A4 ↑

Primidone

100–125 mg at night

Individualize dosing

250 mg 3–4 times daily

12.6–35 mcg/ mL (10-monohydroxycarbazepine [MHD] active metabolite)

Metabolism/ Elimination

Hepatic (moderate inducer/inhibitor doses >1200 mg) Glucuronidation CYP2C19 ↓ CYP3A4/5 ↑

CYP3A4-S CYP3A5-S Sequential glucuronidation Highly protein bound

Hepatic (inducer) CYP2C19-S CYP2E1 (minor)-S CYP2C9 (minor)-S CYP1A2 ↑ CYP2A6 ↑ CYP2B6 ↑ CYP2C8 ↑ CYP2C9 ↑ CYP3A4 ↑

Hepatic (inducer) CYP2C9-S CYP2C19-S CYP3A4 (minor)-S CYP2B6 ↑ CYP2C8 ↑ CYP2C9 ↑ CYP2C19 ↑ CYP3A4 ↑ Highly protein bound

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 836

Neurology

Table 2. Antiepileptic Drug Dosing and Metabolism/Elimination (continued)

Drug

Initial Dose, mg

Maintenance Dose, mg

Maximum Dose/Day

Rufinamide

400–800 mg divided BID

3200 mg divided BID

Stiripentol

50 mg/kg/day in 2–3 divided doses

Tiagabine

4 mg once daily

Reduce dose or 50 mg/kg/day discontinue gradually as clinically indicated

Topiramate

IR: 25–50 mg divided BID

IR: 100–400 mg divided BID

XR: 25–50 mg once daily

XR: 200–400 mg XR: 400 mg once daily

Individualize dosing up to 56 mg/day

Valproic acid

10–15 mg/kg/day May increase by 5–10 mg/kg/day in 2–3 divided at 1-wk intervals doses if total daily dose >250 mg

Vigabatrin

500 mg BID

Zonisamide

100 mg/day

3200 mg divided BID

Not established

Not established

Metabolism/ Elimination

Enzymatic hydrolysis of its carboxamide group CYP3A4 (weak inducer) CYP2E1 (weak inhibitor)

Hepatic CYP1A2, CYP2C19, CYP3A4 CYP1A2, CYP2B6, CYP3A4 both ↓ and ↑

56 mg divided 4 times daily

Not established

Hepatic CYP3A4-S Highly protein bound

IR: 1600 mg

5–20 mcg/mL

Hepatic (inducer/inhibitor in doses >200 mg) Glucuronidation CYP2C19 ↓ CYP3A4 ↑

1000 mg/day

3000 mg/day Individualize dosing up to 1500 BID; may increase by 500 mg/day at weekly intervals

100–600 mg/day in 1-2 divided doses; increase by 100 mg/day every 2 wk

Typical Therapeutic Range

600 mg/day

No additional benefit with dosages >400 mg/day

40–100 mcg/mL Highly protein bound Hepatic: 30%–50% appears in urine as a glucuronide conjugate, 40% mitochondrial β-oxidation, 10% CYP2C9 and CYP2C19 Glucuronidation ↓ CYP2C9 ↓

Not established

Not significantly metabolized CYP2C9 inducer 95% renal elimination

10–40 mcg/mL

Undergoes acetylation to N-acetyl zonisamide and CYP3A4-mediated reduction

↑ = inducer; ↓ = inhibitor BID = twice daily; CYP = cytochrome P450; IR = immediate release; IV = intravenous; MHD = monohydroxy derivative; TID = three times daily; UDPGT = uridine diphosphoglucuronyltransferase; UGT = UDP-glucuronosyltransferase; XR = extended release.

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Table 3. Antiepileptic Drug Interactions, Pregnancy Category, and Drug-Specific Adverse Affectsa Drug

Brivaracetam

Interaction with HBC

FDA Pregnancy Category/Ruleb

None known

Not established; may cause harm, based on animal studies

None known at normal doses

Cannabidiol

Carbamazepine

Decreases HBC efficacy

Cenobamate

Decreases HBC concentration (may reduce efficacy)

Clobazam

C

D

Not established

Drug-Specific Adverse Effects

Somnolence, sedation, dizziness, fatigue, nausea, vomiting, irritability, anxiety, depression, aggressive

Somnolence, sedation, fatigue, hepatotoxicity, suicidal behavior/ideation, decreased appetite, insomnia, irritability, agitation

Nausea, ataxia, visual distortion, diplopia, risk of osteopenia/osteoporosis, life-threatening rash,c,d hyponatremia/SIADH, c leukopenia, and aplastic anemia, dizziness (can occur if dose is too high)

Dizziness, somnolence/sedation (dose related), fatigue, headache, diplopia

Decreases HBC efficacy

C

Somnolence, lethargy, fever, aggressive behavior

Eslicarbazepine Decreases HBC acetate efficacy

C

Ethosuximide

None known

C

Dizziness, somnolence, nausea, diplopia, headache, vomiting, abnormal coordination, blurred vision, vertigo, fatigue

Fosphenytoin

Decreases HBC efficacy

D

Lacosamide

None known

C

Lamotrigine

HBC containing estrogen decreases efficacy of lamotrigine

C

Dose- and titration-dependent rash and life-threatening rash,c visual distortion, dizziness, headache, cardiac rhythm and conduction abnormalitiese

None known

Decreases HBC efficacy at higher doses

C

C

Sedation, behavioral changes, depression,c aggressionc

Decreases HBC efficacy at higher doses

C

Felbamate

Gabapentin

Decreases HBC efficacy

None known

Levetiracetam

Oxcarbazepine Perampanel Phenobarbital

Decreases HBC efficacy

Nightmares, sedation

C

Insomnia, weight loss, HA, nausea, aplastic anemia,c hepatotoxicity,c hepatic failurec Same as phenytoin

C

Myoclonus, pedal edema, weight gain,c irritability

Dizziness, HA, nausea, diplopia, PR-interval increase (minimal),c life-threatening rashc

Hyponatremia/SIADH,c dizziness, visual distortion, risk of osteopenia/osteoporosis, diplopia, lifethreatening rashc

Abnormal gait, dizziness, headache, somnolence, irritability, fatigue, mood disorder,c aggression, anger, homicidal ideationc

D

Connective tissue disorder, erectile dysfunction, sedation, risk of osteopenia/osteoporosis, cognitive impairment,c hyperactivity,c life-threatening rashc

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Table 3. Antiepileptic Drug Interactions, Pregnancy Category, and Drug-Specific Adverse Affectsa (continued) Drug

Interaction with HBC

Phenytoin

Decreases HBC efficacy

Pregabalin

None known

Rufinamide

Decreases HBC efficacy

Primidone

D

C

Decreases HBC efficacy

Stiripentol

None known

Tiagabine

None known

Topiramate

Decreases ethinyl estradiol efficacy at doses >200 mg/day

Valproic acid

FDA Pregnancy Category/Ruleb

HBC may decrease serum concentrations of valproic acid by ~20%

Same as phenobarbital

C

Shortened QT interval,c HA, somnolence, rash

Not established, may cause harm based on animal data C

D D (epilepsy); X (migraine)

None known

C

Zonisamide

None known

C

Ataxia, gingival hyperplasia,c nystagmus, risk of osteopenia/osteoporosis, dizziness, sedation, rash, systemic lupus erythematosus–like syndrome,c lifethreatening rashc IV: hypotension and cardiac arrhythmias when administered too rapidly (maximum 50 mg/min), tissue necrosis on extravasation (increased risk with IM vs. IV administration) Similar to gabapentin

D

Vigabatrin

Drug-Specific Adverse Effects

Somnolence, decreased appetite, agitation, ataxia, weight loss, hypotonia, nausea, tremor, dysarthria, insomnia Encephalopathy, knee-buckling, status epilepticus on abrupt withdrawalc Renal stones,c word-finding difficulties, paresthesia,c weight loss,c glaucoma,c metabolic acidosis,c oligohidrosisc

Tremor, encephalopathy,c pedal edema, hair loss, weight gain, pancreatitis,c hepatotoxicity (age female

Female > male

Female > male

Female > male

Pain Site

Unilateral in temporal and/or orbital regions

Bilateral, occipital, frontal

Usually unilateral

Usually unilateral

Pain Onset

Minutes

Aching, tight, squeezing, dull, band-like Hours

Pulsatile, throbbing, aggravated by physical activity

Pulsatile, throbbing, aggravated by physical activity

Attack Frequency

Daily during cluster periodb

Hours to days

Usually 4–24 hr

Usually 4–24 hr

Aura

No

Pain Characteristics

Pain Duration

Attack Periodicity Associated Symptoms

Searing, excruciating

30–90 min

Yes

No

No

Minutes to hours

Yesa

Minutes to hours

Variable

Variable

Variable

No

No (except for menstrual migraine)

No (except for menstrual migraine)

Ipsilateral nasal Typically no congestion, accompanying rhinorrhea, symptoms lacrimation, miosis, ptosis, restlessness

Nausea, vomiting, Nausea, vomiting, photophobia, photophobia, phonophobia, osmophobia phonophobia, osmophobia,

a Visual auras are most common. Visual symptoms include seeing flashing lights, seeing a zigzag pattern, and decreased vision or loss of vision in half the visual field. Sensory (paresthesias, numbness) and motor (weakness, aphasia) auras are less common. Auras can occur before, during, and after migraine pain. They do not necessarily stop when the migraine pain starts.

Cluster attacks can occur several times per day. Cluster headaches occur in clusters with cluster headaches occurring from every other day up to daily and several times per day. These cluster periods can last for weeks to months; then transition to a remission period with no cluster headaches lasting for months to years.

b

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B. Cluster Headache 1. Nonpharmacologic therapy a. Avoid triggers. i. Tobacco smoke ii. Vasodilators iii. Alcohol iv. Bright lights/glare v. Stress b. Avoid volatile substances. i. Gasoline ii. Oil-based paint c. Medications to avoid: Acetazolamide d. Cold compress/cold air 2. Pharmacologic therapy a. Acute treatment: Centered on fastest-acting abortives i. Oxygen 6–12 L/minute for 15–20 minutes or 100% oxygen at 7–10 L/minute for 15–30 minutes by non-rebreather face mask ii. Triptans (often used first line) (a) Sumatriptan nasal spray (b) Sumatriptan injection (c) Zolmitriptan nasal spray iii. Ergotamines (a) Slow onset of action limits usefulness. (b) Only anecdotal reports support use. iv. Intranasal lidocaine (a) Use when other acute therapies have failed or are contraindicated. (b) Fewer data to support use b. Preventive treatment i. May need to bridge with corticosteroid burst when starting a preventive (specifically verapamil and lithium) ii. Verapamil (a) First line (b) High doses needed (360–960 mg/day) (1) Heart rate, blood pressure, corrected QT (QTc) monitoring needed (2) AEs may limit dose titration (i.e., lower-extremity edema, heart block, fatigue). iii. Lithium (a) Second line (b) Evidence in chronic cluster headache (c) Use lowest effective dose, typically 600–900 mg/day in divided doses. (d) Target serum concentrations of 0.4–0.8 mEq/L. (e) Obtain serum concentrations during the first week and occasionally thereafter. iv. Galcanezumab (Emgality) (a) Approved in 2019 for the treatment of episodic cluster headache (also approved for migraine prevention) (b) Guidelines have not been updated; place in therapy still to be determined (c) Decreases the occurrence of cluster headaches during a cluster attack compared with placebo

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(d) 300 mg subcutaneously (administered as three consecutive injections of 100 mg each) started at the onset of cluster period and continued monthly until the end of cluster period (1) Efficacy/safety of continuing galcanezumab 300 mg monthly for more than 2 consecutive months is currently unknown. (2) Phase III clinical trial only gave two total doses (at baseline and at month 1) and measured outcomes through week 8. (3) Do NOT continue monthly doses chronically after the cluster period ends. v. Limited data with: gabapentin, topiramate, valproic acid, melatonin, memantine C. Tension-Type Headache 1. Nonpharmacologic therapy a. Stress management b. Relaxation therapy c. Mindfulness d. Biofeedback e. Modality treatments i. Ultrasonography ii. Transcutaneous electrical nerve stimulation iii. Hot/cold packs f. Physical therapy: Stretching, exercise, posture training g. Trigger-point injections 2. Pharmacologic therapy a. Acute treatment i. Analgesics (acetaminophen) ii. Nonsteroidal anti-inflammatory drugs (NSAIDs; naproxen, ibuprofen) iii. Combination analgesics with and without caffeine iv. Isometheptene-containing products: (a) Midrin (isometheptene/dichloralphenazone/acetaminophen) and Prodrin (isometheptene/ acetaminophen/caffeine) (b) Manufacturers stopped distribution in early 2018 in response to an FDA request because these products were designated as “DESI” drugs (Drug Efficacy Study Implementation) and lack efficacy data. (c) These products may be available through compounding pharmacies. b. Preventive treatment i. Tricyclic antidepressants (TCAs): Amitriptyline ii. Tetracyclic antidepressants: Mirtazapine iii. Muscle relaxants: Tizanidine has the most data. iv. Onabotulinum toxin A (Botox) for refractory cases D. Migraine 1. Pathophysiology a. Neurovascular pain syndrome i. Cortical spreading depression, leading to neurochemical alterations ii. Often associated with aura and can activate trigeminovascular system b. Trigeminovascular system activation i. Triggers neuropeptide/neurotransmitter release: Nitric oxide, substance P, calcitonin gene-related peptide (CGRP) ii. Results in neurogenic inflammation (vasodilation and leaky blood vessels)

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c. Neuropeptides, neurotransmitters, and specific pathways of migraine pathophysiology i. Studied as potential drug therapy targets for migraine treatment ii. Examples: Trigeminal ganglion, CGRP, glutamate release, pituitary adenylate cyclase-activating polypeptide Patient Case Questions 5–7 pertain to the following case. R.L. is a 32-year-old man who presents to the clinic with a headache. His headache has been ongoing for the past hour, and he describes the pain as “an ice pick through my eye.” The headache is unilateral, and the patient reports no symptoms of nausea or aura, but states that he has nasal congestion. He has had four headaches of this type during the past 2 years, occurring in the spring and fall. He notes that his father has these headaches as well. While interviewing the patient, you notice he is having trouble sitting still. 5. Which type of headache is does this patient most likely have? A. B. C. D.

Cluster headache Tension headache Migraine with aura Migraine without aura

6. Which is the best acute treatment for this patient’s headache? A. B. C. D.

Sumatriptan oral Non-steroidal anti-inflammatory drugs Verapamil Oxygen therapy

7. Which triptan would be best to recommend to this patient? A. B. C. D.

Almotriptan orally Rizatriptan orally Sumatriptan subcutaneous injection Zolmitriptan orally disintegrating tablet

2. Treatment options a. Nonpharmacologic therapy: i. Mindfulness ii. Thermal biofeedback iii. Cognitive behavioral therapy iv. Acupuncture v. Electrical nerve stimulation vi. Exercise vii. Avoid triggers! (keep headache diary to help identify triggers) (Box 3)

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Box 3. Migraine Triggers

Sleep: Increased or decreased Dehydration Stress Emotional liability Skipping meals Medications Alcohol Weather changes Smoking Strong perfumes Chocolate Caffeine Cheeses Hormone changes Physical activity Loud noises b. Pharmacologic therapy (episodic migraine) i. Abortive/acute therapies (Table 10) (a) Treatment pearls (Figure 1) (1) Choose appropriate therapy according to the characteristics of migraine headaches and situation (intensity, presence of nausea/vomiting or gastroparesis, onset of pain, duration of pain, patient is or is unable to sleep [e.g., at work vs. home]) (2) Mild/moderate migraine: Use over-the-counter analgesics as first line. Escalate therapy to prescription abortive options if analgesics are not effective. (3) Moderate/severe migraine: Use prescription options as monotherapy or as part of a combination therapy regimen. Examples: triptans, ergotamines, antiemetics, ditans, gepants (4) Combination therapy: (A) Effective, especially if the patient is receiving partial migraine pain relief from monotherapy (B) Using agents together is often more efficacious than using them as monotherapy. (C) Triptans, NSAIDs, and antiemetics are commonly used as part of combination therapy. (D) Antiemetics can improve absorption, and therefore the effectiveness, of triptans and/ or NSAIDs when taken concomitantly (gastroparesis is common during a migraine attack and can cause nausea/vomiting). (E) Combination therapy data with gepants and ditans are lacking, but according to clinical trials, gepants and ditans appear safe to combine with analgesics/NSAIDs. Ditans and triptans have similar mechanisms of action, and their combination should be avoided until more information is available. (5) Ensure education for patients to limit use of abortive therapies to 2 or 3 days per week to avoid risk of MOH. (6) Ensure adequate trial of acute medication treatment before determining efficacy or tolerability; adequate trial equals treating two or three migraine attacks. (b) Analgesics (1) Over-the-counter: NSAIDs, aspirin, effervescent aspirin, acetaminophen, acetaminophen/ aspirin/caffeine; effervescent aspirin has a faster onset than oral tablets

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(2) Prescription: Ketorolac intranasal spray, diclofenac powder for oral solution, celecoxib oral solution: These formulations have a faster onset of action than oral tablets. (c) Triptans (1) Predominantly partial agonists of serotonin receptor 1B/1D, with little to no activity at serotonin receptor 1F (2) Differ by onset of action, duration of action, route of administration, and cost (3) Failure with one triptan does not predict failure with another; if the first triptan fails to provide benefit, another should be tried. (4) When selecting triptans, consider specific characteristics of the patient’s migraine attack, including time to peak intensity, level of associated symptoms, and frequency of attack recurrence within 24 hours to individualize treatment (Table 11). (A) Examples • Patients who awaken with a migraine at peak intensity and with severe disability, photophobia, phonophobia, and nausea should use a triptan with a fast onset of action. For these patients, consider a non-oral option, if possible, given nausea: nasal spray or injection. If not an option, use the orally disintegrating form (so that patient does not have to drink water with dose) • For patients who have migraine attacks that reach peak intensity within 3 hours with significant disability and obtain relief with rizatriptan, but migraine pain recurs within 8–10 hours: change to a triptan with a longer duration of action, such as naratriptan or frovatriptan, to prevent migraine recurrence. (5) AEs: (A) Chest tightness, throat discomfort, nausea, paresthesia, flushing (B) Vasoconstricting AEs that occur with triptans are caused by activation of serotonin receptor 1B. (C) Contraindicated with vascular conditions: Uncontrolled HTN, coronary artery disease, peripheral vascular disease, stroke (D) Triptans should not be used together with ergot derivatives within 24 hours of each other because of additive vasoconstrictive effects. (6) Serotonin syndrome, a DDI concern? (A) See Psychiatric Disorders chapter for serotonin syndrome definition, presentation, etc. (B) In 2006, the FDA issued a clinical warning on the risks of life-threatening serotonin syndrome with combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) with triptan medications. (C) In 2010, the American Headache Society published a position paper on this drug interaction, concluding that currently available evidence does not support limiting the use of triptans with SSRIs or SNRIs, or use of triptan monotherapy, because of concerns for serotonin syndrome. (D) Data analyses from large patient registries also support the safety of triptan use with concomitant SSRIs or SNRIs. (E) However, caution should be used if the patient often uses triptans, especially with the agents having the longest half-lives (e.g., frovatriptan, naratriptan). (F) Triptans metabolized by monoamine oxidase (MAO) (almotriptan, rizatriptan, sumatriptan, zolmitriptan) should not be used within 14 days of an MAO-A inhibitor because of the risk of serotonin syndrome. (d) Ergotamines/dihydroergotamine (DHE) (1) Oral, intranasal, rectal, and parenteral formulations available

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(2) Strong vasoconstricting effects treat migraine pain but result in cardiovascular AEs; contraindicated in patients with cardiovascular disease, including coronary artery disease, peripheral vascular disease, and uncontrolled HTN (3) Significant nausea and vomiting: Limit use; antiemetics given before injectable DHE therapy to help with nausea and vomiting AEs (4) DHE mesylate (Migranal) nasal spray is better tolerated than other ergotamines; must be primed before use, patients should NOT tilt head back and should NOT inhale. New intranasal DHE product marketed as having improved formulation for drug delivery currently in clinical trials (e) Antiemetics (1) Taken at onset of migraine with/without other abortive therapies (though the most data exist when taken with other abortive therapies) (2) Treats gastroparesis (responsible for nausea/vomiting-associated migraine symptoms) and can improve the absorption of other pain medications it is taken with (e.g., triptan, NSAID) (3) Oral options include metoclopramide, prochlorperazine, and promethazine. (4) Have efficacy in treating acute migraine, even in the absence of nausea and vomiting (5) If possible, avoid newer serotonin antagonist antiemetics (e.g., ondansetron) because these agents are not effective for migraine headache pain; will only treat nausea and vomiting (f) Gepants (1) Small molecule CGRP receptor blockers (2) For acute migraine treatment: Ubrogepant approved 12/2019; rimegepant approved 2/2020 (3) Trials included patients with cardiovascular risk factors or a history of myocardial infarction, transient ischemic attack, or stroke as long as event occurred more than 6 months before enrollment. (4) AEs: Nausea, dizziness, urinary tract infections (5) Triptans, NSAIDs, and combination therapies should be tried as first- and second-line options before a gepant. However, gepants fill a niche because they can be used in patients at high cardiovascular risk or with a history of a cardiovascular/cerebrovascular event. (6) Ubrogepant: Dose adjustments for severe hepatic/renal impairment and weak-moderate CYP3A4, breast cancer resistant protein (BCRP), and/or P-glycoprotein (P-gp) inhibitors. Avoid with strong CYP3A4 inducers and inhibitors. (7) Rimegepant: Dose adjustments for moderate CYP3A4 inhibitors. Avoid with strong CYP3A4 inhibitors, CYP3A inducers, and inhibitors of BCRP and P-gp. (8) According to the available data, overuse of gepants does not appear to cause MOH. (g) Ditans (1) Highly selective agonist for serotonin receptor 1F and blocks trigeminal neurons; lacks the vasoconstricting serotonin effects seen with triptans (2) Lasmiditan approved 10/2019; trials included patients with cardiovascular risk factors, and one trial included patients with a history of cardiovascular disease (3) AEs (dose related): Dizziness, fatigue, lethargy, nausea, paresthesias, and somnolence (related to CNS permeability). Patients should not drive or operate machinery for 8 hours after a dose. (4) Schedule V controlled substance (5) Triptans, NSAIDs, and combination therapies should be tried first as first- and secondline options before a ditan. However, lasmiditan, like gepants, fills a niche because it can be used in patients at high cardiovascular risk or with a history of a cardiovascular/ cerebrovascular event. (6) Avoid in severe hepatic impairment and with P-gp and BCRP substrates.

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(h) Miscellaneous agents: (1) Magnesium: Possibly effective for menstrual migraines and during pregnancy (2) Intranasal lidocaine (i) Opioids and butalbital-containing products (1) Newer data suggest these options should be avoided, except as a last resort. (2) More effective migraine-specific medications are available. (3) Use of opioids and butalbital increases the risk of MOH, dependence, suboptimal outcomes, and chronification of migraine. Table 10. Abortive Therapies for Migraine Drug Class

Analgesics

Combination analgesics

Drug Name

Doses (mg)

Aspirin

APAP

Butalbital, APAP, caffeine (Fioricet)

a

Butalbital, aspirin, caffeine (Fiorinal)

a

NSAIDs

Diclofenac (Cataflam)

APAP 3000 mg

50/325/40 50/325/40 50–100

NTE 6 tablets NTE 6 tablets 150 mg

200–1200

Diclofenac (Cambia)

50

50 mg

1; MR in 4 hr

3–4 sprays/day

Butorphanol IM

1–2 mg

4 mg

Belladonna alkaloids, ergotamine, phenobarbital

0.2/0.6/40

NTE 16 tablets/wk

Caffeine/ergotamine (Cafergot)

1/100

NTE 6 tablets/24 hr

Dihydroergotamine nasal spray (Migranal)

4 mg/mL 0.5 mg each nostril; MR in 15 minutes

Ketorolac nasal spray (Sprix) Butorphanol nasal spray

APAP with codeine

Methadone IM

Meperidine IM/IV Ergotamine alkaloids

250/250/65

3000 mg

Ibuprofen

Naproxen

Opiate analgesicsa

–

325–1000

Aspirin, APAP, caffeine

Maximum Dose/Day

325–650

Ergotamine sublingual (Ergomar)

Dihydroergotamine IM or SC

Dihydroergotamine nasal spray (Trudhesa)

250–500

15.75 mg each nostril every 6-8 hrb Individualize dosing

2; MR after 30 min

1; MR every hr until symptoms resolve

4 mg/mL 0.725 mg each nostril; MR in 1 hr

1200 mg

1250 mg of base 126 mgb

Individualize dosing

NTE 3 tablets/24 hr; 5 tablets/wk

NTE 3 mg/24 hr 2 mg 2.9 mg

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Neurology

Table 10. Abortive Therapies for Migraine (continued) Drug Class

Triptans

Drug Name

6.25 or 12.5; MR in 2 hr

25 mg

Frovatriptan (Frova)

2.5; MR in 2 hr

7.5 mg

Sumatriptan nasal spray (Imitrex)

Sumatriptan nasal powder (Onzetra) Sumatriptan SC injection

1 or 2.5; MR after 4 hr

25, 50, or 100; MR in 2 hr 5, 10, or 20; MR in 2 hr

22 (11 in each nostril); MR in 2 hr

5 mg

200 mg 40 mg

44 mg

4 or 6; MR in 1 hr

12 mg

Sumatriptan/naproxen (Treximet)

85/500; MR in 2 hr

NTE 2 tablets/24 hr

Eletriptan (Relpax)

20 or 40; MR in 2 hr

80 mg

Sumatriptan Dose Pro needle-free delivery system Rizatriptan (Maxalt)

Zolmitriptan tablets (Zomig)

Gepants

Maximum Dose/Day

Almotriptan (Axert)

Naratriptan (Amerge) Sumatriptan tablets (Imitrex)

Ditans

Doses (mg)

Zolmitriptan nasal spray Lasmiditan (Reyvow)

6; MR in 1 hr

5 or 10; MR in 2 hr

1.25, 2.5, or 5; MR in 2 hr 5; MR in 2 hr

50, 100, 200; no more than one dose should be taken within 24 hr

Ubrogepant (Ubrevly)

50 or 100; MR in 2 hr

Rimegepant (Nurtec ODT)

75; do NOT repeat dose within 24 hr

NTE 12 mg in 24 hr

30 mg 10 mg 10 mg

200 mg Safety of treating > 4 migraines in a 30-day period has not been established 200 mg Safety of treating > 8 migraines in a 30-day period has not been established 75 mg Safety of treating > 15 migraines in a 30-day period has not been established

APAP = acetaminophen; IM = intramuscular; IV = intravenous; MR = may repeat; NTE= not to exceed; ODT = orally disintegrating tablet; SC = subcutaneous.

a Although opioids and barbiturates (including butalbital) are options, they are not recommended as first-line agents or on a long-term basis because they are habit-forming and can contribute to the development of medication overuse and rebound headache.

These agents have lower dosing recommendations for patients age 65 yr and older, patients who are renally impaired, and patients weighing less than 50 kg. These agents should not be used for more than 5 days.

b

Information from Sprix [package insert]. Wayne, PA: Egalet US, 2016.

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Recommend nonpharmacologic strategies as appropriate: migraine trigger avoidance, wellness (sleep, exercise, limited caffeine consumption), behavioral interventions (relaxation therapy, biofeedback, cognitive therapy), etc.

Mild to Moderate Migraine Pain Severity

Moderate to Severe Migraine Pain Severity

Little to No Disability

Significant Disability

Lack of response

Choose and adjust triptan on the basis of migraine characteristics, pharmacokinetics, formulation, and risk of adverse effects. May be influenced by insurance restrictions

Triptan

OTC analgesic (APAP or NSAID)

Patients who do not respond to one triptan may respond to another

Lack of response after adequate triala

Reassess and adjust treatment plan as appropriate depending on response

Adjunctive antiemetic for nausea and/or vomiting or to increase absorption of a concomitant oral agent as appropriate

Partial or No Response • Ensure treatment is early

Nausea +/- Vomiting Present

• Increase dose

• Choose a non-oral formulation

• Add NSAID and/or antiemetic

• If nausea only, can try an ODT

• Try a different triptan or formulation

• Add antiemetic

Migraines Quickly Reach Peak Intensity

Migraine Recurs within 24 Hours After Onset

• Ensure treatment is early

• Add a long-acting NSAID

• Use a fast-acting oral triptan or choose a non-oral formulation

• Choose a long-acting triptan

• Add a fast-acting NSAID

• Can combine a long-acting triptan with a faster-acting NSAID

Lack of response after adequate trial of ≥2 triptansa OR Contraindication to triptan class

Lasmiditan, Rimegepant, or Ubrogepant

Choice made according to migraine characteristics, pharmacokinetics, formulation, risk of adverse effects. May be influenced by insurance restrictions

Figure 1. Proposed treatment algorithm for Acute Migraine Management

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Neurology

Table 11. Pharmacokinetic Characteristics of Triptans, Ditans, and Gepants Brand Drug (generic)

Route

Onset

Duration

Half-Life

Metabolism

Amerge (naratriptan)

Oral

1–3 hr

Long

6 hr

Axert (almotriptan)

Oral

30–120 min

Short

3–4 hr

Renal, 50%, CYP (several channels)

Frova (frovatriptan)

Oral

2–3 hr

Longest

26 hr

Imitrex (sumatriptan)

Oral/nasal spray SC injection Needle-free delivery system/auto-injector

20–30 min/ 15 min/ 10–15 min ~10 min

Short

2.5 hr/2 hr/ 115 min

30–120 min

Short

2–3 hr

MAO

Relpax (eletriptan)

Oral

30 min

Short

4 hr

CYP3A4

Zomig/Zomig-ZMT (zolmitriptan)

Oral and nasal spray/ ODT

Oral: 45 min Nasal: 15 min

Short

3 hr

CYP and MAO

Oral

20–40 min

Long

5–6 hr

Non-CYP, nonMAO hepatic metabolism Inhibitor of P-gp and BCRP

Nurtec ODT (rimegepant)

ODT

1 hr

Long

11 hr

Ubrevly (ubrogepant)

Oral

1 hr

Long

5–7 hr

CYP3A4, P-gp, BCRP, and, to a lesser extent, CYP2C9

Triptans

Maxalt/Maxalt-MLT (rizatriptan) Treximet (sumatriptan/ naproxen)

Ditans

Reyvow (lasmiditan)

Gepants

Oral/ODT

Oral

20–30 min

Short

2 hr

Renal 40%, MAO 27%, CYP 12%

CYP1A2, renal 33%a MAO

CYP3A4 and P-gp substrate

BCRP = breast cancer resistance protein; CYP = cytochrome P450; MAO = monoamine oxidase; ODT = orally disintegrating tablets; P-gp = P-glycoprotein; SC = subcutaneous. Minimal risk of drug–drug interactions.

a

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 861

Neurology

Patient Case Questions 8–10 pertain to the following case. R.P. is a 35-year-old female athlete with a low heart rate and a history of migraines who comes to the clinic with a headache. She describes the headache as unilateral and pulsating. It has persisted for the past 24 hours and is aggravated by bright lights and physical activity. The patient also has nausea, but she has not vomited. She has this type of headache about twice per month. She does not currently take prescription drugs for her migraines but is interested in taking them now because her over-the-counter naproxen tablets are not controlling the pain. 8. Which would be best to recommend to this patient for migraine prophylaxis? A. B. C. D.

Continue naproxen. Discontinue naproxen; start topiramate 25 mg orally daily. Discontinue naproxen; start sumatriptan 50 mg orally daily. Discontinue naproxen; start propranolol 20 mg orally three times daily.

9. The patient states that because of the nausea, she would prefer not to swallow a tablet. Which would be the best abortive therapy? A. B. C. D.

Almotriptan Frovatriptan Naratriptan Rizatriptan

10. The patient was given a prescription for eletriptan 20 mg at the onset of migraine. She often flies out of the country for business and has noticed that eletriptan does not last long enough for the migraine to be fully aborted. Which agent would be most appropriate for this patient to take on a long flight? A. B. C. D.

Almotriptan Frovatriptan Rizatriptan Sumatriptan

ii. Preventive treatment (Table 12) (a) Initiated to reduce frequency of migraine headaches; preventive medications are underused (b) Selection is based on level of evidence of preventive option and patient-specific characteristics. (c) Onset of effectiveness: (1) Older oral therapies. Must be initiated at a low dose and then titrated to target dose. Benefit may not be seen until 6–8 weeks at target dose. Consider assessing response after a 2- to 3-month trial. (2) CGRP monoclonal antibodies (CGRP-mAbs). Set doses, titration not needed. Initial benefit may be seen after 4 weeks. Benefit from eptinezumab may be seen sooner than 4 weeks. Full benefit should be assessed after 3 months (if dosed monthly) or 6 months (if dosed quarterly). (3) CGRP oral small-molecule antagonists ("gepants") (rimegepant and atogepant). Set doses, titration not needed. Newly approved; clinical trials assessed benefit after 9–12 weeks as primary end point (4) OnabotulinumtoxinA (for chronic migraine only). Initial benefit may be seen after 4 weeks. Benefit should be assessed after two or three treatments (6–9 months). (d) Goal is to decrease migraine frequency by 30%–50% from baseline.

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Neurology

(e) Can consider tapering off/discontinuing preventive treatment after 3–6 months of successful treatment, but, for fear of migraines increasing, many patients choose to remain on treatment if they are achieving benefit (f) Current guidelines recommend that patients try at least two oral migraine preventive options, unless contraindications exist, before trying a CGRP mAb. Table 12. Preventive Medications for Migraine Medication

Level of Evidencea,b

Metoprolol

A

Propranolol

A

Nadolol

B

Timolol

Clinical Notes/Compelling Indications

HTN Propranolol can be used during pregnancy

A

Atenolol

B

Candesartan

C

Diabetes, HTN

U

HTN

A

Epilepsy, obesity

C

Epilepsy, trigeminal neuralgia

B

Depression, anxiety, insomnia Nortriptyline sometimes used instead in clinical practice because it has fewer anticholinergic effects Caution in older adults

Lisinopril

C

Clonidine

C

Divalproex sodium/ sodium valproate

A

Verapamil

Topiramate

Carbamazepine

Epilepsy

Gabapentin

U

Venlafaxine

B

Depression, anxiety

B

Can cause diarrhea; can be used during pregnancy

Ac

For chronic migraine prevention only In-office administration only, every 12 wk

Amitriptyline

Cyproheptadine

Magnesium

Riboflavin

OnabotulinumtoxinA Frovatriptan

Naratriptan

Zolmitriptan

C

B

A

B B

Neuropathy, epilepsy

Can cause weight gain

For short-term prevention of menstrual migraines only. Usually started 2 days before menses onset and taken daily for 5–7 days; then discontinued until next cycle

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Neurology

Table 12. Preventive Medications for Migraine (continued) Medication

Level of Evidencea,b

Erenumab

Fremanezumab Galcanezumab Eptinezumab Rimegepant Atogepant

Not yet established

Clinical Notes/Compelling Indications

No pharmacokinetic DDIs

In-office administration only No pharmacokinetic DDIs

First and only migraine medication FDA approved for both acute and preventive treatment; has not been shown to cause MOH Approved for migraine prevention only; has not been shown to cause MOH

a Butterbur was previously designated as level A, but it is no longer recommended for prevention because of concerns about its safety regarding hepatotoxicity after changes in the manufacturing process.

According to the American Academy of Neurology (AAN) 2012 guideline update for episodic migraine prevention. Level A = established as effective; Level B = probably effective; Level C = possibly effective; Level U = inadequate or conflicting data to support or refute medication efficacy.

b

According to the AAN botulinum neurotoxin practice guideline update.

c

DDI = drug-drug interaction; HTN = hypertension; MOH = medication-overuse headache.

3. Notable mention: CGRP-targeted medications a. CGRP medications provide a novel, migraine-specific mechanism of action, targeting either the CGRP ligand or the CGRP receptor. b. Small molecule receptor blockers, termed gepants: i. Target the CGRP receptor ii. Orally administered (a) Ubrogepant: Acute migraine only (approved) (b) Rimegepant: Acute migraine: 75 mg at onset of migraine; migraine prevention 75 mg every other day (c) Atogepant: Migraine prevention only; once-daily dosing iii. Zavegepant intranasal: Clinical studies ongoing for acute migraine c. CGRP mAbs (Table 13) i. Erenumab, fremanezumab, galcanezumab, eptinezumab ii. Indication: Preventive migraine treatment; all studied in patients with episodic and chronic migraine headaches iii. Subcutaneous or intravenous administration iv. Because of the long half-lives of these drugs, women should be advised to discontinue treatment at least 3–5 months before pregnancy; safety is unknown during pregnancy/breastfeeding. v. Clinical findings: (a) Published trials with erenumab, fremanezumab, and galcanezumab show statistically significant reductions in mean monthly migraine days over placebo for patients with episodic and chronic migraine headaches, and medications appear to be well tolerated (a low incidence of AEs and similar to placebo). (b) Benefits can occur as soon as 4 weeks after starting treatment and possibly sooner with eptinezumab specifically. (c) Most common AEs: Reactions related to injection (e.g., pain, erythema), upper respiratory infections, back pain, GI symptoms (e.g., constipation, especially with erenumab). (d) Erenumab has been associated with new-onset or worsening of pre-existing HTN and constipation with serious complications.

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Neurology

d. Long-term safety concerns with CGRP blockade i. CGRP is present in the CNS and peripheral nervous system (enteric nervous system being highly innervated with CGRPergic fibers) and is involved in several physiologic processes as follows: (a) Regulation of blood pressure (b) Maintenance of vascular homeostasis during ischemic events (c) Inflammatory processes (d) Wound healing (e) GI motility ii. In CGRP-mAb trials, patients with a history of cardiovascular or cerebrovascular events in the past 12 months were often excluded; hence, the safety of CGRP-mAbs in this patient population largely remains undefined. To date, no increased risks of vascular events have been identified in long-term safety trials, but the populations included in these trials may have had lower vascular risk, given the exclusion criteria used (Ashina 2019; Camporeale 2018). iii. The combination of a CGRP-mAb and a gepant is not contraindicated or given a warning in the respective package labeling, but the combination also was not allowed in either agent’s phase III clinical trials. A limited number of case reports and small population observational studies of this combination have not found significant safety concerns at this time. iv. Little is known about the efficacy and safety of preventively treating chronic migraine with the combination of onabotulinumtoxinA and a CGRP-mAb because patients treated with onabotulinumtoxinA were excluded from CGRP-mAb clinical trials. Small retrospective studies suggest that the combination of onabotulinumtoxinA with a CGRP-mAb is more effective than onabotulinumtoxinA alone, and no adverse reactions related to the combination were observed, but the follow-up periods were limited. v. Overall, more data on the use of these new drugs directed at CGRP in combination for migraine prevention are needed, including long-term efficacy and safety. e. Place in therapy i. Remains unknown because these medications have not fully been incorporated into acute or prevention treatment guidelines and have not been assigned a level of evidence grade. ii. However, in 2019, the American Headache Society published a consensus statement on integrating new migraine medications, including those that target CGRP, into clinical practice (Headache 2019;59:1-18). iii. A trial of a CGRP mAb should generally be reserved for patients who have had an inadequate response or inability to tolerate (due to side effects) at least two oral migraine preventive drugs of Level A or B evidence. Table 13. Anti-CGRP Monoclonal Antibodies Generic (Brand) Name

Target

Dose

Eptinezumab (Vyepti)

CGRP ligand

100 or 300 mg IV every 3 mo

Fremanezumab (Ajovy)

CGRP ligand

225 mg SC once monthly OR 675 mg SC every 3 mo

Erenumab (Aimovig)

Galcanezumab (Emgality)

CGRP receptor CGRP ligand

70 or 140 mg SC once monthly

240 mg SC loading dose; then 120 mg SC once monthly

CGRP = calcitonin gene-related peptide.

4. Chronic migraine a. Risk factors for chronic migraine i. Greater frequency of migraine attacks

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Neurology

ii. Use of pain medication more often iii. Obesity iv. Snoring v. High caffeine consumption vi. Psychiatric comorbidities and stressful life events b. Treatment includes lifestyle changes, nonpharmacologic therapies, and acute and preventive pharmacologic management. c. Evidence and guidelines for acute and preventive treatment of chronic migraine are lacking. d. Treatment recommendations are often extrapolated from the episodic migraine population and guidelines. e. Preventive therapies i. OnabotulinumtoxinA (Botox) (a) First approved treatment for chronic migraine (b) Level A evidence, according to the 2016 AAN botulinum toxin practice guidelines (c) Evidence is insufficient to compare this agent with other preventive approaches, according to the 2016 guidelines; however, results of the 2019 FORWARD study (sponsored by Allergan) indicated greater clinical usefulness and tolerability for onabotulinumtoxinA than for topiramate in chronic migraine. ii. CGRP mAbs (a) Erenumab, fremanezumab, galcanezumab, eptinezumab (b) All with phase II and/or phase III trial efficacy data in chronic migraine (c) Place in therapy not yet fully determined (2019 American Headache Society consensus statement) 5. Patient education a. Abortive therapy i. Routes of administration: Intramuscular, subcutaneous, oral, nasal, and needle-free injection ii. Use products at onset of headache. iii. Package inserts provide detailed patient instructions. iv. Counsel on adequate trials of medication, and set expectations for the results of treatment. v. Treat at least two migraines before determining efficacy and tolerability. b. Preventive therapy i. Efficacious preventive trial = at least a 30%–50% reduction in attack frequency ii. Educate on dose titration needed for oral migraine–preventive medications, expectations for time until benefit can be seen, and importance of adherence to therapy. c. Identify triggers. d. Monitoring, encourage headache diary 6. Cost a. Oral triptans are generically available and are thus often affordable for patients. b. Nasal spray and injectable triptans are more costly and may be cost-prohibitive for patients and/or have formulary restrictions. c. Costs vary for the many different formulations of sumatriptan injection and sumatriptan nasal sprays. d. New abortive medications (ditans, gepants) are more costly; likely have formulary restrictions e. CGRP mAbs are costly medications but may be better tolerated and improve adherence long term compared with traditional oral preventive migraine treatment options (e.g., AEDs, β-blockers).

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Neurology

III.  MULTIPLE SCLEROSIS A. Diagnosis 1. Multiple sclerosis (MS) is diagnosed on the basis of the McDonald criteria (last updated in 2017). 2. Involves attacks (new signs/symptoms) and number/location of T2 lesions revealed on magnetic resonance imaging (MRI) of the brain and spinal cord a. A lumbar puncture and a test for the presence of cerebrospinal fluid-specific oligoclonal bands may also be done to make or confirm the diagnosis. b. Characteristic locations of MS lesions on MRI: periventricular, cortical or juxtacortical, infratentorial brain regions, and spinal cord (e.g., cervical and thoracic spine) c. T2 lesions reflect total lesion load (new and old lesions). d. MRIs with gadolinium contrast will reveal gadolinium-enhancing T1 lesions, which are associated with new or newly active lesions. 3. Major update with the 2017 criteria (updated from 2010) a. Patients with a diagnosis of clinically isolated syndrome (CIS) may now receive an MS diagnosis if cerebrospinal fluid-specific oligoclonal bands are present. b. Based on the 2017 update, more patients may now meet the criteria for a formal MS diagnosis. B. Clinical Presentations and Course of Illness 1. Signs and symptoms a. Often reflective of the area of the brain or spinal cord that is damaged by demyelination and axonal damage i. Examples: optic neuritis/visual concerns, sensory or gait abnormalities, paresthesias, weakness, spasticity, bladder or bowel dysfunction, cognitive changes ii. Most common: fatigue iii. Many patients present with concerns of vision problems or paresthesia (e.g., tingling, numbness, burning) before the formal MS diagnosis. b. Secondary: complications from primary symptoms (e.g., urinary tract infection) c. Tertiary: Effect of disease on everyday life 2. MS relapse/exacerbation/attack a. New neurologic symptom lasting at least 24 hours occurring in the absence of infection, illness, or fever and resulting in either complete or incomplete recovery b. Not to be confused with a pseudo-relapse (also termed pseudo-exacerbation), defined as follows: i. Temporary worsening of symptoms caused by a temperature or stress-related triggers ii. Lasts less than 24 hours iii. Does not involve inflammation of myelin (e.g., fatigue worsened after being outside on a hot day) 3. Defining clinical course of MS a. Previous MS subtypes (1996) were updated in 2013 with MS disease phenotypes. b. The basic MS subtypes remain (Table 14) but have been modified to incorporate disease activity and disease progression (e.g., active or not active and with progression or without progression). i. Activity (active or not active) (a) Determined by clinical relapses and/or MRI activity (gadolinium contrast-enhancing lesions; new or unequivocally enlarging T2 lesions) (b) Assessed at least annually ii. Progression (a) Measured by clinical evaluation, assessed at least annually (b) Example: disability assessment using the Expanded Disability Status Scale

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Neurology

iii. Relapsing MS (a) With this 2013 update, CIS, relapsing remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS) are all considered to be relapsing forms of MS. (b) As such, all package labeling of disease-modifying therapies (DMTs) approved for relapsing MS before implementation of these subtypes were updated in the summer of 2019 to include all three subtypes: CIS, RRMS, and active SPMS. iv. Descriptors of progressive disease (a) Active and with progression (b) Active but without progression (c) Not active but with progression (d) Not active and without progression (stable disease) v. Graphics depicting the disease courses of RRMS, SPMS, and PPMS can be found on the National Multiple Sclerosis Society website at https://www.nationalmssociety.org/What-is-MS/Types-of-MS. Table 14. 2013 Update to Phenotypic Classifications of Multiple Sclerosis Terminology

Relapsing remitting (RR)

Definition

Characterized by relapses that occur from disease onset that are partly or completely reversible

Secondary progressive Gradual progression (disability (SP) accumulation) after an initial relapsing disease course

Notes

Most common type, ~85% of all MS diagnoses New MRI lesions often correlate with true clinical attacks Usually occurs ≥ 15–20 yr after first clinical MS event Diagnosed retrospectively after history of gradual worsening with no discrete relapses

Primary progressive (PP)

Gradually evolving progression without discrete relapses from disease onset

Radiographically isolated syndrome (RIS)

Incidental findings of lesions occurring in an Not considered an official MS phenotype as of MS-like distribution but without symptoms 2013 update

Clinically isolated syndrome (CIS)

Worse prognosis than RRMS

The first neurologic syndrome lasting at least Does not meet criteria for MS 24 hr with or without lesions on an MRI (in Around 60% with abnormal brain MRI will an MS-like distribution) develop MS

C. Pharmacologic Treatment 1. Treatment of acute exacerbations: Decreases time to recovery from relapse; does not prevent future relapses or affect overall MS disease progression a. High-dose corticosteroid i. Methylprednisolone 500–1000 mg intravenously daily for 3–5 days or prednisone 500–1000 mg orally daily for 3–5 days ii. AEs: sleep disturbance, a metallic taste, GI upset, mood alteration, impaired blood glucose control b. Plasma exchange or intravenous immunoglobulin for patients with more severe attacks or whose condition is not responding to intravenous corticosteroids c. Corticotropin hormone: approved for treatment of MS relapse; however, not used often, given high cost and likely similar efficacy to steroids (no head-to-head trials)

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Neurology

2. DMTs—alter the course of the illness and diminish progressive disability over time (Table 15); reduce but do not eliminate MS relapses and MRI activity a. Can be classified as moderately effective (ME) or highly effective (HE) i. ME-DMTs: Immunomodulators and some immunosuppressants ii. HE-DMTs: Immunosuppressants iii. Considerations: ME- and HE-DMT classifications are controversial. Higher efficacy outcomes in clinical trials appear not to always correlate to the outcomes in clinical practice or observational studies. Example: Dimethyl fumarate’s classification as ME-DMT versus HE-DMT is controversial; on the basis of clinical experience, appears to be more ME b. ME-DMT versus HE-DMT i. Determining whether moderately and highly effective is largely based on evidence from placebocontrolled trials, observational studies, and clinical practice, given that head-to-head trials are minimal. ii. In general, with increasing efficacy of DMT, drug risk also increases (e.g., AE potential, safety monitoring needed). 3. Symptomatic therapy to maintain quality of life (Table 16)

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Interferon β-1a: Avonex: IM 30 mcg weekly Rebif: SC: 22–44 mcg TIW Plegridy (pegylated): SC 125 mcg every 14 days

Reduce activation and entry of T cells into CNS; reduce adhesion molecules and helper T cells

870

Relapsing forms of MS

Copolymer mimics myelin basic protein and may act as a decoy; triggers immune system shift toward type 2 helper T cells

Glatiramer acetate (Copaxone/Glatopa)

Relapsing forms of MS

Routine: CBC, LFTs, TSH

Less common: Depression, abnormalities, abnormalities in CBC, LFTs, TFTs

Less common: Transient 15- to 30-min post-injection reaction (anxiety, chest pain, palpitations, flushing)

None

Baseline: CBC, LFTs, TSH

Monitoring

Common: ISR, flu-like symptomsb

Adverse Effects

SC: 20 mg or 40 mg TIW Common: ISR, lipoatrophy

Interferon β-1b: Betaseron/Extavia: SC 250 mcg every other day

SC/IM Slowly titrate doses

Interferon βs (multiple brands)

ME-DMT

Route/Dose

Name of Drug Class/ Generic (brand name) MOA Indicationa

Table 15. Disease-Modifying Therapies for Multiple Sclerosis

• FDA-approved generics available • Product-specific autoinjectors are not interchangeable • Post-injection reaction is not cardiac and is temporary

• Encourage hydration to reduce severity/frequency of flu-like symptoms • May worsen psoriasis • Use with caution in individuals with severe depression

Clinical Pearls/Other Highlights

Neurology

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Route/Dose

871 PO

Relapsing forms of MS

Inhibits pyrimidine synthesis; 7–14 mg daily prevents proliferation of T and B cells

Teriflunomide (Aubagio)

Monomethyl fumarate (Bafiertam): 95 mg BID for 7 days; then 190 mg BID

Fumaric acid ester derivatives PO (multiple brands) Dimethyl fumarate Antioxidant and anti(Tecfidera): 120 mg BID inflammatory effects for 7 days; then 240 mg mediated through nuclear BID factor 2 pathway Diroximel fumarate Relapsing forms of MS (Vumerity): 231 mg BID for 7 days; then 462 mg BID

ME- or HE-DMTc

Name of Drug Class/ Generic (brand name) MOA Indicationa Monitoring

Baseline: CBC, LFTs, BP, pregnancy test, TB test Routine: ALT monthly for first 6 mo; then LFTs and/or CBC as needed

Common: Alopecia, diarrhea, nausea, paresthesias, nasopharyngitis Less common: Leukopenia, increased BP, hepatotoxicity

Common: Flushing, nausea, Baseline: CBC, LFTs diarrhea, abdominal pain Routine: CBC,* LFTs *Consider interruption Less common: of therapy if ALC < 500/ Lymphopenia, elevated mm3 for > 6 mo LFTs, rash

Adverse Effects

Table 15. Pharmacologic Agents for Disease-Modifying Therapy in MS (continued)

• Serum concentrations persist for up to 2 yr. Accelerated elimination procedure option available, if needed (i.e., pregnancy), involves cholestyramine or activated charcoal • Effective contraception needed, even in women whose male partners are taking teriflunomide • Avoid if pregnancy desired, given teratogenicity concerns (black box warning) • Avoid live-attenuated vaccine • Low PML riskd

Diroximel fumarate: • Approved on the basis of bioequivalence data only (made by same manufacturer as dimethyl fumarate) • May have better GI tolerability than dimethyl fumarate Monomethyl fumarate: • Active metabolite of Tecfidera

Dimethyl fumarate: • Poorer tolerability (GI toxicity) than other oral DMTs per observational studies • Use with caution in individuals with GI-related disorders (e.g., irritable bowel syndrome) • Generic pending

• Low PML risk, may be related to severe lymphopeniad • Can take ASA for flushing

Clinical Pearls/Other Highlights

Neurology

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872

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Not FDA approved for MS

Anti-CD20 chimeric monoclonal antibody; depletes B cells

Rituximab (Rituxan)

B cell–directed monoclonal antibody:

Relapsing forms of MS, PPMS

Anti-CD20 humanized monoclonal antibody; depletes B cells

Ocrelizumab (Ocrevus)

B cell–directed monoclonal antibody:

Dosing used in trials and retrospective studies: 1000 mg on days 1 and 15; then 1000 g every 6 mo; thereafter: 1000 mg × 1; then 500 mg every 6 mo; thereafter: 500 mg every 6 mo

Varies, given lack of FDA approval for MS indication

Baseline: CBC, LFTs, SCr, UA, TFT, skin examination, VZV serology, TB test, HIV screen, pregnancy test

Monitoring

Same as ocrelizumab

Same as ocrelizumab

Routine: CBC; immunoglobulins as needed

Baseline: HBV screening, CBC, immunoglobulins

REMS-required monitoring: Starting after the first infusion series and Less common: ITP, autoim- for 48 mo after last treatmune kidney disease ment cycle: CBC, SCR, UA monthly, TSH every 3 mo, skin examination yearly

Common: IRR, nasopharyngitis, nausea, vomiting, UTI, fatigue, URI, herpes viral infections, urticaria, pruritus, secondary thyroid autoimmunity fungal infection, arthralgia, diarrhea, paresthesias, rash

Adverse Effects

IV: 300 mg on days 1 and Common: IRR, infection 15; 600 mg every 6 mo Less common: thereafter Hypogammaglobu­linemia, HBV reactivation

Second course: 12 mg/ day on 3 consecutive days 12 mo after first course

First course: 12 mg/day on 5 consecutive days

Two treatment courses:

Anti-CD52 monoclonal antibody decreases B and T cells

Relapsing forms of MS – For patients with an inadequate response to ≥ 2 DMTs

IV

Route/Dose

Alemtuzumab (Lemtrada)

HE-DMT

Name of Drug Class/ Generic (brand name) MOA Indicationa

Table 15. Pharmacologic Agents for Disease-Modifying Therapy in MS (continued)

Biosimilars: Rituximab-abbs (Truxima), rituximabpvvr (Ruxience)

Same as ocrelizumab

• Premedications can reduce IRR (typically an analgesic, an antihistamine, and a corticosteroid) • May monitor B cells • Avoid live-attenuated vaccine • Low PML riskd

• Black box warning: Fatal autoimmune conditions, infusion reactions, malignancies • Use with caution in individuals with thyroid disorders • 2018 FDA MedWatch Safety Alert: Risk of stroke and blood vessel wall tears • Avoid live-attenuated vaccine • Low PML riskd

Clinical Pearls/Other Highlights

Neurology

Cumulative dose of 3.5 mg/kg PO divided into two treatment courses (1.75 mg/kg per treatment course)

Purine nucleoside analog; selectively depletes peripheral lymphocytes

873 IV: 300 mg every 4 wk

Natalizumab (Tysabri)

Relapsing forms of MS

Selective adhesion molecule inhibitor; prevents migration of inflammatory cells across BBB

Each treatment course is divided into two treatment cycles

RRMS and active SPMS – For patients who have had inadequate response to, or have been unable to tolerate, at least one other DMT a

PO

SC: 20 mg at weeks 0, 1, and 2; then 20 mg every month thereafter

Route/Dose

Cladribine (Mavenclad)

Relapsing forms of MS

Anti-CD20 fully human monoclonal antibody; depletes B cells

Ofatumumab (Kesimpta)

B cell–directed monoclonal antibody:

HE-DMT (continued)

Name of Drug Class/ Generic (brand name) MOA Indicationa

Less common: PML, leukocytosis, hepatotoxicity

Common: Rash, arthralgia, headache, respiratory tract infection

Less common: Liver injury, infections, opportunistic infections, nephrotoxicity, severe dermatologic reactions, malignancy

Common: URI, headache, nausea, lymphopenia

Less common: Hypogammaglobu­linemia, HBV reactivation

Common: ISR, infection

Adverse Effects

• Block box warning: Risk of teratogenicity in women and men. Effective contraception during and 6 mo after last dose of treatment course • Avoid live-attenuated vaccine

• First dose recommended to be performed under guidance of health care professional • Available as prefilled syringes and single-use autoinjector pen • Avoid live-attenuated vaccine • Low PML riskd

Clinical Pearls/Other Highlights

• Highest risk of PML of all DMTs (black box warning). Risk is directly associated with antiJCV antibody–positive status, therapy duration, Routine: Anti-JCV and history of immunosuppressant use antibody every 6 mo (per • Avoid use if anti-JCV antibody positive REMS); CBC, LFTs as • Avoid live-attenuated vaccine needed

Baseline: CBC, LFTs, anti-JCV antibody

Administer anti-herpes prophylaxis if ALC < 200 mm3

Between/after treatment courses: CBC 2 and 6 mo after start of each treatment course; LFTs if clinically indicated

Baseline: CBC, TB, HIV, and HBV screen; pregnancy test; LFTs

Routine: CBC; immunoglobulins as needed

Baseline: HBV screening, CBC, immunoglobulins

Monitoring

Table 15. Pharmacologic Agents for Disease-Modifying Therapy in MS (continued)

Neurology

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

PO: 0.5 mg daily

S1P receptor modulator:

874

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Relapsing forms of MS

S1P1 and S1P5 selective receptor modulator; sequesters T cells in lymphoid tissue

Ozanimod (Zeposia)

S1P receptor modulator:

Relapsing forms of MS

PO Days 1–4: 0.23 mg daily Days 5–7: 0.46 mg/day Day 8 and thereafter: 0.92 mg daily

Dose reduction required in patients with CYP2C9*1/*3 or *2/*3 genotype; maintenance dose: 1 mg daily

Maintenance dose: 2 mg/ day

Initiation: 0.25 mg on days 1–2, 0.5 mg on day 3, 0.75 mg on day 4, 1.25 mg on day 5

Siponimod (Mayzent)

S1P1 and S1P5 selective receptor modulator; sequesters T cells in lymphoid tissue

PO

S1P receptor modulator:

Relapsing forms of MS

S1P nonselective receptor modulator; sequesters lymphocytes in lymphoid tissue

Fingolimod (Gilenya)

HE-DMT (continued)

Route/Dose

Name of Drug Class/ Generic (brand name) MOA Indicationa Monitoring

Clinical Pearls/Other Highlights

Ozanimod: Baseline: CBC, LFTs, VZV serology, OCT test, • FDO not recommended. If ECG abnormalities present, refer to cardiologist ECG, BP, heart rate Less common: Bradycardia, • Drug interactions with CYP2C8 inducers/ macular edema, risk of inhibitors, BCRP inhibitors, and MAO inhibitors Routine: CBC, LFTs BCC, URI • Despite increased receptor selectivity, AEs are similar to fingolimod • Missed doses: If a dose is missed during the first 2 wk of treatment, restart titration. If a dose is missed after the first 2 wk, continue with treatment as planned • Women: Continue to use effective contraception for 3 mo after discontinuing Common: HTN, elevated LFTs

Baseline: CBC, LFTs, All S1P modulators VZV serology, OCT test, • Avoid live-attenuated vaccine ECG, BP, heart rate • Low PML riskd (most data with fingolimod) • Risk of severe MS rebound with discontinuation Initiation: FDO; observe (most data with fingolimod) Less common: Bradycardia, for bradycardia for 6 hr • Avoid or use with caution in individuals with a AV conduction slowafter first dose monitorhistory of skin cancers such as BCC (most data ing, HSV infections, ing heart rate, BP, and with fingolimod) macular edema, asthma ECGs exacerbation, seizure, BCC, Fingolimod: melanoma Routine: CBC, LFTs; • First S1P approved OCT 3–4 mo after • FDO recommended for all starting • Missed doses: If ≥ 15 consecutive doses missed, Common: Headache, HTN, Baseline: CYP2C9 repeat FDO is needed elevated LFTs genotype, CBC, LFTs, • Women: Continue to use effective contraception VZV serology, OCT test, for 2 mo after discontinuing Less common: Bradycardia, ECG, BP, heart rate AV conduction slowing, Siponimod: HSV infections, macular Initiation: FDO only if • FDO only if baseline heart conditions present edema, asthma exacerbapresence of sinus brady- • Starter pack with slow dose titration reduces need tion, risk of BCC cardia (heart rate < 55 for FDO requirement beats/min), heart block, • Despite increased receptor selectivity, AEs similar or history of MI or heart to fingolimod failure • Missed doses: If ≥ 4 consecutive maintenance doses missed, repeat dose titration is needed Routine: CBC, LFTs, • Women: Continue to use effective contraception OCT 3–4 mo after for 10 days after discontinuing starting

Common: Headache, diarrhea, back pain, elevated LFTs, cough, lymphopenia

Adverse Effects

Table 15. Pharmacologic Agents for Disease-Modifying Therapy in MS (continued)

Neurology

Route/Dose

Less common: Bradycardia; macular edema; risk of BCC, URI

Common: HTN, elevated LFTs

Adverse Effects

Clinical Pearls/Other Highlights

Baseline: CBC, LFTs, Ponesimod: VZV serology, OCT test, • FDO recommended only for patients with sinus ECG, BP, heart rate bradycardia (heart rate < 55 beats/min), first- or second-degree AV block, or history of MI or HF Routine: CBC, LFTs, occurring > 6 mo before treatment and in stable OCT test (particularly in condition patients with diabetes) • Starter pack with slow dose titration reduced need for FDO requirement • Despite increased receptor selectivity, adverse effects similar to fingolimod • Missed doses: If ≥ 4 consecutive maintenance doses missed, repeat dose titration is needed • Women: Continue to use effective contraception for 7 days after discontinuing

Monitoring

875

Preinjection acetaminophen or NSAIDs may reduce flu-like symptoms.

ALC = absolute lymphocyte count; ASA = acetylsalicylic acid; AV = atrioventricular; BBB = blood-brain barrier; BCC = basal cell carcinoma; BCRP = breast cancer resistance protein; BID = twice daily; BP = blood pressure; CBC = complete blood cell count; DMT =disease-modifying therapy; ECG = electrocardiogram; FDO = first dose observation; HBV = hepatitis B virus; HE = highly effective; HF = heart failure; HSV = herpes simplex virus; HTN = hypertension; IM = intramuscular(ly); IRR = infusion-related reaction; ISR = injection site reaction; ITP = immune thrombocytopenic purpura; IV = intravenous(ly); JCV = John Cunningham virus; LFT = liver function test; MAO = monoamine oxidase; ME = modestly effective; MI = myocardial infarction; MOA = mechanism of action; MS = multiple sclerosis; OCT = optical coherence tomography; PML = progressive multifocal leukoencephalopathy; PO = oral(ly); PP = primary progressive; RR = relapsing remitting; S1P = sphingosine-1-phosphate; SC = subcutaneous(ly); SP = secondary progressive; TB = tuberculosis; TFT = thyroid function test; TIW = three times weekly; UA = urinalysis; URI = upper respiratory infection; VZV = varicella zoster virus.

d

Most PML cases occur in patients previously exposed to natalizumab. For some, the change from natalizumab was prompted by an anti-JCV antibody positive status and/or > 2 yr of treatment. For patients with no prior natalizumab exposure, some PML cases were associated rarely with severe lymphopenia (as with dimethyl fumarate) or with a history/concomitant use of immunosuppressive therapies. For these reasons, risk of PML for non-natalizumab DMTs is overall considered low.

c

ME- and HE-DMT classifications are controversial. Higher efficacy outcomes in clinical trials appear not to always correlate to the outcomes in clinical practice or observational studies. For this reason, these DMTs are listed as they are in this table.

b

a Relapsing forms of MS are considered CIS, RRMS, and active SPMS according to the 2013 update in MS phenotypes. When siponimod and cladribine were approved (2019), these DMTs may have initially appeared to have been the first to be approved for use in SPMS; however, this is not true when considering the updates in phenotypes. Siponimod and cladribine trials enrolled patients meeting the definition of active SPMS, a relapsing form of MS. Subsequently, all package labeling for DMTs approved for relapsing MS were updated in summer 2019 to reflect the 2013 updates in phenotypes.

PO Days 1 and 2: 2 mg daily Ponesimod (Ponvory) Days 3 and 4: 3 mg daily S1P selector receptor modula- Days 5 and 6: 4 mg daily tor; sequesters lymphocytes Day 7: 5 mg daily in lymphoid tissue Day 8: 6 mg daily Day 9: 7 mg daily Relapsing forms of MS Day 10: 8 mg daily Day 11: 9 mg daily Day 12–14: 10 mg daily Day 15 and thereafter: 20 mg daily

S1P receptor modulator:

Name of Drug Class/ Generic (brand name) MOA Indicationa

Table 15. Pharmacologic Agents for Disease-Modifying Therapy in MS (continued)

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Table 16. Pharmacologic Agents for Symptomatic Management in Multiple Sclerosis Drug

Route/Dose

Clinical Use

Amantadine

PO: 100–200 mg/day

Fatigue

Modafinil

PO: 200–400 mg/day

Fatigue

Oxybutynin

PO: 5–30 mg/day Transdermal (3.9 mg/24 hr): 1 patch, every 3–4 days

Bladder dysfunction

PO: 2–8 mg/day

Bladder dysfunction

Desmopressin

PO: 0.2 mg at bedtime

Nocturia

Sildenafil

PO: 25–100 mg Erectile dysfunction ~1 hr before sexual activity

Baclofen

PO: 5–80 mg/day, usually in three divided doses

Spasticity

Tizanidine

PO: 2–36 mg/day (every 6–8 hr as needed, up to TID)

Spasticity

PO: 200–1200 mg/day, in 2–3 divided doses

Pain (trigeminal neuralgia/ chronic central pain)

Oxcarbazepine

PO: 100–600 mg BID

Pain (trigeminal neuralgia/ chronic central pain)

Phenytoin

PO: 300 mg BID

Pain (trigeminal neuralgia/ chronic central pain), paroxysmal spasms

Tolterodine

Carbamazepine

Adverse Effects

Insomnia, flushing, metallic taste, fluid retention, electrolyte abnormalities, hyperglycemia, livedo reticularis Insomnia, nightmares, dizziness, nausea, HTN, headache, peripheral edema

Insomnia, headache, nausea, asthenia, dry mouth, constipation, decreased sweating Dry mouth, constipation, decreased sweating, drowsiness, headache

Dry mouth, headache, dyspepsia, constipation, dizziness, blurred vision Flushing, headache, nausea, hypotension, HTN, tachycardia, hyponatremia

Headache, flushing, diarrhea, dyspepsia, rash, visual dysfunction, myocardial infarction, priapism, abrupt withdrawal can cause seizures Fatigue, somnolence, muscle weakness/hypotonia, nausea, seizure

Dry mouth, somnolence, mild hypotension, constipation, nausea, muscle weakness, abnormal liver function test results, blurred vision or diplopia, rash, hyponatremia caused by SIADH, osteoporosis, aplastic anemia/ bone marrow suppression Fatigue, sedation, nausea, rash, dizziness, blurred vision or diplopia, rash, hyponatremia caused by SIADH; rarely, Stevens-Johnson syndrome or aplastic anemia/bone marrow suppression, osteoporosis Fatigue, sedation, nausea, rash, dizziness, gingival hyperplasia, osteoporosis, hirsutism, ataxia

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Table 16. Pharmacologic Agents for Symptomatic Management in Multiple Sclerosis (continued) Drug

Route/Dose

Clinical Use

Gabapentin

PO: 100–600 mg/day

Pregabalin

PO: 75–150 mg BID

Duloxetine

PO: 60-120 mg/day

Donepezil

PO: 20–60 mg/day

Memory function

Dalfampridinea

PO: 10 mg BID

Improve walking

Adverse Effects

Pain (trigeminal neuralgia/ Fatigue, ataxia, dizziness, sedation, chronic central pain), nausea, myoclonus, headache, weight paroxysmal spasms, spasticity gain, pedal edema, irritability Pain (trigeminal neuralgia/ Same as for gabapentin chronic central pain), paroxysmal spasms, spasticity Neuropathic pain

Ataxia, nausea, dizziness, somnolence, emotional lability, blurred vision/ diplopia, edema Nausea, dry mouth, diarrhea, insomnia, dysuria, dizziness, decreased appetite, gastritis, HTN; increased risk of suicidal ideation, worsening of depression

Urinary tract infection, insomnia, dizziness, headache, nausea, vomiting, weakness, seizures

BID = twice daily; HTN = hypertension; PO = orally; SIADH = syndrome of inappropriate antidiuretic hormone secretion; TID = three times daily.

a When only available as brand name (Ampyra), dalfampridine was a high-cost medication; however, it is now generically available (as of 2018) and no longer a high-cost medication.

Patient Case Questions 11 and 12 pertain to the following case. M.B. is a 33-year-old woman with recently diagnosed CIS. Her presenting symptom was optic neuritis. An MRI reveals two white matter lesions in the brain. She has no disability and is currently taking sertraline for treating uncontrolled depression. 11. Which is the most appropriate therapy now? A. B. C. D.

Glatiramer acetate Alemtuzumab Cladribine Interferon β-1a

12. M.B. has taken a moderately effective DMT for 3 years. Her condition was previously stable; however, in the past year, she has reported four attacks, and an MRI reveals several new lesions. She now meets the formal diagnostic criteria for MS. Which is the best DMT to recommend currently? A. B. C. D.

Mitoxantrone Interferon β-1b Teriflunomide Ocrelizumab

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D. Approach to MS Treatment (choosing DMT) 1. AAN published a 2018 update to the 2002 guidelines. a. Provides recommendations on initiating, changing, and discontinuing DMTs b. Encourages providers to engage in ongoing dialogue with patients about treatment throughout the disease course c. Patients with RRMS should be offered DMT, whereas patients with PPMS should be offered ocrelizumab. d. Note that the new guidelines were published before the approval of siponimod, ozanimod, ponesimod, cladribine, monomethyl fumarate, diroximel fumarate, and ofatumumab. e. Recommendations for using rituximab in the guidelines are limited because it does not have FDA label approval for MS, despite a great deal of clinical data. Because of these extensive clinical data, however, rituximab is in many cases an appropriate substitute for ocrelizumab. f. New guidelines do not provide a specific DMT algorithm for treating RRMS (e.g., does not identify first-, second-, third-line DMT recommendations) 2. Starting DMT a. Consider adherence, tolerability, AEs, safety monitoring, and, in women of childbearing potential, plans for pregnancy when deciding on DMT. b. Choosing a DMT for a newly diagnosed patient continues to evolve, even after the 2018 published guidelines. i. Risk-stratified approach (a) Choose DMT according to the risk of disease progression. (b) Choose moderately effective DMT for patients with better prognostic risk factors and highly effective DMT for patients with poorer prognostic risks (Table 17). ii. Escalation versus early-intensive approach (a) Long-term outcomes may be better for patients who are started on an HE-DMT (early-intensive) after diagnosis compared with patients for whom an escalation approach is taken (e.g., an MEDMT is started and then escalated to an HE-DMT option if disease breakthrough occurs) (b) Data on the best approach to treatment after diagnosis (escalation vs. early-intensive) continue to evolve, and prescribing practices will likely be influenced pending the results of ongoing prospective, randomized trials on escalation versus early-intensive (TREAT-MS and DELIVERMS trials). 3. Changing DMT a. Consider changing with breakthrough disease activity, intolerable AEs, other AEs (e.g., laboratory abnormalities), safety concerns (e.g., seroconversion to JC virus-antibody positive on natalizumab), nonadherence b. Breakthrough disease activity: one or more relapses, two or more new lesions, or 1 year of worsening disability 4. Discontinuing DMT a. Women should discontinue DMT before conception unless benefits outweigh risks. Some DMTs have specific recommendations before pregnancy because of the following safety concerns: i. Fingolimod, siponimod, and ozanimod should be discontinued before conception (Table 15). ii. Teriflunomide must undergo accelerated elimination procedure (activated charcoal or cholestyramine), and conception should not occur until plasma concentrations are less than 0.02 mg/L. b. In SPMS, treatment discontinuation should be considered for patients who have 2 years of no relapses or MRI activity and use a wheelchair (less than 5 m ambulation with assistance), especially if age 55 or older, but the topic of indefinite discontinuation remains controversial.

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5. Cost a. Over the last 10-15 years, MS DMT costs have increased substantially more than the rates observed for other biologic drugs and beyond inflation. b. Yearly costs for all FDA-approved DMTs are about $70,000 to $125,000. c. DMTs used off-label to treat MS may be less costly. d. Generic availability: i. Glatiramer acetate, both 20- and 40-mg dosage forms ii. Dimethyl fumarate (as of 8/2020) iii. Fingolimod, pending litigation e. Biosimilar rituximab products were approved in 2019 but do not have FDA label approval for MS because brand Rituxan does not have approval for MS. f. Patient copay and availability of copay assistance programs often need to be considered when choosing a DMT. Table 17. Risk-Stratified Treatment Approach for Multiple Sclerosis Better Prognosis/Less Active Disease

• Low lesion load on magnetic resonance imaging • Little to no disability • Low relapse rate

Poor Prognosis/Highly Active Disease

• • • • •

High lesion load on magnetic resonance imaging Spinal cord lesions High relapse rate Incomplete recovery from relapse Sphincter symptoms

↓

↓

Moderately Effective DMT

Highly Effective DMT

IV.  PAIN AND PAINFUL NEUROPATHY A. Categorizing Pain 1. Acute pain a. Patients should be assessed for the physiologic source of their pain and, after reasonable efforts, treated for the underlying cause. b. Pain management should include an assessment of pain severity. 2. Chronic pain a. Examples: Arthritis, fibromyalgia, chronic back pain, neuropathy b. Nonpharmacologic and non-opioid therapies are preferred for chronic pain. c. Opioids should only be used if clinically appropriate. d. The 2018 SPACE trial compared patients using opioids with patients using non-opioids for moderate to severe chronic back pain or hip or knee osteoarthritis (JAMA 2018;319:872-82). Groups did not significantly differ on pain-related function over 12 months; thus, opioid treatment was not superior to non-opioid treatment in this trial. B. Opioid Use: Monitoring and Optimization of Therapy 1. Opioid use disorder is a major concern in the United States. a. Opioid use is associated with increased mortality.

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2.

3.

4.

5.

b. Limits on opioid prescriptions i. Individual states, insurers (commercial and governmental), and pharmacies have implemented laws and/or criteria that limit prescription opioid quantities. ii. Examples: Limits on days’ supply for new opioid restrictions (i.e., no more than a 7-day supply) and limits on total daily morphine milligram equivalent daily dose (MEDD) for acute and/or chronic pain Determine when to initiate or continue opioids for pain. a. Nonpharmacologic and non-opioid therapies are preferred. Consider adjuvant therapy options before prescribing opioids, when appropriate. i. Nonpharmacologic: Exercise, physical therapy, diet, weight loss, tai chi, yoga, acupuncture, massage ii. Non-opioid medication options include acetaminophen, NSAIDs, skeletal muscle relaxants, and other non-opioid medication options that are also used for the treatment of painful neuropathy and listed in Table 20. b. Before starting opioid therapy for chronic pain, take the following steps: i. Establish treatment goals. ii. Discuss discontinuation if benefits do not outweigh risks. iii. Discuss risks and realistic benefits of opioid therapy. iv. Discuss patient responsibilities. Informed consent and agreement for treatment: Consider before initiating opioid therapy. a. Outlines patient and provider responsibilities, including expectations for urine/blood monitoring (at regular and/or random intervals) (Table 18) b. Includes punitive actions. Example: Termination of patient-provider relationship if positive urine drug screen for illicit drugs or patient has filled pain medication from another provider Opioid selection a. Acute pain i. Prescribing opioids for acute pain often results in long-term opioid therapy. ii. When opioids are needed for acute pain, use the lowest effective dose of immediate-release products for the expected duration of pain severe enough to require opioids (i.e., 3–5 days). b. Chronic pain i. Start with immediate-release formulations versus extended/long-acting formulations. ii. Use lowest effective dose. iii. Avoid doses of 90–100 MEDD or greater unless benefits outweigh risks. iv. Continually evaluate risk-benefit. If benefits do not outweigh risks, other therapies should be optimized, and opioids should be tapered or discontinued. Dosage forms: The appropriate dosage form should be chosen according to the patient’s ability to adhere to the dosing regimen, affordability for the patient, risk of AEs, pharmacokinetics of the agent, and characteristics of pain. a. Oral: The most appropriate dosage form for most patients is oral; however, maintaining a consistent concentration can be difficult if the patient does not take the dose consistently. i. Immediate-release (IR) tablets: Not ideal for chronic pain; IR forms should be used instead for acute pain and breakthrough pain ii. Extended-release/long-acting: Less frequent dosing; more consistent drug concentrations; associated with a higher risk of opioid overdose than IR b. Transdermal: For chronic pain, not for opioid naive; see fentanyl package insert for recommendations for conversion from oral opioid to fentanyl transdermal c. Buccal/sublingual: Fentanyl dosage forms are available but should only be used in opioid-tolerant patients for relief of severe breakthrough cancer pain.

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d. Nasal spray i. Butorphanol: Although useful for some patients with migraines for acute relief, it can lead to MOH and is not recommended by the AAN guidelines. ii. Fentanyl nasal spray is indicated only for cancer breakthrough pain in opioid-tolerant patients. 6. Major AEs of opioid analgesics a. Mood changes: Dysphoria, euphoria b. Somnolence, sedation, inability to concentrate c. Respiratory depression d. Constipation e. Histamine release: Urticaria, pruritus f. Tolerance, dependence, addiction Patient Case 13. A patient has taken oxycodone-controlled release for the past 8 years, 90 mg twice daily, for chronic low back pain and diabetic neuropathy. The patient tells you today that there is a national shortage of his medication. Which dose is best to suggest when changing the patient’s medication to morphine-controlled release? A. B. C. D.

60 mg twice daily 30 mg four times daily 120 mg daily 100 mg twice daily

7. Changing opioid therapy: If lack of therapeutic response and/or AEs a. Opioid conversions/rotations i. Determine the total daily dose of all opioids being administered. ii. Using a published equianalgesic ratio, convert the current total daily dose to the new opioid. iii. Round down the new analgesic total daily dose by 25%–50% (to account for the lack of crosstolerance between opioids), but consider the clinical situation and patient-specific variables (e.g., whether the current therapy is providing effective pain relief). iv. Divide total daily dose appropriately (e.g., twice daily). v. If used as needed for breakthrough pain: Use immediate-release formulation at a total daily dose of 10%–15% of the new opioid every 3–4 hours. vi. Reassess, and monitor frequently until new medication reaches steady state. b. Conversion ratios are used as a guide, with attention to the variability in interindividual pharmacokinetics and opioid drug pharmacodynamics (Table 19). c. CYP2D6 polymorphism i. Codeine converts to morphine; poor metabolizers may have reduced response. ii. Oxycodone converts to oxymorphone; poor metabolizers may have increased AEs. iii. Hydrocodone converts to hydromorphone; extensive metabolizers may have increased AEs.

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Table 18. Testing Methods Available for Monitoring Patients Receiving Chronic Opioid Therapy Test

Urine immunoassay Urine GC-MS Quantitative serum testing

Advantages

Disadvantages

• Less expensive • Longer detection window than serum testing • Less invasive than serum testing

May not detect all medications in class (e.g., synthetic opioids)

• More precise results; better detects synthetic opioids • Longer detection window than serum testing

Costly

• Shows results for metabolites • In patient taking high dose, may detect aberrant metabolism pattern • Provides documentation for provider of serum • concentrations

More false positives than GC-MS

More difficult and invasive Costly

GC-MS = gas chromatography–mass spectrometry.

Table 19. Equianalgesic Doses of Outpatient Opioids Equianalgesic Oral Dose, mg

Oral

Morphine

30

Available Brands or Generics

MS Contin, Oramorph SR–Long Acting, Avinza, Kadian

AEs, including nausea and itching) often limit use; may require TID dosing in some patients; should not be used in patients with renal compromise

Various generic products

Patients often describe itching and nausea less often than constipation; conversion to morphine by CYP2D6 metabolism required for analgesia

Hydrocodone

30

Codeine

200

Hydromorphone

7.5

Dilaudid–short-acting

Oxycodone

20

Oxymorphone

10

OxyContin, Percocet, Xartemis, other brands

Tramadol

120

Tapentadol

100

Notes on Use

Zohydro–hydrocodone alone; Lortab, Norco, Vicodin with acetaminophen Reprexain, Vicoprofen with ibuprofen

Short-acting agent that may be suitable to test opioid responsiveness; usually inappropriate for chronic opioid therapy

Can overcome effects of antagonizing agent, naloxone Highly abused drug since the 1960s

Opana

Metabolite of oxycodone; less potent

Nucynta and Nucynta ER

Fewer overall GI AEs than other opioids but is a CII drug; approved for both acute and chronic pain

Ultram, Ultram ER

Can cause nausea and dysphoria; should be avoided with other serotonergic agents; classified as a CIII drug in some states; conversion to O-desmethyl metabolite through 2D6 required for analgesia

AE = adverse effect; CII = Schedule II controlled substance; CIII = Schedule III controlled substance; ER = extended release; GI = gastrointestinal; SR = sustained release; TID = three times daily.

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C. Take-Home Naloxone 1. Naloxone is a mu-opioid blocker that reverses the effects of an opioid overdose. 2. In the absence of opioids, naloxone has no effect. 3. Naloxone reduces mortality and is cost-effective. 4. Recommendations by the 2016 Centers for Disease Control and Prevention guidelines are to offer take-home naloxone to anyone prescribed opioids who may be at an increased risk of opioid overdose, including patients with the following: a. Opioid prescriptions in excess of 50 mg MEDD b. History of overdose c. Use of chronic long-acting opioid formulations d. Concomitant CNS depressants (e.g., benzodiazepines) e. Substance use disorder f. Comorbid mental illness Patient Case 14. Which patient would most likely benefit from duloxetine as a first-line agent for peripheral neuropathy symptoms? A. B. C. D.

29-year-old woman with tension headaches 59-year-old man with osteoarthritis of the knee 42-year-old woman with rheumatoid arthritis 32-year-old man with focal seizures

D. Painful Neuropathy 1. Damage to nerves (neuropathy) and pain that arises as a direct consequence of damage to nerves (neuropathic pain) a. Peripheral neuropathies: Diabetic peripheral neuropathy, HIV-associated peripheral neuropathy, chemotherapy-induced peripheral neuropathy, radiculopathy, postherpetic neuralgia b. Central neuropathies: MS, post-stroke pain, postherpetic neuralgia, spinal cord injury, trigeminal neuralgia 2. Treatment a. Address contributing factors and treat underlying disease: i. Diabetes ii. Thyroid disorder iii. Vitamin B12 deficiency iv. Vitamin B6 deficiency or toxicity v. HIV/AIDS b. Address drug-inducing causes (discontinue/reduce dose, if applicable): i. Chemotherapeutic agents (e.g., vinca alkaloids, taxels, platinums) ii. Antibiotics (e.g., isoniazid, ethambutol, linezolid, nitrofurantoin, metronidazole) iii. Antiretrovirals (e.g., nucleoside reverse transcriptase inhibitors) iv. Cardiovascular agents (e.g., amiodarone, hydralazine) v. Medications that may cause vitamin B12 deficiency (e.g., proton pump inhibitors, histamine-2 receptor antagonists, metformin, colchicine) vi. Alcohol overuse 3. Nonpharmacologic options a. Exercise b. Physical and occupational therapy c. Biofeedback, relaxation therapy, massage therapy, acupuncture d. Cognitive behavioral therapy ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 883

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4. Pharmacologic therapy a. Start with first-line medications and then move to second and third line, as needed. There is no universally agreed-on treatment algorithm; rather, designations of first, second, third, fourth line, etc., medications vary in the literature. Table 20 lists medications in an order that is most similar to what is reported in the literature, together with author expert opinion. b. Choice should consider patient comorbidities and potential AEs. (See Epilepsy section and Psychiatric Disorders chapter for AEs and monitoring.) c. Initiate at typical starting doses and then titrate. A dose started too high or escalated too quickly can result in intolerable AEs and lead to discontinuation. (See Epilepsy section and Psychiatric Disorders chapter for dosing.) d. Depending on the medication, trials of 3–8 weeks are needed before the full effect can be seen. e. Combination therapy i. Use of two or more systemic agents with different mechanisms for peripheral neuropathy is not well studied. ii. Some neuropathic pain reviews recommend combination therapy, using two systemic medications, as a second- or third-line treatment option (e.g., gabapentinoid plus TCA/SNRI). However, other data analyses suggest combination therapy does not improve pain relief and is instead associated with increased levels of AEs. iii. One exception is localized or topical medications: Lidocaine cream/ointment/patches, topical NSAIDs (e.g., diclofenac gel), compounded topical products, capsaicin, botulinum toxin, etc. These agents improve pain relief when added to a systemic medication. Topical/localized agents can also be used as monotherapy, if appropriate, depending on the location of pain. f. Immune-mediated neuropathies (e.g., chronic inflammatory demyelinating polyneuropathy) must be treated with immune modulation such as prednisone, intravenous immunoglobulin, plasmapheresis, or immunosuppressants (e.g., cyclosporine, azathioprine, tacrolimus, cyclophosphamide, rituximab). Table 20. Pharmacologic Treatments for Painful Peripheral Neuropathies Medication

Good for patients with:

Consider avoiding in/with:

Notable Pearls

Duloxetine

Depression, fibromyalgia, anxiety, osteoarthritis, stress urinary incontinence

Hepatic failure

Second-line option for chronic low back pain (per 2017 guidelines)

First line

Venlafaxine Gabapentin

Depression, anxiety, migraine, hot flashes

Focal/partial seizure disorder, restless legs syndrome, fibromyalgia

Avoid in severe renal impairment (CrCl < 30 mL/ min/1.73 m2)

Uncontrolled HTN

Do not abruptly discontinue

Renal impairment (renally excreted; dose adjustment needed), difficulty with medication adherence (dosed several times a day)

Saturable/nonlinear kinetics – Doses increased to large daily doses may not be more efficacious and may instead cause more AEs

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Table 20. Pharmacologic Treatments for Painful Peripheral Neuropathies (continued) Medication

Good for patients with:

Consider avoiding in/with:

Notable Pearls

Pregabalin

Focal/partial seizure disorder, restless legs syndrome, fibromyalgia

Renal impairment (renally excreted; dose adjustment needed)

Nonsaturable/linear kinetics – More quickly and better absorbed than gabapentin

First line (continued)

Amitriptyline/ nortriptyline

Second line

Carbamazepine

Insomnia, migraine, depression, fibromyalgia

Older adult patients (high-risk medication), concomitantly with several serotonergic agents or those that may prolong QTc

Seizure disorder, trigeminal neuralgia

Hyponatremia, osteoporosis, medications metabolized by CYP3A4

Tramadol

Seizure disorders

Available in a controlledrelease formulation

Strong anticholinergic AEs can limit use; anticholinergic effect amitriptyline > nortriptyline

First line for trigeminal neuralgia Titrate dose slowly

Conversion to O-desmethyl metabolite through CYP2D6 required for analgesic effects Use with caution because of potential for dependence

Third/Fourth Line SSRIs (citalopram, paroxetine, escitalopram) Lamotrigine

Opioids (e.g., hydrocodone, oxycodone, morphine)

Second-line option for chronic low back pain (per 2017 guidelines) Depression, anxiety

Paroxetine: Avoid in older adults (high-risk medication)

Seizure disorder

Concomitant interacting medications History of substance use/ abuse

May be more beneficial for HIV-associated neuropathy than typical first-line agents (e.g., TCAs, gabapentin)

Use with caution because of potential for dependence If chronic opioid therapy is needed, fentanyl transdermal patch has efficacy for peripheral neuropathy, but should not be initiated in an opioid-naive patient

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Table 20. Pharmacologic Treatments for Painful Peripheral Neuropathies (continued) Medication

Good for patients with:

Third/Fourth Line (continued)

Consider avoiding in/with:

Notable Pearls Dose-adjust in severe renal impairment (CrCl < 30 mL/ min/1.73 m2): Max dose is 50 mg twice daily

Milnacipran

Fibromyalgia, depression

Uncontrolled HTN, deductible insurance plans (brand name only)

Oxcarbazepine

Seizure disorder, trigeminal neuralgia

Hyponatremia, osteoporosis

Topiramate Valproate Topicals

Lidocaine: Patch, cream, ointment NSAIDs: Diclofenac, ketoprofen Capsaicin cream and patch

Seizure disorder, migraine, overweight/obese

History of nephrolithiasis

Seizure disorder, migraine

Overweight/obese, tremor, polycystic ovary syndrome

Localized areas of neuropathic pain, partial relief from systemic medication, unable to take systemic medications because of drug interactions

Large areas of neuropathic pain

Second line for trigeminal neuralgia Higher incidence of hyponatremia than with carbamazepine

Lidocaine 4% patch and diclofenac gel available OTC Capsaicin 0.1% cream (OTC): Must use for at least 2 wk before benefit seen (until substance P stores are depleted).

Compounded products with ingredients such as ketamine, ketoprofen, amitriptyline, gabapentin, lidocaine, etc

Capsaicin 0.025% patch (OTC): efficacious in HIVassociated neuropathy Capsaicin 8% patch (Qutenza) by prescription only: approved for diabetic peripheral neuropathy of feet and postherpetic neuralgia. Must be applied by health care professional. Patches applied for 30 to 60min every 3 mo.

OTC = over-the-counter.

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V.  PARKINSON DISEASE A. Etiology and Risk Factors 1. Idiopathic disease 2. Risk factors a. Male sex b. Ethnicity: Hispanics and non-Hispanic whites have the highest incidence in the United States. c. Genetic factors include several possible genetic links and mutations. d. Aging-related factors such as oxidative stress and mitochondrial dysfunction e. Environmental factors such as pesticide exposure, previous head injury, living in a rural setting, β-blocker use, and drinking well water f. Of interest, tobacco smoking, coffee consumption, alcohol consumption, and NSAID and calcium channel blocker use may provide elements of protection against Parkinson disease (PD). 3. Drug-induced effects on dopamine a. Antipsychotics—phenothiazines (prochlorperazine, promethazine), typical and atypical antipsychotics b. Antiemetics—metoclopramide c. Dopamine depleters—reserpine, tetrabenazine d. Toxic substances—manganese dust, carbon monoxide poisoning, MPTP (1-methyl-4-phenyl-1,2,5,6tetrahydropyridine) B. Clinical Presentation 1. Cardinal features a. Resting tremor—unilateral or bilateral; reduced/absent with movement and sleep b. Rigidity—limb muscles, cogwheeling c. Bradykinesia—slowed movement d. Postural or gait instability 2. Motor symptoms a. Gait abnormalities, stooped posture, shuffling, festination, lack of arm swing b. Impaired fine movements (e.g., while buttoning a shirt) c. Micrographia (small handwriting) d. Masked face, dysarthric hypophonic speech e. Decreased blinking, dysphagia, drooling 3. Nonmotor symptoms a. Autonomic symptoms i. Orthostatic hypotension may occur because both PD and the drugs used to treat it can cause orthostatic changes. ii. Impaired GI motility (e.g., gastroparesis), constipation iii. Bladder dysfunction, sexual dysfunction b. Cognitive and psychiatric symptoms i. Cognitive decline ii. Hallucinations—can also be disease related or treatment related (e.g., dopaminergic medications) iii. Anxiety, depression, sleep disorders iv. Behavioral symptoms, agitation 4. PD is a progressive disease; thus, motor and nonmotor symptoms may (and often do) worsen over time.

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Neurology

Patient Cases 15. A 72-year-old female patient is assessed in the clinic after a fall 1 week ago. She was seen in the emergency department at that time, but no significant injuries were noted. She states that she was dizzy before her fall. She has a history of HTN, PD, and osteoarthritis. Her current medications include hydrochlorothiazide 25 mg/day, metoprolol XL 50 mg/day, lisinopril 10 mg/day, tramadol 50 mg three times daily as needed for pain, levodopa/ carbidopa controlled release 200/50 mg twice daily, and pramipexole 0.125 mg twice daily. She states that her PD symptoms are much better controlled since adding pramipexole and decreasing levodopa/carbidopa 1 month ago. On physical examination, her blood pressure is 136/72 mm Hg, with a heart rate of 60 beats/minute sitting, and 118/60 mm Hg, with a heart rate of 62 beats/minute standing. Her gait and strength are good. Which is the most appropriate recommendation to reduce her risk of future falls? A. B. C. D.

Discontinue pramipexole and keep other current medications. Keep current medications but decrease metoprolol dose. Add midodrine to current medications. Add fludrocortisone to current medications.

16. A 68-year-old woman with PD has taken levodopa/carbidopa 100/25 mg four times daily for 2 weeks. Previously she took levodopa/carbidopa 100/25 mg three times daily. She calls your clinic to ask about her symptoms, which include nausea, light-headedness, and involuntary movements that she describes similarly to dyskinesias. Her PD symptoms were fairly well controlled on her dose schedule of three times daily, but her physician increased the dose to four times daily for additional benefit. Which is the best recommendation to address this patient’s symptoms? A. B. C. D.

Continue levodopa/carbidopa; add rasagiline. Decrease levodopa/carbidopa dose to 100/25 mg three times daily. Continue levodopa/carbidopa; add ropinirole. Change levodopa/carbidopa dose to 100/10 mg four times daily.

C. Diagnosis 1. Diagnosis is made after ruling out other neurologic disorders with overlapping clinical features and assessing motor signs and symptoms. a. Presence of bradykinesia with at least one of the following cardinal features: resting tremor, rigidity, postural instability b. Other types of parkinsonism or tremor disorders excluded (e.g., essential tremor, drug-induced tremor, neoplasms, stroke, infections) c. Presence of at least three of the following supportive positive criteria: i. Asymmetry of motor signs/symptoms ii. Unilateral onset iii. Progressive disorder iv. Resting tremor v. Response to levodopa 2. United Parkinson’s Disease Rating Scale a. Mainly used for evaluating symptom severity in PD studies b. Assesses mood and behavior, daily function, and motor symptoms and complications D. Clinical Management 1. Approach to treatment a. Treat motor/cardinal symptoms (with pharmacologic therapies targeted toward dopamine). b. Manage complications related to motor symptom management (e.g., dyskinesias, wearing-off)

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Neurology

c. Treat and address nonmotor symptoms. d. Improve quality of life. 2. Nonpharmacologic therapy a. Physical therapy b. Balance and gait training 3. Pharmacologic therapy (Table 21) a. Available therapies to treat motor/cardinal symptoms work in one of the following ways: i. Mimic dopamine ii. Increase dopamine iii. Decrease ACh—loss of dopamine tilts dopamine/ACh balance to too much ACh b. Anticholinergics (benztropine, trihexyphenidyl) i. Help correct imbalance between dopamine and ACh ii. Mainly beneficial for tremors; can be used as initial therapy if tremors are predominant iii. Limited use because of AEs, particularly among older patients (confusion, urinary retention, constipation) c. Dopamine precursor i. Levodopa is the most clinically effective therapy for PD symptoms. ii. Effective for all cardinal features iii. Dopa decarboxylase inhibitor (carbidopa) added to prevent peripheral conversion of levodopa to dopamine (a) Reduces levodopa dose requirement (b) Reduces AEs of levodopa (nausea, orthostasis, cardiac AEs) (c) Carbidopa 75–100 mg daily is needed to saturate DOPA decarboxylase enzyme peripherally. iv. Most patients eventually develop motor complications (Table 22) while taking levodopa because of PD progression. v. Several formulations of levodopa have been developed to reduce/treat motor complications: (a) IR, sustained-release, extended-release tablet (b) Intestinal gel (Duopa) (surgical procedure required) (c) Inhaled levodopa (Inbrija) for intermittent treatment of “off” episodes (approved in 2018) d. Dopamine agonists i. Directly stimulate dopaminergic receptors to increase dopamine ii. Can be used for initial therapy or as adjunctive therapy with levodopa iii. Not as clinically effective as levodopa, but fewer long-term motor complications than levodopa iv. Impulse control disorders most likely with dopamine agonists (though possible with other dopaminergic therapies as well) v. Nonergot derivatives (pramipexole, ropinirole, rotigotine patch) preferred to ergot derivatives (bromocriptine) because of the risk of cardiac valvulopathy and fibrosis vi. When adding to levodopa, may need to decrease levodopa dose to avoid dopaminergic-related AEs such as nausea, hallucinations, or dyskinesias vii. Apomorphine—nonergot dopamine agonist (a) Used for treatment of acute, intermittent “off” episodes associated with advanced PD (b) Traditionally, only available as a subcutaneous injection, and its route of administration, together with significant AEs of nausea and vomiting, limits use (c) In May 2020, a sublingual apomorphine film formulation was approved for improved administration, but nausea and vomiting still occurred; antiemetic is recommended with use, but serotonin 5HT3 antagonists are contraindicated. e. MAO-B inhibitors i. Block degradation of dopamine through MAO-B inhibition ii. Can be used as initial therapy or as adjunctive therapy with levodopa ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 889

Neurology

iii. Control of motor symptoms with MAO-B agents considered inferior to that with dopaminergic agents (levodopa, dopamine agonists) iv. When adding MAO-B inhibitors to levodopa, may need to decrease levodopa dose because of excessive dopaminergic effects (e.g., nausea, vomiting, hallucinations, dyskinesias) v. Selegiline and rasagiline most commonly used; safinamide more recently introduced to market (approved in 2018) vi. Selegiline is metabolized to an amphetamine metabolite, which can cause insomnia; thus, the second daily dose is usually given in the early afternoon rather than later in the day. vii. MAO-B selective inhibition should not be an issue with tyramine-containing foods or serotonergic agents (e.g., SSRIs, TCAs) when MOA-B selective inhibitors are used at recommended doses. (a) MAO-B is the predominant MAO in the brain. (b) MAO-A is the predominant MAO in the GI tract and is associated with a risk of hypertensive crisis (also known as cheese reaction). (c) In PD, selective MAO-B inhibition in the brain increases dopamine concentrations. viii. Many DDIs with MAO-B selective agents are theoretical (e.g., amphetamines, anorexiants, antidepressants, dextromethorphan, meperidine, methadone, propoxyphene, trazodone, St. John’s wort, sympathomimetics). (a) When used at recommended doses, the potential for DDIs is relatively low with selegiline, rasagiline, and safinamide. (b) Orally disintegrating selegiline tablets are contraindicated for use with dextromethorphan, methadone, propoxyphene, tramadol, and other MAO inhibitors (according to package labeling). (c) Patch formulation of selegiline (Emsam) is contraindicated with serotonergics and should not be used for PD; higher doses result in nonselective MAO inhibition with the potential for DDIs. f. Catechol-O-methyl transferase (COMT) inhibitors i. Inhibits metabolism of levodopa ii. Not useful as monotherapy (a) Useful only in combination with levodopa (b) May need to decrease levodopa dose when added to avoid adverse dopaminergic effects iii. Entacapone is preferred to tolcapone because tolcapone is associated with fatal hepatotoxicity; also, severe diarrhea is more common with tolcapone. iv. Opicapone recently approved (4/2020); advantage of once-daily dosing g. Amantadine i. Thought to increase the synthesis and release of dopamine, to decrease dopamine reuptake, and to have anticholinergic effects; some evidence of N-methyl-d-aspartate (NMDA) modulation, similar to that of memantine for Alzheimer disease ii. Can be used as initial monotherapy for mild to moderate disease or as adjunctive therapy with levodopa for advanced disease iii. Most commonly used in addition to dopaminergic therapies to manage motor symptom complications, specifically dyskinesias iv. Requires renal dose adjustment if creatinine clearance is less than 60 mL/minute/1.73 m2; contraindicated with end-stage renal disease. Failure to renally dose-adjust may result in amantadineinduced hallucinations. h. Selective adenosine A2A receptor blocker (not included in Table 21) i. Istradefylline (Nourianz) was FDA approved in mid-2019 as an add-on treatment to levodopa/ carbidopa to improve “off” episodes. ii. Previously rejected by the FDA in 2007; has been marketed in Japan since 2013 iii. Remains unclear how this medication may fit into current PD treatment strategies, given mixed evidence from clinical trials

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Neurology

iv. Once-daily dosing (20 mg daily), avoid with concomitant CYP3A4 inducers, increase dose if patient smokes 20 or more cigarettes or equivalent per day (40 mg daily), may worsen dyskinesias i. Disease-modifying therapy i. An ideal pharmacologic therapy will provide neuroprotection. ii. Not yet available in PD iii. Agents have been investigated, but none are FDA approved or generally effective at providing neuroprotection. (a) Vitamin E: Theoretical antioxidant properties, lack of evidence, guidelines do not recommend (b) Coenzyme Q10 (1) National Institute for Health and Care Excellence guidelines recommend in context of clinical investigation. (2) Movement Disorder Society guidelines state that coenzyme Q10 is not useful. (3) Most coenzyme Q10 studies in PD had negative results; one low-quality study had positive results. (c) Dopamine agonists: Overall non-efficacious as neuroprotective agents (d) MAO-B inhibitors (1) Historically had the most promise for providing neuroprotection (2) Rasagiline: TEMPO and ADAGIO trials (3) Selegiline: DATATOP trial (4) Trials had some positive results but not convincing enough to support use for neuroprotection; thus, guidelines do not endorse rasagiline or selegiline for disease modification

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Tablet, injections

Antiviral with unknown effects on dopamine and NMDA

Amantadine Amantadine ER (Gocovri, Osmolex ER) 100–200 mg BID Gocovri: 137–274 mg daily Osmolex ER: 129–322 mg daily

Anticholinergic/ 1–6 mg antimuscarinic

Capsule, tablet, syrup ER: Capsules (Gocovri), tablets (Osmolex ER)

Tablet, elixir

Minimum–Maximum Daily Dose Dosage Forms

Anticholinergic/ 0.5–4 mg antimuscarinic

Mechanism

Trihexyphenidyl (Artane)

Benztropine (Cogentin)

Drug Name

Table 21. Medications for the Treatment of Symptoms in PD

Orthostatic hypotension, syncope, peripheral edema, insomnia, livedo reticularis

Confusion, dry mouth, constipation, blurred vision, tachycardia, urinary retention

Confusion, dry mouth, constipation, blurred vision, tachycardia, urinary retention

Adverse Effects

892

Gocovri and Osmolex ER both offer once-daily dosing but are significantly more expensive (brand only) than amantadine IR

Osmolex ER tablet consists of an IR outer layer and ER inner core

Osmolex ER was approved for PD (not specifically PD-related dyskinesias) based on bioavailability studies comparing Osmolex ER to amantadine IR

Gocovri is approved for dyskinesias related to levodopa therapy for PD based on RCTs

Live influenza vaccine not recommended if taking amantadine

Must dose adjust for renal function; can cause hallucinations if not dose adjusted

Most useful for dyskinesias

Most useful for tremor, but not well tolerated, particularly in patients >65–70 yr

Most useful for tremor, but not well tolerated, particularly in patients >65–70 yr

Comments

Neurology

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Dopamine agonist

Dopamine precursor

Levodopa for inhalation (Inbrija)

Pramipexole (Mirapex; Mirapex ER)

Dopamine precursor

Mechanism

Levodopa/ carbidopa (Sinemet, Parcopa ODT, Rytary, Duopa)

Drug Name

0.375–4.5 mg; divided doses

84 mg (2 capsules)– 420 mg (10 capsules)

300–1000 mg of levodopa; several daily doses

IR tablet: 0.125, 0.25, 0.5, 1, 1.5 mg ER tablet: 0.375, 0.75, 1.5, 3, 4.5 mg

42-mg capsules for inhalation

IR tablet and ODT: 100/10, 100/25, 250/25 mg; SR tablet: 100/25, 200/50 mg Rytary: 95/23.75, 145/36.25, 195/48.75, 245/61.25 mg; Duopa: 4.63–20 mg/ mL

Minimum–Maximum Daily Dose Dosage Forms

Table 21. Medications for the Treatment of Symptoms in PD (continued)

Nausea, vomiting, hallucinations, somnolence, postural hypotension, dizziness, confusion, edema, dyskinesia compulsive behavior, impulse control disorder

Cough, nausea, upper respiratory infection, sputum discoloration

Nausea, vomiting, hallucinations, delusions, syncope, arrhythmias, edema, hypotension

Adverse Effects

893

When changing from IR to ER, use ER dose that most closely matches daily IR dose

Not as clinically effective as levodopa, but associated with fewer motor complications long term

Monitor for increased dyskinesias and other effects associated with increased/ too much dopamine (e.g., hallucinations, delusions, impulse control disorders)

Onset of inhaled levodopa 10–30 min (vs. levodopa/carbidopa tablets 30–180 min)

Inhale contents of 2 capsules (84 mg) as needed

For as-needed treatment of “off” episodes in conjunction with carbidopa/levodopa

Duopa is an intestinal gel delivered into the duodenum by a gastrostomy tube that increases “on” periods by providing more consistent plasma levodopa concentrations

Counsel patients to avoid taking with high-protein meals because this timing can delay absorption of levodopa

Most clinically effective treatment available for PD motor symptoms

Comments

Neurology

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894

2–6 mg per injection

10-30 mg per dose

Dopamine agonist

Apomorphine (Kynmobi) sublingual film

1–8 mg patch daily

Dopamine agonist

Dopamine agonist

Rotigotine (Neupro patch)

0.75–24 mg; divided doses

Nausea, vomiting, hallucinations, somnolence, postural hypotension, dizziness, confusion, edema, dyskinesia, compulsive behavior, impulse control disorder, application-site reactions

Nausea, vomiting, hallucinations, somnolence, postural hypotension, dizziness, confusion, edema, dyskinesia compulsive behavior, impulse control disorder

Adverse Effects

Sublingual film: 10, 15, 20, 25, 30 mg

Nausea/vomiting, syncope, hypotension, oral mucosal irritation, falls may occur or increase, hallucinations/psychotic-like behavior, impulse control disorders, may prolong QTc

Injection: 10 mg/mL, Angina, drowsiness, 2- or 3-mL multidose hypotension, severe cartridge nausea/vomiting, edema, falls

24-hr patch: 1, 2, 3, 4, 6, 8 mg

IR tablet: 0.25, 0.5, 1, 2, 3, 4, 5 mg; XL tablets: 2, 4, 6, 8, 12 mg

Minimum–Maximum Daily Dose Dosage Forms

Apomorphine (Apokyn)

Dopamine agonist

Mechanism

Ropinirole (Requip, Requip XL)

Drug Name

Table 21. Medications for the Treatment of Symptoms in PD (continued)

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course

Doses should be separated by at least 2 hr; maximum five doses per day; max single dose 30 mg

Contraindicated with serotonin antagonist antiemetics (e.g., ondansetron, granisetron).

Treatment with concomitant antiemetic is recommended, beginning 3 days before initial dose

Pretreatment with antiemetic started 3 days before initiation and continued throughout to control N/V

Administered SC for intermittent freezing episodes

Expensive alternative to oral dopamine agonists; available as brand only

Not as clinically effective as levodopa, but associated with fewer motor complications long term May be beneficial in patients with gastroparesis

Not as clinically effective as levodopa, but associated with fewer motor complications long term When changing from IR to XL, use XL dose that most closely matches daily IR dose

Comments

Neurology

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895

MAO-B inhibitor

MAO-B inhibitor

MAO-B inhibitor

Selegiline (Eldepryl, Zelapar ODT)

Rasagiline (Azilect)

Safinamide (Xadago)

50–100 mg daily

0.5–1 mg

Tab: 5–10 mg ODT: 1.25– 2.5 mg

50 mg at bedtime

200–1600 mg in divided doses; 200 mg with each levodopa dose

Tablet: 50 mg, 100 mg

Tablet: 0.5, 1 mg

Tablet: 5 mg ODT:1.25 mg

Capsules: 25 mg and 50 mg

Tablet (entacapone): 200 mg Tablet (levodopa/ carbidopa/entacapone [Stalevo]): 50/12.5/200, 100/25/200, 150/37.5/200 mg

Minimum–Maximum Daily Dose Dosage Forms

Dose should be reduced to 0.5 mg/day with concomitant CYP1A2 inhibitors such as ciprofloxacin

Risk of tyramine reactions very low within recommended dosage range

Risk of tyramine reactions very low within recommended dosage range

ODT has better bioavailability than oral tablet

Dose reduce to 25 mg at bedtime in moderate hepatic impairment. Avoid in severe hepatic impairment

Not to be used as monotherapy; use only in combination with levodopa treatment

Comments

Given selectivity, serotonin syndrome and tyramine reactions are likely not to be clinically significant at recommended doses of ≤100 mg/day

Package insert lists serotonergic Nausea, dyskinesias, hallucinations, impulse medications as contraindications; however, pharmacokinetic studies have control found safinamide to be selective to MAO-B

Postural hypotension, dyskinesias, headache, nausea, weight loss

Headache, insomnia, hallucinations, dizziness

Dyskinesia, hallucinations, insomnia, hypotension/syncope, impulse control disorders

Nausea, dyskinesias, postural hypotension, diarrhea, abdominal pain, brown-orange urine, hyperkinesia

Adverse Effects

BID = twice daily; COMT = catechol-O-methyl transferase; CYP = cytochrome P450; ER = extended release; IR = immediate release; MAO-B = monoamine oxidase; NMDA = N-methyl-d-aspartate; N/V = nausea and vomiting; ODT = orally disintegrating tablet ; PD = Parkinson disease; RCT = randomized controlled trial; SC = subcutaneous; XL = extended release.

COMT inhibitor

COMT inhibitor

Mechanism

Opicapone (Ongentys)

Entacapone (Comtan, Stalevo)

Drug Name

Table 21. Medications for the Treatment of Symptoms in PD (continued)

Neurology

Neurology

Patient Case 17. A 63-year-old man received a diagnosis of early PD about 6 months ago but is otherwise healthy. He did not receive treatment with any medications when his PD was first diagnosed; however, on his physician’s advice, he started therapy with selegiline 5 mg twice daily about 4 weeks ago. He is in the clinic today because of difficulty sleeping and difficulty with his memory; on most days he feels tired but cannot fall asleep. He notes that his wife has a prescription for lorazepam 0.5 mg and that he has taken 1 tablet when he has had difficulty sleeping. He asks for a prescription for lorazepam to help him sleep. Which is the best recommendation for this patient? A. B. C. D.

Continue selegiline; add lorazepam 0.5 mg at bedtime. Continue selegiline; add diphenhydramine 50 mg at bedtime. Continue selegiline, but change the twice-daily dose timing to morning and noon. Continue selegiline; add levodopa/carbidopa.

4. Approach to therapy a. In general, therapy is initiated when symptoms become sufficiently difficult to tolerate for patient functioning. b. Levodopa is the most effective treatment for motor symptoms (preferred to dopamine agonists and MAO-B inhibitors). c. Traditionally, the approach to PD treatment was either levodopa-centered or levodopa-sparing, depending on the patient’s age; a levodopa-sparing approach specifically was derived from concerns about levodopaassociated motor complications that can be difficult to control with long-term levodopa use. However, these difficult-to-control motor complications appear to be more related to progression of the disease itself and not because of medications used in its treatment. i. Levodopa-centered approach: Use levodopa for motor symptom control in older patients (65 and older). ii. Levodopa-sparing: Avoid/delay use of levodopa for motor symptom control in younger patients (65 and younger). Use dopamine agonist and/or MAO-B inhibitor as first- and second-line treatment of motor symptoms. d. Levodopa-sparing approach has been falling out of favor in clinical practice; thus, levodopa can and should be used, regardless of patient age, when needed to control cardinal/motor symptoms. e. Combination therapy with levodopa i. If symptoms are not controlled with levodopa monotherapy (e.g., total daily levodopa dose is 800– 1000 mg), other dopaminergics can be added (e.g., MAO-B inhibitor, COMT inhibitor, or dopamine agonist). ii. When adding on, the levodopa dose may need to be decreased to avoid excess dopaminergic response (e.g., dyskinesias, nausea and vomiting, hallucinations). f. Rescue therapy: i. For acute, intermittent “off” episodes ii. Unpredictable; can occur at any time relative to levodopa doses iii. Mainly present in patients with advanced/severe PD iv. Inhaled levodopa or sublingual/subcutaneous apomorphine can be used as needed. 5. Motor complications (Table 22)

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Neurology

Table 22. Treatment and Management of Motor Complications Motor Symptom Treatment Complication Delayed “on”

Wearing “off”

Freezing episodes

Dyskinesias

Description/Cause

Treatment Approach

Motor symptoms return before next treatment dose Results from too little dopamine As disease progresses, wearing “off” occurs earlier, necessitating shorter dosing intervals

Increase frequency of levodopa dosing (more doses throughout the day) Change to sustained- or extended-release levodopa formulation Add MAO-B inhibitor, COMT inhibitor, or DA Rescue therapy for severe PD

Motor symptoms occur upon awakening and take 1-2 hr to respond to treatment

Unpredictable Inability to initiate motor function; hesitation to start movement Can be trigged by environmental factors (e.g., doorways, obstacles in path, busy crowds), emotional factors (e.g., being rushed, stress), or decrease in dopamine

Take levodopa on empty stomach Use IR levodopa formulation Assess/address constipation Rescue therapy for severe PD

Use PT and OT (assistive walking devices, sensory cues) Usually not influenced by dopamine changes; can track episodes in relation to medication dosing to determine whether correlated Rescue therapy for severe PD

Use smaller levodopa doses and/or administer Uncontrolled, involuntary choreiform smaller levodopa doses more often movements involving neck, trunk, and Change to sustained- or extended-release upper extremities levodopa formulation Results from too much dopamine Decrease dose or discontinue non-levodopa Highest risk with levodopa, followed by dopaminergic therapies (MAO-B inhibitor, dopamine agonists COMT inhibitor, DA) Usually associated with peak drug effects Add amantadine Change to continuous infusion with levodopa intestinal gel (for severe PD)

COMT = catechol-O-methyl transferase; DA = dopamine agonist; MAO-B = monoamine oxidase B; OT = occupational therapy; PD = Parkinson disease; PT = physical therapy.

6. Nonmotor symptoms a. Psychiatric symptoms i. Depression (a) Can occur in 40%–70% of patients with PD (b) Limited evidence to support use of specific antidepressants in PD (c) TCAs may theoretically be beneficial because of anticholinergic effects; however, cognitive effects limit their use. ii. Hallucinations (a) Can be associated with PD itself as well as with PD therapies (given that they increase dopamine) (b) Addressing/treating hallucinations involves identifying any underlying factors (e.g., metabolic, psychologic) and decreasing dopaminergic therapies (if possible); if still troublesome, add antipsychotic after careful review of risk-benefit.

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(c) Decrease dopaminergic therapies. (1) Reduce doses and/or discontinue therapies, if possible. (2) This approach is limited by worsened PD motor symptom control. (3) Evaluate option to decrease dose/discontinue dopamine agonist, if possible (given highest risk of causing hallucinations); should be done gradually (d) Antipsychotics (1) Only specific antipsychotics should be used to avoid worsening of PD symptoms. (2) Clozapine and quetiapine (A) Rapidly dissociate from dopamine-2 receptor binding and therefore do not worsen PD motor symptom control (B) Clozapine has more data than quetiapine. (C) Quetiapine is often tried first, given the risks with clozapine (agranulocytosis and extensive monitoring requirements according to REMS). (D) Start at the lowest available dose, and titrate slowly, depending on clinical response. (3) Pimavanserin (Nuplazid) is a selective serotonin-2A inverse agonist and blocker approved for the treatment of hallucinations and delusions associated with PD (approved in early 2016). Indication pending for dementia-related psychosis according to positive phase III HARMONY trial results (A) Recommended dose is 34 mg orally once daily. (B) Reduce dose to 10 mg daily with concomitant strong CYP3A4 inhibitors. (C) Dose may need to be increased when used with strong CYP3A4 inducers; monitor for reduced efficacy. (D) No hematologic monitoring is required. (E) Avoid with concomitant QT-prolonging drugs. (F) Lack of direct comparisons with clozapine or quetiapine, high cost, and less robust efficacy data limit their use. b. Orthostasis i. Orthostatic hypotension can be a complication of the disease itself as well as of the medications used to it, specifically dopaminergic treatments. ii. Identification, assessment, and treatment are important because falls and fall-related injuries are common among patients with PD. iii. Encourage nonpharmacologic therapies (e.g., elevating head of bed, using compression stockings, increasing sodium intake). iv. Reduce dose/discontinue antihypertensives. v. Reduce dose/discontinue dopaminergics, if possible (may worsen PD motor control). vi. Pharmacologic treatments (a) Midodrine (b) Fludrocortisone (c) Droxidopa (Northera) (1) A synthetic amino acid precursor of noradrenaline that is approved for the treatment of neurogenic orthostatic hypotension (2) Patients should not lie down for at least 5 hours after dose (given the risk of supine HTN). (3) Generically available as of 2021 7. Surgical treatment a. Deep brain stimulation (DBS) is a surgically implanted neurostimulator that delivers stimulation to targeted areas of the brain to control motor symptoms. b. DBS can be considered when motor symptoms are inadequately controlled with medications.

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c. DBS was previously reserved for patients with moderate to severe PD with longer disease duration (around 10–13 years). d. However, the 2013 EARLYSTIM trial showed that DBS in earlier disease (mean disease duration 7.5 years) improved patient quality of life. Patient Case Questions 18 and 19 pertain to the following case. 18. A 66-year-old man with a diagnosis of PD is examined today in the clinic. He has taken levodopa/carbidopa for 6 years. His current levodopa/carbidopa dose is 100/25 mg, taken as 1.5 tablets in the morning, 1 tablet at 11 a.m., 1 tablet at 2 p.m., 1 tablet at 5 p.m., and a 0.5 tablet at 8 p.m. He has had motor complications for about 3 months, including on-off symptoms and freezing episodes. On physical examination, he has some weakness, gait and balance abnormalities, and rigidity. His ability to ambulate and perform self-care activities during the past 3 months has continued to decline. Which is the most appropriate recommendation for his symptoms? A. B. C. D.

Continue levodopa/carbidopa; add benztropine. Decrease the levodopa/carbidopa dose to 4 tablets daily. Change the levodopa/carbidopa formulation to controlled release. Continue levodopa/carbidopa; add entacapone.

19. The patient returns to the clinic 2 weeks after your recommendation. He says he thinks he is doing better overall, but that he often feels nauseated and occasionally feels light-headed or dizzy. He also describes some abnormal movements, which are identified as dyskinesias on physical examination. He also states that he has had hallucinations on two occasions, which was rather disturbing to him. Which is the most appropriate recommendation for this patient? A. B. C. D.

Add prochlorperazine for nausea. Decrease the daily dose of levodopa/carbidopa. Initiate rasagiline therapy. Initiate ropinirole therapy.

VI.  ALZHEIMER DISEASE A. Clinical Presentation 1. Cognition a. Mild cognitive impairment (MCI) i. Preclinical AD ii. Memory impairment that may be noticeable to others but that does not interfere with daily life; not severe enough to meet the definition of dementia iii. Patients with MCI develop AD at a higher rate; however, not all patients with MCI go on to develop dementia. iv. Lack of clear evidence to recommend the use of medications to slow the progression of MCI to dementia b. Cognitive loss i. Insidious onset; chronic gradual loss of memory and other cognitive abilities ii. Inability to retain new information; remote memory spared until late disease

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 899

Neurology

iii. Affects many areas of cognition (a) Language (b) Abstract reasoning (c) Executive function (d) Decision-making iv. Of sufficient severity to affect daily life, work, social interactions 2. Activities of daily living a. Typically occurs later in the course of disease compared with cognitive loss b. Gradual loss of ability to perform self-care activities i. Bathing ii. Toileting iii. Feeding iv. Dressing v. Transfer vi. Ambulation c. Instrumental activities of daily living i. Managing finances ii. Managing medications iii. Cooking iv. Shopping v. Using telephone 3. Behaviors and psychiatric symptoms a. Early disease i. Depression ii. Anxiety iii. Less commonly, delusions or hallucinations b. Later disease i. Delusions/hallucinations ii. Wandering iii. Agitation or aggression, which are common causes for nursing home placement Patient Case 20. A 76-year-old widowed woman in the clinic today, accompanied by her daughter, for evaluation of cognitive concerns. The patient has a history of osteoarthritis, HTN, and atrial fibrillation. Her daughter states that she has had difficulties with her memory for almost 1 year. Her daughter states that initially the symptoms were minor, such as forgetting names or recent events; however, more recently, her mother’s memory concerns have been more severe, and it is becoming more difficult to care for her at home alone. The patient states that she does not think she has memory problems. There is no known family history of AD. The patient’s father died of a stroke, and her mother died of colon cancer. The patient has no recent history of falls, head trauma, or substance abuse. On evaluation today, the neurologic examination is normal. On an MMSE, the patient scores 22/30. She has a 12th-grade education. Her score on the Geriatric Depression Scale is 2/30. Blood is obtained for laboratory testing, and the patient is scheduled for a computed tomography. Which best describes the findings observed in this case? A. B. C. D.

Pseudodementia AD Multi-infarct dementia Cognitive impairment

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 900

Neurology

B. Evaluation and Diagnosis 1. Medical history and physical examination—optimally obtained from a family member or caregiver a. Family history of dementia b. Head injuries, falls c. Alcohol or substance use disorder d. Depression (pseudodementia) e. Acute illness (delirium) f. Medication review g. Language impairment h. Extrapyramidal signs (tremor, rigidity, bradykinesia) i. Focal weakness, gait disturbances 2. Differential diagnosis a. Cerebrovascular disease/vascular brain injury, Lewy body dementia, frontotemporal dementia, PD, normal pressure hydrocephalus, Pick disease, Huntington disease b. Other causes, including “reversible” causes i. Depression ii. Thyroid disease—specifically hypothyroidism iii. Vitamin deficiencies (vitamin B12, folate); some evidence to suggest vitamin D deficiency is associated with an increased risk of AD iv. Drug-induced cognitive impairment (Table 23) (a) Many medications can cause cognitive impairment or make cognition worse in patients who have cognitive issues at baseline. (b) Anticholinergic medications are a common cause of cognitive impairment especially in elderly patients, but several other medications/mechanisms can produce cognitive changes if acting in the CNS. (c) Studies suggest that about 10% of patients who present to memory impairment clinics have symptoms caused, at least in part, by medication-related effects. (d) A medication thought to contribute to cognitive impairment should be discontinued, or at a minimum, the dose should be reduced and reevaluated closely. v. Substance use disorder vi. CNS infections 3. Diagnosis a. AD is usually considered “probable” AD after other possible causes of cognitive impairment have been ruled out (as just discussed in outline point 2: Differential Diagnosis); AD diagnosis is usually based on patient presentation and history because there is no definitive test to diagnose it. b. Diagnosis criteria i. DSMV (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) ii. National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and Alzheimer’s Disease and Related Disorders Association (ADRDA) NINCDS-ADRDA

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 901

Neurology

Table 23. Medications That May Contribute to Impaired Cognitiona Anticholinergic Effects

Benzodiazepines

Other Central Nervous System Effects

Amitriptyline

Clorazepate

Carisoprodol

Chlorpheniramine

Diazepam

Cimetidine

Benztropine

Cyclobenzaprine Darifenacin

Desipramine

Chlordiazepoxide Flurazepam Lorazepam Oxazepam

Dicyclomine

Diphenhydramine Doxepin

Fesoterodine

Temazepam

Chlorzoxazone Clonidine

Esomeprazole Guanethidine Guanadrel

Indomethacin Meperidine

Methocarbamol

Hydroxyzine

Omeprazole

Imipramine

Opioids

Nortriptyline

Pantoprazole

Oxybutynin

Phenobarbital

Solifenacin

Propoxyphene

Thioridazine

Reserpine

Tolterodine

Topiramate

Trospium

This list is not exhaustive.

a

4. Assessment instruments a. Mini-Mental State Examination (MMSE) (most common test used in clinical practice) i. Screening tool for cognitive impairment; not intended to diagnose AD/dementia ii. Range of scores 0 (worst) to 30 (best) (a) 24–30 considered normal (b) 17–23 considered mild impairment (c) 10–16 considered moderate impairment (d) Less than 10 considered severe impairment iii. Educational bias (a) For patients with low levels of education, a maximum score of 30 may not be feasible. (b) Consequently, depending on the patient’s level of education, a lower score may not suggest cognitive impairment. (c) Conversely, if a patient has a very high level of education, a score of 27 or 28 may indicate cognitive changes. b. Alzheimer Disease Assessment Scale (ADAS, ADAS-cog) i. Longer, more comprehensive test, relative to MMSE; mostly used in research ii. Assesses language and memory skills iii. Often used for drug studies to evaluate change over time c. Neuropsychiatric Inventory (NPI) i. Assessment of psychiatric and behavioral symptoms; most commonly used in research

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 902

Neurology

ii. 12 disturbances common in dementia (a) Delusions (b) Hallucinations (c) Agitation (d) Dysphoria (e) Anxiety (f) Apathy (g) Irritability (h) Euphoria (i) Disinhibition (j) Aberrant motor behavior (k) Nighttime behavior disturbances (l) Eating disturbances iii. Range of scores (a) 0–144, with higher score associated with worse symptoms (b) Frequency of 12 symptoms rated 1–4 (c) Severity of 12 symptoms rated 1–3 (d) Product of frequency multiplied by severity and summed for the 12 symptoms gives the total score. d. Clinician Interview-Based Impression of Change (CIBIC) i. Global subjective assessment by provider ii. May include caregiver assessments (CIBIC-Plus); mainly used for research iii. Scored 1–7: 1 is very much improved; 2 much improved; 3 minimally improved; 4 no change; 5 minimally worse; 6 moderately worse; 7 markedly worse e. Severe impairment battery i. Assessment of cognitive function in those with severe neurologic impairment ii. Composed of simple one-step commands presented together with gestures iii. Assesses several cognitive areas including attention, orientation, language, memory, visual-spatial abilities, construction, praxis, and social interaction f. Geriatric Depression Scale i. Depression scale developed specifically for older adult patients ii. 30 questions, self-rated; also available in short form with 15 questions iii. Higher score indicates depressive symptoms; score of 20/30 or 5/15 (short form) indicates depression C. Clinical Management 1. Treatment goals a. Improve quality of life b. Maximize/maintain functional status and independence c. Maintain/enhance cognitive status d. Minimize mood and behavioral problems e. Minimize safety hazards (e.g., driving, cooking, wandering) 2. Nonpharmacologic therapy a. Group support, such as Alzheimer’s Association (https://alz.org) b. Education of patient, family, and caregivers i. Expectations ii. Planning iii. Realistic goals

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 903

Neurology

c. Physical and mental activities, including aerobic exercise, socialization, cognitive activities such as crossword puzzles, and reading d. Avoid inappropriate medications (Table 23) Patient Case 21. The daughter of an 81-year-old woman with AD asks the physician to begin treating the patient with a drug for her memory difficulties. Her mother was given a diagnosis of probable AD 4 years ago and is now in a nursing home; she can perform some of her activities of daily living, but only with assistance. Her most recent MMSE score was 14/30. She has been admitted to the emergency department twice in the past 6 months for bradycardia secondary to sick sinus syndrome. Which is the safest AD treatment to recommend for this patient? A. B. C. D.

Donepezil Memantine Rivastigmine Galantamine

3. Pharmacotherapy a. Cholinesterase inhibitors i. Specific agents (Table 24) (a) Donepezil (b) Rivastigmine (c) Galantamine (d) Combination product: memantine plus donepezil ER ii. Treatment initiation (a) Guidelines suggest initiating therapy early, as soon as the diagnosis is made, to maximize clinical benefits. (b) Initiating therapy at higher doses increases the risk of intolerable AEs, including nausea and vomiting, which may be severe enough to cause esophageal ruptures. (c) Therapy should be initiated at the starting dose and then titrated. (d) Interruption of therapy for more than a few days requires retitration from the starting dose and dose increases at the recommended intervals to avoid the possibility of significant AEs. iii. Choice of agent (a) Little to do with clinical efficacy because the agents are essentially equally efficacious (b) Choice is more often related to AE profile, tolerability, and cost. (c) Donepezil is the most commonly used agent because it is generally tolerated the best. (d) Newer high-dose agents (donepezil 23 mg and rivastigmine patch 13 mg) should be used cautiously because they are associated with an increased incidence of AEs. For many patients, a dose increase does not lead to a significant increase in efficacy. iv. Patient/caregiver education on the benefits of treatment (a) Both clinicians and patients should understand that these medications do not reverse the underlying pathophysiology of the disease—the patient’s condition will continue to progress with or without treatment. (b) Treatment benefits may not be clearly apparent to patients and family members. (c) At best, these medications may very modestly slow cognitive decline relative to no treatment, and in some patients, little or no cognitive/functional benefit may be achieved. As such, treatment should be reviewed periodically for continued benefit. (d) In addition, these medications can be associated with significant AEs that must be balanced with clinical benefit. ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 904

Neurology

(e) The American Geriatrics Society Choosing Wisely Workgroup has highlighted the use of cholinesterase inhibitors as one of 10 items that should be questioned by clinicians and patients (J Am Geriatr Soc 2013;61:622-31; J Am Geriatr Soc 2014;62:950-60). v. Cautions/Warnings (a) Chronic obstructive pulmonary disease or asthma: Cholinergic effects can increase bronchoconstriction and secretions. (b) Sick sinus syndrome or bradycardia: Cholinergic effects can worsen bradycardia, which can lead to hypotension or syncope in certain individuals; also, use caution in individuals taking β-blockers or non-dihydropyridine calcium channel blockers. (c) Peptic ulcer disease: Cholinergic effects increase gastric acid production; these effects are of particular concern in patients with a history of ulcer disease or in those taking steroids or NSAIDs vi. Monitoring (a) Efficacy and expectations (1) Changes in MMSE scores with treatment can be variable. (2) May experience slight improvement with MMSE scores (1 or 2 points) in some patients, but many patients will not experience significant changes in MMSE scores. (3) With time, MMSE scores will continue to decline, despite continued treatment. (b) Safety issues are presented in the Adverse Effects information in Table 24 and in the Cautions/ Warnings information just presented. vii. Discontinuing therapy (a) Lack of clear recommendations for when to discontinue therapy (b) Important to include family and caregivers when discussing therapy discontinuance, including risks versus benefits (c) May experience clinical deterioration when discontinued, depending at what stage medications are discontinued (d) Rather than discontinuing therapy abruptly, consideration should be given to tapering treatment over a few weeks to avoid withdrawal syndrome. (e) When patients cannot speak, ambulate, or provide any self-care, there is little reason to continue these medications—the risks of therapy exceed the benefits at this point. (f) Some suggest that the need for nursing home care defines the limit of usefulness for these medications, thus signifying the need to discontinue.

ACCP/ASHP 2022 Ambulatory Care Pharmacy Preparatory Review and Recertification Course 905

906

Mild, moderate AD

AChEI

AChEI

Galantamine (Razadyne, Razadyne ER) Mild, moderate AD

Rivastigmine (Exelon, Exelon patch)

AChEI

Mechanism

Donepezil (Aricept) Mild, moderate, severe AD

Drug/Indications Approved

Start oral dosing at 1.5 mg BID and titrate at 2-wk intervals; max dose of 6 mg BID; for patch, begin with 4.6 mg/24 hr; after 4 wk may increase to 9.5-mg/24-hr patch; if well tolerated and after an additional 4 wk, may consider increase to 13.3-mg/24-hr patch dose in select pts; increase to 13.3-mg dose is associated with limited clinical benefit

Start at 4 mg BID (8 mg/day with ER product); after ≥4 wk, increase to 8 mg BID (16 mg/ day with ER); after ≥4 wk, may increase to max dose of 12 mg BID (24 mg/day with ER); 24 mg/day is max dose

Start at 5 mg/day at bedtime; after 4–6 wk may increase to 10 mg/day; after 3 mo of tolerating 10 mg/day may consider increase to 23 mg/ day in moderate to severe disease for select pts; increase to 23-mg dosage form associated with limited clinical benefit

Dose/Titration

Table 24. Medications Approved for the Treatment of AD

16 mg/day is the minimum effective dose (target dose); has presynaptic nicotinic receptor effects, but clinical relevance is unknown

Nausea, vomiting, diarrhea, dyspepsia, dizziness, headache, syncope, bradycardia, muscle weakness Nausea, vomiting, diarrhea, dyspepsia, dizziness, headache, syncope, bradycardia, muscle weakness; adverse effects increase with increasing dose

Tablets 4, 8, 12 mg; ER capsules 8, 16, 24 mg; solution 4 mg/mL; generic available Capsules 1.5, 3, 4.5, 6 mg; solution 2 mg/mL; transdermal patch 4.6-, 9.5-, or 13.3-mg/24-hr patch (patch is removed and changed to a new patch every 24 hr); generics available

Patch seems better tolerated than oral dosage forms; oral dose of 6 mg BID or patch dose of 9.5 mg/day is the recommended effective (target) dose; for oral daily dose