Orphan Drugs in Epilepsy [1 ed.] 9782742012343, 9782742008100

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M. Nikanorova P. Genton S. I. Johannessen C. Johannessen Landmark

M

978-2-7420-0810-0

™xHSMHOCy008100z

M. Nikanorova, P. Genton, S. I. Johannessen, C. Johannessen Landmark

ore than half of the epilepsies begin before the age of 20 and almost 25% of these are intractable. Epilepsy in children is different from epilepsy in aldults. Indeed, seizures occur in various age-dependent syndromes, they are part of epilepsy and syndrome phenotypes not seen in adults, and in addition occur at an age of brain maturation and differentiation. Rare diseases occur in less than 200,000 individuals in the United States, or less than 5 per 10,000 individuals in the European Union. Thus the development of new drugs to treat this small population of patients is slowed down because of the expense risk. However, various drugs called “orphan drugs” have been allocated for the treatment of some epilepsy syndromes in childhood with grave prognosis. This book on pharmacological and clinical aspects of orphan antiepileptic drugs is unique. It is divided into six chapters that cover various pharmacological and clinical issues of orphan antiepileptic drugs used in the treatment of some devastating epileptic syndromes so-called epileptic encephalopathies. While there is a need to develop new drugs having a specific action in this age group. This book book written by experts in the field of epileptology offers valuable information about orphan drugs and their approved clinical use.

Orphan Drugs in Epilepsy

Orphan Drugs in Epilepsy

Orphan Drugs in Epilepsy M. Nikanorova P. Genton S. I. Johannessen C. Johannessen Landmark

M. Nikanorova P. Genton S. I. Johannessen C. Johannessen Landmark

M

M. Nikanorova, P. Genton, S. I. Johannessen, C. Johannessen Landmark

ore than half of the epilepsies begin before the age of 20 and almost 25% of these are intractable. Epilepsy in children is different from epilepsy in aldults. Indeed, seizures occur in various age-dependent syndromes, they are part of epilepsy and syndrome phenotypes not seen in adults, and in addition occur at an age of brain maturation and differentiation. Rare diseases occur in less than 200,000 individuals in the United States, or less than 5 per 10,000 individuals in the European Union. Thus the development of new drugs to treat this small population of patients is slowed down because of the expense risk. However, various drugs called “orphan drugs” have been allocated for the treatment of some epilepsy syndromes in childhood with grave prognosis. This book on pharmacological and clinical aspects of orphan antiepileptic drugs is unique. It is divided into six chapters that cover various pharmacological and clinical issues of orphan antiepileptic drugs used in the treatment of some devastating epileptic syndromes so-called epileptic encephalopathies. While there is a need to develop new drugs having a specific action in this age group. This book book written by experts in the field of epileptology offers valuable information about orphan drugs and their approved clinical use.

Orphan Drugs in Epilepsy

Orphan Drugs in Epilepsy

Orphan Drugs in Epilepsy M. Nikanorova P. Genton S. I. Johannessen C. Johannessen Landmark

Orphan Drugs in Epilepsy

Topics in Epilepsy series, vol. 4 Series Editors Pierre Genton, Centre Saint-Paul, Hôpital Henri-Gastaut, Marseille, France. Renzo Guerrini, Hospital A. Meyer, Firenze, Italy. Günter Kramer, Swiss Epilepsy Center, Zurich, Switzerland. Pierre Thomas, Hôpital Pasteur, Nice, France.

ISBN: 978-2-7420-0710-3 Éditions John Libbey Eurotext 127, avenue de la République 92120 Montrouge, France Tél.: 01 46 73 06 60 e-mail: [email protected] http://www.jle.com Éditrice : Anne Chevalier John Libbey Eurotext 42-46 High Street Esher KT109QY United Kingdom

© 2011 John Libbey Eurotext. All rights reserved. It is prohibited to reproduce this work or any part of it without authorisation of the publisher or of the Centre Français d’Exploitation du Droit de Copie (CFC), 20, rue des Grands-Augustins, 75006 Paris.

Orphan Drugs in Epilepsy Editors Marina Nikanorova, Pierre Genton, Svein I. Johannessen, Cecilie Johannessen Landmark

List of contributors

Marina Nikanorova, Danish Epilepsy Centre, Dianalund, Denmark Pierre Genton, Centre Saint-Paul, Hôpital Henri-Gastaut, Marseille, France Svein I. Johannessen, The National Center for Epilepsy, Department of Pharmacology, Oslo University Hospital, Oslo, Norway Cecilie Johannessen Landmark, Department of Pharmacy, Oslo University College, Oslo, Norway

V

Contents Foreword ..........................................................................................................................

IX

Bromides ..........................................................................................................................

1

Adrenocorticotropic hormone and corticosteroids ....................................................

9

Vigabatrin........................................................................................................................

21

Stiripentol........................................................................................................................

39

Felbamate.........................................................................................................................

49

Rufinamide......................................................................................................................

65

VII

Foreword

Although up to date, several books have tackled the topic “antiepileptic drugs in epilepsy”; this book on pharmacological and clinical aspects of orphan antiepileptic drugs is unique. The book is divided into six chapters that cover various pharmacological and clinical issues of orphan antiepileptic drugs used in the treatment of some devastating epileptic syndromes so-called epileptic encephalopathies. Children, particularly infants, are not little adults and their seizures as well as their agedependent EEG abnormalities differ in their expression and response to treatment. Several syndromes in this young age-group carry a severe mental prognosis due to the impact of diffuse electrical activity on organization of the immature brain that significantly affects normal development and cognition. Treatment in this group of children is not only aimed at preventing seizures, but also at abolishing ictal and interictal EEG abnormalities. It is therefore important to know if the drug in development displays anti-seizure activity only or if it has a potential for antiepileptogenesis as well. More than half of the epilepsies begin before the age of 20 and almost 25% of these are intractable. Epilepsy in children differs from epilepsy in adults by the facts that seizures occur in various age-dependent syndromes, they are part of epilepsy and syndrome phenotypes not seen in adults, and in addition occur at an age of brain maturation and differentiation. Traditionally the new AEDs have all been evaluated in add-on studies in adult patients refractory to previous therapies and some compounds that are ineffective in adult seizure type may be effective in age-dependent seizures/epilepsy syndromes and vice-versa. Rare diseases occur in less than 200,000 individuals in the United States, or less than 5 per 10,000 individuals in the European Union. The potential market to develop new drugs to treat this small population of patients is too small to justify the expense risk. However, various drugs called “orphan drugs” have been allocated for the treatment of some epilepsy syndromes in childhood with grave prognosis. Vigabatrin, a GABA-transaminase inhibitor, has become a first-choice agent for infantile spasms alone or combined with adenocorticotropic hormone. Stiripentol, a direct allosteric modulator of GABA receptors combined with valproic acid and clobazam has given encouraging results in the treatment of Dravet syndrome. Rufinamide, a fast sodium channel blocker, has been approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children 4 years and older and adults.

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Orphan Drugs in Epilepsy

While there is a need to develop new drugs having a specific action in this age-group. this book written by experts in the field of epileptology offers valuable information about orphan drugs and their approved clinical use. Athanasios Covanis Former Head Department of Neurology & Neurophysiology, Athens, Greece Consultant Peadiatric Neurologist, Makarios Hospital, Cyprus

X

Bromides

History Bromide, an anorganic ion similar to chloride, is present in the environment, especially in seawater (at around 65 mg/L), and consumption of seafood and fish results in significant presence of brome salts in human blood. Bromides were widely used in the XIXth and early XXth centuries usually in combined preparations, as sedatives, also against headache. Lithium bromide was used against bipolar disorder. Bromides are still used nowadays, at low concentrations, as mild antiseptic agents in swimming pools. Due to chronic toxicity, their use as pharmaceutical agents has dramatically diminished in the latter XXth century. Bromides, especially potassium bromide (KBr), were considered the first “modern” anticonvulsants, i.e. the first agents that were used following clinical reports of efficacy presented in a scientific setting. The actual “birth” of bromides as anticonvulsants occurred during a session of the Royal Medical and Chirurgical Society of London on May 11th, 1857, when Sir Charles Locock reported that he had used potassium bromide successfully in 13 out of 14 women with hysterical (mostly catamenial) epilepsy, during the discussion of a report by Sievking on patients with epilepsy (Locock, 1857). His initiative was probably based on a previous observation of impotence in a patient on bromide, and to the general acceptance of seizures as consequences of onanism and hypersexuality (Friedlander, 1986). Bromides remained the only scientifically approved anticonvulsant agent for over 50 years, until the emergence of phenobarbital in 1912 (Hauptmann, 1912). The positive effect of bromides on the EEG was discussed as soon as this technique appeared as useful in patients with epilepsy (Gibbs et al., 1936). Bromides lost ground in the treatment of epilepsy over the years, in great part because of the emergence of significant toxicity, but are still useful in the treatment of very severe forms of infancy- or childhood-onset epileptic encephalopathies. In most countries, their prescription in patients with epilepsy requires a special procedure. They apparently still belong to the main drugs used for the treatment of epilepsy in animals, e. g. in cats (Boothe et al., 2002), although animals, e. g. dogs, may clearly present the same type of side-effects (“bromism”) as humans (Rossmeisl & Inzana, 2009). Bromides were also recently used to demonstrate an anticonvulsant action in an original seizure model, the drosophilia fly (Tan et al., 2004) and are thus still considered classical antiepileptic drugs.

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Orphan Drugs in Epilepsy

Pharmacology Chemical structure of potassium bromide K-Br

Chemical characteristics This is the potassium salt of bromine, a simple inorganic ion with anticonvulsant activity, that behaves in ways very similar to chloride.

Mechanisms of action At present it is not exactly known how bromides act to prevent seizures. The bromide ion is handled similarly to chloride, and because its hydrated diameter is less than that of chloride it may pass through the membrane channels more readily and cause hyperpolarization of the transmembrane potential, making neurons less likely to initiate a seizure discharge or to participate in the spread of the seizure (Woodbury & Pippenger, 1982). Another possible mechanism of action in the nervous system is potentiation of GABAergic inhibition. The GABAA receptor constitutes a chloride channel, and following activation of the receptor, the influx of chloride causes the neuron to hyperpolarize, leading to decreased neuronal excitability. The effect of bromide on the benzodiazepine binding site might be related to cellular hyperpolarization (Palacios et al., 1979). It may also inhibit the action of carbonic anhydrase, affecting the acid-base balance within the brain, similarly to acetazolamide (Woodbury & Pippenger, 1982).

Pharmacokinetics Bioavailability All the inorganic bromide salts are water soluble and rapidly and completely absorbed from the gastrointestinal tract after oral ingestion. The absorption of bromide is saturable at very high doses. There is no significant difference in the serum concentration curves for oral and intravenous doses. Maximum serum concentrations are attained after less than 2 hours after dosing (Woodbury & Pippenger, 1982).

Distribution and protein binding As for chloride the distribution of bromide is mostly into extracellular water space. The drug is not bound to proteins and is freely diffusible. The volume of distribution is similar to that of chloride and has been estimated at 408 ± 17 mL/kg. Bromide is present in body secretions like tears, sweat and saliva, and it readily crosses the placenta. Fetal levels closely parallel those of the mother. The concentration of bromide in saliva is 1.5 times that of serum. CSF concentrations are somewhat lower than in serum (Woodbury & Pippenger, 1982).

2

Bromides

Metabolism and renal excretion Because bromide is a simple monovalent inorganic ion, it is not metabolized. It is primarily excreted via the kidney. It is somewhat better reabsorbed in the renal tubules compared to chloride. The concentration/dosage ratio increases with increasing age (Korinthenberg et al., 2007).

Elimination half-life

f:\2000\image\139709\bromide\1

Since the excretion of bromide is very slow, its elimination half-life is rather long, 12-14 days after oral administration and is in accordance with first order kinetics. Renal clearance is in the order of 267 ± 1.7 mg/kg/day (Vaiseman et al., 1986). A high chloride load will shorten the half-life, and conversely a salt-deficient diet would increase it. The time to achieve steadystate serum concentrations with chronic dosing is dependent of the half-life, and 4-5 times the half-life has to elapse before steady-state is reached. This means that for bromide it may take about 7-8 weeks. In their recent work, however, Korinthenberg et al. (2007) noted that the steady state was reached after a median of 28 days.

Drug interactions Since bromide is a CNS depressant, enhancement of the inhibitory effect of other CNS-active drugs is likely. Bromide does not induce or inhibit the activity of drug-metabolizing liver enzymes. No protein binding displacement takes place as bromide is not bound to proteins. Bromide concentrations are higher in patients receiving lithium salts.

Figure 1. Pharmacokinetic scheme for bromide.

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Orphan Drugs in Epilepsy

Therapeutic drug monitoring In fact bromide was the first antiepileptic drug for which it was suggested that the correlation existed between serum concentration and clinical toxicity. Thus, bromide serum concentrations should be carefully monitored because toxic effects may occur when the concentration exceeds 150 mg/100 mL. The therapeutic/reference range is in the order of 100-200 mg/mL (8.4-16.8 μmol/L), although some patients require higher concentrations to obtain best seizure control, but often with considerable side effects (Steinhoff & Kruse, 1992). Very importantly, one has to keep in mind the long half-life when dosage is increased as it takes a number of weeks before a new steady-state is achieved. Rapid dose escalation may lead to toxic concentrations lasting for several months. Bromide concentrations may be analysed using a manual gold chloride photometric assay that is not widely available. Potentiometric flow injection determination may yield more precise results (Katsu et al., 1997).

Clinical indications Little remains of the first historical indication of bromides, in “hysterical” (premenstrual) epilepsy. Recent work has focused on the use of bromides in difficult-to-treat epilepsies, especially in the paediatric age classes. The efficacy profile of bromides is concentrated around their effect against generalized convulsive seizures, although other seizure types may respond. None of the papers reporting efficacy of bromides fulfils the criteria of a controlled, randomized study, but some reports are indeed in favour of a noteworthy efficacy, especially in childhood-onset severe epilepsies with convulsive seizures. The archetype of the encephalopathic, drug-resistant epilepsies of childhood is the LennoxGastaut syndrome (LGS), a concept often used to describe various forms of severe epilepsies, but nowadays considered in a more restricted manner (Genton & Dravet, 2007). This disorder is characterized, in particular, by the association of several seizure types. Bromides have little efficacy against absences and tonic seizures, and may even aggravate the latter (Browne et al., 2008). Among 11 children with severe epilepsy treated with bromides, including three with the LGS, Woody (1990) reported two became seizure-free, four were significantly improved and three only transiently improved. In patients with a significant improvement, the mean daily dose was 33 mg/kg/d, and the mean blood level was 14.1 mmol/L (range 4-30.5 mmol/l). Steinhoff and Kruse (1992) retrospectively evaluated the efficacy of bromides in 60 patients with generalized tonic-clonic seizures, most with mental handicap and early brain lesions, but did not specificy specific diagnoses of LGS, although their sample probably included such patients: they considered the effect as positive, with around 60% responders. Overall, it can be stated, however, that there are no reliable data demonstrating the efficacy of bromides in the LGS, and, as many other, modern and comparatively safer therapeutic options are available in this condition, bromides will probably not be considered a major alternative. On the other hand, bromides have shown efficacy in the Dravet syndrome (DS), or severe myoclonic epilepsy in infancy, a very severe condition with multiple seizure types and a high degree of drug resistance (Dravet et al., 2002). In an add-on trial of potassium bromide

4

Bromides

in 22 patients with DS or its borderline variant, Oguni et al. (1994) noted an excellent shortterm improvement in eight and a moderate improvement in nine. This efficacy was noted primarily against major convulsive seizures (generalized tonic-clonic (GTCS), generalized clonic), but also in complex partial seizures, while myoclonias and absences did not respond. Such efficacy had been noted earlier in children with “intractable” epilepsy in childhood (Tanaka et al., 1990), in patients with GTCS (most of them with longstanding handicaps) at an older age (Steinhoff & Kruse, 1992), and patients with intractable epilepsy with GTCS and onset in early childhood (Ernst et al., 1988). All these series most probably included patients with DS. A recent Japanese review of treatment procedures in 99 DS patients with serial seizures and/or convulsive status epilepticus (Tanabe et al., 2008) classified bromides as the most potent curative or preventive agent in this situation: efficacy was reported in 41.7% of cases for potassium bromide, vs. 13.5 for zonisamide, 10.0% for clobazam, 8.0% for valproate, 6.7% for phenobarbital and 2.6% for phenytoin. This study did not mention stiripentol or felbamate (or the ketogenic diet). It thus appears that bromides remain a therapeutic option in DS, especially in dramatic situations with frequent convulsive seizures. Bromides have also been used in other circumstances. In malignant migrating partial seizures in infancy, a very severe, often lethal, cryptogenic condition with onset in early infancy (Dulac, 2005), several authors have reported high efficacy. Okuda et al. (2000) have reported seizure control in two cases. It was again recently mentioned, in an abstract, that a combination of bromides, stiripentol, and levetiracetam relieved this condition in two 2-month old infants. Given the absence of effective, recommended therapy in this condition, bromides may appear as a therapeutic option in the syndrome of malignant partial seizures in infancy. Takayanagi et al. (2002) have reported efficacy in the treatment of two children with resistant focal epilepsy and focal status. Korinthenberg et al. (2007) recently confirmed that potassium bromide (started at 45 mg/kg and given at a median dose of 70 mg/kg) showed efficacy in a pediatric population with severe epilepsy and GTCS: the latter were controlled in 49% and improved by 50% or more in a further 31%. It has also been noted that bromides are not hepatic enzyme-inducing agents and are thus indicated in the treatment of patients with porphyria and epilepsy (Browne et al., 2008). In summary, it can be stated that bromides nowadays have few indications. Given their comparatively unfavourable safety profile, they can be considered as last resort, or “third line” medications in very difficult situations involving convulsive seizures that resist conventional treatment, including modern and orphan drugs. However, they should not be completely forgotten or abandoned, especially during difficult periods in patients with DS, or in truly intractable cases like in the syndrome of malignant migrating partial seizures in infancy. Their use in other situations is a matter of personal judgment.

Use of bromides in clinical practice In recent years, bromides have been used only in selected patients, mostly in the pediatric age classes, and have remained fairly popular among epileptologists and neuropediatricians in Japan and Germany, who produced most of the clinical observations that can be quoted. The commercial preparation that is available in Europe comes as Dibro-Be® tablets containing

5

Orphan Drugs in Epilepsy

850 mg potassium bromide, licensed in Germany for the treatment of severe generalized epilepsies in children; it is produced by Dibropharm GmbH Distribution & Co, a company based in Baden-Baden, Germany. In most countries, treatment with bromides requires a special request at health authorities and a special import procedure. There are several veterinary preparations (Bromapex® solution, 250 mg/mL; Epibrom® tablets, 200 mg ; Epilease® tablets, 250 mg).

Tolerability and side effects Paradoxical, pharmacodynamic seizure aggravation may occur with bromides, and has been mentioned by several authors (Boenigk et al., 1989; Tanaka et al., 1990; Ryan & Baumann, 1999). However, there is no specific rationale to account for this, nor are there specific seizureor epilepsy-related parameters that may predict a risk of aggravation. Bromides have a significant side-effect potential. Ingestion of high doses irritates the gastric mucosa and provokes vomiting. Acute intoxication is now very uncommon, it is ototoxic and nephrotoxic, acute renal insufficiency may be lethal. The most commonly noted sideeffects of bromides are chronic, and have been referred to as “bromism”. They include CNSrelated effects: lethargy and depression, loss of appetite, tremor, ataxia, clonic seizures, headache and papilledema (with cerebral edema), confusion and delirium, abnormal speech, memory loss, aggressivity, psychosis. Cutaneous complications occur in 25% of patients: an acneiform dermatitis, often described as bromoderma, aphtous stomatitis, or even a rare form of panniculitis (Diener et al., 1998). There may also be mucous hypersecretion, obstipation, rhinitis, aggravation of asthma. Toxicity is related to dose and to blood level. Anzai et al. (2003) reported a case of bromoderma which appeared in a 3-year old girl after daily doses of potassium bromide had been increased from 500 to 800 mg/d: the blood level had risen from 43.7 mEq/L to 114 mEq/L (untreated, “normal” range: 0-5 mEq/L); the skin lesions disappeared within 10 days of cessation of bromide therapy. It is thus important to monitor the therapeutic concentration of bromides. Daily doses range from 30 to more than 150 mg/kg/d (recommended: 30 to 80 mg/kg/d). The starting dose should be at 10 mg/kg/d, in several divided doses because of poor gastric tolerability. Given the long half-life of bromides, a steady state is not reached before 7 to 8 weeks As with other anticonvulsants, the therapeutic scheme should be individually tailored to the patient’s situation, and the treatment should be monitored closely, especially when higher doses are required, because of the high incidence of CNS-related or dermatological side effects. REFERENCES • Almeida ACG, Scorza FA, Rodrigues AM, Arida RM, Carlesso FN, Batista AG, et al. Combined effect of bumetanide, bromide, and GABAergic agonists: An alternative treatment for intractable seizures. Epilepsy Behav 2011; 20: 147-9.

• Anzai S, Fujiwara S, Inuzuka M. Bromoderma. Int J Dermatol 2003; 42: 370-1. • Boenigk HE, Saelke-Treumann A, May T, et al. Bromides: useful for treatment of generalized epilepsies in children and adolescents? Cleve Clin J Med 1989; 56: S272.

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Bromides

• Boothe DM, George KL, Couch P. Disposition and clinical use of bromide in cats. J Am Vet Med Assoc 2002; 221: 1131-5.

• Korinthenberg R, Burkart P, Woelfle C, Moenting J, Ernst J. Pharmacology, efficacy, and tolerability of potassium bromide in childhood epilepsy. J Child Neurol 2007; 22: 414-8.

• Browne TR, LeDuc BW, Kosta-Rokosz MD, Bromfield EB, Ramsay RE, De Toledo J. Trimethadione, Paraldehyde, Phenacemide, Bromides, Sulthiame, Acetazolamide, and Methsuximide. In: Engel J, Pedley TA, eds. Epilepsy. A Comprehensive Textbook (2nd ed). Philadelphia: Lippincott-Raven, 2008, 1703-19.

• Locock L. Discussion of a paper by EH Sievking. Analysis of 52 cases of epilepsy observed by the author. Lancet 1857; 1: 527. • Oguni H, Hayashi K, Oguni M, Mukahira A, Uehara T, Fukuyama Y, et al. Treatment of severe myoclonic epilepsy in infants with bromide and its borderline variant. Epilepsia 1994; 35: 1140-5.

• Diener W, Sorni M, Ruile S, Rude P, Kruse R, Becker E, et al. Panniculitis due to potassium bromide. Brain Dev 1998; 20: 83-7.

• Okuda K, Yasuhara A, Kamei A, et al. Successful control with bromide of two patients with malignant migrating partial seizures in infancy. Brain Dev 2000; 22: 56-9.

• Djuric M, Kovacevic G, Kravljanac R, Zamurovic D. Two patients with malignant migrating partial seizures in infancy. Epilepsia 2010; 51 (Suppl 5): 112.

• Palachios JM, Niehoff DL, Kuhar MJ. Ontogeny of GABA and benzodiazepine receptors: effects of Triton X-100, bromide and muscimol. Brain Res 1979; 179; 390-5.

• Dravet C, Bureau M, Oguni H. Severe myoclonic epilepsy in infancy. In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence (4th ed). Montrouge: John Libbey Eurotext, 2005, 89-113.

• Rossmeisl JH, Inzana KD. Clinical signs, risk factors, and outcomes associated with bromide toxicosis (bromism) in dogs with idiopathic epilepsy. J Am Vet Med Assoc 2009; 234: 1425-31.

• Dulac O. Malignant migrating partial seizures in infancy. In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence (4th ed). Montrouge: John Libbey Eurotext, 2005, 73-6.

• Ryan M, Baumann RJ. Use and monitoring of bromides in epilepsy treatment. Pediatr Neurol 1999; 21: 523-8.

• Ernst J, Doose H, Baier W. Bromides were effective in intractable epilepsy with generalized tonic-clonic seizures and onset in early childhood. Brain Dev 1988; 10: 385-8.

• Sourkes TL. Early clinical neurochemistry of CNSactive drugs: bromides. Mol Chem Neuropathol 1991; 14: 131-42.

• Friedlander WJ. Who was “the father of bromide treatment of epilepsy”? Arch Neurol 1986; 43: 505-6.

• Steinhoff BJ, Kruse R. Bromide treatment of pharmacoresistant epilepsies with generalized tonic-clonic seizures: a clinical study. Brain Dev 1992; 14: 144-9.

• Genton P, Dravet C. The Lennox-Gastaut syndrome. In: Engel J, Pedley TA, eds. Epilepsy. A Comprehensive Textbook (2nd ed). Philadelphia: Lippincott-Raven, 2007, 2417-27.

• Takayanagi M, Yamamoto K, Nakagawa H, Munakata M, Kato R, Yokoyama H, et al. Two successful cases of bromide therapy for refractory symptomatic localizationrelated epilepsy. Brain Dev 2002; 24: 194-6.

• Gibbs FA, Lennox WG, Gibbs EL. The electro-encephalogram in diagnosis and in localization of epileptic seizures. Arch Neurol Psychiatry 1936; 36: 1225-35.

• Tan JS, Lin F, Tanouye MA. Potassium bromide, an anticonvulsant, is effective at alleviating seizures in the Drosophila bang-sensitive mutant bang senseless. Brain Res 2004; 1020: 45-52.

• Hauptmann A. Luminal bei Epilepsie. Münchner Medizin Wochenschrift 1912; 59: 1907-9.

• Tanabe T, Awaya Y, Matsuishi T, Iyoda K, Nagai T, Kurihara M, et al. Management of and prophylaxis against status epilepticus in children with severe myoclonic epilepsy in infancy (SMEI; Dravet syndrome) – A nationwide questionnaire survey in Japan. Brain Dev 2008; 30: 629-35.

• Joynt R. The use of bromides for epilepsy. Am J Dis Child 1974; 128: 362-3. • Katsu T, Mori Y, Matsuka N, Gomita Y. Potentiometric flow injection determination of serum bromide in patients with epilepsy. J Pharm Biomed Anal 1997; 15: 1829-32.

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• Tanaka J, Mimaki T, Tagawa T, Ono J, Itagaki Y, Onodera T, et al. Efficacy of bromide for intractable epilepsy in childhood (in Japanese). J Jpn Epil Soc 1990; 8:105-9.

• Woodbury DM, Pippenger CE. Other antiepileptic drugs: bromides. In: Woodbury DM, Penry JK, Pippenger CE, eds. Antiepileptic Drugs (2nd ed). New York: Raven Press, 1982, 791-801.

• Vaiseman N, Koren G, Pencharz P. Pharmacokinetics of oral and intravenous bromide in normal volunteers. J Toxicol Clin Toxicol 1986; 24: 403-13.

• Woody RC. Bromide therapy for pediatric seizure disorder intractable to other antiepileptic drugs. J Child Neurol 1990; 5: 65-7.

8

Adrenocorticotropic hormone and corticosteroids

History The history of adrenocorticotropic hormone (ACTH) and corticosteroid use in treating patients with epilepsy dates back to the 1950s (Dorfman et al., 1951; Friendlander & Rottgers, 1951). The initial results, however, were controversial. Some investigators reported the negative influence of ACTH on epilepsy, whereas the others demonstrated the clinical and EEG improvement after hormonal treatment. In 1950, Klein and Livingston performed a study on ACTH efficacy in 6 children with refractory epilepsy. A significant reduction of seizure frequency was observed in 4 out of 6 patients. Later, Sorel and Dusansy-Bouloye (1958), using ACTH at the doses 4-10 IU/kg in children with infantile spasms, showed a marked clinical and electrographic improvement in the majority of patients. In 1959, successful treatment of infantile spasms with ACTH or oral steroids was reported by Dumermuth. Since then ACTH and corticosteroids have been widely used for the treatment of epileptic encephalopathies of childhood.

9

f:\2000\image\139709\acth\1 f:\2000\image\139709\acth\2 f:\2000\image\139709\acth\3

Orphan Drugs in Epilepsy

Chemical structure

Figure 1. Chemical structure of ACTH.

Figure 2. Chemical structure of prednisone.

Figure 3. Chemical structure of prednisolone (active metabolite of prednisone).

10

Adrenocorticotropic hormone and corticosteroids

Chemical characteristics ACTH is a 39-amino acid polypeptide that is secreted from the anterior pituitary. The first 24 from the N-terminal end of the chain is required for full biologic activity. The sequence of these 24 amino acids is the same in humans and many animals and is considered to exert identical biological effects. Commercial sources of natural ACTH generally are obtained from porcine pituitaries, but synthetic preparations are also available. Prednisone is a synthetic glucocorticoid with anti-inflammatory and immunosuppressant effects. It is a white, odourless crystalline powder only slightly soluble in water, alcohol and chloroform (McEvoy, 2005).

Mechanisms of action Partly because the knowledge about the pathogenesis of epileptic encephalopathies is limited, little is also known about the mechanism of action of ACTH and corticosteroids. Several hypotheses have been emphasized. ACTH and corticosteroids down-regulate serotonin 5-HT2 receptors in the cerebral cortex, they modulate GABA and dopamine receptors, an effect that is age-dependent in animals. Furthermore, ACTH and corticosteroids have immunosuppressant properties and their mechanism of action may be related to their anti-inflammatory and immunosuppressant effects. For the time being the most eligible hypothesis is related to the effects of ACTH and corticosteroid actions through the hypothalamic-pituitary-adrenal axis related to studies in infantile spasms (Brunson et al., 2001; Nalin et al., 1985). Decreased levels of ACTH have been detected in CSF of children with infantile spasms. It has been postulated that the pathophysiological background for this condition activates a stress-response, leading to increased production and higher levels of corticotrophin-releasing hormone (CRH). This hormone has a proconvulsant action by increasing neuronal excitability in the limbic system and the brain stem, and thus ACTH and corticosteroids might act through a negative feedback mechanism by suppressing CRH synthesis and release (Brunson et al., 2001; Nalin et al., 1985).

Pharmacokinetics Bioavailability ACTH is rapidly degraded by proteolytic enzymes in the gastrointestinal tract and must therefore be administered parentally either by intramuscular or by subcutaneous route. Intravenous administration is not suitable (Schimmer & Parker, 2006). Natural ACTH is readily absorbed from the injection site, time to peal serum concentrations being 1-2 hours. With sustained release preparations absorption is prolonged for several hours. Oral bioavailability of ACTH is not applicable (McEvoy, 2005). Prednisone is well absorbed following oral administration, and peak serum concentrations are attained in 1-2 hours. Oral bioavailability of prednisone is more than 70% in terms of

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Orphan Drugs in Epilepsy

metabolically derived prednisolone, the active metabolite of prednisone. After oral dosing the serum concentration profile for prednisone is similar to that of prednisolone (Di Santo & De Sante, 1975; McEvoy, 2005).

Distribution and protein binding ACTH is transported with Cohn protein fractions II and III in the blood. It is rapidly removed from the plasma by many tissues. The volume of distribution is 0.4 L/kg (it refers to the 1-24β-tetracosactide, the principle contained in Synachten Depot). Prednisone is about 70% protein-bound. Prednisolone is also extensively bound to serum proteins, mainly transcortin in addition to albumin (60-95%). The binding of the latter is non-linear, i.e. the unbound fraction increases with increasing drug concentration. The volume of distribution of prednisone is 0.5-0.9 L/kg (it increases with increasing doses) (McEvoy, 2005; Rose et al., 1981).

Metabolism and renal excretion ACTH is metabolized by enzymatic hydrolysis. Prednisone itself is inactive and is rapidly metabolized in the liver to prednisolone by oxidative metabolism and conjungation, partly through a first-pass effect, and prednisolone is responsible for the pharmacological effects. The clearance of prednisolone increases with increasing dose partly due to the concentration-dependent protein binding and is higher in children than in adults (Bartoszec et al., 1987; McEvoy, 2005).

Elimination half-life ACTH has an elimination half-life of about 15 min, but can be considerably increased when using sustained-release formulations, maintaining the serum concentrations for several hours. Prednisolone has an elimination half-life of 1.5-4 hours, with the shortest values in children (Bartoszec et al., 1987; Hill et al., 1990).

Drug interactions Concomitant administration of enzyme inducing antiepileptic drugs like phenytoin, phenobarbital and carbamazepine increases the metabolism of corticosteroids resulting in lower serum concentrations and possibly reduced clinical efficacy, also for ACTH. Conversely, many drugs may inhibit the metabolism of prednisolone, such as inhibitors of CYP3A4, certain macrolides and ritonavir (Bartoszec et al., 1987; McEvoy, 2005) (Figures 4 and 5).

Therapeutic drug monitoring In general, serum level monitoring of drugs may facilitate clinical management because of pharmacokinetic variability due to drug interactions and disease states. However, for ACTH and corticosteroids this is not routinely performed, and the patients are followed by clinical observations (Hill et al., 1990).

12

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Adrenocorticotropic hormone and corticosteroids

Figure 4. Pharmacokinetic scheme for ACTH.

Figure 5. Pharmacokinetic scheme for prednisolone.

Clinical indications During the last 20 years ACTH and corticosteroids have been mostly used in the treatment of West syndrome (Singer et al., 1980; Lombroso, 1983; Ito et al., 1990; Riikonen, 2001). However, several aspects are still the subject of ongoing controversy: • the type of corticosteroid, ACTH or prednisone; • low or high doses; • duration of treatment and outcome.

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Orphan Drugs in Epilepsy

Generally, a reduction or cessation of infantile spasms and normalization of the EEG in 50-75% of patients is reported after therapy with either ACTH or prednisone (Lombroso, 1983; Riikonen, 1982). Nevertheless, a prospective, randomized, blinded study performed by Baram et al. (1996) demonstrated a superior efficacy of high dose ACTH (150 IU/m2 for two weeks) compared to prednisone (2 mg/kg/d for two weeks). In a prospective study from the United Kindom (Lux et al., 2004), 107 patients were randomized to tetracosacide (synthetic ACTH), given at a dose of 0.5 mg/d (40 IU) on alternate days, and prednisolone 40 mg/day. The response rates comprised 76 and 70%, respectively. The difference was not significant on day 14 of treatment. Patients with tuberous sclerosis were excluded from this study, since evidence suggests that vigabatrin is the best choice in the treatment of infantile spasms associated with tuberous sclerosis. The doses of ACTH and corticosteroids vary in different countries: 3-14 IU/d in Japan (Oguni et al., 2006), 18-36 IU/d in Finland (Heiskala et al., 1996; Riikonen, 2001), 80 IU/d in the US (Snead et al., 1989). In a series by Hrachovy et al. (1994) and Riikonen (2001), no significant differences in either response or relapse rates have been observed between the patients assigned to high dose (80-120 IU) or low dose (20-40 IU) of ACTH. The protocols of ACTH administration also differ (Table I). In the Finnish prospective study (Riikonen, 2001, 2009) in 30 children, therapy was individualized according to the aetiology (Table II). This modified treatment schedule was low dose ACTH for short periods. If a relapse occurred, a new course of ACTH was found to be effective in two thirds of patients. In refractory cases, valproate, nitrazepam, topiramate, vigabatrin, and zonisamide were recommended. Nine prospective studies have been analyzed in a recent large data-based review undertaken by the American Academy of Neurology and Child Neurology Society (Mackay et al., 2004). It was concluded that insufficient data exists to define the optimal dose and treatment duration with ACTH, for patients with infantile spasms. However, the usually recommended doses comprise: ACTH: 40 IU/d; hydrocortisone: 15 mg/kg/d, prednisolone: 2 mg/kg/d (Hrachovy et al., 1991; Chiron et al., 1997; Riikonen, 2001). In a few recent studies pulsatile corticoid therapy has been reported as an alternative treatment to ACTH in West syndrome (Karenfurt et al., 2002; Haberlandt et al., 2010). Haberlandt et al. (2010) compared the efficacy of ACTH (15-20 IU/d i.m., increased every 2 weeks, up to

Table I. Protocols of ACTH use in infantile spasms. Week

ACTH dose

Snead et al. (1989) 1 2 3 4-12

75 IE/m2 x 2 daily 75 IE/m2 x 1 daily 37.5 IE/m2 x 1 every 2nd day Stepwise dose decrease and withdrawal

Hrachovy et al. (1991) 1-2 3-6 7-8

20 IE/d 30 IE/d Stepwise dose decrease and withdrawal

14

Adrenocorticotropic hormone and corticosteroids .

Table II. Treatment schedule for the use of ACTH in infantile spasms (Riikonen, 2001; 2009). All cases: start with tetracosatide* 0.03 mg/kg every 2nd day. Assess at 2 weeks Cryptogenic, responding Week 3: tetracosatide 0.01 mg/kg every 2nd day Week 4: tetracosatide 0.0075 mg/kg every 2nd day Start hydrocortisone 1 mg/kg/d with later reduction and withdrawal once ACTH response is normal Symptomatic, responding Weeks 3 and 4: continue tetracosatide 0.03 mg/kg every 2nd day Week 5 onwards: half dose each week: 0.015 mg/kg, 0.0075 mg/kg every 2nd day, etc. Start hydrocortisone 1 mg/kg/d with later reduction and withdrawal once ACTH response is normal Cryptogenic or symptomatic, non-responding Weeks 3 and 4: tetracosatide 0.06 mg/kg every 2nd day Week 5 onwards: half dose of tetracosatide each week Add nitrazepam/valproate/vigabatrin/topiramate/zonisamide as necessary If relapse occurs, return to the lowest preceding effective dose of ACTH * Tetracosatide (synthetic analogue of ACTH) 0.03 mg/kg is equivalent to natural ACTH 3 IU.

a maximum of 120 IU/d) with dexamethasone (20 mg/m2 i.v. daily, given for 3 days, with an interval of 4 weeks between each cycle). Seizure response for both therapy options was likewise comparable. ACTH treatment resulted in seizure control in 9/11 patients, pulsatile corticoid therapy in 5/7 patients. Normalization of the EEG was demonstrated in 4/11 and 4/7 children, respectively. To summarize, clear therapeutic strategies concerning administration of steroids are lacking. Studies differ in dosages and therapy duration, and prospective studies are rare. However, early administration of steroids after the second week of hypsarrhythmia is relevant for controlling seizures and provides a better cognitive outcome (Willig & Lagenstein, 1982; Riikonen, 2005).

Epileptic syndromes with continuous spike-waves during sleep Epilepsy with continuous spike-waves during sleep (CSWS), including Landau-Kleffner syndrome, is another main indication for the steroid treatment. Compared to the conventional antiepileptic drugs, steroids seem to have more lasting effect. Several studies have been focused on steroid efficacy in patients with epilepsy and CSWS, using different treatment regimes. In a series by Marescaux et al. (1990), three patients received either prednisone or hydrocortisone during 4 to 12 months. In the second study, four patients received early and prolonged ACTH or corticosteroid therapy, with high initial doses (Lerman et al., 1991). Tsuru et al. (2000) reported two patients on the high dose intravenous methylprednisolone pulses for 3 days followed by a one-month oral prednisolone cure. Improvement of language, cognition and behavior was demonstrated in all but one patient of these 4 series. Clinical improvement was at time spectacular, especially in children treated relatively early in the course of the disease, and was usually accompanied by an EEG improvement, with complete disappearance

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Orphan Drugs in Epilepsy

of the epileptiform activity in some cases. In several patients there were relapsed during steroid withdrawal. The risk of relapse seems to be related to brief duration of treatment. Buzatu et al. (2009) administered hydrocortisone (initial dose of 5 mg/kg/d and tapered over 21 months) to 44 children who had CSWS and evaluated its effects on EEG, behavior, and cognition. Positive response to steroids was found during the first 3 months of treatment in 34 children (77.2%), with normalization of EEG in 21 and relapse in 14. Twenty patients (45.4%) were long-term responders after steroid treatment, with shorter duration of CSWS and significantly higher IQ. Sinclair and Snyder (2005) assessed the efficacy of corticosteroids in eight children with Landau-Kleffner syndrome and two with CSWS. The patients received prednisone 1 mg/kg/day for 6 months, 1 year, then yearly. Follow-up was for 1 to 10 years (mean 4 years). All but one patient exhibited significant improvement in language, cognition, and behaviour, which continued after the corticosteroid trial. The authors concluded that corticosteroids are a safe and effective treatment for children with Landau-Kleffner syndrome and CSWS.

Other epilepsy syndromes The use of steroids in the treatment of epilepsy beyond West syndrome/infantile spasms has been limited to only a few studies. Good response to ACTH was described in some patients with Ohtahara syndrome (Ohtahara et al., 1997; Yamatogi & Ohtahara, 2002). Steroid treatment might be sometimes effective in the early course of the Lennox-Gastaut syndrome but effect is generally transitory, and therefore steroids are rarely used (Yamatogi et al., 1979; Nair & Snead, 2008). Two recent publications reported the efficacy of steroid treatment in the wide spectrum of refractory childhood epilepsies (Sinclair, 2003; Verhelst et al., 2005). In a study performed by Sinclair (2003), prednisone 1 mg/kg/d was used for 12 weeks in 28 children with intractable generalized epilepsies: 10 Lennox-Gastaut syndrome, 7 absence epilepsy, 6 Dravet syndrome, 3 childhood myoclonic epilepsy, and 2 West syndrome. Thirteen patients (46%) became seizure-free after the steroid trial and 10 (36%) had a decrease > 50% in seizure frequency. The best response was observed in children with absence epilepsy. Patients with Lennox-Gastaut syndrome had also a good response when treated early in the course of their illness. Verhelst et al. (2005) retrospectively assessed 36 treatment courses with ACTH and steroids in 32 children with intractable epilepsy, not including West syndrome. The following treatment regimes have been used: ACTH 2-5 IU/kg/d for 3 weeks, dexamethasone 0.5-5 mg/kg/d for 3 days to 8 months (continue or in pulse therapy), hydrocortisone 5-20 mg/kg/d for 4 weeks to 20 months, prednisone 0.3-3 mg/kg/d for 7 days to 24 months, and methylprednisolone 2 mg/kg/d for 2 months. Thirteen patients (36%) were responders of whom nine (25%) became seizure-free, four (11%) had a seizure reduction > 50%, and four (11%) showed no effect to steroid treatment.

Tolerability and side effects Most frequently observed side effects include hypertension, infections, Cushing syndrome, weight gain, obesity, behavioural disturbances (Table III). Haberlandt et al. (2010) reported

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Adrenocorticotropic hormone and corticosteroids

less adverse effects during pulsatile therapy with corticosteroids compared to ACTH treatment. Verhelst et al. (2005) found positive correlation between duration of treatment and side effects. However, the same authors have not demonstrated any correlation between steroid type and severity of side effects. To avoid infections while treating with ACTH, Riikonen et al. (2001) recommend prophylactic trimethoprim-sulfaxazole therapy, especially to infants with a history of frequent respiratory infections. Table III. Side effects of ACTH and corticosteroids (Sinclair, 2003; Verhelst et al., 2005; Haberlandt et al., 2010). Side effect

Frequency

Hypertension

71% on ACTH therapy 7-13% on corticosteroids

Infections

36-40%

Cushing syndrome

19-30%

Obesity/weight gain

17-26%

Behavioural problems

17-25%

To minimize the side effects, therapy should be given at the minimal effective dose and for the shortest effective time course. REFERENCES • Baram T, Michell W, Tournay A, et al. High-dose corticotrophin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study. Pediatrics 1996; 97: 375-9.

• Di Santo AR, De Sante KA. Bioavailability and pharmacokinetics of of prednisone in humans. J Pharm Sci 1975; 64: 109-12. • Dorfman A, Apter NS, Smull K, et al. Status epilepticus coincident with use of pituitary ACTH: report of 3 cases. J Am Med Assoc 1951; 146: 27-31.

• Bartoszek M, Brenner AM, Szefler SJ. Predisolone and methylprednisolone kinetics in children receiving anticonvulsant therapy. Clin Pharmacol Ther 1987; 42: 424-32.

• Dumermuth G. On-flash-nodding-salaam convulsions and their treatment with ACTH and hydrocortisone: preliminary report. Helv Paediatr Acta 1959; 14: 250-70.

• Brunson KL, Khan N, Eghbal-Ahmadi M, et al. Corticotropin (ACTH) acts directly on amygdala neurons to down-regulate corticotropin-releasing hormone expression. Ann Neurol 2001; 49: 304-12.

• Friendlander W, Rottgers E. The effects of cortisone on the electroencephalogram. Electroenceph Clin Neurophys 1951; 3: 313-20.

• Buzatu M, Bulteau C, Altuzarra C, Dulac O, Van Bogaert P. Corticosteroids as treatment of epileptic syndromes with continuous spike-waves during slow-wave sleep. Epilepsia 2009; 50 (Suppl 7): 68-72.

• Haberlandt E, Weger C, Baumgartner S, et al. Adrenocorticotropic hormone versus pulsatile dexamethasone in the treatment of infantile epilepsy syndromes. Ped Neurol 2010; 42: 21-7.

• Chiron C, Dumas C, Jambaque I, et al. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res 1997; 26: 389-95.

• Heiskala H, Riikonen R, Santavuori P, et al. West syndrome: individualized ACTH therapy. Brain Dev 1996; 18: 456-60.

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• Hill MR, Szefler SJ, Ball BD, et al. Monitoring glucocorticoid therapy: a pharmacokinetic approach. Clin Pharmacol Ther 1990; 48: 390-8.

togenic infantile spasms with hypsarrhytmia. Epilepsia 1985; 26: 446-9.

• Hrachovy R, Glaze D, Frost J. A retrospective study of spontaneous remission and long-term outcome in patients with infantile spasms. Epilepsia 1991; 32: 212-4.

• Nair RR, Snead O. ACTH and steroids. In: Pollock J, Bourgeois B, Dodson W, et al., eds. Pediatric Epilepsy. Diagnosis and Therapy (3rd ed). New York: Demos, 2008, 543-56.

• Hrachovy R, Frost J, Glaze D. High-dose, long-duration versus low-dose, short duration corticotrophin therapy for infantile spasms. J Pediatr 1994; 124: 803-6.

• Novartis Pharmaceuticals. Synachten Depot (CCosyntropin-Zinc Hydroxyde Adrenocorticotropic Hormone), 2005.

• Ito M, Okuno T, Fuji T, et al. ACTH therapy in infantile spasms: relationship between dose of ACTH and initial effect or long term prognosis. Pediatr Neurol 1990; 6: 240-4.

• Oguni H, Yanagaki S, Hayashi K, et al. Extremely lowdose ACTH step-up protocol for West syndrome: maximal therapeutic effect with minimal side effects. Brain Dev 2006; 28: 8-13.

• Jaseja H. A plausible explanation for superiority of adreno-corticotrophic hormone (ACTH) over oral corticosteroids in management of infantile spasms (West syndrome). Med Hypotheses 2006; 67: 721-4.

• Ohtahara S, Ohtsuka Y, Yamatogi Y, et al. The early infantile epileptic encephalopathy with suppression-burst : developmental aspects. Brain Dev 1997; 9: 371-6. • Riikonen R. A long term follow up study of 214 children with the syndrome of infantile spasms. Neuropediatrics 1982; 13: 14-23.

• Karenfurt M, Wilken B, Hanefeld F. Pulsatile dexamethasone puls therapy in symptomatic infantile spasms. Neuropediatrics 2002; 6: A52.

• Riikonen R. ACTH therapy of West syndrome: Finnish views. Brain Dev 2001; 23: 642-6.

• Klein R, Livingston S. The effect of adrenocorticotropic hormone in epilepsy. J Pediatr 1950; 37: 733-42.

• Riikonen R. The latest on infantile spasms. Curr Opin Neurol 2005; 18: 91-5.

• Lerman P, Lerman-Sagie T, Kivity S. Effect of early corticosteroid therapy for Landau-Kleffner syndrome. Dev Med Child Neurol 1991, 33: 257-60.

• Riikonen R. West syndrome. In: Nikanorova M, Genton P, Sabers A, eds. Long-Term Evolution of Eepileptic Encephalopahties. Montrouge: John Libbey Eurotext 2009, 13-28.

• Lombroso C. A prospective study of infantile spasms: clinical and therapeutic correlations. Epilepsia 1983; 24: 135-58.

• Rose JQ, Yurchak AM, Jusko WJ. Dose dependent pharmacokinetics of prednisone and prednisolone in man. J Pharmacokinet Biopharm 1981; 9: 389-417.

• Lux A, Edwards S, Hancock E, et al. The United Kindom intantile spasms study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre randomized controlled trial. Lancet 2004; 364: 1773-8.

• Schimmer BP, Parker KL. Adrenocorticotropic hormone, adrenocortical steroids and their synthetic analogs. In: Goodman and Gilman’s Pharmacology. (11th ed). New York: McGraw-Hill, 2006, 1587-611.

• Mackay M, Weiss S, Adams-Webber T, et al. Practice parameter: medical treatment of infantile spasms. Report of the American Academy of Neurology and Child Neurology Society. Neurology 2004; 62: 1668-81.

• Sinclair DB. Prednisone therapy in pediatric epilepsy. Pediatr Neurol 2003; 28: 194-8.

• Marescaux C, Hirsch E, Finck S, Maquet P, Schlumberger E, Sellal F, et al. Landau-Kleffner syndrome: a pharmacologic study of five cases. Epilepsia 1990; 31: 768-77.

• Sinclair DB, Snyder T. Corticosteroids for the treatment of Landau-kleffner syndrome and continuous spike-wave discharge during sleep. Pediatr Neurol 2005; 32: 300-6.

• McEvoy GK, ed. AHFS (American Hospital Formulary Service) Drug Information. Bethesda: American Society of Health-System Pharmacists, 2005.

• Singer W, Rabe E, Haller T. The effect of ACTH therapy upon infantile spasms. J Pediatr 1980; 96: 485-9. • Snead O, Benton J, Hosey L, et al. Treatment of infantile spasms with high dose ACTH: efficacy and plasms

• Nalin A, Facchinetti F, Galli V, et al. Reduced ACTH content in cerebrospinal fluid of children affected by cryp-

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levels of ACTH and cortisol. Neurology 1989; 39: 1027-31.

• Willig RP, Lagenstein I. Use of ACTH fragments of children with infantile spasms. Neuropediatrics 1982; 13: 55-8.

• Sorel L, Dusaucy-Bauloye A. A propos de 21 cas d’hypsarrythmia de Gibbs : son traitement spectaculaire par l’ACTH. Acta Neurol Belg 1958; 58: 130-41.

• Yamatogi Y, Ohtsuka Y, Isheda T, et al. Treatment of the Lennox-Gastaut syndrome with ACTH : a clinical and electroencephalographic study. Brain Dev 1979; 4: 267-76.

• Tsuru T, Mori M, Mizuguchi M, Momoi M. Effects of high-dose intravenous corticosteroid therapy in LandauKleffner syndrome. Pediatr Neurol 2000; 22: 145-7.

• Yamatogi Y, Ohtahara S. Early-infantile epileptic encephalopathy with suppression-bursts. Ohtahara syndrome; its overview referring to our 16 cases. Brain Dev 2002; 24: 13-23.

• Verhelst H, Boon P, Buyse G, et al. Steroids in intractable childhood epilepsy: clinical experience and review of the literature. Seizure 2005; 14: 412-21.

19

Vigabatrin

History Vigabatrin (Vinyl-GABA-transaminase inhibitor – VGB; chemically, gamma vinyl GABA, or 4-amino-5-hexenoic acid; Sabril® in most countries, Sabrilex® in some Northern European countries) occupies a special place among the anticonvulsants that are considered “orphan”. Not unlike felbamate, it was launched with great momentum and great expectations, as the first really “new” major antiepileptic drug (AED) with broad indications since valproate: in the UK in 1989, and in other European countries soon after. It was approved in the US in 1997 with restrictions. After a promising start, chronic, dose-related toxicity leading to progressive visual loss in a significant proportion of patients became apparent, and its use was thereafter restricted to more specific indications (especially in the treatment of infantile spasms) and associated with strict visual monitoring. However, vigabatrin remained popular as a very effective AED and its career is far from finished. Vigabatrin, which was marketed by various companies in various markets, may indeed become a more widely used AED again. In 2011, its use in difficult-to-control focal epilepsies is advertised again. It may thus loose the orphan status it had over the past decade, when it was used primarily in infantile spasms. Vigabatrin is a child of the 1970s. It was first synthesized in 1974, as a structural analog of GABA, the major CNS inhibitor, which had been shown to play a major part in the generation and spread of epileptic seizures. It was the first AED created rationally (Cereghino, 1993), and was demonstrated to be an irreversible inhibitor of GABA catabolism, producing long-lasting increased inhibition in the brain. It can be considered as the first, and indeed the only designed AED that produced the expected pharmacological effect. The first placebo-controlled clinical trials in patients with resistant focal epilepsy were published in the mid-1980s (Rimmer & Richens, 1984; Gram et al., 1985; Loiseau et al., 1986). It was first approved as an adjunctive in resistant epilepsies, in adults and within a few years in children. The first reviews on vigabatrin in epilepsy stressed a responder rate equal or above 50% in patients with complex partial seizures, the lack of significant pharmacodynamic interactions and a very satisfactory tolerability, with only mild and infrequent adverse effects (Grant, 1991; Connelly, 1993). It was quickly used in children (first on a compassionate basis) and its specific efficacy in infantile spasms was reported in 1991 (Chiron et al., 1991). An even more specific indication in the treatment of infantile spasms in the tuberous sclerosis complex was highlighted a few years later (Chiron et al., 1997). The first controlled study in this indication was published by Appleton et al. in 1998.

21

f:\2000\image\139709\vigabratin\1

Orphan Drugs in Epilepsy

The occurrence of severe visual field defects (VFD), i.e. concentric constriction, was signalled in 1997 (Eke et al., 1997): nerve toxicity had already been seen in animal studies, and this major, chronic, dose-related side-effect was soon found to be frequent. The clinical use of vigabatrin was subsequently restricted and conditioned to close monitoring of the visual field. Together with the emergence of newer, promising AEDs, this led to a considerable decrease in the clinical use of vigabatrin, which was from then on considered as a last-resort drug for refractory focal epilepsies, but was still more commonly used in infantile spasms. The European Medicines Evaluation Agency (EMEA) published in November 1999 an opinion that stated that it considered the benefit-risk profile of vigabatrin as positive as add-on in drugresistant focal epilepsies, and as monotherapy in infantile spasms. There is a recent, renewed interest in this original and effective compound, which is far from obsolete, and the pharmacological and clinical properties of vigabatrin were recently reviewed in detail (Krämer & Wohlrab, 2008; Ben Menachem et al., 2008; Willmore et al., 2009). In 2011, vigabatrin is being actively promoted again for use in epilepsy (see http://www.sabril.net).

Pharmacology Chemical structure

Figure 1. Chemical structure of vigabatrin: (±)-amino-5-hexenoic acid.

Chemical characteristics Vibabatrin is a structural analog of the major inhibitory neurotransmitter of the brain γ-amino-butyric acid (GABA). It is an off-white crystalline amino acid, highly soluble in water but only slightly soluble in alcohol. The drug is a racemate 50/50 mixture of R(-) and S(+) isomers. The pharmacological activity and toxic effects of vigabatrin is only associated with the S(+) enantiomer (Schechter, 1998).

Mechanisms of action Vigabatrin (γ-vinyl-GABA) was the first AED designed to have a specific mechanism of action, as it is an irreversible inhibitor of GABA transaminase, the enzyme responsible for the conversion of GABA to succinate seminaldehyde. This action results in an ubiquitous increase in brain GABA concentrations and concequently, increased GABAergic inhibitory neurotransmission (Johannessen Landmark, 2007; Perucca, 2004; Preece et al., 1994).

22

f:\2000\image\139709\vigabratin\2

Vigabatrin

Figure 2. Vigabatrin: mechanisms of action.

Pharmacokinetics Bioavailability Vigabatrin is rapidly absorbed after oral administration, and peak concentrations are attained within 1-2 hours. The bioavailability is about 80% and is independent of food intake (Schechter, 1998).

Distribution and protein binding Vigabatrin is widely distributed in the body, it is not bound to serum proteins, and its approximate volume of distribution is 0.8 L/kg. The CSF concentration is about 10% of the serum concentration (Patsalos & Duncan, 1995; Schechter, 1989). The passage across placenta is slow, and the concentration ratio between breast milk and serum is less than 0.5 (Tran et al., 1998).

Metabolism and renal excretion Vigabatrin is eliminated by renal excretion. 70% of the initial dose is eliminated in the urine. Vigabatrin is not involved in the CYP P450 system. The clearance of vigabatrin is highly correlated with creatinine clearance, and thus the clearance of vigabatrin is reduced in the

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Orphan Drugs in Epilepsy

elderly. Dose adjustments should be made in patients with impaired renal function (Patsalos & Duncan, 1995; Schechter, 1989)

Elimination half-life The elimination half-life of vigabatrin in serum is 6-8 hours. Within the clinically used dose range vigabatrin concentrations are linearly related to dosage. Children have a higher clearance of vigabatrin compared to adults and therefore require higher doses in mg/kg to attain comparable serum concentrations (Armijo et al., 1997). Their renal blood flow and function is increased compared to adults.

f:\2000\image\139709\vigabratin\3

Drug interactions Theoretically, vigabatrin is not susceptible to pharmacokinetic interactions. Since vigabatrin is excreted unchanged renally, this drug is not susceptible to drug interactions through CYP or other enzymes in the liver, but a decrease in phenytoin serum concentrations of about 20-30% has been reported and is most pronounced in children, when co-prescribed with phenytoin (Rimmer & Richens, 1989). The mechanism is unknown (metabolism, protein binding and absorption have been excluded as possible mechanisms) (Gatti et al., 1993). A decrease in rufinamide serum concentrations of about 25% has also been reported in the presence of vigabatrin (Perucca et al., 2008). To date no other pharmacokinetic or pharmacodynamic interactions involving vigabatrin have been reported.

Figure 3. Pharmacokinetic scheme for vigabatrin.

24

Vigabatrin

Therapeutic drug monitoring In contrast to most other AEDs, therapeutic drug monitoring of vigabatrin is not suitable as a guide to therapy, as its serum concentration does not reflect the pharmacological activity of the drug because of its mechanism of action (irreversible enzyme inhibition). The effects remain present long after the drug has been excreted and its length of action depends on the rate of synthesis of new uninhibited GABA transaminase. Measurement of serum vigabatrin concentrations may, however, be useful to check on recent compliance (Johannessen & Tomson, 2006). For doses of 1,000-3,000 mg, the expected through serum vigabatrin concentrations are 0.8-36 μg/mL (6-278 μmol/L). Various HPLC methods are available for determination of vigabatrin (Patsalos et al., 2008).

Clinical indications There are no confirmed clinical uses of vigabatrin besides treating epilepsy. However, this molecule has been shown to exert pharmacological actions in several fields outside epilepsy, or in very specific indications, that should be mentioned here: – Vigabatrin reduced cholecystokinin (CCK) tetrapeptide-induced symptoms of panic disorder in 10 volunteers treated for 7 days; it specifically reduced the CCK-induced increase in cortisol and ACTH (Zwanzger et al., 2001). – In succinic semialdehyde dehydrogenase deficiency, a GABA degradative defect with a severe phenotype of mental retardation and hypotonia, epilepsy, which affects 50% of patients, may respond to vigabatrin, although only low doses (25 mg/kg) should be used (Matern et al., 1996); vigabatrin may also improve paroxysmal dystonia in this condition (Leuzzi et al., 2007). – Cocaine and metamphetamine dependence may respond to vigabatrin, as previously shown in animal studies (Stromberg et al., 2001): in a short (9-week) controlled trial, 14 vigabatrintreated patients out of 50 were able to stay off the illicit drug, vs. 4 out of 53 on placebo (Brodie et al., 2009); vigabatrin-treated patients were also more likely to abstain from alcohol at the end of the study. There were no side-effects associated with vigabatrin in this trial. – The outcome of a controlled trial of vigabatrin in patients with cerebellar ataxia (9 with Friedreich’s ataxia, 5 with olivopontocerebellar atrophy) was negative: it showed that only one patient had long-term benefit from vigabatrin 2,000 mg/d (Bonnet et al., 1986). Likewise, vigabatrin showed little if any efficacy against the symptoms of Huntington’s chorea (Scigliano et al., 2004). – Contrary to other anticonvulsants, vigabatrin has no efficacy in the prevention of migraine (Mulleners & Chronicle, 2008). – There are single case reports of a major clinical benefit to patients with the “stiff man syndrome” treated with vigabatrin, usually in association with other GABAergic drugs (benzodiazepines and/or baclofen) (Vermeij et al., 1996; Prevett et al., 1997; Drozdowski et al., 2003).

25

Orphan Drugs in Epilepsy

The clinical indications of vigabatrin in epilepsy have been outlined by the EMEA in 1999: Restriction of the indications to treatment in combination with other anti-epileptic drugs for patients with resistant partial epilepsy with or without secondary generalisation, that is where all other appropriate drug combinations have proved inadequate or have not been tolerated and to monotherapy in the treatment of infantile spasms (West syndrome). Initiation of the treatment and follow-up should be arranged under supervision of a specialist in epileptology, neurology or paediatric neurology. The primary indication for vigabatrin was as add-on in resistant focal epilepsies. A recent Cochrane review (Hemming et al., 2008) integrating 11 controlled trials, with doses of vigabatrin ranging from 1,000 to 6,000 mg/d, confirmed that vigabatrin was more likely than placebo to obtain a greater than 50% reduction in seizure frequency and to develop shortterm side-effects like fatigue and drowsiness. A comparative randomized trial of vigabatrin and valproate in patients who were not controlled by carbamazepine yielded comparable results for both drugs: 53% vs. 51% of responders. Vigabatrin has also been used in milder focal epilepsies, and as monotherapy in new onset focal epilepsies: among 397 mostly adult patients with 3.7 ± 1.9 seizures per month, add-on vigabatrin, at a mean dose of 2.3 g/d 13.4% became seizure-free, while another 57.2% had meaningful improvement (Arzimanoglou et al., 1997). In Poland, vigabatrin monotherapy (n = 26) was compared with carbamazepine monotherapy (n = 28) in children with focal epilepsy: > 75% seizure reduction was observed in 84.6% with vigabatrin compared to 60.7% with carbamazepine (it was noted that two children on vigabatrin developed myoclonic jerks) (Sobianec et al., 2005). Head-on comparison with reference AED were performed with carbamazepine in newly diagnosed focal epilepsy, and the drugs were shown to be approximately as potent against focal seizures. Kälviäinen et al. (1995) reported satisfactory control in 60% of patients in both treatment groups, with a slightly better cognitive tolerability for vigabatrin. Tanganelli and Regesta (1996) reported 45.9% of patients with total seizure control at 4 months with vigabatrin, vs. 51.3% with carbamazepine; vigabatrin had a slightly better tolerability profile. The other core indication of vigabatrin is for epileptic spasms, following the first reports by Chiron et al. in1991. Appleton et al. (1998) performed a placebo-controlled study and showed that within the 5 days of the double-blind phase, 35% of vigabatrin-treated infants were free of spasms, and 25% no longer had hypsarrhythmia on the EEG, vs. 10% and 5% on placebo; vigabatrin monotherapy brought spasm-freedom to 46% of the patients at the end of the study. Comparisons with steroids were done in several studies. In a randomized trial, vigabatrin (100-150 mg/kg) was compared with ACTH (10 IU/d) in 42 newly diagnosed infants, the alternative drug being administered within 20 days in case of intolerance or lack of efficacy; spasms stopped in 48% in the vigabatrin group vs. 70% in the ACTH group, but there were more relapses in the ACTH group (Vigevano & Cilio, 1997). Numerous studies confirmed the efficacy of vigabatrin in infantile spasms (review in Krämer & Wohlrab, 2008). Infantile spasms in tuberous sclerosis were shown to be selectively responsive to vigabatrin (Aicardi et al., 1996; Chiron et al., 1997): in this etiology, vigabatrin is an undisputed first choice of therapy. This is also the case in infantile spasms due to cortical dysplasia, where the control rate is close to 90% with vigabatrin (Lortie et al., 2002). In other cases, attitudes vary, many authors preferring to use steroids as first-line agents (Riikonen, 2005). However, the combination of vigabatrin with steroids is considered syner-

26

Vigabatrin

gistic and is recommended in cases which resist either of these first-line therapies (Granstrom et al., 1999). Severe neonatal epileptic encephalopathies may respond to vigabatrin, as reported in two cases of Ohtahara syndrome due to polymicrogyria (Baxter et al., 1995); the same authors included in their study a third patient with Aicardi syndrome, also a responder to vigabatrin; two of these three infants survived with a better-than-expected evolution. There are few studies reporting the effect of vigabatrin in epileptic encephalopathies in older children. A positive effect was reported in Lennox-Gastaut syndrome (LGS) (Feucht & Brantner-Inthaler, 1994): in 20 children who had not responded adequately to valproate, add-on vigabatrin produced a 50-100% reduction in seizure frequency in 85%; one patient experienced dyskinesia, but none of the side-effect observed with the usual add-ons (according to the authors, phenobarbital, primidone or benzodiazepines), e. g. sedation, mood changes or ataxia, occurred. Other evaluations of vigabatrin in the LGS were not so optimistic: for Livingston et al. (1989), only six out of 26 patients showed a response, and several were aggravated; for Luna et al. (1989), among seven children with the LGS, two experienced more than 50% seizure reduction, but two were aggravated; Gibbs et al. (1992) found no responder among seven patients. There is a single case report of vigabatrin (associated with ethosuximide and valproate) improving a patient with the continuous spike-waves during sleep syndrome (Popovic et al., 2005).

Use of vigabatrin in clinical practice It is estimated that more than 1,500,000 patients have been exposed to vigabatrin worldwide. Its use is overshadowed by the risk of VFD: however, most studies point out the fact that this complication occurs slowly, that it can be detected early, at a stage where there will be no significant impairment in daily life, and that it concerns up to 40% of all patients on longterm therapy. This means that more than 50% of patients will not have VFD and thus might tolerate vigabatrin well over the long term. Besides the above mentioned restrictions due to unwanted side effects, the clinical use of vigabatrin should be monitored, in daily clinical practice, with two further problems in mind: the risk of paradoxical aggravation, and the occurrence of tolerance to the anticonvulsant effect. Paradoxical aggravation due to vigabatrin was noted by Lortie et al. in 1993, mainly occurring in resistant generalized epilepsies with multiple seizure types. In a later study, Lortie et al. (1997) reported on a large group of 196 children followed over 1.5 to 5.5 years: seizure aggravation occurred in only 10%, but mostly within the first month of treatment, and in patients with atypical absences (38% of these), patients with the Lennox-Gastaut syndrome (28%) or with non-progressive myoclonic epilepsy (38%). A few reports mentioned possible seizure worsening in a minority of patients: two out of 36 with mostly drug-resistant focal seizures (Pedersen et al., 1985). Three patients experienced severe status epilepticus after introduction of vigabatrin (de Krom et al., 1995). Two adult patients with focal epilepsy presented with multifocal myoclonus under vigabatrin, without associated EEG changes, and the myoclonus resolved after dose reduction or withdrawal of vigabatrin (Neufeld & Vishnevska, 1995). Among 101 patients with refractory epilepsy, most of them with focal seizures, one had

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Orphan Drugs in Epilepsy

absence status and four experiences increased seizures after addition of vigabatrin (Italian Study Group on Vigabatrin, 1992). A more specific type of aggravation was noted in idiopathic generalized epilepsies: in association with other aggravating agents, mostly carbamazepine, vigabatrin can be responsible for the occurrence of myoclonic status in such patients (Thomas et al., 2006). Two children with absences were aggravated by vigabatrin, and improved quickly upon withdrawal (Parker et al., 1998). Aggravation may also occur with vigabatrin in patients with Angelman syndrome (Guerrini et al., 2003; Valente et al., 2008). Paradoxical aggravation isn’t usually well reported, and one would expect that it is a fairly common occurrence in patients with generalized epilepsies treated with vigabatrin. Patients with multiple seizure types, including myoclonias and absences, should be particularly monitored in this respect. Vigabatrin has also been reported to have worsened two cases of early myoclonic encephalopathy associated with nonketotic hyperglycinemia (Tekgul et al., 2006). Tolerance has been associated with most GABAergic drugs, like phenobarbital and benzodiazepines, and was shown to occur with vigabatrin in animal models. In amygdala-kindled rats, vigabatrin produced a strong anticonvulsant effect which was however lost after 2 weeks of chronic treatment (Rundfeldt & Löscher, 1992). In rat cortical slices, GABA-release was markedly reduced in chronic (17 days) vs. acute conditions (Neal & Shah, 1990). Early clinical studies failed to show tolerance to the anticonvulsant effect of vigabatrin: tolerance to sedative side effects without tolerance to anticonvulsant effect after 19 months of treatment in 41 of 62 patients with secondarily generalized seizures (Dam, 1989); maintenance of therapeutic effect in more than 50% of responders over several years (Ylinen et al., 1995). However, the occurrence of tolerance was noted in clinical practice, and confirmed by some open studies: Michelucci et al. (1994) found that about 1/3 of the patients experienced loss of efficacy of the long term. A correlate of tolerance is the occurrence of withdrawal symptoms, especially increased seizures: in a specifically designed study, 28 pediatric patients who had partially responded to vigabatrin were randomized into a vigabatrin maintenance group and a placebo (withdrawal) group: 93% vs. 46% failed to have a 50% increase in seizures, which apparently demonstrates a withdrawal effect (Chiron et al., 1996). A major withdrawal effect with nearly continuous seizures in four out of 16 patients after withdrawal of vigabatrin was reported by Tassinari et al. (1987). In clinical practice, it will thus be wise to withdraw vigabatrin progressively, at least over several weeks, even when there has been no obvious clinical improvement in seizures, but especially if the seizure history points to tolerance. Vigabatrin is available in the form of 500 mg tablets and 500 mg powder for solution (higher dosages for soluble powder were formerly available, and may still be in some countries). In spite of a very short plasma half-life, the pharmacodynamic effect is very prolonged, and a single daily intake can be implemented in most patients; a twice daily intake is possible in large doses (over 4,500 mg tablets per day), in order to increase acceptability. The dosage increase should be progressive, in order to minimize sedation and other dose-related unwanted side-effects. There is no influence of food in the absorption of vigabatrin. Also on the positive side, there is no need or usefulness for therapeutic drug monitoring, and there are no biological parameters to monitor. The main practical guidelines for the introduction, dosing and discontinuation of vigabatrin have been summarized on Table I. The final dose of vigabatrin will be chosen according to clinical response (seizures and sideeffects). In adults, the starting dose is usually set at 1,000 mg and the increments are by 500 or 1,000 mg weekly; the target daily dose ranges between 2,000 and 4,000 mg, but lower and

28

Vigabatrin

Table I. Summarized practical management of patients treated with vagabatrin (VGB). Adults

Pediatric

Indications

Add-on in drug-resistant focal epilepsy

Infantile spasms (monotherapy or add-on) Add-on in drug-resistant focal epilepsy

Before initiation of VGB

Evaluation of visual field (static or dynamic)

Evaluation of visual field if possible (evoked potentials before age 3)

Initial daily dose

1,000 mg

40 mg/kg

Target daily dose

2,000 to 4,000 mg

Up to 100 mg/kg

Increments/titration

1,000 mg/d/week

According to clinical response

Blood levels, biology

No

No

Visual field monitoring

Every 6 months Discontinuation of VGB in case VFD is detected

Every 3 months (clinical or otherwise) during 18 months, every 6 months thereafter Discontinuation of VGB in case VFD is detected

Monitoring of efficacy

Discontinue if no clear beneficial effect at 3 months

Discontinue if no clear beneficial effect at 3 months

Monitoring of tolerability

Weight, mood, behaviour

Weight, behaviour

Discontinuation

Progressive (over 4-8 weeks or longer)

Progressive (over 4-8 weeks or longer)

higher doses may be used in some patients. In children, the starting dose is usually around 40 mg/kg, and increments of 250 or 500 mg/d can be implemented at 2-7 day intervals. The dose should be reduced in renally impaired patients due to the exclusively renal elimination of the drug. The monitoring of patients treated with vigabatrin has been outlined by health authorities around Europe, in accordance with EMEA recommendations (EMEA, 1999), and has not changed over the past decade. In summary, the visual field should be explored adequately using a standard static (Humphrey or Octopus) or dynamic (Goldman) perimetric method before the initiation of vigabatrin and every six months thereafter. Such procedures are usually possible only in patients aged 9 or more. A method based on visual-field specific evoked potentials was developed for peripheral vision but has not been validated for the detection of vigabatrin-related visual field defects. Electroretinography will only be used in adults who are not able to cooperate for perimetry, or in children aged less than 3 years. There are no recommendations on the possible cessation of VFD detection in long-term patients who fail to develop any complication after many years; in the UK, the recommendations are that systematic assessment be performed only at yearly intervals if no VFD is found after 3 years on vigabatrin: an enquiry among ophtalmologists in the UK showed, however, that most were unaware of these recommendations, and that the systematic monitoring was probably not performed adequately in vigabatrin-treated patients (Kumar & Jivan, 2006). In the present

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Orphan Drugs in Epilepsy

situation, the obligation to continue visual field monitoring may represent a burden on the patient and on the health care system. There is a consensus that vigabatrin, like other potentially toxic AEDs, should not be continued unless a clear benefit in terms of seizure control has been obtained. The risk of VFD is low in case of short-term (weeks to 6 months) exposure, which makes vigabatrin a reasonable drug proposal for many patients with severe epilepsy in whom the efficacy of the drug has never been assessed. After 3 months of treatment, the patient’s situation should be reappraised and vigabatrin should be discontinued if the benefit is judged low (Wilmore et al., 2008). In practice: – in infantile spasms, a clinical, EEG and behavioural response will usually appear very quickly, within days: the problem is whether the drug should be continued in infants who are doing well. Alternative therapies (e. g. steroids) are very toxic. Decisions pertaining to the (dis)continuation of vigabatrin will be made on an individual basis, taking into account all the parameters involved, including the overall prognosis of the condition and the etiology of the infantile spasms. This clinical behaviour may also be applied to infants and young children treated with vigabatrin for other types of epilepsies, besides infantile spasms; – in older children and in adults with resistant focal epilepsies, the therapeutic response may not be so clear, and individual assessment of the benefit/risk ratio is necessary, following adequate information of patient and caretakers.

Adverse effects: visual field defects (VFD) and related problems A possible neurotoxicity of vigabatrin had been demonstrated during preclinical studies, with intramyelinic vacuolization and edeam in hippocampus, cerebellum, visual pathways, and fornix found in rats and dogs exposed to VGB (review in Graham, 1989), these changes appearing as reversible after cessation of the drug. Monkeys treated with 300 mg/kg daily over 16 months failed to show significant changes at autopsy when compared to naive animals (Gibson et al., 1990). An MRI study of rats treated with vigabatrin 250 mg/kg/d demonstrated increased T2 relaxometry in the cerebellar white matter, which was correlated with the presence of microvacuoles (Jackson et al., 1994a). However, the same group (Jackson et al., 1994b) could not find similar white matter changes in 45 patients exposed to vigabatrin studied by the same MRI methods. Pedersen et al. (1987) found no microvacuoles in the CNS of a 38-yr old woman with astrocytoma, who died after having been treated with high doses of vigabatrin for nearly a year. Neither microvacuoles nor intramyelinc edema were found in the hippocampal resection material from a 36-yr old female patient who had been on vigabatrin for nearly a year (Agosti et al., 1990). In their review of all available published and “on file” data at the time, Cannon et al. (1991) found no evidence of vacuolisation in humans exposed to vigabatrin. In spite of knowledge of the potential neurotoxicity of vigabatrin, which probably delayed the introduction of the drug in clinical practice, there were thus no major concerns during the first years of use of vigabatrin. Indeed, during the clinical development of vigabatrin, visual field constriction and/or retinal defects were thought to have a very low prevalence of less than 1/1,000. In 1997, Eke et al.

30

Vigabatrin

sent out a red flag signalling the occurrence of severe visual field constriction in three patients on vigabatrin. This was confirmed from many sides, this unexpected side effect occurring mostly in fully unaware patients, although many had reached a stage of marked clinical impairment due to severe restriction of their visual field. Kälviäinen et al. (1999) examined 32 patients successfully treated with vigabatrin for 29 to 119 months, and compared them to 18 patients on carbamazepine (32 to 108 months) and to healthy controls: 40% of the vigabatrin patients had visual field constriction (9% severe, 31% mild, none being aware of this), vs. none in the carbamazepine and control groups. Vanhatalo et al. (2002) examined 91 children aged 5.6 to 17.9 years collected in fifteen neuropediatric departments, and found visual field constrictions in 18.7% of them ; affected patients had received higher doses ; there was no correlation with age at study, age at onset, neuroimaging finding, duration of treatment, or cognitive level; the shortest duration of treatment associated with VFC was 15 months, and the lowest total dose 914 g. Retrospective and ophtalmologist-based studies showed highest incidence of visual field defects, up to 71.4% of children exposed to vigabatrin (in the small series reported by Russell-Eggitt et al. in 2000), while prospective studies show a lower incidence. Frisen and Malmgren (2003) studied 25 patients with VFD, and found a characteristic pattern in 21: a subtle, diffuse atrophy of the retinal nerve fibre layer, with scores correlated to total vigabatrin dose and remaining visual field; their data point to irreversible lesions. Buncic et al. (2004) reported a detailed prospective follow-up of 3 children on vigabatrin, and defined a characteristic form of peripheral retinal atrophy and nasal or “inverse” optic disc atrophy. Reversibility of the VFD has been a matter of controversy. There were several case reports, and the observation by Vesino & Veggiotti (1999) of a 10-year old girl who had clinically apparent visual field constriction after 2 years on vigabatrin, and who improved markedly after withdrawal of vigabatrin, is convincing. However, maintenance of vigabatrin in patients with demonstrated VFD may not systematically lead to worsening of the visual problem. Best and Acheson (1995) studied 18 such patients who had been on vigabatrin for 5 to 12 years, and found deterioration of visual field in only one patient (who discontinued vigabatrin as a consequence). They concluded that established VFD did not usually progress in spite of continuing medication, and that this reaction is rather an idiosyncratic complication than a chronic, dose-related effect. Although the minimal duration and the lowest dose of vigabatrin associated with the ophthalmologic side effects remain unknown, but short-term treatment, over several weeks or a maximum of 6 months, appears to be relatively safe. This knowledge may help in the decision to use vigabatrin in the treatment of devastating conditions like infantile spasms, of for a short trial in severe focal epilepsies. The importance and the apparent irreversibility of VFD, on the other hand, do not militate for the use of vigabatrin in milder types of epilepsies, where other, less dangerous treatment options are available.

Other adverse effects There are no data on teratogenicity in humans. Animal studies showed, however, a teratogenic potential. In rabbits, cleft palates were found in 2% of pups of mothers treated with 150 mg/d, and 9% if the mother had received 200 mg/d (unpublished data on file at Sanofi, France). In mouse foetuses, exposure to vigabatrin induced growth retardation, and a variety

31

Orphan Drugs in Epilepsy

of malformations, including cleft palate, exophthalmos and limb defects, but no neural tube defect (Abdulrazzaq et al., 1997). In another study in mice, administration of vigabatrin 450 mg during late gestation resulted in abortion, growth deficiency, axial and peripheral skeleton hypoplasia, and was correlated to folate and vitamin B12 deficiency (Padmanabhan et al., 2010); folate and vitamin B12 supplementation partially corrected the changes. In rats, prenatal exposure to valproate or vigabatrin was associated with cortical or hippocampal dysplasia, not found after exposure to carbamazepine or to generalized seizures (Manent et al., 2007). Also in rats, pups whose mothers had received 250-500 mg/kg/day before birth had poorer performance in cognitive tasks, rats in the 750-mg group were hypotrophic at birth, and rats in the 1,000-mg group did not survive pregnancy. What we know about children born to mothers on vigabatrin is that they do no exhibit visual field defects, as shown in two children examined at age 6 and 8 years (Sorri et al., 2005), and according to perimetry and imaging of the retinal nerve fiber layer of four children born to three different mothers (Lawthorn et al., 2009).

Idiosyncratic allergic reactions They are not frequent with vigabatrin: in their report on hypersensitivity to anticonvulsants, Galindo et al. (2002) gathered 23 cases of skin rash ascribed to carbamazepine (8), phenytoin (5), lamotrigine (4), phenobarbital (4), valproate (1) and felbamate (1); they did not find positive skin patch reaction with vigabatrin. In a large collaborative study comparing vigabatrin (n = 228) with carbamazepine (n = 229) in newly diagnosed focal epilepsy, there were three skin rash reaction in the vigabatrin group vs. 10 in the carbamazepine group. Common, dose-related side-effects occur with vigabatrin, but at a lower rate than with other AEDs and vigabatrin is considered a well-tolerated, easy to titrate drug. Most side-effects are CNS-related: out of 2,081 subjects, somnolence (12.5%), headache (3.8%), dizziness (3.8%), nervousness (2.7%), depression (2.5%), memory disturbances (2.3%), diplopia (2.2%), aggression (2.0%), ataxia (1.9%), vertigo (1.9%), hyperactivity (1.8%), vision abnormalities (1.6%), confusion (1.4%), insomnia (1.3%), impaired concentration (1.2%), personality disorder (1.1%) (Long PW, internet mental health 1995-2003). It compares rather favourably with carbamazepine in this respect, with lesser incidence of drowsiness and fatigue (Chadwick, 1999). The occurrence of cognitive difficulties is not considered a significant problem under vigabatrin (Dodrill et al., 1995).

Psychiatric side-effects They are not uncommon with vigabatrin, leading to withdrawal in 2.2 to 7.3% of patients in drug trials (Ben Menachem et al., 2007). Depression and insomnia were noted in 7% of patients each on vigabatrin (vs. 3% and 2% on carbamazepine) (Chadwick, 1999). In children, restlessness and agitation may occur, especially with high doses (Appleton, 1993). The attention was drawn to more severe psychiatric reactions in 14 out of 210 patients under vigabatrin (Sander & Hart, 1990), and vigabatrin was considered as an AED with a high incidence of psychotic behavioural changes. In a review of controlled trials of vigabatrin in drug-resistant focal epilepsies, an increase incidence of depression and psychosis was noted in the vigabatrin patients, but there were no significant differences for aggression, mania, agitation, emotional lability, anxiety, or suicide attempts (Levinson & Devinsky, 1999). There are many factors associated with this phenomenon, including severe epilepsies, right-sided EEG focus, and

32

Vigabatrin

suppression of seizures in two patients (Thomas et al., 1996). However, psychotic reactions may occur in patients without any prior psychiatric history (Jawad et al., 1994).

Weight gain It is commonly seen in patients on vigabatrin, especially during long-term treatment, and was detected as the most frequent side-effect with sedation in the early open studies (Italian study group on vigabatrin, 1992; Tartara et al., 1992). Curiously, vigabatrin appears to produce dose-related anorexia in rats (Huot & Palfreyman, 1982). Weight increase of 3.7 ± 0.2 kg was noted after one year on vigabatrin in a Canadian study (Guberman & Bruni, 2000). Weight gain occurred in 11% of patients on vigabaqtrin vs. 5% of those on carbamazepine in the comparative study of Chadwick (1999), and may lead to obstructive sleep apnea (Lambert & Bird, 1997) or to withdrawal (Raucci et al., 1994). Otherwise, gastrointestinal side-effects are most uncommon.

MRI changes Their occurrence has been noted in infants treated with vigabatrin for infantile spasms. In their retrospective study, Wheless et al. (2008) found 22% of MRI changes in infants with infantile spasms treated with vigabatrin vs. 4% in vigabatrin-naive subjects, and the changes resolved on subsequent MRI in 67%; these authors found no increase in the incidence or prevalence of MRI changes in children or adults treated with vigabatrin for complex partial seizures. Among 22 patients who had MRI during vigabatrin therapy, 7 (32%) had hyperdensities of basal ganglia, thalamus and corpus callosum, brainstem and/or dentate nucleus: all findings were reversible after discontinuation of vigabatrin. None of the 56 infantile spasms patients not treated with vigabatrin had such changes; positive patients were younger and had received higher doses of vigabatrin (Pearl et al., 2009). Desguerre et al. (2008) found a mitochondrial disorder due to T8993G MT DNA mutation, resulting in a Leigh-like syndrome, in three patients with infantile spasms (controlled by vigabatrin or steroids) who had basal ganglia MRI changes; all had elevated CSF lactate levels. Only two cases of vigabatrin overdose have been reported (Davie et al., 1996). One patient accidentally took 14 g daily for 3 days and had only transient vertigo and tremor. Another patient, an18-year old female, attempted suicide with 30 g of vigabatrin and 250 mg of clorazepate: she was admitted to hospital in coma which lasted 4 days and recovered without sequelae.

Conclusions In spite of its many limitations, vigabatrin is highly effective and can still be considered a major drug for the treatment of severe epilepsies. In clinical practice, its use is facilitated by simple pharmacodynamics, paucity of interactions and good overall clinical tolerability (including quasi-absence of cognitive side-effects), but hampered by the occurrence of other unwanted reactions, like weight gain and mood/personality changes, also by the possible occurrence of paradoxical seizure aggravation, especially in generalized epilepsies. The most disturbing problem is a risk of visual restriction that imposes continuous, twice-a-year moni-

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Orphan Drugs in Epilepsy

toring of the visual field once the treatment has been started. There are still major indications for vigabatrin, which is consensually used early in the treatment of infantile spasms nearly worldwide, and which may still be used in selected patients with resistant focal epilepsies. In some respects, vigabatrin is now back among anticonvulsants, and may even lose its status of “orphan drug” as its use is likely to increase again following a new marketing effort of drug companies. REFERENCES • Abdulrazzaq YM, Bastaki SM, Padmanabhan R. Teratogenic effects of vigabatrin in to mouse fetuses. Teratology 1997; 55: 165-76.

• Bonnet AM, Esteguy M, Tell G, Schechter PJ, Hardenberg J, Agid Y. A controlled study of oral vigabatrin (gamma-vinyl GABA) in patients with cerebellar ataxia. Can J Neurol Sci 1986; 13: 331-3.

• Agosti R, Yasargil G, Egli M, Wieser HG, Wiestler OD.Neuropathology of a human hippocampus following long-term treatment with vigabatrin: lack of microvacuoles. Epilepsy Res 1990; 6: 166-70.

• Brodie MJ, Mumford JP; 012 Study Group. Doubleblind substitution of vigabatrin and valproate in carbamazepine-resistant partial epilepsy. Epilepsy Res 1999; 34: 199-205.

• Aicardi J, Sabril IS Investigator and Peer Review Groups, Mumford J, Dumas C, Wood S. Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Epilepsia 1996; 37: 638-42.

• Brodie JD, Case BG, Figueroa E, Dewey SL, Robinson JA, Wanderling JA, Laska EM. Randomized, doubleblind, placebo-controlled trial of vigabatrin for the treatment of cocaine dependence in Mexican parolees. Am J Psychiatry 2009; 166: 1269-77.

• Appleton R. The role of vigabatrin in the management of infantile epileptic syndromes. Neurology 1993; 43 (Suppl 5): S21-S23.

• Buncic JR, Westall CA, Panton CM, Munn JR, MacKeen LD, Logan WJ. Characteristic retinal atrophy with secondary “inverse” optic atrophy identifies vigabatrin toxicity in children. Ophthalmology 2004; 11: 1935-42.

• Appleton RE, Peters ACB, Mumford JP, Shaw DE. Randomised, placebo-controlled study of vigabatrin as firstline treatment of infantile spasms. Epilepsia 1999; 40: 1627-33.

• Cannon DJ, Butler WH, Mumford JP, Lewis PJ.Neuropathologic findings in patients receiving long-term vigabatrin therapy for chronic intractable epilepsy. J Child Neurol 1991; 6: S17-S24.

• Armijo JA, Cuadrado A, Bravo J, et al. Vigabatrin serum concentration to dosage ratio: influence of age and associated antiepileptic drugs. Ther Drug Monit 1997; 19: 491-8.

• Cereghino JJ. New antiepileptic drugs. In: Dodson WE, Pellock JM, eds. Pediatric Epilepsy; Diagnosis and Therapy. New York: Demos, 1993: 343-55.

• Arzimanoglou A, Dumas C, Ghirardi L. Multicentre clinical evaluation of vigabatrin (Sabril) in mild to moderate partial epilepsies. French Neurologists Sabril Study Group. Seizure 1997; 6: 225-31.

• Chadwick D. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: A multicenter randomized double-blind study. Vigabatrin European Monotherapy Study Group. Lancet 1999; 354: 13-91.

• Baxter PS, Gardner-Medwin D, Barwick DD, Ince P, Livingston J, Murdoch-Eaton D. Vigabatrin monotherapy in resistant neonatal seizures. Seizure 1995; 4: 57-9.

• Chiron C, Dulac O, Beaumont D, Palacios L, Pajot N, Mumford J. Therapeutic trial of vigabatrin in refractory infantile spasms. J Child Neurol 1991; 6 (Suppl 2): 552-7.

• Ben-Menachem E, Dulac O, Chiron C. Vigabatrin. In: Engel J, Pedley TA, eds. Comprehensive Epileptology, 2nd edition. Philadelphia: Lippincott-Raven, 2007: 1683-93.

• Chiron C, Dulac O, Gram L. Vigabatrin withdrawal randomized study in children. Epilepsy Res 1996; 25: 209-15.

• Best JL, Acheson JF. The natural history of vigabatrin associated visual field defects in patients electing to continue their medication. Eye 2005; 19: 41-4.

• Chiron C, Dumas C, Jambaqué I, Mumford J, et al. Randomized trial comparing vigabatrin and hydrocortisone in

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infantile spasms due to tuberous sclerosis. Epilepsy Res 1997; 26: 389-95.

not involve a change in phenytoin bioavailability. Br J Clin Pharmacol 1993; 36: 603-6.

• Dam M. Long-term evaluation of vigabatrin (gamma vinyl GABA) in epilepsy. Epilepsia 1989; 30 (Suppl 3): S26-S30.

• Gibbs JM, Appleton RE, Rosenbloom L. Vigabatrin in intractable childhood epilepsy: a retrospective study. Pediatrc Neurol 1992; 8: 338-40.

• Davie MB, Cook MJ, Ng C.Vigabatrin overdose. Med J Aust 1996; 165: 403.

• Gibson JP, Yarington JT, Loudy DE, Gerbig CG, Hurst GH, Newberne JW. Chronic toxicity studies with vigabatrin, a GABA-transaminase inhibitor. Toxicol Pathol 1990; 18: 225-38.

• de Krom MC, Verduin N, Visser E, Kleijer M, Scholtes F, De Groen JH.Status epilepticus during vigabatrin treatment: a report of three cases. Seizure 1995; 4: 159-62.

• Graham D. Neuropathology of vigabatrin. Br J Clin Pharmacol 1989; 27 (Suppl 1): 43S-45S.

• Desguerre I, Pinton F, Nabbout R, Moutard ML, N’Guyen S, Marsac C, Ponsot G, Dulac O. Infantile spasms with basal ganglia MRI hypersignal may reveal mitochondrial disorder due to T8993G MT DNA mutation. Neuropediatrics 2008; 34: 265-9.

• Gram L, Klosterskov P, Dam M. Gamma-vinyl GABA: A double-blind, placebo-controlled trial in partial epilepsy. Ann Neurol 1985; 17: 262-6. • Granstrom ML, Gaily E, Liukkonen E. Treatment of infantile spasms: results of a population-based study with vigabatrin as the first drug for spasms. Epilepsia 1999; 40: 950-7.

• Dodrill CB, Arnett JL, Sommerville KW, Sussman NM. Effects of differing dosages of vigabatrin (Sabril) on cognitive abilities and quality of life in epilepsy. Epilepsia 1995; 36: 164-73.

• Grant SM, Heel RC. Vigabatrin. A review of its pharmacodynamic and pharmacokientic properties, and therapeutic potential in epilepsy. Drugs 1991; 41: 889-926.

• Drozdowski W, Kułakowska A, Pogorzelski R. Stiff man syndrome successfully controlled with glucocorticoids and GABA-ergic drug administration: case report. Neurol Neurochir Pol 2003; 37: 721-8.

• Guberman A, Bruni J. Long-term open multicentre, add-on trial of vigabatrin in adult resistant partial epilepsy. The Canadian Vigabatrin Study Group. Seizure 2000; 9: 112-18.

• Eke T, Talbot JF, Lawdon MC. Severe persistent visual field constriction associated with vigabatrin. BMJ 1997; 314: 180-1.

• Guerrini R, Carrozzo R, Rinaldi R, Bonanni P. Angelman syndrome: etiology, clinical features, diagnosis, and management of symptoms. Paediatr Drugs 2003; 5: 647-61.

• European Medicines Evaluation Agency. Opinion of the committee for proprietary medicinal products pursuant to article 12 of Council Directive 75/319/EEC as amended for vigabatrin. , 1999.

• Hemming K, Maguire MJ, Hutton JL, Marson AG. Vigabatrin for refractory partial epilepsy. Cochrane Database Syst Rev 2008 Jul 16; (3): CD007302.

• Feucht M, Brantner-Inthaler S. Gamma-vinyl-GABA (vigabatrin) in the therapy of Lennox-Gastaut syndrome: an open study. Epilepsia 1994, 35: 993-8.

• Huot S, Palfreyman MG. Effects of gamma-vinyl GABA on food intake of rats. Pharmacol Biochem Behav 1982; 17: 99-106.

• Frisén L, Malmgren K. Characterization of vigabatrinassociated optic atrophy. Acta Ophthalmologica Scandinavica 2003; 81: 466-73.

• Jackson GD, Williams SR, Weller RO, van Bruggen N, Preece NE, Williams SC, et al. Vigabatrin-induced lesions in the rat brain demonstrated by quantitative magnetic resonance imaging. Epilepsy Res 1994a; 18: 57-66.

• Galindo PA, Borja J, Gómez E, Mur P, Gudín M, García R, et al. Anticonvulsant drug hypersensitivity. J Investig Allergol Clin Immunol 2002; 12: 299-304.

• Jackson GD, Grünewald RA, Connelly A, Duncan JS. Quantitative MR relaxometry study of effects of vigabatrin on the brains of patients with epilepsy. Epilepsy Res 1994b; 18: 127-37.

• Gatti G, Bartoli A, Marchiselli R, et al. Vigabatrininduced decrease in serum phenytoin concentration does

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• Jawad S, Clarke E, Richens A. Vigabatrin-induced psychosis-management problems. Seizure 1994; 3: 309-10.

• Lombardo SA, Leanza G, Meli C, Lombardo ME, Mazzone L, Vincenti I, Cioni M. Maternal exposure to the antiepileptic drug vigabatrin affects postnatal development in the rat. Neurological Sciences 2005; 26: 89-94.

• Johannessen Landmark C. Targets for antiepileptic drugs in the synapse. Med Sci Monit 2007; 13: RA1-7. • Johannessen SI, Tomson T. Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed? Clin Pharmacokinet 2006; 458: 1061-75.

• Lortie A, Chiron C, Mumford J, Dulac O. The potential for increasing seizure frequency, relapse, and appearance of new seizure types with vigabatrin. Neurology 1993; 43 (Suppl 5): S24-S27.

• Kälviäinen R, Nousiainen I, Mäntyjärvi M, Nikoskelainen E, Partanen J, Partanen K, Riekkinen P Sr. Vigabatrin, a gabaergic antiepileptic drug, causes concentric visual field defects. Neurology 1999; 53: 922-6.

• Lortie A, Chiron C, Dumas C, Mumford JP, Dulac O. Optimizing the indication of vigabatrin in children with refractory epilepsy. J Child Neurol 1997; 12: 253-9. • Lortie A, Plouin P, Chiron C, Delalande O, Dulac O. Characteristics of epilepsy in focal cortical dysplasia in infancy. Epilepsy Res 2002; 51: 133-45.

• Krämer G, Wohlrab G. Vigabatrin. In: Pellock JM, Dodson WE, Bourgeois BFD. Pediatric Epilepsy: Diagnosis and Therapy, 3rd edition. New York: Demos Medical Publishing, 2008: 699-710.

• Luna D, Dulac O, Pajot N, Beaumont D. Vigabatrin in the treatment of childhood epilepsies: a single-blind placebo-controlled study. Epilepsia 1989; 30: 430-7.

• Italian Study Group on vigabatrin. Single-blind, placebo-controlled multicenter trial of vigabatrin in the treatment of epilepsy. Ital J Neurol Sci 1992; 13: 741-7.

• Manent JB, Jorquera I, Mazzucchelli I, Depaulis A, Perucca E, Ben-Ari Y, Represa A. Fetal exposure to GABA-acting antiepileptic drugs generates hippocampal and cortical dysplasias. Epilepsia 2007; 48: 684-93.

• Kälviäinen R, Aikiä M, Saukkonen AM, Mervaala E, Riekkinen PJ Sr.Vigabatrin vs. carbamazepine monotherapy in patients with newly diagnosed epilepsy. A randomized, controlled study. Arch Neurol 1995; 52: 989-96. • Kumar N, Jivan S. The natural history of vigabatrinassociated visual field defects in patients electing to continue their medication. Eye 2006; 20: 1082-3.

• Matern D, Lehnert W, Gibson KM, Korinthenberg R. Seizures in a boy with succinic semialdehyde dehydrogenase deficiency treated with vigabatrin (gamma-vinylGABA). J Inherit Metab Dis 1996; 19: 313-8.

• Lambert MV, Bird JM.Obstructive sleep apnoea following rapid weight gain secondary to treatment with vigabatrin (Sabril). Seizure 1997; 6: 233-5.

• Michelucci R, Veri L, Passarelli D, Zamagni M, et al. Long-term follow-up study of vigabatrin in the treatment of refractory epilepsy. J Epilepsy 1994; 7: 88-93.

• Lawthom C, Smith PE, Wild JM. In utero exposure to vigabatrin: no indication of visual field loss. Epilepsia 2009; 50: 318-21.

• Mulleners WM, Chronicle EP. Anticonvulsants in migraine prophylaxis: a Cochrane review. Cephalalgia 2008; 28: 585-97.

• Leuzzi V, Di Sabato ML, Deodato F, Rizzo C, Boenzi S, Carducci C, et al. Vigabatrin improves paroxysmal dystonia in succinic semialdehyde dehydrogenase deficiency. Neurology 2007; 68: 1320-1.

• Neal MJ, Shah MA. Development of tolerance to the effects of vigabatrin (gamma-vinyl-GABA) on GABA release from rat cerebral cortex, spinal cord and retina. Br J Pharmacol 1990; 100: 324-8.

• Levinson DF, Devinsky O. Psychiatric adverse events during vigabatrin therapy. Neurology 1999; 53: 1503-11.

• Neufeld MY, Vishnevska S. Vigabatrin and multifocal myoclonus in adults with partial seizures. Clin Neuropharmacol 1995; 18: 280-3.

• Livingston JH, Beaumont D, Arzimanoglou A, Aicardi J. Vigabatrin in the treatment of epilepsy in children. Br J Clin Pharmacol 1989; 27 (Suppl 1): 109-112.

• Padmanabhan R, Abdulrazzaq YM, Bastaki SM, Nurulain M, Shafiullah M. Vigabatrin (VGB) administered during late gestation lowers maternal folate concentration and causes pregnancy loss, fetal growth restriction and skeletal hypoplasia in the mouse. Reprod Toxicol 2010; 29: 366-77.

• Loiseau P, Hardenberg JP, Pestre M, Guyot M, Schechter PJ, Tell GP. Double-blind, placebo-controlled study of vigabatrin (gamma-vinyl GABA) in drug-resistant epilepsy. Epilepsia 1986; 27: 115-20.

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• Parker AP, Agathonikou A, Robinson RO, Panayiotopoulos CP. Inappropriate use of carbamazepine and vigabatrin in typical absence seizures. Dev Med Child Neurol 1998; 40: 517-9.

• Rimmer EM, Richens A. Double-blind study of gammavinyl GABA in patients with refractory epilepsy. Lancet 1984; 1: 189-90. • Rimmer EM, Richens A. Interaction between vigabatrin and phenytoin. Br J Clin Pharmacol 1989; 27: 27-33.

• Patsalos PN, Berry DJ, Bourgeois BFD, et al. Antiepileptic drugs – Best practice guidelines for therapeutic drug monitoring: A position paper by the Subcommision on therapeutic drug monitoring, ILAE Commission on therapeutic strategies. Epilepsia 2008; 49: 1239-76.

• Rundfeldt C, Löscher W. Development of tolerance to the anticonvulsant effect of vigabatrin in amygdala-kindled rats. Eur J Pharmacol 1992; 213: 351-66. • Russell-Eggitt IM, Mackey DA, Taylor DS, Timms C, Walker JW. Vigabatrin-associated visual field defects in children. Eye 2000; 14: 334-9.

• Patsalos, PN, Duncan JS, The pharmacology and pharmacokinetics of vigabatrin. Rev Contemp Pharmacother 1995; 6: 447-56.

• Shechter PJ. Clinical pharmacology of vigabatrin. Br J Clin Pharmacol 1989; 27: 19-22.

• Pearl PL, Vezina LG, Saneto RP, McCarter R, MolloyWells E, Heffron A, et al. Cerebral MRI abnormalities associated with vigabatrin therapy. Epilepsia 2009; 50: 184-94.

• Scigliano G, Giovannini P, Girotti F, Grassi MP, Caraceni T, Schechter PJ. Gamma-vinyl GABA treatment of Huntington’s disease. Neurology 2004; 34: 94-6.

• Pedersen B, Højgaard K, Dam M.Vigabatrin: no microvacuoles in a human brain. Epilepsy Res 1987; 1: 74-6.

• Sobaniec W, Kułak W, Strzelecka J, Smigielska-Kuzia J, Bo?kowski L.A comparative study of vigabatrin vs. carbamazepine in monotherapy of newly diagnosed partial seizures in children. Pharmacol Rep 2005; 57: 646-53.

• Pedersen SA, Klosterskov P, Gram L, Dam M. Longterm study of gamma-vinyl GABA in the treatment of epilepsy. Acta Neurol Scand 1985; 72: 295-8.

• Sorri I, Herrgard E, Viinikainen K, Pääkkönen A, Heinonen S, Kälviäinen R. Ophthalmologic and neurologicfindings in two children exposed to vigabatrin in utero. Epilepsy Res 2005; 65: 117-20.

• Preece NE, Jackson GD, Houseman JA, et al. Nuclear magnetic resonance detection of increased GABA in vigabatrin-treated rats in vivo. Epilepsia 1994; 35: 431-6.

• Stromberg MF, Mackler SA, Volpicelli JR, O’Brien CP, Dewey SL. The effect of gamma-vinyl-GABA on the consumption of concurrently available oral cocaine and ethanol in the rat. Pharmacol Biochem Behav 2001; 68: 291-9.

• Perucca E. An introduction to antiepileptic drugs. Epilepsia 2004; 46: 31-7. • Perucca E, Cloyd J, Critchley D, Fuseau E. Rufinamide: clinical pharmacokinetics and concentration-response relationships in patients with epilepsy. Epilepsia 2008; 49: 1123-41.

• Tanganelli P, Regesta G. Vigabatrin vs. carbamazepine monotherapy in newly diagnosed focal epilepsy: a randomized response conditional cross-over study. Epilepsy Res 1996; 25: 257-62.

• Popovi? Miocinovi? L, Durrigl V, Kapitanovi? Vidak H, Grubesi? Z, Sremi? S. Electroencephalography in status epilepticus in sleep (ESES) in various clinical pictures. Acta Med Croatica 2005; 59: 69-74.

• Tartara A, Manni R, Galimberti CA, Morini R, Mumford JP, Iudice A, Perucca E. Six-year follow-up study on the efficacy and safety of vigabatrin in patients with epilepsy. Acta Neurol Scand 1992; 86: 247-51.

• Prevett MC, Brown P, Duncan JS. Improvement of stiffman syndrome with vigabatrin. Neurology 1997; 48: 1133-4.

• Tassinari CA, Michelucci R, Ambrosetto G, Salvi F. Double-blind study of vigabatrin in the treatment of drugresistant epilepsy. Arch Neurol 1987; 44: 907-10.

• Raucci U, Spalice A, Basile LA, Guardalà C, Nasta L, Terenzi S, Iannetti P. New drugs in the treatment of childhood epilepsy: vigabatrin (study of 61 subjects). Pediatr Med Chir 1994; 16: 575-8.

• Tekgul H, Serdaro?lu G, Karapinar B, Polat M, Yurtsever S, Tosun A, et al. Vigabatrin caused rapidly progressive deterioration in two cases with early myoclonic encephalopathy associated with nonketotic hyperglycinemia. J Child Neurol 2006; 21: 82-4.

• Riikonen R. The latest on infantile spasms. Curr Opin Neurol 2005; 18: 91-5.

37

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• Thomas L, Trimble M, Schmitz B, Ring H. Vigabatrin and behaviour disorders: a retrospective survey. Epilepsy Res 1996; 25: 21-7.

• Vigevano F, Cilio MR. Vigabatrin versus ACTH as firstline treatment for infantilespasms: a randomized, prospective study. Epilepsia 1997; 38: 1270-4.

• Thomas P, Valton L, Genton P.Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy. Brain 2006; 129: 1281-92.

• Wheless JW, Carmant L, Bebin M, Conry JA, Chiron C, Elterman RD, et al. Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy. Epilepsia 2009; 50: 195-205.

• Valente KD, Koiffmann CP, Fridman C, Varella M, Kok F, Andrade JQ, et al. Epilepsy in patients with angelman syndrome caused by deletion of the chromosome 15q11-13.Arch Neurol 2006; 63: 122-8.

• Willmore LJ, Abelson MB, Ben-Menachem E, Pellock JM, Shields WD. Vigabatrin: 2008 update. Epilepsia. 2009 Feb; 50: 163-73.

• Vanhatalo S, Nousiainen I, Eriksson K, Rantala H, Vainionpää L, Mustonen K, et al. Visual field constriction in 91 Finnish children treated with vigabatrin. Epilepsia 2002; 43: 748-56.

• Ylinen A, Kälviäinen R, Riekkinen PJ Sr. Long-term efficacy and cognitive effects of vigabatrin. Acta Neurol Scand 1995; 162 (Suppl): 47-50. • Zwanzger P, Baghai TC, Schuele C, Strohle A, Padberg F, Kathmann N, et al. Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers. Neuropsychopharmacology 2001; 25: 699-703.

• Vermeij FH, van Doorn PA, Busch HF. Improvement of stiff-man syndrome with vigabatrin. Lancet 1996; 348: 612. • Versino M, Veggiotti P. Reversibility of vigabatrininduced visual field defect. Lancet 1999; 354: 486.

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Stiripentol

f:\2000\image\139709\stiripentol\1

History Stiripentol (STP) is an antiepileptic drug marketed as Diacomit® by Biocodex, France. In 2001 it was designated as an orphan drug for the adjunctive treatment of Dravet syndrome (severe myoclonic epilepsy in infancy) and in 2007 has been approved by the European Medicines Agency (EMA).

Pharmacology Chemical structure

Figure 1. Chemical structure of stiripentol: 4,4-dimethyl-1[3,4(methylenedioxy)-phenyl]-1-pentan-3-ol.

Chemical characteristics Stiripentol is structurally unrelated to other AEDs, belonging to the aromatic allylic alcohols. It is a chiral molecule with an asymmetric carbon at position 3. Both enantiomers are active, and the drug substance used is an equimolar racemate. Stiripentol is a white to pale yellow crystalline powder, practically insoluble in water, soluble in ethanol and acetone.

Mechanisms of action The exact mechanisms of action of stiripentol are not fully elucidated. In addition to its direct anticonvulsant properties, stiripentol partly inhibits several isoenzymes (in particular CYP450 3A4 and 2C19) and is therefore responsible for an elevation of the plasma levels

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Orphan Drugs in Epilepsy

of other antiepileptic drugs, notably clobazam. The anticonvulsant properties in vitro have suggested that the compound possesses its effect through enhancement of GABAergic neurotransmission by increasing GABA release, inhibiting GABA reuptake and activation of GABAA receptors in a barbiturate-like manner (Quilichini et al., 2006; Perucca, 1999). These findings suggest that stiripentol has an independent anticonvulsant effect, and that the clinical effect of the drugs is not just a consequence of increasing serum concentrations of concomitantly used AEDs (Chiron, 2007). Recently, the possible mechanism of anticonvulsant action of stiripentol was further investigated. Fisher (2009) confirmed that stiripentol potentiates GABA currents, and showed that stiripentol acts as a direct positive allosteric modulator of the GABA-A receptors at a site that is distinct from other modulator sites, as for the benzodiazepines. By whole-cell patch clamp recordings, the response to four benzodiazepines (diazepam, clonazepam, clobazam and norclobazam) alone and in combination with stiripentol was measured (Fisher, 2011). All these modulators were equally effective in the presence or absence of stiripentol. The δ-containing receptors were insensitive to modulation by benzodiazepines, and did not affect potentiation by stiripentol. It is therefore suggested that stiripentol and benzodiazepines act independently at GABA-A receptors and that polytherapy could be expected to give a synergistic pharmacodynamic effect (Fisher, 2011). This result emphasized that stiripentol displays a clinical activity independent of its benzodiazepine potentiating action.

Figure 2. Stiripentol: mechanisms of action.

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Stiripentol

Pharmacokinetics Bioavailability Stiripentol is rapidly absorbed and maximal serum concentrations are attained 1.5 hours after oral intake. Stiripentol is well absorbed by the oral route since the majority of an oral dose is excreted in urine. However, relative bioavailability is dependent on the formulation capsules and powder for oral suspension in sachet are bioequivalent in terms of AUC and Tmax, but not in terms of Cmax. As the Cmax of the sachet is slightly higher compared with the capsule, clinical supervision is recommended if switching between the capsule and sachet formulations.

Distribution and protein binding Stiripentol has a large volume of distribution. It is 99% bound to serum proteins (Levy et al., 1983; 1984). Due to the extensive binding possible interactions should be considered when combining stiripentol with other highly protein-bound drugs.

Metabolism and excretion Stiripentol is extensively metabolized by four main pathways (oxidation, hydroxylation, O-methylation and glucoronidation) to 13 different metabolites and mostly stiripentol is excreted via the kidney. Urinary metabolites of stiripentol account collectively for the majority (73%) of an oral acute dose whereas a further 13-24% is present in faeces as unchanged drug. The clearance of stiripentol decreases with increasing dosage due to non-linear (Michaelis-Menten) pharmacokinetics (Perucca, 1999). Patients treated with enzyme inducing AEDs (phenytoin, phenobarbital, carbamazepine) exhibit higher clearance of stiripentol (Bialer et al., 2007). Pharmacokinetic data on stiripentol in special patient groups are sparse (children, elderly, pregnant women, patients with hepatic or renal dysfunction). The use of stiripentol during breast-feeding has not been studied.

Elimination half-life The elimination half-life of is in the range of 4.5 hours to 13 hours, increasing with dose.

Drug interactions Stiripentol is a potent inhibitor of CYP3A4, CYP1A2, CYP2D6 and CYP2C19 and thereby potentially impacting the pharmacokinetics of other drugs, and in particular increasing plasma levels of phenytoin, carbamazepine, phenobarbital, valproic acid and clobazam and its pharmacologically active metabolite N-desmethyl-clobazam (Levy et al., 1984; Tran et al., 1996). Enzyme inducing AEDs (carbamazepine, phenobarbital, phenytoin and primidone) induce the metabolism of stiripentol so that stiripentol clearance is increased and lower stiripentol serum concentrations occur (Bialer et al., 2007). Stiripentol is a potent inhibitor of CYP 3A4, 1A2 and 2C19 and thereby affecting numerous other drugs,

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f:\2000\image\139709\stiripentol\3

including other AEDs as phenytoin, carbamazepine, phenobarbital, valproic acid, and clobazam. The concentrations of their metabolites are consequently decreased, and it is thought that this is the mechanism responsible for an increase in tolerability of the original drugs, as for carbamazepine and its epoxide metabolite in particular (Quilichini et al., 2006). The additive effect of the combination of clobazam and stiripentol was studied in the MES-test and has been suggested to be associated with a concurrent pharmacokinetic interaction, as seen by a 18.6-fold increase in clobazam by stiripentol (Luszczki et al., 2010). To date no significant pharmacokinetic interactions between stiripentol and other non-AED drugs have been reported (Johannessen Landmark and Patsalos, 2010). However, because stiripentol is a potent inhibitor of CYP2C19, CYP1A2, CYP3A4 and CYP2D6 caution needs to be exercised if clinical circumstances require combining stiripentol with drugs that are metabolised by these isoenzymes (e.g. citalopram, omeprazole (CYP2C19); astemizole, chlorpheniramine, calcium channel blockers, statins, codeine (CYP3A4); propranolol, fluoxetine, sertraline, haloperidol, tramadol (CYP2D6) (Chiron, 2007; Johannessen and Johannessen Landmark, 2010). It is not known whether stiripentol can have a clinically important effect on hormonal contraception but it could theoretically increase serum concentrations of hormonal contraceptives, implying that lower doses might need to be prescribed.

Figure 3. Pharmacokinetic scheme for stiripentol.

Therapeutic drug monitoring Non-linear kinetics makes individual dosing and drug monitoring of especial importance, since a small change in the drug dosage may lead to a considerable unexpected large change in the serum concentration of the drug (Johannessen and Johannessen Landmark, 2008; Johannessen Landmark and Johannessen, 2008). A reference range for stiripentol in serum has not yet been established, but serum concentrations of 2-22 μg/mL (8.5-94 μmol/L) corre-

42

Stiripentol

late with control of absence seizures in children (Farwell et al., 1993). Till now, the daily dose of stiripentol prescribed by the physicians has actually been based on the observed clinical effect of the drug rather than its serum concentrations. However, therapeutic drug monitoring may be useful despite the short-comings of existing reference ranges, by utilization of the concept of individual therapeutic concentrations (Johannessen, Johannessen Landmark, 2008). An HPLC method has been reported for the analysis of stiripentol in serum (Arends et al., 1994)

Clinical indications Stiripentol is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with Dravet syndrome when seizures are not adequately controlled with the association of these two medications.

Dravet syndrome The significant efficacy of stiripentol in children with Dravet syndrome has been proved in two independent randomized placebo-controlled syndrome-dedicated trials performed in France and Italy (the STICLO France and STICLO Italy studies) (Chiron et al., 2000; Kassai et al., 2008). In STICLO French study 41 patients aged between 3 and 16 years were included, and after 1 month baseline were randomized to stiripentol (n = 21) or placebo (n = 20) at the dose 50 mg/kg/day. The doses of co-medication were limited to 30 and 0.5 mg/kg/d for valproate and clobazam, respectively. Two months after treatment initiation nine children from stiripentol group were seizure free compared to none in placebo group. The number of responders (reduction of seizures > 50%) was markedly higher in stiripentol group than in placebo group (71 and 5%, respectively). The STICLO Italian study required an even smaller number of patients (n = 23) to confirm the efficacy of stiripentol. At the end of follow up 8 out of 12 patients (67%) on stiripentol were responders, and 3 of them were seizure-free. Both trials demonstrated that efficacy studies can be conducted in orphan diseases as long as the drug tested actually displays a marked effect. The efficacy of stiripentol in children with Dravet syndrome was further confirmed in several open-label uncontrolled studies. In a retrospective long-term study (Thanh et al., 2002) 46 patients have received stiripentol in combination with valproate and clobazam for a median follow-up duration of 3 years. The best efficacy was reported in the youngest patients, and the worst tolerability in children older than 12 years. The authors reported dramatic improvement in terms of seizure frequency and duration in 10 out of 46 patients, moderate improvement in 20, and no response to stiripentol treatment in 4 patients. In a series by Inoue et al. (2009), seizure reduction of > 50% was shown in 61% (n = 14) of patients after 4 week therapy with stiripentol in combination with a wide variety of AEDs, including bromide. In a study performed by Vari et al. (2010) six children with Dravet syndrome have been treated with stiripentol for 3-9 years. At the end of follow up one patient was seizure-free and four experienced > 75% reduction of seizures.

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The fact that some patients achieve better seizure control while others have insufficient response demonstrates the variable efficacy of stiripentol. Difference in response might suggest the influence of genetic factors that affect efficacy. SCN1A mutations have been identified in > 70% of patients with Dravet syndrome (Claes et al., 2001; Harkin et al., 2007), whereas the other mutations, SCN1B, SCN2A, PCDH19, are less frequently observed (Shi et al., 2009; Depienne et al., 2009). The two following case vignettes illustrate different response to stiripentol and probable influence of genetic factors.

Case 1 A girl, born in February 2009 from a normal pregnancy and uneventful delivery. No family predisposition to epilepsy or febrile seizures. Epilepsy manifested at the age 9 moths with a long-lasting (30 min) febrile generalized tonic-clonic seizure. During next 6 months she had 12 generalized tonic-clonic and hemoclonic seizures, both febrile and afebrile. Eight seizures out of 12 were lasting more than 15 min. MRI, metabolic screening and chromosomal analysis failed to identify pathological findings. Two first EEGs were normal. The diagnosis of Dravet syndrome was suspected. The genetic analysis revealed SCN1A mutation. The child has been treated with valproate which had insufficient effect and was combined later with stiripentol and clobazam. One month after stiripentol initiation the child became seizure-free. Drug doses were: stiripentol 750 mg/day, valproate 300 mg/day, clobazam 5 mg/day; weight 13.9 kg. Serum levels: stiripentol and clobazam – not measured, valproate 325 μmol/L (range 250-700 μmol/L). The girl has normal psychomotor development and goes to the usual daycare.

Case 2 A girl, born in November 2006 from an uneventful pregnancy and delivery. Familial disposition – two aunts from the mother's side have epilepsy. The child had normal psychomotor development before epilepsy manifestation. Epilepsy onset at the age 14 months with febrile generalized tonic-clonic seizure. Later had several febrile seizure episodes, and since the age 2 years exhibited tonic, hemiclonic and myoclonic seizures which occurred in clusters within 2-3days with a 2-3 month seizure-free interval. MRI, metabolic screening, chromosomal analysis, two initial interictal EEGs without pathology. Genetic testing: SCN1A mutation – negative, PCDH19 mutation – positive. The two aunts with epilepsy have the same mutation (Figure 4). Interictal EEG at the age 3 years 3 months (February 2010) – asymmetric irregular delta activity, spikes from multiple foci. The child has been treated with valproate, topiramate, levetiracetam, rufinamide in different combinations. Has been seizure-free for 11 months on valproate and levetiracetam. Because of seizure relapse the combination of stiripentol 750 mg/day, valproate 600 mg/ day and clobazam 10 mg/day was administered. Serum levels: stiripentol and clobazam – not measured, valproate 301 μmol/L (range 250-700 μmol/L); weight 15.6 kg. However the decrease of seizure frequency was less than 50%.

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Stiripentol

Figure 4. Familial pedigree (Case 2).

Different studies have demonstrated that the initial stiripentol dose in children comprises 50 mg/kg/day and can be increased to 75-100 mg/kg/day. The doses of valproate and clobazam when used in association with stiripentol should be decreased by 25-50% to avoid the drug interactions and probable side effects.

Tolerability and side effects As stiripentol is a potent inhibitor of CYP3A4, CYP1A2, CYP2D6 and CYP2C19 and increases serum levels of the other drugs, the incidence of adverse effects while treating with stiripentol can be minimized by optimizing the doses of co-medication. The most frequently observed side effects are due to an increase in plasma levels of other AEDs, mainly valproate (anorexia, loss of weight) and clobazam (drowsiness, hypotonia and irritability). These effects may regress when the dose of these drugs is reduced. Other adverse events mainly include ataxia, insomnia and nausea (Perez et al., 1999; Chiron et al., 2000; 2006).

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REFERENCES • Inoue Y, Ohtsuka Y, Oguni H, Tohyama J, Baba H, et al. Stiripentol open study in Japanese patients with Dravet syndrome. Epilepsia 2009; 50: 2362-8.

• Arends RH, Zhang K, Levy RH, Baillie TA, Shen DD. Stereoselective pharmacokinetics of stiripentol: An explanation for the development of tolerance to anticonvulsant effect. Epilepsy Res 1994; 18: 91-6.

• Johannessen Landmark C, Johannessen SI. Pharmacological management of epilepsy. Recent advances and future prospects. Drugs 2008; 68: 1925-39.

• Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Eighth Eilat conference (Eilat VIII). Epilepsy Res 2007; 73: 1-52.

• Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second and third generation antiepileptic drugs. Expert Rev Neurotherapeutics 2010; 10: 119-40.

• Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. Lancet 2000; 356: 1638-42.

• Johannessen SI, Johannessen Landmark C. Value of therapeutic drug montoring in epilepsy. Expert Rev Neurotherapeutics 2008; 8: 929-39.

• Chiron C, Tonnelier S, Rey E, Brunet M-L, Tran A. et al. Stiripentol in childhood partial epilepsy: randomized placebo-controlled trial with enrichment and withdrawn design. J Child Neurol 2006; 6: 496-502.

• Johannessen SI, Johannessen Landmark C. Antiepileptic drug interactions-Basic principles and clinical implications. Current Neuropharm 2010; 8: 254-67.

• Chiron C. Stiripentol. Neurotherapeutics 2007; 4: 123-5.

• Kassai B, Chiron C, Augier S, Cucherat M, Rey E, et al. Severe myoclonic epilepsy in infancy: a systematic review and meta-analysis of individual patient data. Epilepsia 2008; 49: 343-8.

• Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, et al. De novo mutations in the sodiumchannel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001; 68: 1327-32.

• Levy RH, Lin HS, Blehaut HM, Tor JA. Pharmacokinetics of stiripentol in normal man: evidence of nonlinearity. J Clin Pharmacol 1983; 23: 523-33.

• Depienne C, Bouteiller D, Keren B, Cheuret E, Poirier K, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLos Genet 2009; 5: e1000381.

• Levy RH, Loiseau P, Guyot M, Blehaut HM, Tor J, Moreland TA. Stiripentol kinetics in epilepsy: nonlinearity and interactions. Clin Pharmacol Ther 1984; 36: 661-9.

• Farwell JR, Anderson GD, Kerr BM, Tor JA, Levy RH. Stiripentol in atypical absence seizures in children: An open trial. Epilepsia 1993; 34: 305-11.

• Luszczki JJ, Trojnar MK, Ratnaraj N, Patsalos PN, Czuczwar SJ. Interactions of stiripentol with clobazam and valproate in the mouse maximal electroshock-induced seizure model. Epilepsy Res 2010; 90: 188-98.

• Fisher JL. The anticonvulsant stiripentol acts directly on the GABA-A receptor as a positive allosteric modulator. Neuropharmacology 2009; 56: 190-7.

• Perez J, Chiron C, Musial C, Rey E, Blehaut H, et al. Stiripentol: efficacy and tolerability in children with epilepsy. Epilepsia 1999; 40: 1618-26.

• Fisher JL. Interactions between modulators of the GABA(A) receptor: Stiripentol and benzodiazepines. Eur J Pharmacol 2011; 654: 160-5.

• Perucca E. Drugs under clinical trial. In: Eadie MJ, Vajda FJE, eds. Antiepileptic Drugs-Handbook of Experimental Pharmacology. Berlin: Springer-Verlag, 1999, 515-51.

• Giraud C, Treluyer JM, Rey E, Chiron C, Vincent J, et al. In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism. Drug Metab Dispos 2006; 34: 608-11.

• Quilichini PP, Chiron C, Ben-Ari Y, et al. Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels. Epilepsia 2006; 47: 704-16.

• Harkin LA, McMahon JM, Iona X, Dibbens L, Pelekanos JT, et al. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 2007; 130: 843-52.

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• Shi X, Yasumoto S, Nakagawa E, Fukasawa T, Uchiya T, Hirose S. Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome. Brain Dev 2009; 31: 758-62.

• Tran A, Vauzelle-Kervroedan F, Rey E, et al. Effect of stiripentol on carbamazepine plasma concentration and metabolism in epileptic children. Eur J Clin Pharmacol 1996 ; 50 : 497-500.

• Thanh N, Chiron C, Dellatolas G, Rey E, Pons G, et al. Long term efficacy and tolerance of stiripentol in severe myoclonic epilepsy of infancy (Dravet's syndrome). Arch Pediatr 2002; 9: 1120-7.

• Vari MS, Prato G, Siri L, Striano P, Mancardi M, Baglietto MG, et al. Long term efficacy of stiripentol in Dravet syndrome: an open label trial of 6 cases. Bolletino Lega Italiana contro l'epilepsia 2010; 140: 215-6.

47

Felbamate History Felbamate (FBM) gained its orphan drug status in a fairly dramatic context. It was launched in 1993 in the United States and in 1994 in Europe as a broad-spectrum, highly effective and safe anticonvulsant unrelated to existing AEDs. The molecule belongs to the family of carbamates, and its structure is close to that of meprobamate, which can be considered its parent drug. Meprobamate was synthetized in 1950 and launched with success in 1955 in the United States as a promising anxiolytic agent, later re-labelled as a sedative agent, and is still used, e. g. in the treatment f alcohol dependency; it also had myorelaxant and anticonvulsant properties. However, it was supplanted by the emerging benzodiazepines. With meprobamate, there were rare instances of severe side-effects, such a those found later with felbamate. Felbamate was also synthetized in the early 1950s but found less sedative and anxiolytic than meprobamate, and shelved for many years. It went, however, through the NIH screening procedures and was found to be a very effective and very safe anticonvulsant in animal models (Swinyard et al., 1986). The phase 2 clinical trials were published in 1991 (Leppik et al., 1991), as well as add-on studies (Theodore et al., 1991), and monotherapy studies were performed in the following years (Sachdeo et al., 1992; Faught et al., 1993; Devinski et al., 1995; Sachdeo et al., 1997). The drug was finally approved in 1992 and marketed by Wallace Laboratories in the US in the summer of 1993; it was licensed to Schering-Plough for some overseas markets, including Europe, to be launched in the spring of 1994. Felbamate was introduced with the help of a massive advertising campaign that stressed efficacy, simplicity (no need for monitoring) and safety, as the first “new” anticonvulsant agent to reach the North American market in years. Within a year, more than 100,000 epilepsy patients had been exposed to felbamate (versus about 1,600 in the controlled trials). Within the same year, however, there were several cases of aplastic anaemia, including 14 deaths, and 5 deaths related to hepatic failure. In August 1994, health authorities and the manufacturer agreed to suspend the drug. It had been introduced on a compassionate basis in several European countries, and patients had to abruptly stop their medication during the summer holidays of 1994. The felbamate story had an influence on safety regulations governing the release of new therapeutic agents. However, this drama did not mean the end of the career of felbamate as an anticonvulsant. Given its high efficacy, it was decided to keep it on the market with due restrictions. It is estimated that around 10,000 patients remain on felbamate worldwide. Although recommendations may slightly vary between countries, the drug has been restricted to use in patients with Lennox-Gastaut syndrome (any age) and in patients with severe focal epilepsies (adults), as an add-on. Actual, and

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useful clinical indications, may be slightly different. According to local legislation, the drug may be prescribed on a named-patient basis, and only with proper biological monitoring.

Pharmacology Chemical structure

Figure 1. Chemical structure of felbamate: (3-carbamoyloxy-2-phenylpropyl)carbamate.

Chemical characteristics Felbamate is chemically related to the anxiolytic drug meprobamate. It is a white crystalline powder, it is lipophilic and relatively insoluble in water and alcohol.

Mechanisms of action A clear mechanism of action of felbamate is not known, but multiple mechanisms may be involved, affecting both excitatory and inhibitory CNS systems. These include inhibition of voltage-sensitive sodium and calcium channels that will reduce the firing of action potentials and release of neurotransmitters from synaptic vesicles. Furthermore, glutamergic transmission is reduced through modulation of NMDA receptors, which is an uncommon mechanism of action among other AEDs. Potentiation of GABA transmission has also been suggested to be involved in the pharmacological effect of felbamate (Kleckner et al., 1999). But there are conflicting data regarding the effect on GABA receptors, as responses are potentiated at high felbamate concentrations, but with no effect on ligand biding at the receptor itself (Bourgeois, 2008).

Pharmacokinetics Bioavailability Felbamate is rapidly absorbed after oral ingestion with a bioavailability of 90-95%. Peak serum concentrations are attained after 2-6 hours (Palmer & McTavish, 1993).

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Figure 2. Felbamate: mechanisms of action.

Distribution and protein binding According to animal studies felbamate distributes rapidly into various tissues, including brain and crosses placenta. The volume of distribution is about 0.8 L/kg. Felbamate is about 30% bound to serum proteins, mainly to albumin (Palmer & McTavish, 1993).

Metabolism and renal excretion Felbamate is eliminated partly by renal excretion and also by oxidative hepatic metabolism with formation of parahydroxy- and 2-hydroxymetabolites, which are subsequently excreted renally. Hydrolysis to monocarbamoyl felbamate also takes place, in addition to the formation of the intermediate metabolite atropaldehyde, which is considered to be responsible for the idiosyncratic adverse effects of felbamate (Palmer & McTravish, 1993; Thompson et al., 1994). Felbamate is a substrate of CYP3A4 and CYP2E1.

Elimination half-life Felbamate has an elimination half-life of 14-23 hours in healthy volunteers, which is shortened to about 15 hours in patients receiving enzyme-inducing AEDs. Impaired renal function results in higher serum felbamate concentrations and longer half-lives in the order of 27-34 hours, dependent upon the degree of renal impairment. The clearance is up to 50% higher in children compared to adults and about 20% higher in young adults than in the elderly (Wagner et al., 1991, Glue et al., 1997, Banfield et al., 1996, Kelley et al., 1997).

Drug interactions Felbamate is a potent inhibitor of hepatic enzymes and may increase plasma concentrations of phenobarbital, phenytoin, valproic acid, carbamazepine-10,11-epoxide (the pharmacologically active metabolite of carbamazepine), and N-desmethyl-clobazam (the pharmacologi-

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cally active metabolite of clobazam) (Graves et al., 1989; Wagner et al., 1994; Reidenberg et al., 1995; Albani et al., 1991; Contin et al., 1991). As mentioned above the metabolism of felbamate is enhanced by the enzyme-inducing AEDs (carbamazepine, phenobarbital, phenytoin, and primidone) resulting in an increase in felbamate clearance by about 40-50% (Palmer & McTravish, 1993; Wagner et al., 1991). These interactions are the consequence of induction of CYP3A4. Conversely, valproate decreases felbamate clearance by up to 20%. Gabapentin can reduce the elimination half-life of felbamate by 46% and reduce clearance by 37%, and these effects are considered to be the consequence of an interaction at the level of renal excretion (Hussein et al., 1996). Felbamate inhibits the metabolism of warfarin necessitating a dose reduction in warfarin so as to maintain anticoagulant control (Tisdel et al., 1994). Felbamate can decrease the AUC (area under the concentration versus time curve) of gestodone by 42%, but not ethinyl estradiol and therefore may reduce the effectiveness of oral contraception (Saano et al., 1995). No clinically significant pharmacodynamic interactions involving felbamate have been reported.

Figure 3. Pharmacokinetic scheme for felbamate.

Therapeutic drug monitoring There is a wide range of clearances of felbamate resulting from co-medications and other sources of individual variability, and concentrations are not predictable from the doses, and thus monitoring of serum concentrations can be useful to guide dosing. Recently, a reference range of 30-60 μg/mL (126-252 μmol/L) has been suggested. However, there is a considerable variability in response at these concentrations, and higher concentrations may give additional benefit although there is a risk of increased adverse effects. A number of liquid- and gas chromatographic methods are available for measurements of serum felbamate concentrations (Patsalos et al., 2008).

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Clinical indications There are no known indications for felbamate in other neurological conditions, although it should be mentioned that it has shown efficacy in painful hemifacial spasm (Mellick, 1995) and in trigeminal neuralgia (Cheshire, 1995). The drug was developed as an all-round, broad-spectrum anticonvulsant with many potential indications. After the initial large-scale trials, there were fewer reports but felbamate may indeed be useful in a variety of epilepsy types, especially in epileptic encephalopathies. Given the restricted labelling imposed in most countries, it will nowadays be used only after several less problematic anticonvulsants have failed. Like most new AEDs, felbamate was developed as an add-on in drug-resistant focal epilepsies. The first add-on studies (Theodore et al., 1991) and the subsequent add-on and monotherapy studies, using variable designs (Sachdeo et al., 1992; Faught et al., 1993; Devinski et al., 1995; Sachdeo et al., 1997), all showed efficacy against focal seizures, albeit with variable results. Leppik et al. (1991) used a cross-over design and concluded that part of the efficacy vs. placebo was linked to a seizure increase on placebo. In an open-label setting, felbamate was given to 36 patients who had resisted several other drugs, and 5% became seizure-free, 11% had seizures reduced by more than 75% and 23% by more than 50% (Canger et al., 1999). Overall, the pilot studies demonstrated mild efficacy against focal seizures, and the use of felbamate in this context is a matter of personal judgment. In a recent Cochrane review based on all published controlled trials, Shi et al. (2011) concluded that “there is no reliable evidence to support the use of felbamate as an add-on therapy in patients with refractory partial-onset epilepsy”. It was actually noted by early investigators that felbamate had the potential of a broad-acting, large-spectrum anticonvulsant. The Lennox-Gastaut syndrome (LGS) was recognized as a specific indication for felbamate in the early stages of its development. A 10-week placebo-controlled trial showed significant seizure reduction (19%, vs. 4% increase on placebo), with marked efficacy against atonic seizures (-19%), and increased perceived quality of life (The Felbamate Study Group in Lennox-Gastaut Syndrome, 1993). In LGS patients with better seizure control, felbamate is also associated with cognitive improvement (Gay et al., 1995). Siegel et al. (1999) used felbamate in combination with valproate in a placebo-controlled design, in 13 patients with LGS: drop attacks decreased by 40% on felbamate, and total seizure count by 60%. Pharmacokinetic interactions may have played a part, since valproate blood levels rose by 12.7% on felbamate. Given the high degree of drug resistance found in LGS, felbamate was licensed in this condition as an add-on. It is still recommended today in the LGS. The risk-benefit ratio in this indication remains favourable (Schmidt & Bourgeois, 2000). Recent reviews have kept felbamate among the add-on treatment options in the LGS (Hancock & Cross, 2003; Genton et al., 2009). Figure 4 shows the EEG of a young boy with cryptogenic LGS before and after addition of felbamate, with a dramatic effect which was reflected in the disappearance of all visible seizures save for some possible persisting minor motor seizures during sleep.

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Figure 4. Patient aged 12 years before (left) and 6 months after (right) addition of felbamate. Cryptogenic generalized epilepsy with onset of atypical absences and tonic seizures at age 3, moderate mental retardation and behavioural disturbances. Seizures improved markedly on felbamate, but the patient, who tended to be stuporous before felbamate, became more active and restless.

Clinical vignette The following case vignette illustrates: • the marked efficacy of felbamate in some patients with generalized symptomatic epilepsies; • possible interactions between felbamate and other anticonvulsants, e. g. here a marked increase in concentrations of phenobarbital following the introduction of FBM. However, the efficacy of felbamate was not related to this pharmacokinetic interaction, since seizure control persisted after withdrawal of Phenobarbital; • the excellent tolerability of felbamate in this case. Liver and blood cell parameters were monitored according to the official guidelines of the French health authorities. It shows the case of a male patient, born in 1987. Delivery was difficult and a delay in motor and speech development became apparent by age 3 with special schooling from kindergarden on. He was diagnosed with Lennox-Gastaut syndrome at age 8, following the onset of absences and falls. MRI showed mild diffuse atrophy and posterior periventricular hyperdensities evocative of perinatal anoxia. The seizure situation worsened with numerous absences, rare falls, slight tonic seizures during sleep. Behavioral disorders set in around age 12. He had been on valproate (VPA) from the start, tried topiramate, stopped because of severe weight loss, ethosuximide, which led to the appearance of generalized tonic-clonic seizures, but had enjoyed a one-year remission of seizures on the VPA and lamotrigine combination, with relapse later. He was first referred in March 2004 at age 17 for therapeutic advice. He was very slow, walking with help. The EEG showed nearly continuous discharges of diffuse spike-waves while awake (Figure 5). He was on valproate 1,500 mg/d, phenobarbital (PB) 100 mg/d

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Figure 5. Case vignette. Waking EEG at referral, in April 2004, on valproate 1,500 mg/d, nitrazepam 15 mg/d and phenobarbital 100 mg/d (duration of EEG abstract: 28 seconds).

and nitrazepam 15 mg/d (blood levels : VPA : 92 mg/L, NTZ 140μg/L, PB 18.6 mg/L). The latter was replaced with clobazam 30 mg/d without clinical change (blood levels: VPA: 115 mg/L, CLB 105 μg/L, PB 26.3 mg/L). Keppra® (1,000 mg/d) caused marked seizure aggravation and was stopped after 2 weeks. Felbamate 1,800 mg/d was added in May 2004: seizures stopped during titration of FBM, and the EEG was markedly improved, with normal waking tracings without spike-waves (blood levels: FBM 56.5 mg/L, PB 44.2 mg/L, VPA 121 mg/L). PB was withdrawn over 4 months, and clobazam reduced to 10 mg/d. In November 2004, he was on FBM 1,800 mg/d, VPA 1,500 mg/d, and clobazam 10 mg/d (blood levels: VPA: 132 mg/L, FBM 58.5 mg/d, CLB 101 μg/L). The waking EEG remained normal (Figure 6). Over the following two years, VPA was reduced to 1,000 mg/d and clobazam stopped (blood levels in 2008: FBM 79.6 mg/L, VPA 122 mg/L). Liver enzyme tests and blood cell counts were controlles at 2-week intervals during the first 6 months of FBM therapy, then at monthly intervals during the 6 following months, then at yearly interval. No change was seen. The patient has had no significant copathology under FBM. The patient has thus remained apparently seizure-free on the same dose of FBM (1,800 mg/d) and VPA (1,000 mg/d) with normal waking EEG at yearly controls since 2004. He was last seen in March, 2011: the waking EEG was normal, and during light sleep there were no spike-wave or fast discharges (Figure 7). The only symptom of possible persisting seizures during sleep was the occurrence of enuresis several times per year. His behaviour has remained calm and friendly.

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Figure 6. Case vignette. Waking EEG in November 2004, on felbamate 1,800 mg/d, valproate 1,500 mg/d and clobazam 10 mg/d (duration of EEG abstract: 28 seconds).

Figure 7. Case vignettte. Waking (left) and sleep (right) EEG in March, 2011, on felbamate 1,800 mg/d and valproate 1,000 mg/d (duration of abstract: 26 seconds). Note the alpha background activity and the diffuse slowing during sleep, without physiological sleep transients.

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Patients who do well on felbamate may not always fulfil the diagnostic criteria of the LGS. Recent reports have confirmed the efficacy of felbamate in series of difficult-to-treat patients with variable epilepsy syndromes. Kearney and Delanty (2009) report on 9 responders among 13 adult patients with refractory epilepsies. Severe epilepsies of childhood may also benefit from felbamate. In a series of 38 pediatric cases (22 with LGS, 6 with myoclonic-astatic epilepsy (Doose syndrome), 5 with generalized and 5 with focal symptomatic epilepsies), Zupanc et al. (2010) reported that 6 patients (including 4 with Doose syndrome) became seizure-free, while 63% had a greater than 50% decrease of seizure activity. Cilio et al. (2001) reported on 36 pediatric patients first treated with felbamate between 1994 and 1997 (13 with focal epilepsies, 9 with LGS, 8 with infantile spasms, and 6 with other generalized epilepsies): more than 50% seizure reduction was observed in 69% at three months, but decreased to 47% at one year. There are no published reports on the efficacy of felbamate in specific conditions like the Dravet syndrome, although interesting efficacy has been repeatedly reported in poster form at international meetings.

Use of felbamate in clinical practice It is estimated that felbamate, in spite of the restrictions and costs, is used in approximately 10,000 patients with epilepsy worldwide, with more than 1,000 patients newly exposed per year. Felbamate is available in most markets as 400 and 600 mg tablets, and as an oral solution (suspension) dosed at 600 mg/5 mL. Maximal daily dose is 3,600 mg and pharmacokinetics allow two intakes per day, usually with equal doses in the morning and evening. The average dose used in adults was reported as 3,211 mg (Chahem & Bauer, 2007). Titration should be progressive, over a few weeks, up to the best tolerated dose and optimal clinical effect: slow progression may minimize skin rash and will lessen dose-related adverse effects. Doses up to 50 mg/kg/d are possible. Serum level monitoring is available and reliable (Tribut et al., 2010): the usual levels range between 30 and 80 μg/mL. There is a wide range of clearances of felbamate resulting from co-medications and other sources of individual variability, and concentrations are not predictable from the doses, and thus monitoring of serum concentrations can be useful to guide dosing. Recently, a reference range of 30-60 μg/mL (126-252 μmol/L) has been suggested. However, there is a considerable variability in response at these concentrations, and higher concentrations may give additional benefit although there is a risk of increased adverse effects. Because of significant pharmacokinetic interactions, that may lead in particular to increased serum levels of co-medications like valproate and phenytoin, concomitant AEDs should also be monitored until a steady state has been reached. Patients receiving felbamate should indeed be closely monitored clinically and biologically (Table I). Clinical parameters include (besides seizure count): detection of skin rash, weight, cognitive function, mood and behaviour. Initial weight loss may correct itself during long-term therapy: among 77 patients aged 10 to treated over an average of 7.4 years, weight loss averaged 5.1 kg after one year, but was no longer apparent at last follow-up (White et al., 2009). Biological parameters should include (besides AED serum level monitoring guided by clinical detection of possible dose-related toxicity of felbamate and co-therapies): blood cell count and liver enzymes. In recent years, such monitoring, which led to the withdrawal of felbamate in some patients due to progressive changes in

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biological markers, has prevented the occurrence of severe hematological or hepatic complications. Patients who tolerate felbamate well at initiation of therapy are not likely to develop adverse effects later. Table I. Clinical and biological monitoring of patients receiving felbamate (FBM). Parameter Clinical Weight Skin Excitation, insomnia Seizures CNS-related (ataxia, sedation...) Biological Blood cell count& liver enzymes

FBM blood levels Co-prescribed AED

Duration/effect As long as FBM is continued Risk of rash (first weeks) During titration Exacerbation (rare) No improvement During titration

Management Stop FBM only if progressive weight loss continues ; many compensate spontaneously in the long run Stop FBM if rash Slower titration, dose reduction Stop FBM Stop FBM Check blood levels, mind interactions

2-week intervals 6 months monthly intervals 1 year later: only if clinical reason

Stop FBM (clinical judgment)

any time (clinical judgment) interactions

Adjust dosage of FBM Adjust dosage of AED

Paradoxical seizure exacerbation has not been specifically studied with felbamate. As with any other AED, it may occur. It was reported in one patient out of 30 in the early study of Theodore et al. (1991) of felbamate in resistant focal epilepsy. If a decision of withdrawal of felbamate is made, there is a risk of transient seizure exacerbation (Welty et al., 1998), thus withdrawal should be gradual and compensated by other AEDs. Tolerance to the therapeutic effect of felbamate does not seem to be a major problem. In clinical responders, with good seizure control on felbamate, the therapeutic response is likely to persist over a long period: in their long-term follow-up study of 77 patients, White et al. (2009) do not find differences in seizure control at one year compared to last follow-up (average: 7.4 years, range 2-20.3 years). On the other hand, in a pediatric population with mostly encephalopathic epilepsies, Cilio et al. (2001) noted that the rate of patients with 6 50% seizure reduction decreased between the early period (3 months, 69%) and later evaluations (1 year, 47%; last follow-up, 41%). This may have more to do with an epilepsy-related than with a felbamaterelated tolerance. There is thus a consensus among epileptologists who deal with severe, multi-resistant epilepsy patients, that felbamate should not be forgotten (Pellock et al., 2006). It may bring great benefits to patients with a variety of severe, encephalopathic seizure disorder. When adequately monitored, such patients do not run any risk of severe complications. Felbamate may be continued over many years with persisting benefit and without tolerability problems. Unfortunately, the drug was not further developed after 1994: there are thus limited data on its best clinical indications. Clearly, the Lennox-Gastaut syndrome and related conditions are excellent candidates, but felbamate may also be used in other indications, with benefit. In

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practice, its use is complicated, especially during the first year, by the obligate frequent biological monitoring. As an orphan drug, felbamate is also expensive. It should not be continued beyond a few weeks if it does not bring significant benefits in terms of seizure control and/or causes adverse effects.

Adverse effects: dose-related and idiosyncratic This section is dominated by the problem of the rare, but potentially lethal hematological and hepatic adverse effects. Felbamate is also associated with frequent, albeit usually benign, dose-related toxicity. Felbamate was considered well-tolerated in the pilot add-on trials: adverse effects caused premature interruption of the trial in about only 7% of patients. Symptoms associated with felbamate more than with placebo were nausea and vomiting, diplopia, blurred vision, headache, and ataxia (Graves, 1993). In monotherapy trials, the symptoms most commonly observed in adults were insomnia, weight loss, gastrointestinal distress and headache. Most adverse effects observed in add-on trials were attributed to the cumulative effects with comedications, especially phenytoin, some in relation with pharmacokinetic interactions. Many uncommon dose-related adverse effects were reported after the first tidal wave of felbamate prescriptions in 1993-1994, and very few in recent years, probably due to the lesser use of the drug. Similarly, the concerns about liver and blood marrow toxicity produced a large amount of publications in the late 1990s, but much fewer studies in recent years. Headache was reported, as the most common adverse effects, by 33% of 60 patients receiving felbamate (followed by gastrointestinal problems (27%) and insomnia (25%) (Ettinger et al., 1996). Headache occurred after an average of 19 days on felbamate, and responded in a majority of those affected to dose reduction. Anorexia was a frequent side-effect and may result in significant weight loss. Bergen et al. (1995) reported that 75% of 65 patients lost weight during a 6-116-week open follow-up after introduction of felbamate, with an average weight loss of 4.11% body weight in adults, and 1.77% in children. In contrast to the weight-increase noted with other AEDs, weight loss is not usually considered a major complication but may be an additional handicap in some severely affected epilepsy patients with pre-existing feeding difficulties. Felbamate has been associated with only mild sedation and even a stimulant-like effect, which may result in insomnia. Among 60 patients who initiated felbamate, insomnia was reported by 25% and restlessness by 23% (these were the most common side-effects after headache (33%) and gastrointestinal symptoms (27%) (Ettinger et al., 1996). In their study of rapid withdrawal of existing AEDs with blinded introduction of felbamate monotherapy in the context of presurgical seizure recordings, Ketter et al. (1996) showed that felbamate had both anticonvulsant and stimulating effects (anxiety, insomnia and anorexia). They consider that baseline insomnia and anxiety are markers of poor prospective psychiatric tolerability of felbamate. Other uncommon neurological or psychiatric adverse effects were reported: mania (1 case, Hill et al., 1995); choreoathetosis and acute dystonia in 2 children (Kerrick et al., 1995); psychosis (1 case, Knable & Richter, 1995; another case on felbamate monotherapy, McConnell et al., 1996).

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A 15-year old boy on felbamate 3,000 mg/d developed painful urolithiasis and the stone material was felbamate (no recurrence after cessation of the drug) (Sparagara et al., 2001). Sharp crystals made of felbamate were detected in the urine of a 3-year old child who had ingested a massive dose of felbamate solution (serum level of felbamate was at 138 mg/L, 15 hours after the ingestion) (Meier et al., 2005), and a combined overdose of valproate and felbamate (blood level: 200 mg/L) was associated with crystalluria and acute renal failure. The crystals were made of felbamate, and the renal function recovered (Rengstoff et al., 2000). Studies in rodents failed to show evidence of teratogenicity, but there are no data in humans. Clinical trials, which included around 1,600 patients, did not show evidence of specific severe hepatic or hematologic changes, only mild serum liver enzymes changes had been noted (Jensen, 1993). Far larger numbers of patients had to be exposed to felbamate before the most severe complications of felbamate could be detected. Acute allergic reactions had been noted on felbamate in 3-4% of patients during the clinical trials. Among 15 patients referred to a department of dermatology because of a total of 28 AED-triggered skin rash, felbamate was the trigger in one case (compared to carbamazepine (8), phenytoin (5), phenobarbital and lamotrigine (4 each), and valproate (1) (Galindo et al., 2002). A case of acute epidermal necrolysis was reported in a 33-year old woman after 16 days on felbamate 3,600 mg/d in monotherapy, extending to 45% of the body surface within 24 hours. The patient required a 25-day hospital stay (Travaglini et al., 1995). The most significant concerns raised by felbamate, however, refers to the occurrence of hematologic abnormalities, including fatal aplastic anemia, and liver toxicity, including subacute fatal liver failure. Kaufmann et al. (1997) retrospectively analyzed 31 cases of aplastic anaemia, which had occurred usually within 6 months of initiation of felbamate, but up to one year in some cases. They could exclude other causes (e. g. auto-immune disease, co-therapies) in a majority and concluded that 23 cases could be ascribed to felbamate. The most likely incidence of aplastic anaemia was 127 cases per million, i. e. one patient out of eight thousand; women are more at risk. A total of 14 fatal hepatic failures had been reported by 1996 (Leppik, 1996), from an estimated 100,000 patients exposed to felbamate. Liver failure occurs also usually within six months of felbamate initiation. The liver and bone marrow toxicity of felbamate seems to be species-specific. It is not found in rodents, but occurs in humans. It cannot be explained simply by the production of 2-phenylpropenal, a prospective toxic metabolite with concentration five-fold greater in humans than in rats (Dieckhaus et al., 2000). The respective part played by allergic and toxic mechanisms in these severe adverse effects is still debated. Among felbamate metabolites, alpha, beta-unsaturated aldehyde (atropaldehyde) has been considered a candidate with significant toxicity at cellular levels (Kapetanovic et al., 2002). Husain et al. (2002) have pointed to the toxic mechanisms involved in aplastic anemia that may include the effect of both felbamate and of toxic metabolites, 2-phenyl-1,3-propanediol monocarbamate (MCF) and [2-(4-hydroxyphenyl)-1,3 propanediol dicarbamate, all three of which may induce apoptosis in murine and human bone marrow stem cell lines. A recent study has shown that felbamate produces marked effects on an oxidative stress/reactive metabolite gene expression signature (Leone et al., 2007), also in comparison with other AEDs with potential liver toxicity, like valproate. MCF was shown to trigger immune reactions in experimental models (Popovic et al., 2004).

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For all practical purposes, there is no selective population at risk for the severe liver and bone marrow adverse effects of felbamate, and early detection should be enforced in all patients treated with felbamate. The severe complications occur early (usually within 6 months) and progressively. A systematic evaluation of liver enzymes and blood cell count is recommended at 2-week intervals during the first 6 months of treatment, at one month interval during the following six months, and later whenever there is a clinical suspicion of adverse effects. Both the application of such precautions (officially recommended in several European countries, including France) and the lesser use of felbamate in patients with epilepsy has to our knowledge, suppressed the occurrence of fatalities related to these adverse effects. Keeping these recommendations in mind, clinicians will find that felbamate is usually, even in the presence of newer compounds, a well-tolerated anticonvulsant that renders important services in patients with difficult-to-treat epilepsies, especially with epileptic encephalopathies. Further progress in the knowledge of the mechanisms involved in felbamate toxicity has also led to the development of parent compounds with different metabolic pathways that are designed to retain the efficacy without exposing patients to the rare severe adverse effects; fluorofebamate is one of such promising compounds (Roecklein et al., 2007). REFERENCES • Albani F, Theodore WH, Washington P, et al. Effect of felbamate on plasma levels of carbamazepine and its metabolites. Epilepsia 1991; 32: 130-2.

• Contin M, Riva R, Albani F, Baruzzi AA. Effect of felbamate on clobazam and its metabolite kinetics in patients with epilepsy. Ther Drug Monit 1999; 21: 604-8.

• Banfield CR, Zhu GR, Jen JF, et al. The effect of age on the apparent clearance of felbamate: a retrospective analysis using nonlinear mixed-effects modeling. Ther Drug Monit 1996; 19: 19-29.

• Curry WJ, Kulling DL. Newer antiepileptic drugs: gabapentin, lamotrigine, felbamate, topiramate and fosphenytoin. Am Fam Physician 1998; 57: 513-20. • Devinsky O, Faught RE, Wilder BJ, Kanner AM, Kamin M, et al. Efficacy of felbamate monotherapy in patients undergoing presurgical evaluation of partial seizures. Epilepsy Res 1995; 20: 241-6.

• Bergen DC, Ristanovic RK, Waicosky K, Kanner A, Hoeppner TJ. Weight loss in patients taking felbamate. Clin Neuropharmacol1995; 18: 23-7. • Bourgeois B, Leppik IE, Sackellares JC, Laxer K, Lesser R, et al. Felbamate: a double-blind controlled trial in patients undergoing presurgical evaluation of partial seizures. Neurology 1993; 43: 693-6.

• Dieckhaus CM, Miller TA, Sofia RD, Macdonald TL. A mechanistic approach to understanding species differences in felbamate bioactivation: relevance to drug-induced idiosyncratic reactions.Drug Metab Dispos 2000; 28: 814-22.

• Bourgeois BFD. Felbamate. In: Pellock JM, Bougeois BFD, Dodson WE, Nordli DR Jr, Sankar R, eds. Pediatric Epilepsy: Diagnose and Therapy (3rd ed). New York: Demos Medical Publishing, 2008, 585-91.

• Ettinger AB, Jandorf L, Berdia A, Andriola MR, Krupp LB, et al. Felbamate-induced headache. Epilepsia 1996; 37: 503-5. • Faught E, Sachdeo RC, Remler MP, Chayasirisobhon S, Iragui-Madoz VJ, et al. Felbamate monotherapy for partial-onset seizures: an active-control trial. Neurology 1993; 43: 688-92.

• Canger R, Vignoli A, Bonardi R, Guidolin L. Felbamate in refractory partial epilepsy. Epilepsy Res 1999; 34: 43-8. • Cheshire WP. Felbamate relieved trigeminal neuralgia. Clin J Pain 1995; 11: 139-42.

• FBM Study Group in the Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med 1993; 328: 29-33.

• Cilio MR, Kartashov AI, Vigevano F. The long-term use of felbamate in children with severe refractory epilepsy. Epilepsy Res 2001; 47: 1-7.

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• Kapetanovic IM, Torchin CD, Strong JM, Yonekawa WD, Lu C, et al. Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro. Chem Biol Interact 2002; 142: 119-34.

• Galindo PA, Borja J, Gómez E, Mur P, Gudín M, et al. Anticonvulsant drug hypersensitivity. J Investig Allergol Clin Immunol 2002; 12: 299-304. • Gay PE, Mecham GF, Coskey JS, Sadler T, Thompson JA. Behavioral effects of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). Psychol Rep 1995 ; 77: 1208-10.

• Kaufman DW, Kelly JP, Anderson T, Harmon DC, Shapiro S. Evaluation of case reports of aplastic anemia among patients treated with felbamate. Epilepsia 1997; 38: 1265-69.

• Genton P, Gélisse P, Crespel A, eds. Le syndrome de Lennox-Gastaut. Montrouge: John Libbey Eurotext, 2009.

• Kearney H, Delanty N. Felbamate in an adult population with severe refractory epilepsy. Ir Med J 2009 102: 326-8.

• Glue P, Sulowicz W, Colucci R, et al. Single-dose pharmacokinetics of felbamate in patients with renal dysfunction. Br J Clin Pharmacol 1997; 44: 91-3.

• Kelley MT, Walson PD, Cox S, et al. Population pharmacokinetics of felbamate in children. Ther Drug Monit 1997; 19: 29-36.

• Graves M. Felbamate. Ann Pharmacother 1993; 27: 1073-81.

• Kerrick JM, Kelley BJ, Maister BH, Graves NM, Leppik IE. Involuntary movement disorders associated with felbamate. Neurology 1995; 45: 1951.

• Graves NM, Holmes GB, Fuerst RH, Leppik IE. Effect of felbamate on phenytoin and carbamazepine serum concentrations. Epilepsia 1989; 30: 225-9.

• Ketter TA, Malow BA, Flamini R, Ko D, White SR, et al. Felbamate monotherapy has stimulant-like effects in patients with epilepsy. Epilepsy Res 1996; 23:129-37.

• Hancock E, Cross H. Treatment of Lennox-Gastaut syndrome. Cochrane Database Syst Rev 2003; 3: CD003277.

• Kleckner NW, Glazewski JC, Chen CC, et al. Sub-typeselective antagonism of N-methyl-D- aspartate receptors by felbamate: insights into the mechanism of action. J Pharmacol Exp Ther 1999; 289: 886-94.

• Hill RR, Stagno SJ, Tesar GE. Secondary mania associated with the use of FBM. Psychosomatics 1995; 36: 404-6. • Husain Z, Pinto C, Sofia RD, Yunis EJ. Felbamateinduced apoptosis of hematopoietic cells is mediated by redox-sensitive and redox-independent pathways. Epilepsy Res 2002; 48: 57-69.

• Knable MB, Rickler K. Psychosis associated with felbamate treatment. J Clin Psychopharmacol 1995; 15: 292-3.

• Hussein G, Troupin AS, Montouris G. Gabapentin interaction with felbamate. Neurology 1996; 47: 1106.

• Leone AM, Kao LM, McMillian MK, Nie AY, Parker JB, et al. Evaluation of felbamate and other antiepileptic drug toxicity potential based on hepatic protein covalent binding and gene expression. Chem Res Toxicol 2007; 20: 600-8.

• Jensen PK. Felbamate in the treatment of refractory partial onset seizures. Epilepsia 1993; 34 (Suppl 7): S25-9.

• Leppik IE, Dreifuss FE, Pledger GW, Graves NM, Santilli N, et al. Felbamate for partial seizures: results of a controlled clinical trial. Neurology 1991;41: 1785-9.

• Jensen PK. Felbamate in the treatment of Lennox-Gastaut syndrome. Epilepsia 1994; 35 (Suppl 5): S54-7. • Johannessen Landmark C, Johannessen SI. Pharmacological management of epilepsy. Recent advances and future prospects. Drugs 2008; 68: 1925-39.

• Leppik IE. Felbamate. In: Shorvon S, Dreifuss F, Fish D, Thomas D, eds. The Treatment of Epilepsy. Oxford: Blackwell Science, 1996, 421-8.

• Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second and third generation antiepileptic drugs. Expert Rev Neurotherapeutics 2010; 10: 119-40.

• McConnell H, Snyder PJ, Duffy JD, Weilburg J, Valeriano J, et al. Neuropsychiatric side effects related to treatment with felbamate. J Neuropsychiatry Clin Neurosci 1996; 8: 341-6.

• Johannessen SI and Johannessen Landmark C. Value of therapeutic drug montoring in epilepsy. Expert Rev Neurotherapeutics 2008; 8: 929-39.

• Meier KH, Olson KR, Olson JL. Acute felbamate overdose with crystalluria. Clin Toxicol 2005; 43: 189-92.

• Johannessen SI, Johannessen Landmark C. Antiepileptic drug interactions-Basic principles and clinical implications. Current Neuropharm 2010; 8: 254-67.

• Mellick GA. Hemifacial spasm: successful treatment with felbamate. J Pain Symptom Manag 1995; 10: 392-5.

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• O’Neil MG, Perdun CS, Wilson MB, McGown ST, Patel S. Felbamate-associated fatal acute hepatic necrosis. Neurology 1996; 46: 1457-9.

• Shi LL, Dong J, Ni H, Geng J, Wu T. Felbamate as an add-on therapy for refractory epilepsy. Cochrane Database Syst Rev 2011; 1: CD008295.

• Palmer KJ, McTavish D. Felbamate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in epilepsy. Drugs 1993; 45: 1041-65.

• Siegel H, Kelley K, Stertz B, Reeves-Tyer P, Flamini R, et al. The efficacy of felbamate as add-on therapy to valproic acid in the Lennox-Gastaut syndrome. Epilepsy Res 1999; 34: 91-7.

• Parker RJ, Hartman NR, Roecklein BA, Mortko H, Kupferberg HJ, et al. Stability and comparative metabolism of selected felbamate metabolites and postulated fluorofelbamate metabolites by postmitochondrial suspensions. Chem Res Toxicol 2005; 18: 1842-8.

• Sparagana SP, Strand WR, Adams RC. Felbamate urolithiasis Epilepsia 2001; 42: 682-5. • Swinyard EA, Sofia RD, Kupferberg HJ. Comparative anticonvulsant activity and neurotoxicity of felbamate and four prototype antiepileptic drugs in mice and rats. Epilepsia 1986; 27:27-34.

• Pellock JM, Faught E, Leppik IE, Shinnar S, Zupanc ML. Felbamate: consensus of current clinical experience. Epilepsy Res 2006; 71: 89-101.

• Theodore WH, Raubertas RF, Porter RJ, Nice F, Devinsky O, et al. Felbamate: a clinical trial for complex partial seizures. Epilepsia 1991; 32: 392-7.

• Popovic´ M, Nierkens S, Pieters R, Uetrecht J. Investigating the role of 2-phenylpropenal in felbamate-induced idiosyncratic drug reactions. Chem Res Toxicol 2004; 17: 1568-76.

• Thompson CD, Gulden PH, Macdonald TL. Identification of modified atropaldehyde mercapturic acids in rat and human urine after felbamate administration. Chem Res Toxicol 1997; 10: 457-62.

• Reidenberg P, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of phenobarbital. Clin Pharmacol Ther 1995; 58: 279-87.

• Tisdel KA, Israel DS, Kolb KW. Warfarin-felbamate interaction. First report. Ann Pharmacother 1994; 28: 805.

• Rengstorff DS, Milstone AP, Seger DL, Meredith TJ. Felbamate overdose complicated by massive crystalluria and acute renal failure. J Toxicol Clin Toxicol 2000; 38: 667-9.

• Travaglini MT, Morrison RC, Ackerman BH, Haith LR Jr, Patton ML. Toxic epidermal necrolysis after initiation of felbamate therapy. Pharmacotherapy 1995; 15: 260-4.

• Rho JM, Donevan SD, Rogawski MA. Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate. J Pharmacol Exp Ther 1997; 280: 1383-91.

• Tribut O, Bentué-Ferrer D, Verdier MC, le groupe Suivi Thérapeutique Pharmacologique de la Société Française de Pharmacologie et de Thérapeutique. Therapeutic drug monitoring of felbamate. Therapie 2010 ; 65: 35-8.

• Roecklein BA, Sacks HJ, Mortko H, Stables J. Fluorofelbamate. Neurotherapeutics 2007; 4: 97-101.

• Wagner ML, Graves NM, Leppik IE, et al. The effect of felbamate on valproic acid disposition. Clin Pharmacol Ther 1994; 56: 494-502.

• Saano V, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive. Clin Pharmacol Ther 1995; 58: 523-31.

• Welty TE, Privitera M, Shukla R. Increased seizure frequency associated with felbamate withdrawal in adults. Arch Neurol 1998; 55: 641-5.

• Sachdeo R, Kramer LD, Rosenberg A, Sachdeo S. Felbamate monotherapy: controlled trial in patients with partial onset seizures. Ann Neurol 1992; 32: 386-92.

• White JR, Leppik IE, Beattie JL, Walczak TS, Tran TA, et al. Long-term use of felbamate: clinical outcomes and effect of age and concomitant antiepileptic drug use on its clearance. Epilepsia 2009; 50: 2390-6.

• Sachdeo R, Narang-Sachdeo SK, Shumaker RC, et al. Tolerability and pharmacokinetics of monotherapy felbamate doses of 1,200-6,000 mg/day in subjects with epilepsy. Epilepsia 1997; 38: 887-92.

• Zupanc ML, Roell Werner R, Schwabe MS, O’Connor SE, Marcuccilli CJ, et al. Efficacy of felbamate in the treatment of intractable pediatric epilepsy. Pediatr Neurol 2010; 42: 396-403.

• Schmidt D, Bourgeois B. A risk-benefit assessment of therapies for Lennox-Gastaut syndrome. Drug Saf 2000; 22: 467-77.

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Rufinamide

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History Rufinamide (RFM), a triazole derivative, was developed in 2004 by Novartis Pharma and is manufactured by Eisai. It is marketed in the EU as Inovelon®, and has a brand name Banzel® in the United States. In 2008, rufinamide was designated as an orphan drug for the adjunctive treatment of Lennox-Gastaut syndrome in patients 4 years of age and older and approved by the European Medicines Agency (EMEA) and the U.S. Food and Drug Administration (FDA). It is also approved by FDA for the adjunctive treatment for partial-onset seizures in individuals older than 12 years.

Pharmacology Chemical structure

Figure 1. Chemical structure of rufinamide: 1-[(2,6-difluorophenyl) methyl]-1-hydro-1,23-triazole-4carboxamide.

Chemical characteristics Rufinamide (1-[(2,6-difluorophenyl)methyl]-1-hydro-1,2,3-triazole-4 carboxamide) is a novel lipophilic compound unrelated to other AEDs. It is a white, odourless and slightly bitter crystalline substance with a low solubility in water.

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Mechanisms of action These are still under investigation, but it is suggested from in vitro studies that rufinamide prolongs the inactivation state of voltage-gated sodium channels and limits sustained firing of neuronal sodium dependent action potentials like many other AEDs. There is no significant binding to GABA, glutamate or monoaminergic receptors (Bialer et al., 2007). A recent study demonstrated anticonvulsant efficacy of rufinamide in several rodent models for partial and generalized seizures (MES and chemically induced seizures) (White et al., 2008).

Figure 2. Rufinamide: mechanisms of action.

Pharmacokinetics Bioavailability The absorption of rufinamide following oral administration is rather slow. Maximal serum concentrations are attained within 4-6 hours. The bioavailability of rufinamide is dose limited, and food intake increases the bioavailability by about 34% and the peak concentration by about 56% (Perucca et al., 2008).

Distribution and protein binding The volume of distribution of rufinamide is 50-80 L, dependent on the dose and body surface area (Perucca et al., 2008). The drug is likely to be excreted in breast milk. Rufinamide has a low serum protein binding (26-35%) and is mainly bound to albumin.

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Metabolism and renal excretion Rufinamide is extensively metabolized by enzymatic hydrolysis of the carboxylamide group by carboxylesterases and by oxidative cleavage at the benzylic carbon atom to the metabolite CGP 47292, independent of CYPs. This pharmacologically inactive metabolite is subsequently eliminated via renal excretion, and thus the pharmacokinetics of rufinamide is not influenced by impaired renal function (Perucca et al., 2008). The effect of hepatic impairment has not been studied.

Elimination half-life The elimination of rufinamide is mainly via renal excretion (85%). The elimination half-life is 6-10 hours (Bialer et al., 2007, Perucca et al., 2008). There are no significant differences among various ethnic groups, but oral clearance may be significantly lower in women compared to men. Plasma clearance increases with increasing dose and is higher in children than in adults. Rufinamide pharmacokinetics is not altered in the elderly compared to non-elderly adults.

Drug interactions The enzyme inducing AEDs carbamazepine, phenobarbital, phenytoin, and primidone and also vigabatrin may increase rufinamide clearance and decrease rufinamide serum concentrations by about 25% (Perucca et al., 2008). In contrast, valproic acid may decrease the clearance of rufinamide by about 17% (but 60% in children) and thus increase rufinamide serum concentrations (Perucca et al., 2008, Brodie et al., 2008). Recently, in a population kinetic study with rufinamide given as add-on to valproic acid, it was demonstrated an increase in the rufinamide serum concentration that was more prominent in children than adolescents and adults (70% vs. 26 and 16%, respectively), possibly due to the higher serum concentrations in the children (Perucca et al., 2008). In addition, rufinamide may decrease serum concentrations of carbamazepine and lamotrigine and increase serum concentrations of phenobarbital and phenytoin. The effect on carbamazepine clearance is probably secondary to a minor induction of CYP3A, while the effect on lamotrigine is probably secondary to an induction of UDP-GT. Rufinamide does not affect the serum concentrations of topiramate or valproic acid (Perucca et al., 2008). Rufinamide can induce the metabolism of other drugs, like triazolam, possibly via an effect on CYP3A4, increasing its clearance by 55% resulting in decreased serum triazolam concentrations (Perucca et al., 2008). Rufinamide may also increase the clearance of oral contraceptives by induction of CYP 3A4, with a decrease in serum concentrations of ethinyl estradiol and norethindrone of 22% and 14%, respectively (Perucca et al., 2008, Brodie et al., 2008). Rufinamide is possibly not an inducer of CYP 1A2, since the clearance of the substrate for this enzyme, olanzapine, had an unaffected clearance (Perucca et al., 2008, Glauser et al., 2008). To-date, no clinically significant pharmacodynamic interactions involving rufinamide have been reported and has no clinically relevant interactions with other AEDs (Johannessen, Landmark & Patsalos, 2010).

Therapeutic drug monitoring There is a positive correlation between rufinamide serum concentrations and improved seizure frequency, and higher concentrations have been observed in patients with adverse effects than in those without. These observations suggests that monitoring rufinamide serum

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Figure 3. Pharmacokinetic scheme for rufinamide.

concentrations might be of value in clinical practice, even if a reference range has not yet been defined. Patients taking doses of 1,800 mg/day or 40 mg/kg had a median steady state serum concentration of about 15 μg/mL. In the clinical trials the highest concentration measured was 45.9 μg/mL in a patient taking 50 mg/kg. Several HPLC methods are available for measurement of rufinamide serum concentrations (Perucca et al., 2008).

Clinical indications The broad antiepileptic spectrum of rufinamide was shown in experimental studies, where the drug was efficacious against generalized and partial seizures (Schmutz et al., 2000; McLean et al., 2005; White et al., 2005). In humans, the efficacy of rufinamide in patients with partial seizures and Lennox-Gastaut syndrome has been demonstrated by placebo-controlled, randomized and as well non-controlled trials.

Focal epilepsy Three placebo-controlled, randomized trials have proved the efficacy of rufinamide adjunctive therapy in patients with refractory focal epilepsy (Table I). Pa˚hlgren et al. (2001), comparing the weekly-ascending doses of rufinamide to placebo in 50 adult patients with partial and generalized seizures, showed the significant decrease of seizure frequency in rufinamide group versus placebo – 39 and 16% respectively. The number of patients with low seizure frequency was three times higher in rufinamide group. In a series by Elger et al. (2010), rufinamide doses 400, 800 and 1,600 mg/day were effective in decreasing the seizure frequency with a linear trend of dose-response for patients with 6 50% reduction in seizure frequency from baseline. Brodie et al. (2009) reported a median reduction in partial seizures in 20.4% of patients receiving 3,200 mg rufinamide daily compared with 1.6% median increase for placebo.

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Table I. Efficacy of rufinamide in patients with partial seizures: double-blind placebo controlled trials. Reference

Population

Pa˚lhagen et al., 2001 N = 50* 18-60 years

Interventions Comparison of weekly-ascending doses of RFM (400, 800, 1200, 1,600 mg/day) to placebo; 28 days double-blind phase

Key outcomes Total seizure frequency (median): 41% reduction – RFM 52% increase – placebo • 50% reduction of seizure frequency: 39% – RFM 16% – placebo Patients with low seizure frequency (• 4 per 28 days): 61% – RFM 21% – placebo

Elger et al., 2010

Comparison of 200, 400, 800, N = 647 1,600 mg/day RFM vs. placebo; 15-65 years 28 days double-blind phase • 3 AEDs • 4 seizures during 6 months prior to baseline

• 50% seizure reduction per 28 days: 9% – placebo 4.7% – RFM 200 mg/day 16% – RFM 400 mg/day 11.6% – RFM 800 mg/day 14.3% – RFM 1,600 mg/day The means of 50% response rate: 61.2% – RFM 200 mg/day 66.4% – RFM 400 mg/day 75.4% – RFM 800 mg/day 68% – RFM 1,600 mg/day

Brodie et al., 2009

N = 313 • 16 years

Total seizure frequency (median): 20.4% – RFM 1.6% increase – placebo • 50% reduction of seizure frequency: 28.2% – RFM 18.6% – placebo

3200 mg/day RFM vs. placebo; 13 week double-blind phase

* Patients with partial and generalized seizures.

Comparable results of rufinamide efficacy in refractory focal epilepsy have been obtained in retrospective non-controlled studies (Kluger et al., 2009; 2010; Vendrame et al., 2010). Kluger et al. (2009) reported 23.5% response rate in patients with focal epilepsy after 12 weeks treatment with rufinamide. After 18 months of rufinamide therapy the response rate (6 50% seizure reduction/ seizure-free) in this group comprised 11.8% (Kluger et al., 2010). Vendrame et al. (2010) demonstrated the highest responder rate in cryptogenic focal epilepsies (83.3%) compared to symptomatic focal epilepsy, Lennox-Gastaut syndrome and West syndrome – 31.3, 38. and 14.3% respectively. Case vignette The following case vignette illustrates rufinamide efficacy and good tolerability in a patient with focal epilepsy. A boy, born in May 2006. Uneventful pregnancy and delivery. Normal psychomotor development. Epilepsy onset at the age 3 years (May 2009) with seizures characterized by a

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sudden fall, head and eye deviation, loss of contact, inability to move right leg during the seizure. Seizure frequency 15-20 per month, seizure duration 30-40 sec. MRI – normal, metabolic screening and chromosome analysis without pathological findings. EEG – focus of sharp-waves/spikes followed by 2-5 Hz acitivity in the left fronto-central and midparietal region (Figure 4). Has been treated initially with valproate, then consistently with combinations of valproate and carbamazepine, valproate and lamotrigine without sufficient effect. Had some decrease of seizure frequency while treated with valproate and topiramate. However, topiramate was substituted by levetiracetam because of appetite and weight loss. On combination of valproate and levetiracetam the seizure frequency reduced from 15 to 8-10 seizures per month. In November 2009 therapy with levetiracetam 750 mg/day and rufinamide 800 mg/day was initiated. Since December 2009 until now the child is seizure-free (16 months), no side effects have been observed.

Figure 4. Interictal EEG, awake: spikes in the left fronto-central and midparietal regions.

In some focal epilepsies, especially of frontal lobe origin, the electroclinical features can overlap with those characteristic for the Lennox-Gastaut syndrome. Thus, a patient with frontal lobe epilepsy may have combination of tonic axial and complex partial seizures but without atypical absences, or slow spike-waves on the EEG but without fast rhythms during sleep (Chauvel & Bancaud, 1994; Dravet, 2003). Moreover, secondary bilateral synchrony is a significant EEG-pattern for both frontal lobe epilepsy and Lennox-Gastaut syndrome. These data might be the rationale for rufinamide use in the frontal lobe epilepsy associated with tonic seizures and secondary bilateral synchrony. An observational prospective study evaluating

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rufinamide efficacy in children with frontal lobe epilepsy associated with axial tonic seizures and secondary bilateral synchrony on the EEG has been performed at the Danish Epilepsy Centre (personal data). The study population comprised 25 patients aged between 6 and 15 years who received adjunctive therapy with rufinamide at the doses 40-45 mg/kg/day for a minimum one year. After 12 months of treatment, four patients (16%) were seizure-free, 13 (52%) had seizure reduction for 6 50% and eight (32%) reduction of seizures < 50%. The results of this preliminary study indicate that rufinamide can be used as add-on therapy in patients with frontal lobe epilepsy associated with tonic axial seizures.

Lennox-Gastaut syndrome Lennox-Gastaut syndrome constitutes a life-long disease and is one of the most difficult to treat epilepsy syndromes. No single antiepileptic drug regime has been demonstrated superior to the others, polytherapy is needed in all cases, and the choice of antiepileptic drug combinations corresponds to the respective seizure types. Rufinamide is used as adjunctive therapy for the treatment of Lennox-Gastaut syndrome in children older than 4 years and adults (Genton et al., 2009). To evaluate efficacy and tolerability of rufinamide as add-on therapy in Lennox-Gastaut syndrome, Glauser et al. (2005, 2008) performed a randomized, double-blind placebo controlled trial in 138 patients aged 4-30 years who were treated with rufinamide during 84 days. All Table II. Rufinamide efficacy in treatment of Lennox-Gastaut syndrome: open-label uncontrolled studies. Reference

Study design, therapy duration

Population

Key outcomes

Kluger et al., 2009

Observational retrospective, 12 weeks

45 children, 15 adults LGS – 31 MAE – 5 Partial epilepsy – 17 Other generalized epilepsy – 7

Response rate: 54.8% 100% 23.5% 42.8%

Kluger et al., 2010

Extension protocol of the previous study, 18 months

45 children, 15 adults LGS – 31 MAE – 5 Partial epilepsy – 17 Other generalized epilepsy – 7

Response rate: 35.5% 33.3% 11.8% 38.6%

Vendrame et al., 2010

Retrospective, 1-10 months (mean 4.4 months)

77 patients, 1-27 years LGS – 26 West syndrome – 7 Focal cryptogenic epilepsy – 12 Focal symptomatic epilepsy – 32

Response rate: 38.4% 14.3% 83.3% 31.3%

Coppola et al., 2010

Open-label, prospective, 3-21 months

43 patients with LGS, 4-34 years

Seizure reduction: Seizure-free – 9.3% 50-99% – 51.1% 25-50% – 4.7% Unchanged – 30.2%

LGS: Lennox-Gastaut syndrome; MAE: myoclonic-astatic epilepsy.

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patients received ^ 3 antiepileptic drugs and had more than 90 seizures in month prior to baseline. The higher reduction of mean seizure frequency was observed in rufinamide group compared to placebo: for all seizure types – 32.7 versus 11.7% respectively, for tonic-atonic seizures – 42.5% decrease versus 1.4% increase respectively. The greater responder rate was also reported in patients treated with rufinamide than in patients received placebo: for all seizure types – 31.1 and 10.9% respectively, for tonic-atonic seizures – 42.5 and 16.7%. rufinamide treatment was well-tolerated. The most often side effects were somnolence (24.3% with rufinamide vs. 12.5% with placebo) and vomiting (21.6% with rufinamide vs. 6.3% with placebo). The efficacy of rufinamide as adjunctive therapy in patients with Lennox-Gastaut syndrome has been as well proved in several recent open-label uncontrolled studies (Coppola et al., 2010; Kluger et al., 2010; Vendrame et al., 2010). The results of these studies are summarized in Table II. All studies demonstrated relatively high efficacy of rufinamide therapy in patients with Lennox-Gastaut syndrome. The response rate varied between 35.5 and 54.8%, and the clinical effect sustained during the long-term treatment.

Case vignette A boy, born in December 2001. Uneventful pregnancy and delivery, normal psychomotor development. Epilepsy onset in March 2005 (age 3 years 3 months) with a generalized tonic-clonic seizure. During next 3 months atonic seizures, atypical absences and nocturnal tonic seizures had consistently occurred. EEG showed diffuse slow spike-wave complexes, 1.5-2 Hz (Figure 5a). MRI without pathological findings. Metabolic screening and chromosomal analysis normal. In June 2005 had episode of non-convulsive status epilepticus. Has been initially treated with valproate and lamotrigine with the shortlasting effect. Later in the course has received different combinations of valproate, lamotrigine, topiramate, ethosuximide, clonazepam, levetiracetam and the ketogenic diet without sufficient clinical effect. In November 2005 rufinamide at the dose 800 mg/day was administered in combination with levetiracetam 1,000 mg/day and ethosuximide 750 mg/day. The child became seizure-free after 2 months since rufinamide treatment initiation. EEG normalized (Figure 5b). After 3 years of complete seizure control levetiracetam and ethosuximide were withdrawn. The boy is still seizure-free (for 5 years) and receives only rufinamide which should be withdrawn soon. Goes to the usual public school, has no problems with school achievement. This case illustrates high clinical efficacy and good tolerability of rufinamide in LennoxGastaut syndrome. The use of new antiepileptic drugs (rufinamide, levetiracetam) early in the course may provide the better seizure and social outcome for the patients with this severe epileptic encephalopathy.

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Rufinamide

Figure 5a. Interictal EEG, awake: diffuse slow spike-wave complexes, 2-2.5 Hz.

Figure 5b. Same patient. Normal EEG.

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In clinical trials, the best rufinamide efficacy results have been seen with doses 3,200 mg/day in adults and 45 mg/kg/day in children. In adults, treatment should be initiated with a daily dose of 400 to 800 mg/day, as twice-daily dosing. In children, treatment should be initiated at a daily dose 10 mg/kg/day administered in two equally divided doses. The dose should be increased by approximately 10 mg/kg increments every third-fifth day to a maximum of 45 mg/kg/day.

Other epilepsy syndromes Despite the marked anticonvulsant effect in experimental animals, the clinical experience in treatment of patients with generalized seizures is still lacking. There are only few publications on rufinamide therapy in patients with generalized epilepsies (Kluger et al., 2010; Vendrame et al., 2010). In a series by Kluger et al. (2010) five patients with myoclonic-astatic and seven with unclassified generalized epilepsy were treated with rufinamide during 18 months. At the end of follow-up the responce rate in myoclonic-astatic epilepsy comprised 33% and in unclassified generalized epilepsy 38.6%. In a study performed by Vendrame et al. (2010) seven children with West syndrome have been receiving add-on rufinamide therapy for a mean 4.4 months (range 1-10 months) and had the response rate 14.3%. Häusler et al. (2011) reported three patients with myoclonic absences treated with rufinamide for 4, 12 and 24 months respectively. Two patients have been seizure-free during the whole treatment period (4 and 24 months), in the third child 6 50% reduction of seizure frequency was observed and sustained during 12 months. The preliminary results of these studies indicate that rufinamide can be used as add-on therapy in generalized epilepsies other than Lennox-Gastaut syndrome. However rufinamide efficacy in that category of patients remains to be proven.

Tolerability and side effects Rufinamide is generally well-tolerated, and all reported side effects were usually mild and transient. The frequency of side effects among patients treated with rufinamide is not exceeding 23-29% (Vendrame et al., 2010; Coppola et al., 2010). Most frequently observed side effects are fatigue (18-20%), somnolence (13-24%), headache (12-25%), nausea/vomiting (5-21%), dizziness (5-13%), loss of appetite (2-10%) (Pa˚hlgren et al., 2001; Glauser et al., 2008; Coppola et al., 2010; Kluger et al., 2010; Vendrame et al., 2010). The skin rash occurs rare – less than 10% of patients (Coppola et al., 2010; Kluger et al., 2010; Vendrame et al., 2010). REFERENCES • Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Eighth Eilat conference (Eilat VIII). Epilepsy Res 2007; 73: 1-52.

partial seizures in adults and adolescents: A randomized placebo-controlled trial. Epilepsia 2009; 50: 1899-909. • Chauvel P, Bancaud J. The spectrum of frontal lobe seizures: with a note on frontal lobe symptomatology. In: Wolf P, ed. Epileptic Seizures and Syndromes. London: John Libbey, 1994, 331-4.

• Brodie M, Rosenfeld W, Vazquez B, Ko D, Perdomo C, Arroyo S. Rufinamide for the adjunctive treatment of

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• Coppola G, Grosso S, Franzoni E, Veggiotti P, Zamponi N, et al. Rufinamide in children and adults with LennoxGastaut syndrome: First Italian multicenter experience. Seizure 2010; 19: 587-91.

children and adults with refractory epilepsy: First European experience. Epilepsy Behav 2009; 14: 491-5. • Kluger G, Haberlandt E, Kurlemann G, Ernst JP, Runge U, et al. First European long-term experience with the orphan drug rufinamide in childhood-onset refractory epilepsy. Epilepsy Behav 2010; 17: 546-8.

• Dravet C. Generalized epilepsies and frontal lobe epilepsies in children. In: Beaumanoir A, Andermann F, Chauvel P, Mira L, Zifkin B, eds. Frontal Lobe Seizures and Epilepsies in Children. Montrouge: John Libbey Eurotext, 2003: 121-32.

• McLean MJ, Schmutz M, Pozza M, Wamil A. The influence of rufinamide on sodium currents and action potential firing in rodent neurons. Epilepsia 2005; 46 (Suppl 8): 296.

• Elger C, Stefan H, Mann R, Narurkar M, Sun Y, Perdomo C. A 24-week, multicenter, randomized, doubleblind, parallel-group, dose-ranging study of rufinamide in adults and adolescents with inadequately controlled partial seizures. Epilepsy Res 2010; 88: 255-63.

• Perucca E, Cloyd J, Critchley D, Fuseau E. Rufinamide: Clinical pharmacokinetics and concentration-response relationships in patients with epilepsy. Epilepsia 2008; 49: 1123-41.

• Genton P, Gélisse P, Crespel A, eds. Le syndrome de Lennox-Gastaut. Montrouge: John Libbey Eurotext, 2009.

• Pa˚lhagen S, Canger R, Henriksen O, van Parys JA, Riviere ME, Karolchyk MA. Rufinamide: a double-blind, placebo-controlled proof of principle trial in patients with epilepsy. Epilepsy Res 2001; 43: 115-24.

• Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Efficacy and safety of rufinamide adjunctive therapy in patients with Lennox-Gastaut syndrome (LGS): a multicenter, randomized, double blind trial. Neurology 2005; 64 (Suppl 1): 1826.

• Schmutz M, Allgeier H, Pozza MF, Stables JP, White HS. Rufinamide (CGP 33101): Broad anti-convulsant spectrum and excellent tolerability in rodents. Epilepsia 2000; 41 (Suppl 8): 159.

• Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology 2008; 70: 1950-8.

• Vendrame M, Loddenkamper T, Gooty VD, Takeoka M, Rotenberg A, et al. Experience with rufinamide in a pediatric population: A single center’s experience. Pediatr Neurol 2010; 43: 155-8.

• Häusler M, Kluger G, Nikanorova M. Epilepsy with myoclonic absences: Favourable response to add-on rufinamide treatment. Neuropaediatrics 2011; 42: 28-9.

• White S, Schmutz M, Pozza MF, et al. Rufinamide (CGP 33101): a broad-spectrum anticonvulsant with excellent tolerability profile in rodents. Epilepsia 2005; 46 (Suppl 6): 373.

• Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second and third generation antiepileptic drugs. Expert Rev Neurotherapeutics 2010; 10: 119-40.

• White HS, Franklin MR, Kupferberg HJ, et al. The anticonvulsant profile of rufinamide (CGP 33101) in rodent seizure models. Epilepsia 2008; 49: 1213-20.

• Kluger G, Kurlemann G, Haberlandt E, Ernst JP, Runge U, et al. Effectiveness and tolerability of rufinamide in

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Achevé d’imprimer par Corlet, Imprimeur, S.A. 14110 Condé-sur-Noireau o N d’Imprimeur : 139709 - Dépôt légal : août 2011 Imprimé en France