Litt's Drug Eruption & Reaction Manual [30 ed.] 1032663758, 9781032663753

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DRUG ERUPTION & REACTION MANUAL 30th EDITION

2024 Neil H. Shear, MD, FRCPC, FACP Professor Emeritus Medicine, Clinical Pharmacology & Therapeutics, and Dermatology University of Toronto, Canada

Designed cover image: Shutterstock Thirtieth edition published 2024 by CRC Press 2385 NW Executive Center Drive, Suite 320, Boca Raton FL 33431 and by CRC Press 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN

CRC Press is an imprint of Taylor & Francis Group, LLC © 2024 Taylor & Francis Group, LLC This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact [email protected]

Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. ISBN: 9781032663753 (hbk) ISBN: 9781032663593 (pbk) ISBN: 9781032663784 (ebk) DOI: 10.1201/9781032663784

CONTENTS Introductory notes Drug profiles: generic names A–Z Descriptions of important reactions Drugs that cause important reactions Main classes of drugs Class reactions ACE inhibitors Antiarrhythmics Antibiotics, macrolide Anticonvulsants Antidepressants, tricyclic Antifungal, Imidazole Antimalarials Antineoplastics Antipsychotics Antiretrovirals Benzodiazepines Beta blockers Bisphosphonates Calcium channel blockers Cephalosporins Corticosteroids, topical Dipeptidyl-Peptidase 4 (DPP4) inhibitors Disease-modifying antirheumatic drugs (DMARDS) Epidermal growth factor receptor (EGFR) inhibitors Fluoroquinolones H1 receptor antagonists HMG-CoA reductase inhibitors/statins Immune checkpoint inhibitors Monoclonal antibodies Non-steroidal anti-inflammatories (NSAIDS) Proton pump inhibitors (PPI) TNF inhibitors Tyrosine-kinase inhibitors Genetic associations Concordance of synonyms and trade names with generic names

v 1 379 385 419 425 425 427 429 431 435 436 437 439 444 447 450 452 453 454 456 457 458 459 462 465 467 469 471 473 479 482 484 487 491 503

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A Note from the Editor All of us involved with Litt’s are very excited about reaching the milestone 30th edition of the Manual! It is hard to comprehend the number of new drugs and therapies that have emerged over those last three decades. Yet the great expansion in treatments to help patients is also associated with an exponential increase in adverse reactions. So therapeutic safety remains the heart and soul of Litt’s DNA. At a recent summer gathering of our Clinical Pharmacology group I was very pleased to hear how the Drug Safety Clinic was using Litt’s on a regular basis. They very much depend on more than just the literature or experience and need up-to-date data on new and emerging adverse events. I heard how data like this help the team make clinical decisions, and they were especially using the online database updates. As the founder of this clinic I can tell you how truly happy I was to hear all of this. With purchase of a new print copy of this year’s manual in 2024 we are delighted to offer a 12-month free access to the full database so that you also can try using it for your own practice!* Neil H. Shear, MD, FRCPC, FACP *Please contact Robert Peden at the publishers ([email protected]) with documented purchase of a new print copy of the 30th edition in 2024

Litt’s Drug Eruption & Reaction Manual – at a glance This 30th edition has been revised and updated throughout to present a quick clinical reference guide to adverse drug reactions (ADRs), side effects, drug interactions and other safety information for prescription and over-the-counter medications. There is material on reactions caused by classes of drugs, enabling you to see at a glance whether a reaction is common to all the drugs in that particular class, or to a majority of them, or only to a significant few. The aims of this edition remain: 1. To help medical practitioners make informed and safe decisions when diagnosing and prescribing, and also when generally seeking information. 2. To help healthcare professionals remain pharmacovigilant. 3. To provide all physicians, lecturers, educators, and pharmacists with an easy-to-use and reliable quick reference tool. Space in the manual is, unfortunately, constrained. The full and comprehensive picture for all drugs – from which our information derives – can be found in the Litt database (www.drugeruptiondata.com), which is updated continually; it currently holds over 1800 drug profiles with over 73,000 documented drug reactions, as evidenced by well over 156,000 references on PubMed. The Litt database was originated by Jerome Z. Litt; and now edited by Neil H. Shear, with advice and input by Rupert Purchase, DPhil, CChem, FRSC.

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A note on ADRs The incidence and severity of ADRs are influenced by a number of factors: 1. Patient-related factors:  Age – geriatric, pediatric, adolescent . . . older patients are taking more medications-hence more of a possibility of develop-

ing reactions; pediatric patients have more delicate skins; hormonal changes occur in adolescents . . . All these factors play roles in the development of possible adverse reactions.  Gender – male or female – and if the latter, then pregnant/breast-feeding/menopausal . . .  Disease – not only the disease being treated, but also other pre-existing health conditions and comorbid diseases. For

example, atopic patients are at increased risk for serious allergic reactions; also, there would be an increased risk for hypersensitivity drug reactions if the patient has asthma or lupus erythematosus.  Genetics – a patient could have abnormal drug metabolism due to inheriting abnormal alleles (see further the section of

Genetic Tables).  Geography – patients living in sunny climes could develop phototoxicities from photosensitizing drugs more readily than

those who inhabit cooler, less sunny climates. 2. Drug-related factors:  Type/class of drug – for example, there is a heightened risk of angioedema with the use of ACE inhibitors (see further the

section of tables of class reactions).  Duration of therapy – the longer a patient maintains the therapy, the more possible it becomes that he/she could develop a

reaction due to their changes in drug metabolism (e.g. renal insufficiency) or drug interactions.  Dosage – the greater the dosage, the more likely an adverse side effect.  Bioavailability – the extent to and rate at which the drug enters systemic circulation, thereby accessing the site of action.  Interactions with other drugs – for example, synergistic QT prolongation can occur when two QT prolonging agents, such

as erythromycin + ritonavir, are used together.  Route of administration – intramuscular, intravenous, subcutaneous, and topical administrations are more likely to cause

hypersensitivity reactions; oral medications are less likely to result in drug hypersensitivity. The terms “drug allergy,” “drug hypersensitivity,” and “drug reaction” are often used interchangeably. “Drug allergy” specifically refers to a reaction mediated by IgE; “drug hypersensitivity” is an immune-mediated response to a drug agent in a sensitized patient; and “drug reactions” comprise all adverse events related to drug administration, regardless of etiology. Vigilance at point of care: While the possibilities for adverse drug reactions seem endless, we must be on the lookout for any new medication(s) the patient might be taking. A thorough, detailed history of all medications must be made in order to elicit any remote possibility that the drug in question might be the culprit for the side effect. People do not often realize that the common over-thecounter analgesics – aspirin, Tylenol, Advil, Motrin, Naprosyn, and others – are actually medications. Herbals and supplements such as St. John’s wort, ginkgo biloba, and echinacea can be responsible for various hypersensitivity reactions. For example, St. John’s wort, in particular, interacts adversely with SSRIs and tricyclic antidepressants.

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Contents of the book, and how to use them 1.

The A–Z The major portion of the manual lists in alphabetical order the 1500 most consulted and most important generic drugs, biologics, and supplements, and the adverse reactions that can arise from their use. If you do not find a drug in the main A–Z listing under the name you know it by, you can turn to the concordance of synonyms and trade names to find the generic name it will be listed under. Trade (brand) name(s) are listed alphabetically. When there are many trade names, the ten (or so) most commonly recognized ones are listed. Following the trade names is – in parentheses – the latest name of the pharmaceutical company that markets the drug. Many of the names of companies have changed from earlier editions of this manual because of acquisitions, mergers, and other factors in the pharmaceutical industry. Next appear the Indication(s), the Class in which the drug belongs, and the Half-life of each drug, where known. Drug interactions: many severe, hazardous drug-drug interactions are recorded. Only clinically significant drug interactions that have been reported to trigger potential harm and that could be life threatening have been included here in the profile. These interactions are predictable and well documented in controlled studies; they should be avoided. Pregnancy category: for new drugs approved on or after 30 June 2015 this field gives (where available) a brief summary of the full statement reflecting the risk for pregnant women as given in the prescribing guidelines; health care providers are advised to check the individual label where necessary. An explanation of the categories for older drugs (A, B, C, D and X) can be found on our website – www.drugeruptiondata.com. Any “Black box” Warning required by the FDA or Notes on use then follow. Adverse Drug Reactions: under each drug profile is a list of related ADRs. These adverse events have been classified under the following categories: Skin, Hair, Nails, Mucosal; Cardiovascular, Central Nervous System, Endocrine/ Metabolic, Gastrointestinal/Hepatic, Genitourinary, Hematologic, Local, Neuromuscular/Skeletal, Ocular, Otic, Renal, Respiratory, Other. Within each category, the reactions are listed alphabetically. Thus, the order of listing does not reflect severity or frequency in any way. The terminology used to list reaction patterns has been simplified as far as possible by eliminating, for the most part, tags such as “like” (as in “-Psoriasis-like”), “-reactivation,” “-syndrome,” “-dissemination,” etc. The number of reports is given for each reaction in square brackets. The incidence of the most important reactions is given in parentheses where indicated (usually from the full prescribing information for the relevant drug). For example, the profile for Amoxicillin begins: Skin AGEP [28] Anaphylactoid reactions/Anaphylaxis [17] Angioedema (5%. This is not the final step, but it gives me some evidence to demonstrate that, although each of these drugs could cause rash, one is much more likely than the others.

Figure 1 ix

After we have the background rate from Litt we can think of data that might modify the background rate. Nothing is as helpful as knowing the timing of drug exposure to onset of a rash. In this instance we know that aminopenicillin rashes come on around day 8 to 10 after exposure. That is very powerful additional information. Ceftriaxone There are comparatively few (7) reports and lower reported background rates (none in the package insert information) for this reaction in the database (Fig 2) and manual for a drug that is widely used. Clearly exanthems are not a major clinical issue, and the figures here are reassuringly low – not nearly as high as Amoxicillin, although not impossible.

Figure 2 Clarithromycin Figure 3 shows the very few (3) reports from the database and manual of this drug causing a rash; the lack of any reported background rate supports the conclusion it is not a major clinical issue.

Figure 3 We have to come to some conclusion and all possibilities need to be represented. Based on Amoxicillin being a common cause of an exanthem (AND on the timing), we have to give it a big lead. Then we think of “I don’t know” and “I will never know”, which I always mark down as 15% each. We now know the other antibiotics have a much small risk. So 30% for the unknowns, 5% or so for the drugs that were unlikely, leaves the remainder for Amoxicillin. The numbers are approximations based on the data to hand. Having other unknowns reflects real life: maybe it was due to some contrast media? Or a comorbid risk? Or dozens of other possibilities. And truly sometimes we never know. Now I am ready (and armed with data I can defend rationally) to send my report back to the referring doctor: “Dear colleague Thank you for sending information about your patient. I have not seen the patient and some key information is missing. My report is based on what information I have but clearly that could change with more data. Assuming the patient had a simple exanthem and no fever etc., the estimated likelihood of what caused the rash is as follows: Amoxicillin: 65% Ceftriaxone: 4% Clarithromycin: 1% Other unknown exposures or risks: 15% We will never know: 15%” CONCLUSIONS LESSON 1: Look for good quality clinical data. LESSON 2: Give opinions in text, not conversation. LESSON 3: Use a structured summary that is uniform, every time, to increase the impact and be on target. LESSON 4: Be quantitative; it is clear and respected. I hope this enhances your search for quality information and enhanced patient safety.

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Bone or joint pain (5–6%) Myalgia/Myopathy (5–6%) [2]

ABACAVIR Trade names: Epzicom (ViiV), Triumeq (ViiV), Trizivir (ViiV), Ziagen (ViiV) Indications: HIV infections in combination with other antiretrovirals Class: Nucleoside analog reverse transcriptase inhibitor Half-life: 1.5 hours Clinically important, potentially hazardous interactions with: alcohol, arbutamine, argatroban, arsenic, darunavir, ganciclovir, lopinavir, methadone, phenobarbital, phenytoin, protease inhibitors, ribavirin, rifampin, tipranavir, valganciclovir Pregnancy category: C Important contra-indications noted in the prescribing guidelines for: nursing mothers Note: Check for presence of HLA B*57:01 Epzicom is abacavir and lamivudine; Triumeq is abacavir, dolutegravir and lamivudine; Trizivir is abacavir, lamivudine and zidovudine. Warning: HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS and SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS B

Renal Fanconi syndrome [2]

Respiratory Bronchitis (4%) Cough [2] Pneumonia (4%) Upper respiratory tract infection [2]

Other Adverse effects / adverse reactions [4] Infection (5%)

Cardiovascular Myocardial infarction [10]

Central Nervous System Abnormal dreams (10%) [2] Anxiety (5%) Chills (6%) Depression (6%) Fever (pyrexia) (includes hyperpyrexia) (6%) [2] Headache (7–13%) [4] Insomnia [2] Migraine (7%) Neuropsychiatric / neuropsychological adverse effect [4] Sleep-related disorder (10%) Vertigo / dizziness (6%) [3]

Endocrine/Metabolic ALT increased (6%) AST increased (6%) Hyperamylasemia (2–4%) Hypertriglyceridemia (includes triglycerides increased) (2–6%)

Gastrointestinal/Hepatic Abdominal pain (6%) Diarrhea (7%) [4] Gastritis / pangastritis / gastric irritation (6%) Hepatotoxicity / liver injury / acute liver injury / drug-induced liver injury (DILI) [4] Nausea (7–19%) [6] Vomiting (2–10%)

Hematologic Agranulocytosis / severe selective neutropenia (see also ‘Neutropenia’) [3] Neutropenia (neutrophils decreased) (2–5%)

Neuromuscular/Skeletal Asthenia / fatigue (7–12%) [2]

Headache (12%) Pain (31%) Vertigo / dizziness (12%)

Endocrine/Metabolic Gynecomastia (30%) Mastodynia (20%)

Neuromuscular/Skeletal Asthenia / fatigue (10%) Back pain (31%)

Respiratory Upper respiratory tract infection (12%)

Other

ABALOPARATIDE Trade name: Tymlos (Radius Health) Indications: Osteoporosis in postmenopausal women Class: Parathyroid hormone analog Half-life: