the epilepsy prescriber's guide to antiepileptic drugs 2010

5/24/2018 The Epilepsy Prescriber's Guide to Antiepileptic Drugs 2010


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The Epilepsy Prescribers Guideto Antiepileptic Drugs


The Epilepsy Prescribers Guide toAntiepileptic Drugs

Philip N. PatsalosFRCPath, PhD

Professor of Clinical Pharmacology & Consultant Clinical PharmacologistUCL Institute of Neurology,

The National Hospital for Neurology and Neurosurgery,London, and the National Society for Epilepsy,

Chalfont St Peter,UK

Blaise F. D. BourgeoisMD

Professor of Neurology, Harvard Medical SchoolDirector, Division of Epilepsy and Clinical Neurophysiology

William G. Lennox Chair in Pediatric EpilepsyChildrens Hospital

Boston, USA

and


CAMBRIDGE UNIVERSITY PRESS

Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore,

So Paulo, Delhi, Dubai, Tokyo

Cambridge University Press

The Edinburgh Building, Cambridge CB2 8RU, UK

First published in print format

ISBN-13 978-0-521-68716-4

ISBN-13 978-0-511-72947-8

P. N. Patsalos and B. F. D. Bourgeois 2010

Every effort has been made in preparing this book to provide accurate and

up-to-date information which is in accord with accepted standards and practiceat the time of publication. Although case histories are drawn from actual cases,

every effort has been made to disguise the identities of the individuals involved.evertheless, the authors, editors, and publishers can make no warranties that

the information contained herein is totally free from error, not least because

clinical standards are constantly changing through research and regulation.The authors, editors, and publishers therefore disclaim all liability for direct or

consequential damages resulting from the use of material contained in this book.Readers are strongly advised to pay careful attention to information provided by

the manufacturer of any drugs or equipment that they plan to use.

2010

Information on this title: www.cambridge.org/9780521687164

This publication is in copyright. Subject to statutory exception and to the

provision of relevant collective licensing agreements, no reproduction of any partmay take place without the written permission of Cambridge University Press.

Cambridge University Press has no responsibility for the persistence or accuracyof urls for external or third-party internet websites referred to in this publication,

and does not guarantee that any content on such websites is, or will remain,accurate or appropriate.

Published in the United States of America by Cambridge University Press, New York

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CONTENTS

Preface page vii

Introduction ix

Acetazolamide 1

ACTH 11

Carbamazepine 19

Clobazam 31

Clonazepam 40

Diazepam 49

Eslicarbazepine acetate 59

Ethosuximide 68

Felbamate 77

Fosphenytoin 86

Gabapentin 95

Lacosamide 104

Lamotrigine 111

Levetiracetam 124

Lorazepam 134

Methsuximide 145Midazolam 153

Oxcarbazepine 163

Paraldehyde 173

Phenobarbital 181

Phenytoin 192

Piracetam 204

Pregabalin 212

Primidone 220Rufinamide 230

Stiripentol 238

Sulthiame 246

Tiagabine 255

Topiramate 263

Valproate 274

Vigabatrin 288

Zonisamide 297

Abbreviations 307Interaction Table 308Index 310

v


PREFACE

vii

PREFACE

With the rapidly increasing number of available antiepileptic drugs to

choose from, those involved in any aspect of the treatment of patientswith epilepsy face the challenge of remaining familiar with all rele-vant aspects of every medication that is currently available, including thenewest ones. The purpose of The Epilepsy Prescr ibers Guide to AntiepilepticDrugsis to present all the necessary information in a format that allowsthe prescriber to easily and rapidly find the specific answer to any ques-tion that may arise in the process of initiating and monitoring a medi-cation for the treatment of epilepsy. As opposed to standard textbooks,this unique guide focuses, in a systematic and didactic manner, on allthe information that the prescriber will need to choose and use a medi-

cation, as well as on features of the drug that may need to be discussedwith the patient before or during treatment.

The topics covered for each drug follow an identical sequence andinclude chemical name and structure; brand names in major countries;generics available; licensed indications; nonlicensed use; seizure typesfor which the drug is ineffective or contraindicated; mechanism ofaction; pharmacokinetic parameters; interaction profile; common, life-threatening, or dangerous adverse effects; dosing and use; laboratorymonitoring; use in special populations (renal and hepatic impairment,

children, the elderly, pregnant, and breast-feeding women); the overallplace of the drug in the treatment of epilepsy; suggested reading.

The reader can use this guide in many different ways and for variouspurposes, such as to rapidly review a synopsis of all relevant aspects ofa given drug, to choose a drug for a patient by reviewing the spectrumof efficacy and adverse effects of several drugs, to find the answer to onespecific question about a specific drug, or as a guide to discuss precau-tions and adverse effects with a patient before or during treatment. In al linstances, this information will be rapidly and easily found.


ix

INTRODUCTION

INTRODUCTION

The purpose of The Epilepsy Prescribers Guide to Antiepileptic Drugs

(AEDs) is to provide practical and concise information so as to allow theoptimum use of AEDs in clinical practice. This quick reference guideprovides a wealth of invaluable information for use by all who treatpatients with epilepsy, including neurologists, neurosurgeons, generalphysicians, those caring for the elderly, emergency medicine doctors,medical students and trainees at all levels, general practitioners, nursesand epilepsy nurse specialists, and practice pharmacists.

All of the drugs are presented in the same design format and in alpha-betical order to facil itate rapid access to information. Specifically, eachdrug is divided into eight sections and each section is designated by aunique color background: therapeutics, pharmacokinetics, drug interac-tion profile, adverse effects, dosing and use, special populations, and theoverall place of the drug in the treatment of epilepsy, followed by sug-gested reading of key references.

Section 1: TherapeuticsCovers the chemical name and structure; brand names in major coun-tries; generics available; licensed indications as approved by the UnitedStates Food and Drug Administration (FDA) and the European

Medicines Agency (EMA) or the United Kingdom Medicines andHealthcare products Regulatory Agency (MHRA); nonlicensed use;seizure types for which the drug is ineffective or contraindicated; mech-anism of action; efficacy profile.

Section 2: PharmacokineticsHighlights the pharmacokinetic parameters relevant to each drugs clin-ical therapeutics and includes absorption and distribution, metabolism,and elimination parameters.

Section 3: Drug interaction profileThe interaction profile of each drug is divided into three major sec-tions which include pharmacokinetic interactions, pharmacodynamicinteractions, and interaction with hormonal contraception. The phar-macokinetic interaction section is further subdivided into interactionsbetween AEDs and interactions between AEDs and non-AED drugs.Noninteracting drugs have been omitted.

Section 4: Adverse effects

Explains how the drug causes adverse effects; contains a list of com-mon, life-threatening, or dangerous adverse effects; an effect on weightis noted, and advice about what to do about adverse effects.

Section 5: Dosing and useProvides the usual dosing range; available formulations; how to dose anddosing tips; how to withdraw drug; symptoms of overdose and how to


x

INTRODUCTION

manage; what tests and therapeutic drug monitoring are needed; otherwarnings and precautions; and when not to use.

Section 6: Special populations

Gives information about use of the drugs in the presence of renal andhepatic impairments, and any precautions to be taken for treating chil-dren, the elderly, and pregnant and breast-feeding women.

Section 7: The overall place of the drug in the treatment ofepilepsyThis section provides an overview, based on the authors opinions, as towhere each AED can be placed in relation to the treatment of patientswith epilepsy and summarizes the primary and secondary seizure types

for which it shows efficacy, and finally highlights the potential advan-tages and disadvantages of each AED.

Section 8: Suggested readingIn this section, the authors highlight the key references that were usedin compiling the information contained in each drug section and read-ers are advised to read these if more information is needed. Readers arealso encouraged to consult standard comprehensive reference books onepilepsy and AED textbooks for more in-depth information.

At the back of the guide is an index by drug name. In addition, there

is a list of abbreviations and a table highlighting the interactions that canoccur between the different AEDs.


1

A

THERAPEUTICS

ACETAZOLAMIDE

Therapeutics

Chemical name and structure:Acetazolamide, N-(5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl)-aceta-mide, is a white to faintly yellowish white odorless crystalline powderwith a molecular weight of 222.25.

Although a sulfonamide compound, it is unlike sulfonamide anti-biotic compounds. It does not contain an arylamine group at theN4-position, which contributes to allergic reactions associated withsulfonamide antibiotics. The structure of acetazolamide bears somesimilarity to that of zonisamide. Its empirical formula is C

4H

6N

4O

3S

2.

Brand names:

Acetadiazol; Acetak; Albox; Apo-Acetazolamide; AzolCarbinib; Cetamid

Diamox; Diamox Sequals; Diamox Sustets; Diluran; Diural;Diuramid

EvamoxFonuritGlaupax

Huma-ZolamideLedamox; LediamoxMedene

OptamideRenamid

Stazol; SynomaxUramox

Zolmide

Generics available:Yes

Licensed indications for epilepsy:Adjunctive treatment of generalized tonicclonic and partial

seizures (UK-SPC)Adjunctive treatment of atypical absences, atonic, and tonic

seizures (UK-SPC)

Intermittent therapy of catamenial seizures (UK-SPC)

Licensed indications for non-epilepsy conditions:Adjunctive treatment of glaucoma (UK-SPC; FDA-PI)

Prevention or amelioration of symptoms associated with acutemountain sickness (FDA-PI)

CH3 C NH SO2NH2

S

N NO


2

A

ACETAZOLAMIDE

Nonlicensed use for epilepsy:Lennox-Gastaut syndrome

Nonlicensed use for non-epilepsy conditions:There are none

Ineffective (contraindicated):

Acetazolamide is not contraindicated for any seizure type or epi-lepsy; does not commonly exacerbate seizures

Mechanism of action:Potent inhibitor of brain carbonic anhydrase, the enzyme that

reversibly catalyses the hydration of CO2and the dehydration of

carbonic acidThe carbonic anhydrase inhibition results in an elevation of intra-

cellular CO2, a decrease of intracellular pH and depression of

neuronal activityAcetazolamide increases the concentration of weak acids (such as

certain antiepileptic drugs, e.g., phenytoin and phenobarbital) intotissue; this may account for part of the efficacy of acetazolamide asadd-on therapyTolerance to the effect of acetazolamide often develops, possiblyas a consequence of increased carbonic anhydrase production inglial cells

Efficacy profile:

The goal of treatment is complete remission of seizuresOnset of action may be rapid and usually within a few days

Tolerance to the effect of acetazolamide often develops within16 monthsDiscontinuation of treatment may re-establish efficacy, making

acetazolamide particularly appropriate for intermittent use, such

as in catamenial epilepsyAcetazolamide is used more commonly as an add-on antiepilepticdrug than as monotherapyIf acetazolamide is ineffective or only partial ly effective, it can be

replaced by or combined with another antiepileptic drug that isappropriate for the patients seizure type or epilepsy syndrome

PharmacokineticsAbsorption and distribution:

Oral bioavailability: >90%Food co-ingestion: neither delays the rate of absorption nor reducesthe extent of absorptionTmax: 24 hoursTime to steady state: 2 daysPharmacokinetics: linear


3

A

DRU

GINTERACTIONPROFILE

Protein binding: 9095% (90% of the drug in the body is bound totissue carbonic anhydrase)Volume of distribution: 0.3 L/kg for total concentration, 1.8 L/kg

for free concentrationSalivary concentrations: it is not known whether acetazolamide issecreted into saliva and whether such concentrations are similar tothe unbound levels seen in plasma

Metabolism:Acetazolamide is not metabolized

Elimination:

Half-life values in adults are 1015 hours

Renal excretion: 100% of an administered dose is excretedunchanged in urine

Drug interaction profilePharmacokinetic drug interactions:

Interactions between AEDs: effects on acetazolamide:To date, there have been no reports of AEDs affecting theclearance of acetazolamide and affecting acetazolamide plasmalevels

Interactions between AEDs: effects by acetazolamide:

Acetazolamide can increasecarbamazepine plasma levelsAcetazolamide can increasethe free fraction of phenytoinAcetazolamide can increase the tissue concentration of otherAEDs (e.g., phenytoin and phenobarbital)Acetazolamide can decreasethe absorption of primidone

Interactions between AEDs and non-AED drugs: effects onacetazolamide:

To date, there have been no reports of other non-AED drugs

affecting the clearance of acetazolamide and affecting acetazola-mide plasma levels

Interactions between AEDs and non-AED drugs: effects by

acetazolamide:Acetazolamide can increasecyclosporin plasma levelsAcetazolamide can decreaselithium plasma levels

Pharmacodynamic drug interactions:

It has been suggested that the efficacy of acetazolamide in thetreatment of seizures may be due in part to a pharmacodynamic

interaction with other antiepileptic drugsAcetazolamide prolongs the effects of amphetamines and quinidineAnorexia, tachypnea, lethargy, coma, and death have been reported in

patients receiving concomitant high-dose aspirin and acetazolamideAcetazolamide and sodium bicarbonate in combination increasethe risk of renal calculus formation


4

A

ACETAZOLAMIDE

Hormonal contraception:Acetazolamide does not enhance the metabolism of oral contra-

ceptives so as to decrease plasma levels of hormonal contraceptives

and, therefore, does not compromise contraception control

Adverse effectsHow drug causes adverse effects:

Carbonic anhydrase inhibition by acetazolamide is likely to be

the mechanism responsible for the clinical adverse effects, such asmetabolic acidosis, paresthesias, and kidney stones

Common adverse effects:Paresthesias, mostly tingling in the fingers and toes

DrowsinessAtaxia

Blurred visionFrequent urinationAlteration of taste (parageusia), especially for carbonated beverages

Metabolic acidosis (lowered serum bicarbonate or CO2)

Appetite suppressionGastrointestinal disturbances (nausea, vomiting, diarrhea)

Allergic rash

Life-threatening or dangerous adverse effects:Very rarely Stevens-Johnson syndrome, toxic epidermal necroly-sis, fulminant hepatic necrosisAgranulocytosis, aplastic anemia, and other blood dyscrasias

Rare and not life-threatening adverse effects:

Nephrolithiasis (secondary to decrease in urinary citrate)

Blood dyscrasiasVisual changes and transient myopiaTinnitusDepression

Loss of libido

Weight changeWeight loss can occur

What to do about adverse effects:

Discuss common and severe adverse effects with patients or parentsbefore starting medication, including symptoms that should bereported to the physicianDiscuss symptoms associated with kidney stones

Some CNS-related adverse effects may be lessened by slow titra-tion, but they may persist at low doses despite slow titration


5

A

DOSING

AND

USE

Metabolic acidosis is usually compensated, but patients may be treatedwith oral bicarbonate for CO

2values of 1518 mEq/L or less

If possible, acetazolamide should not be administered to patients on

topiramate, zonisamide, or on the ketogenic diet, because these treat-ments also predispose to metabolic acidosis and to kidney stonesPatients should be encouraged to drink liberally while on aceta-zolamideAnorexia and weight loss may improve with dosage reduction

Dosing and useUsual dosage range:

Adults and children over 12 years of age: 2501000 mg/day

Children under 12 years of age: 1020 mg/kg/dayCatamenial epilepsy: 830 mg/kg/day

Available formulations:Tablets: 125 mg, 250 mgExtended release capsule: 500 mg

Parenteral solution: 500 mg powder per vial (requires reconstitu-tion with at least 5 mL of sterile water)

How to dose: For adults and children over 12 years of age: start treatment with

250 mg/day, once or twice daily; at intervals of 37 days increaseas needed and as tolerated by 250 mg/day; maintenance dose gen-erally 250 1000 mg/day

Children under 12 years of age: start treatment with 36 mg/kg/day,once or twice daily; at intervals of 37 days increase as neededand as tolerated by 36 mg/kg/day; maintenance dose generally1020 mg/kg/day; doses of 2030 mg/kg/day may be necessaryand are well tolerated

Catamenial epilepsy: acetazolamide has been used in women withcatamenial epilepsy both continuously and intermittently duringthe days of identified seizure exacerbation; maintenance dose gen-erally 830 mg/kg/day, doses up to 1000 mg/day may be necessaryand are well tolerated

Dosing tips:Slow dose titration may delay onset of therapeutic action but

enhance tolerability to sedating effectsSome patients may do very well at relatively low doses of aceta-

zolamide, such as 500 mg/day in adults or 10 mg/kg/day in chil-dren; the response to treatment should be assessed at these dosesbefore increasing the dose furtherAcetazolamide may be most effective as add-on therapy and tol-erance may develop later when acetazolamide is given as adjuncttherapy


6

A

ACETAZOLAMIDE

When tolerance has developed, temporary withdrawal of aceta-zolamide usually restores the previous therapeutic effectIn patients with catamenial epilepsy, once an effective and well-

tolerated dose has been determined, this dose can be administeredduring the necessary number of days without gradual titration

How to withdraw drug:

May need to adjust dosage of concurrent medications as acetazola-mide is being discontinued, because plasma levels of other drugsmay change (see Pharmacokinetic drug interactions section)No data are available on potential for withdrawal seizures or symp-toms upon rapid discontinuation of acetazolamide; however, rapiddiscontinuation after chronic use may increase the risk of seizuresIf possible, taper dose over a period of 13 months

In patients receiving intermittent treatment for a few days, such asfor catamenial epilepsy, gradual tapering is usually not necessary

Overdose:To date, there have been no cases of overdose reported withacetazolamideSevere metabolic acidosis could develop, which can usually be cor-rected by the administration of bicarbonate

The stomach should be emptied immediately by lavage or by induc-tion of emesisHemodialysis removes acetazolamide from blood and, therefore,

serves as a useful procedure in cases of overdose

Tests and therapeutic drug monitoring:Serum bicarbonate (CO

2) can be measured before treatment and

then periodically, but it is not routine practice to do soOther routine laboratory testing is not necessary

Therapeutic drug monitoring:

Optimum seizure control in patients on monotherapy is mostlikely to occur at acetazolamide plasma concentrations of 1014mg/L (4563 mol/L)The conversion factor from mg/L to mol/L is 4.50 (i.e.,1 mg/L = 4.50 mol/L)The reference range of acetazolamide in plasma is considered tobe the same for children and adults, although no data are avail-able to support this clinical practiceThere are no data indicating the usefulness of monitoring aceta-

zolamide by use of saliva

Other warnings/precautions:Patients should be monitored careful ly for evidence of an allergic

rashPatients should be monitored carefully for evidence of kidney stones


7

A

SPECIALPOPULATIONS

In combination with carbamazepine or oxcarbazepine, there is anincreased risk of hyponatremia

Do not use:Use with caution in patients undergoing treatments that are associ-ated with an increase in risk of kidney stones, such as topiramate,zonisamide, and the ketogenic dietDo not use in patients with hyperchloremic acidosisDo not use in patients with cirrhosis because of the risk of severe

hyperammonemiaUse with caution in patients with a history of allergic rash toanother medicationA history of al lergic reaction to an antibiotic sulfonamide doesnot appear to be an absolute contraindication for the use ofacetazolamide, because there seems to be no specific cross-reactivityLong-term administration of acetazolamide is contraindicated in

patients with chronic noncongestive angle-closure glaucomaAcetazolamide should not be administered to patients receivinghigh-dose aspirin anorexia, tachypnea, lethargy, coma, anddeath have been reported to occurBecause of its tendency to cause potassium loss, acetazolamide is

contraindicated in Addison disease and adrenal insufficiency

Special populationsRenal impairment:

Acetazolamide is renally excreted, so the dose may need to belowered particularly in patients with a CrCl of < 60 mL/min; theclearance of unbound acetazolamide correlates with the creatinineclearance

Because acetazolamide can be removed by hemodialysis, patients

receiving hemodialysis may require supplemental doses of aceta-zolamide

Hepatic impairment:Acetazolamide is not metabolized and consequently dose adjust-ment will not be necessaryAcetazolamide can increase hyperammonemia in patients withliver failure; the mechanism is probably increased renal tubu-lar reabsorption of ammonium secondary to alkalinization of

urine

Children:Children have an increased metabolic capacity and consequentlyhigher doses on a mg/kg/day basis are usually required to achievethe equivalent therapeutic plasma levels seen in adults


8

A

ACETAZOLAMIDE

Age-specific higher incidence of adverse effects of acetazolamidein the pediatric age range has not been described

Elderly:Available data on the pharmacokinetics of acetazolamide in elderlypatients suggest that they have a higher unbound fraction in theplasmaThe renal clearance of unbound acetazolamide is significantlylower in the elderly, and correlates with the creatinine clearanceElderly patients are more susceptible to adverse effects and, there-

fore, tolerate lower doses betterBecause of an age-related reduction in renal and hepatic function,

lower acetazolamide doses may be appropriate

Invariably the elderly are prescribed drug therapies for concurrentcomorbidities and, therefore, the risk of pharmacokinetic interac-tions is high

Pregnancy:Specialist advice should be given to women who are of childbearingpotential; they should be informed about the teratogenicity of allantiepileptic drugs and the importance of avoiding an unplannedpregnancy; the antiepileptic drug treatment regimen should be

reviewed when a woman is planning to become pregnantRapid discontinuation of antiepileptic drugs should be avoided asthis may lead to breakthrough seizures, which could have seriousconsequences for the woman and the unborn childAcetazolamide is classified by the US Food and Drug Administration

as risk category C [some animal studies show adverse effects, nocontrolled studies in humans]Use in women of childbearing potential requires weighing poten-

tial benefits to the mother against the risks to the fetusUse with other antiepileptic drugs in combination may cause a higher

prevalence of teratogenic effects than acetazolamide monotherapyTaper drug if discontinuingSeizures, even mild seizures, may cause harm to the embryo/fetus

Data on the pharmacokinetic changes of acetazolamide duringpregnancy have not been identified

Breast feedingBreast milk: in a single case report of a mother taking 1000 mg/day

of acetazolamide while breast feeding, acetazolamide concentra-

tions in breast milk were 1.32.1 mg/L whereby plasma levels were5.26.4 mg/L. It was calculated that the infant ingested 0.6 mg/dayand the infants plasma levels were 0.20.6 mg/L.Breastfed infants: acetazolamide plasma levels c/o above case are

49% of maternal plasma levelsIf adverse effects are observed recommend bottle feed


9

A

ACETAZOLAMIDE,OVERALLROLE

The overall place of acetazolamide in the treatmentof epilepsyAcetazolamide is a relatively safe drug which can be used for long

periods without serious adverse effects. It is used more often as asecond line add-on therapy rather than as monotherapy and in somepatients dramatic effects have been observed, and a worthwhileeffect has been reported widely in many patients and in differingtypes of seizures.

Primary seizure types:Absence seizures

Partial seizures

Secondary seizure types:

Generalized tonicclonic seizuresMyoclonic seizures

Juvenile myoclonic epilepsyCatamenial epilepsy

Potential advantages:Broad spectrum of seizure protection

Rapid onset of action

Associated with few and minor pharmacokinetic interactionsFavorable adverse event profile with very rare serious adverse

effectsDoes not commonly exacerbate seizures

Potential disadvantages:Tolerance to the effect of acetazolamide often develops within

16 monthsPotential teratogen, but not more than most other antiepileptic drugs

Suggested readingChapron DJ, Sweeney KR, Feig PU, Kramer PA. Influence of

advanced age on the disposition of acetazolamide. British Journalof Clinical Pharmacology1985; 19: 363371.

Forsythe WI, Owens JR, Toothil l C. Effectiveness of acetazolamidein the treatment of carbamazepine-resistant epilepsy in children.Developmental Medicine and Child Neurology1981; 23: 761769.

Holowach J, Thurston DL. A clinical evaluation of acetazolamide

(Diamox) in the treatment of epilepsy in children. Journal ofPediatrics1958; 53: 160171.

Katayama F, Miura H, Takanashi S. Long-term effectiveness and sideeffects of acetazolamide as an adjunct to other anticonvulsantsin the treatment of refractory epilepsies. Brain and Development2002; 24: 150154.


10

A

ACETAZOLAMIDE

Lim LL, Foldvary N, Mascha E, Lee J. Acetazolamide in womenwith catamenial epilepsy. Epilepsia2001; 42: 746749.

Oles KS, Penry K, Cole DLW, Howard G. Use of acetazolamide as an

adjunct to carbamazepine in refractory partial seizures. Epilepsia1989; 30: 7478.

Reiss WG, Oles KS. Acetazolamide in the treatment of seizures.Annalsof Pharmacotherapy1996; 30: 514519.

Resor SR, Resor LD. Chronic acetazolamide monotherapy in the treat-ment of juvenile myoclonic epilepsy. Neurology1990; 40: 16771681.

Soderman P, Hartvig P, Fagerlund C. Acetazolamide excretion into breastmilk. British Journal of Clinical Pharmacology1984; 17: 599600.

Tawil R, Moxley RT, Griggs RC. Acetazolamide-induced nephro-lithiasis: implications for treatment of neuromuscular disorders.Neurology1993; 43: 11051106.

Vaziri ND, Saiki J, Barton CH, Rajudin M, Ness RL. Hemodialyzabilityof acetazolamide. South Medical Journal1980; 73: 422423.

Watson WA, Garrelts JC, Zinn PD, Garriott JC, McLemore TL,Clementi WA. Chronic acetazolamide intoxication. ClinicalToxicology1984; 22: 549563.


11

A

THERAPEUTICS

ACTH

Therapeutics

Chemical name and structure:Adrenocorticotropic hormone, ACTH, is a peptide consisting of 39amino acids in its natural form and 24 amino acids in its syntheticform. Its empirical formula is C

207H

308O

58N

56S,2AcOH,32H

20.

Brand names:Acortan

ACTHActhar

Acthelea

CortrosynSynacthen

Trofocortina

Generics available:

No

Licensed indications for epilepsy:

ACTH is not licensed for the treatment of epileptic seizures

Licensed indications for non-epilepsy conditions:Acute exacerbations of multiple sclerosisDiagnostic aid in adrenocortical insufficiency

Severe muscle weakness in myasthenia gravis

Nonlicensed use for epilepsy:Infantile spasms (West syndrome)Lennox-Gastaut syndrome

Myoclonic astatic epilepsy

Severe myoclonic epilepsy of infancy (Dravet syndrome)Acquired epileptic aphasia (Landau-Kleffner syndrome)Ohtahara syndromeRasmussen encephalitis



ACTH should not be considered as a standard antiepileptic treat-ment and should be used only for a restricted group of severeencephalopathic epilepsies as listed above

Mechanism of action:

ACTH stimulates the secretion of cortisol in the adrenal glandIs effective in patients with adrenal suppression


12

A

ACTH

Its effect on the brain and on epilepsy may be independent of ster-oid secretionACTH suppresses the expression of corticotrophin-releasing hor-

mone, a proconvulsant neuropeptide whose expression may beenhanced in patients with infanti le spasms

Efficacy profile:

The goal is elimination of spasms and suppression of the hyps-arrhythmic pattern on the EEGA response is often seen within the first few days of treatmentRelapse after full response and discontinuation of ACTH is notuncommonA second course of ACTH may again be effectiveIn case of lack of efficacy, partial efficacy, or relapse, consider othertreatments such as vigabatrin, valproic acid, topiramate, zonisamide,levetiracetam, a benzodiazepine, or vitamin B6

PharmacokineticsConventional pharmacokinetic parameters do not apply to ACTH

Absorption and distribution:

Because ACTH is inactivated in the gastrointestinal tract it mustbe administered parenterally by intramuscular injection

Metabolism:Although the precise metabolic fate of ACTH is not known, cir-

culating ACTH is probably enzymatically cleaved at the 1617lysine-arginine bond by the plasma-plasminogen system

Elimination:

Half-life values are considered to be ~ 15 minutes


Interactions between AEDs: effects on ACTH:To date, there have been no reports of AEDs affecting the clear-ance of ACTH and affecting ACTH plasma levels

Interactions between AEDs: effects by ACTH:

To date, there have been no reports of ACTH affecting theclearance of other AEDs and affecting their plasma levels

Interactions between AEDs and non-AED drugs: effects on ACTH:

To date, there have been no reports of other non-AED drugsaffecting the clearance of ACTH and affecting ACTH plasmalevels


13

A

ADVERSEEFFECTS

Interactions between AEDs and non-AED drugs: effects by ACTH:To date, there have been no reports of ACTH affecting the clear-ance of other non-AED drugs and affecting their plasma levels

Pharmacodynamic drug interactions:To date, none have been identified

Hormonal contraception:The effect of ACTH on hormonal contraception is unknown, but

ACTH is virtually never administered to women of childbearing age


Most adverse effects of ACTH are shared by steroids and are likelyto be related to the stimulation of cortisol secretion by the adrenalgland

Common adverse effects:

Irritability, at times severeCushingoid featuresHypertension

Hyperglycemia, glycosuriaElectrolyte imbalances

Life-threatening or dangerous adverse effects:Immunosuppression and possibly impaired function of polymor-

phonuclear leukocytesPneumonia, in particular pneumocystis pneumoniaeSepsis

Congestive heart failure

Rare and not life-threatening adverse effects:

Brain atrophyPeptic ulcer

Subaortic hypertrophic cardiomyopathyCataractsGlaucoma

Seizure exacerbation

Weight change:Weight gain is common, as part of the cushingoid features

What to do about adverse effects:Discuss common and severe adverse effects with parents before

starting medication, including symptoms that should be reportedto the physician


14

A

ACTH

Always start ACTH treatment in the hospitalACTH is contraindicated in the presence of serious bacterial or

viral infection such as tuberculosis, varicella, or cytomegalovirus

Prophylaxis of pneumocystis pneumonia with trimethoprim-sulfamethoxazole may be consideredElevated blood pressure may require treatment, initially mostly witha diuretic


The optimal dosage (calculated in IU/m 2body surface/day) andschedule have not been determinedThe highest dose is usually given at the onset, followed by a grad-

ual tapering until discontinuationThe initial dose used most commonly is 150 IU/m 2/day given intwo divided doses, with a range between 85 and 250 IU/m 2/day;this is given for 12 weeks and the dose is then tapered graduallyto achieve a total treatment duration of 46 weeks

Available formulations:Corticotropin (porcine pituitary extract, 39 amino acids, short-

acting)Gel 80 IU/mL 100 IU = 0.72 mgLyophylized powder 100 IU = 0.72 mg

Cosyntropin/Tetracosactrin (synthetic, 24 amino acids, short-acting)100 IU = 1.0 mg

Cosyntropin/Tetracosactrin (synthetic, 24 amino acids, long-acting)100 IU = 2.5 mg

How to dose:ACTH is administered intramuscularly as a treatment course for a

limited amount of time, usually a few weeksA typical (but not exclusive) dosage schedule would consist of a4-week course, with 150 IU/m2/day given in two divided doses for2 weeks, 30 IU/m2/day for 3 days, 15 IU/m2/day for 3 days, 10 IU/m2/day for 3 days, then 10 IU/m2every other day for three doses;other schedules may consist of a somewhat longer tapering period

Dosing tips:Treatment with ACTH is always initiated in the hospital for threemain reasons:

It is essential to undertake a baseline clinical and laboratory assess-ment of the patientEnables observation of early significant adverse effects


15

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DOSING

AND

USE

Allows the teaching of intramuscular administration to parentsand/or carers

How to withdraw drug:There is no need to adjust dosage of concurrent medications asACTH is being discontinued, because plasma levels of other drugsdo not change (see Pharmacokinetic drug interactions section)All schedules for the administration of ACTH consist of a limitedcourse with a predetermined withdrawal phaseACTH should never be stopped abruptly because it suppressesendogenous ACTH secretionThe purpose of the tapering phase is to gradually restore normal

endogenous ACTH secretionMonitoring of morning levels of cortisol may be useful during

withdrawal

Overdose:

Doses of ACTH greater than 250 IU/m 2/day are commonly asso-ciated with serious and at times fatal complications that do notdiffer from those described under the adverse effects section

Tests and therapeutic drug monitoring:

Before initiation of ACTH therapy:Place a PPD (purified protein derivative) skin test to rule outtuberculosisObtain chest x-ray in the presence of symptoms of respiratoryillnessDo not administer any immunization for 10 days before andduring treatment with ACTHVital signs, including blood pressurePhysical examination to exclude evidence of infection

Test urine for glucose and for evidence of urinary infectionTest stool for blood (guaiac)Blood for CBC (complete blood count), electrolytes, BUN(blood urea nitrogen), Cr, Ca, Mg, phosphateConsider baseline echocardiogram

During ACTH therapy:

Blood pressure daily for 1 week, then three times weekly untilACTH discontinuationTest urine for glucose twice weeklyTest stool for blood (guaiac)

Prescribe an H 2antagonist, especial ly if stool is guaiac positiveBlood for CBC, electrolytes, Cr, Ca, Mg, phosphate after24 weeksConsider follow-up echocardiogram after 24 weeks (hyper-trophic cardiomyopathy)Patient should be examined if fever develops


16

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ACTH

Other warnings/precautions:Patients should be monitored carefully for evidence of infection

ACTH may accentuate electrolyte loss associated with diuretic

therapy

Do not use:ACTH is contraindicated in the presence of serious bacterial or

viral infection such as tuberculosis, varicella, or cytomegalovirus


There is no evidence that renal impairment requires changes inACTH doses

Hepatic impairment:

There is no evidence that hepatic impairment requires changes inACTH doses

Children:ACTH for the treatment of epilepsy is used almost exclusively inchildren

Elderly:

It is very unlikely that ACTH would ever be used in elderlypatients for the treatment of seizures

Pregnancy:It is very unlikely that ACTH would ever be used in a pregnantpatient for the treatment of seizuresACTH is classified by the US Food and Drug Administration asrisk category C [some animal studies show adverse effects, no con-

trolled studies in humans]

Breast feeding

It is very unlikely that ACTH would ever be used in a nursingmother for the treatment of seizures

The overall place of ACTH in the treatment of epilepsyACTH is used for the treatment of infantile spasms (West syndrome),a condition consisting of infantile spasms, disturbed psychomotor

development and the characteristic EEG pattern of hypsarrhythmia.ACTH has an all or nothing effect and typically in 7075% of chil-dren total seizure suppression occurs. In those children that do notrespond to ACTH other medications should be considered includingvigabatrin, valproic acid, topiramate, zonisamide, levetiracetam, abenzodiazepine, or vitamin B6.


17

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ACTH,OVERALLROLE

Primary seizure types:Infantile spasms (West syndrome)

Secondary seizure types:Lennox-Gastaut syndromeMyoclonic astatic epilepsySevere myoclonic epilepsy of infancy (Dravet syndrome)

Acquired epileptic aphasia (Landau-Kleffner syndrome)Ohtahara syndrome

Rasmussen encephalitis

Potential advantages:

ACTH has the best documented evidence of efficacy in the treat-ment of infantile spasmsA single course of 46 weeks of ACTH treatment can have a long-

lasting or permanent anticonvulsant effect

Potential disadvantages:ACTH has several potentially serious or even life-threateningadverse effects

Suggested readingBaram TZ, Mitchell WG, Tournay A, Snead OC, Hanson RA,

Horton EJ . High-dose corticotropin (ACTH) versus prednisonefor infantile spasms: a prospective, randomized, blinded study.Pediatrics1996; 97: 375379.

Hrachovy RA, Frost JD, Kellaway P, Zion TE. Double-blind studyof ACTH vs prednisolone therapy in infantile spasms. Journal ofPediatrics1983; 103: 641645.

Kivity S, Lerman P, Ariel R, Danziger Y, Mimouni M, Shinnar

S. Long-term cognitive outcomes of a cohort of children withcryptogenic infantile spasms treated with high-dose adrenocor-ticotropic hormone. Epilepsia2004; 45: 255262.

Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR,Newton RW, OCallaghan FJ, Verity CM, Osborne JP; UnitedKingdom Infantile Spasms Study. The United Kingdom InfantileSpasms Study (UKISS) comparing hormone treatment with viga-batrin on developmental and epilepsy outcomes to age 14 months: amulticentre randomized trial. Lancet Neurology2005; 4: 712717.

Mackay MT, Weiss SK, Adams-Webber T, Ashwal S, Stephens D,

Ballaban-Gill K, Baram TZ, Duchowny M, Hirtz D, PellockJM, Shields WD, Shinnar S, Wyllie E, Snead OC III; AmericanAcademy of Neurology; Child Neurology Society. Practice param-eter: medical treatment of infantile spasms: report of the AmericanAcademy of Neurology and the Child Neurology Society. Neurology2004; 62: 16681681.


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ACTH

Maekawa K, Ohta H, Tamai I. Transient brain shrinkage in infantilespasms after ACTH treatment. Report of two cases. Neuropaediatrie1980; 11: 8084.

Tacke E, Kupferschmid C, Lang D. Hypertrophic cardiomyopathyduring ACTH treatment. Klinka Padiatrika1983; 195: 124128.

Vigevano F, Cilio MR. Vigabatrin versus ACTH as first-line treatmentfor infantile spasms: a randomized, prospective study. Epilepsia1997; 38: 12701274.


19

C

THERAPEUTICS

CARBAMAZEPINE

Therapeutics

Chemical name and structure:Carbamazepine, 5H-dibenz[b,f]azepine-5-carboxamide, is a whiteor yellowish-white, crystal line powder, with a molecular weight of236.27 and an empirical formula of C

15H

12N

2O.

Brand names:

Actebral; Actebral Retard; Actinerval; Amizepin; Apo-Carbama-zepine; AzepalBamgetol; Basitrol; Brucarcer

Carba; Carbagen SR; Carbatrol; Camapine; Carazepin; Carbabeta;Carbadac; Carbalex; Carbamazepin-B; Carbapsy; Carbatol; Carbatol

CR; Carbazene; Carbazep; Carbazina; Carmapine; Carmaz;Carmian; Carmine; Carpin; Carzepin; Carzepine; ClostedalDegranol

Elpenor; Epazin; Epazin; Epikor; Epileptol; Epileptol CR; EposalRetard; Espa-lepsinFinlepsinGericarb SRHermolepsin

Karbamazepin

Lepsitol

Neugeron; Neurolep; Neurotol; Neurotop; Neurotop Retard

PanitolSepibest; Sirtal; Stazepine

Taver; Tegol; Tegral; Tegretal; Tegretol; Tegretol CR; TegretolRetard; Temporol; Teril-CR; Timonil; Timonil Retard; TrepinaVulsivan

Zeptol CR


Licensed indications for epilepsy:Partia l and secondary generalized seizures (UK-SPC; FDA-PI)

Primary generalized tonicclonic seizures (UK-SPC; FDA-PI)

N

O NH2


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CARBAMAZEPINE

Licensed indications for non-epilepsy conditions:Trigeminal neuralgia (UK-SPC; FDA-PI)

Bipolar disorder unresponsive to lithium (UK-SPC)

Nonlicensed use for epilepsy:

There are none


Ineffective (contraindicated):Juvenile myoclonic epilepsy

Juvenile absence epilepsyEpileptic encephalopathies (e.g., Lennox-Gastaut syndrome)Neonatal and febrile seizures

Exaggerates myoclonic jerks, absences, and atonic seizures

Mechanism of action:Acts as a use-dependent blocker of voltage-sensitive sodiumchannelsInhibits L-type calcium channelsInhibits release of glutamate

Has a moderate anticholinergic action which is responsible forsome of its adverse effects

Efficacy profile:The goal of treatment is complete remission of seizuresContinue treatment until all symptoms are gone or until improve-

ment is stable and then continue treating indefinitely as long asimprovement persistsContinue treatment indefinitely to avoid recurrence of seizuresIf carbamazepine is ineffective or only partial ly effective, it can be

replaced by or combined with another antiepileptic drug that isappropriate for the patients seizure type or epilepsy syndrome


Oral bioavailability: 7585%Food co-ingestion: neither delays the rate of absorption nor reduces

the extent of absorption

Tmax: 29 hours (immediate release tablets); 17 hours (chewabletablets); 0.54 hours (liquid suspensions). Extended release formu-lations have prolonged Tmax valuesTime to steady state: 24 days (adults); 23 days (children)

Pharmacokinetics: nonlinear due to autoinductionProtein binding: 75%


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DRU

GINTERACTIONPROFILE

Volume of distr ibution: 0.82.0 L/kgSalivary concentrations: carbamazepine is secreted into saliva and

concentrations are similar to the unbound levels seen in plasma

Metabolism:Metabolized in the liver, primarily by CYP3A4 with some con-tribution by CYP2C8, to carbamazepine-10,11-epoxide, which ispharmacologically activeCarbamazepine-10,11-epoxide is in turn metabolized, by means of

epoxide hydrolase, to an inactive transcarbamazepine diolCarbamazepine undergoes autoinduction so that clearance canincrease three-fold within several weeks of starting therapy and

this often requires an upward dosage adjustment

Elimination:Following a single dose, half-li fe values in adults and children are1855 hours and 332 hours, respectivelyDuring maintenance carbamazepine monotherapy half-lifevalues in adults and children are 820 hours and 1013 hours,respectivelyIn the elderly carbamazepine half-life values are 3050 hoursHalf-life of carbamazepine-10,11-epoxide is ~34 hours

Renal excretion:


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CARBAMAZEPINE

metronidazole, nefazodone, propoxyphene, ritonavir, ticlopi-dine, trazodone, troleandomycin, verapamil, and viloxazine canincreasecarbamazepine plasma levels

Efavirenz, nevirapine, rifampicin, and St Johns wort can decreasecarbamazepine plasma levels

Interactions between AEDs and non-AED drugs: effects bycarbamazepine:

Carbamazepine can increaseplasma levels of verapamilCarbamazepine can decrease plasma levels of acetaminophen,albendazole, amiodarone, amitriptyline, benzodiazepines, bupro-pion, citalopram, clomipramine, clozipine, cortisol, cyclosporin,delavirdine, desipramine, dexamethasone, dicoumarol, doxepin,doxycycline, efavirenz, erythromycin, felodipine, fluphenazine,haloperidol, imipramine, indinavir, itraconazole, ketoconazole,mebendazole, methotrexate, methylprednisolone, mianserin,mirtazapine, nefazodone, nelfinavir, nevirapine, nimodipine,nivadipine, nortriptyline, olanzapine, omeprazole, paclitaxel,paroxetine, phenprocoumon, praziquantel, prednisolone, pro-triptyline, quetiapine, risperidone, ritonavir, saquinavir, sertra-line, teniposide, theophylline, thioridazine, vincristine, warfarin,zidovudine, and ziprasidone

Pharmacodynamic drug interactions:Co-medication with lamotrigine: neurotoxicity may present asheadache, nausea, diplopia, and ataxia this occurs in the absenceof any change in lamotrigine, carbamazepine, or carbamazepine-epoxide plasma levelsCo-medication with levetiracetam: neurotoxicity may present as

nystagmus, diplopia, ataxia, nausea, and vomiting this occursin the absence of any change in levetiracetam, carbamazepine, orcarbamazepine-epoxide plasma levels

Hormonal contraception:Carbamazepine enhances the metabolism of oral contraceptivesso as to decrease plasma levels of hormonal contraceptives and toreduce their effectiveness, leading to breakthrough bleeding andcontraceptive failure; medium- or high-dose oral contraceptivepreparations are indicated in patients taking carbamazepine


CNS adverse effects theoretically due to excessive actions at volt-age-sensitive sodium channelsMajor pharmacologically active metabolites (carbamazepine-10,11-epoxide) may be the cause of many adverse effectsMild anticholinergic effects may contribute to sedation and blurred

vision


23

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ADVERSEEFFECTS

Common adverse effects:Sedation, dizziness, confusion, unsteadiness, headache

Nausea, vomiting, diarrhea

Blurred visionBenign leukopenia (transient; in up to 10%)Hyponatremia, neutropeniaRash

Life-threatening or dangerous adverse effects:

Rare aplastic anemia, agranulocytosis (unusual bleeding or bruis-ing, mouth sores, infections, fever, sore throat)Rare severe dermatologic reactions (Stevens-Johnson syndrome)

Rare cardiac problems (e.g., bradycardia, arrhythmia, atrioven-

tricular block)Rare induction of psychosis or mania

SIADH (syndrome of inappropriate antidiuretic hormone secre-tion) with hyponatremiaIncreased frequency of generalized convulsions (in patients withatypical absence seizures)Vitamin K-deficient hemorrhagic disease in newborns of mothers

treated with carbamazepine; can be prevented by administration ofvitamin K to the mother before delivery

Rare and not life-threatening adverse effects:Aseptic meningitis accompanied by myoclonus and peripheral

eosinophiliaAnaphylactic reactionAngioneurotic edema

Osteomalacia/osteoporosisTaste disturbances

Arthralgia, muscle pain, muscle spasm

Weight changeNot usual; weight gain could be related to water retention, how-ever, increased appetite and increased weight without edema canalso occur

What to do about adverse effects:

Discuss common and severe adverse effects with patients or par-ents before starting medication, including symptoms that shouldbe reported to the physicianRisk of serious adverse effects is greatest in the first few months

of treatmentCNS-related adverse effects are usually dose-dependent, arereversible and are prevented by slow and upward titration follow-ing initiation of treatmentCommon adverse effects such as sedation often abate after a fewmonths


24

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CARBAMAZEPINE

Take with food or split dose to avoid gastrointestinal effectsSwitch to extended release carbamazepine because dosage fre-

quency as well as sedation, diplopia, confusion, and ataxia may

be reducedExtended release carbamazepine can be sprinkled on soft food



Children 612 years of age: 6001000 mg/dayChildren under 6 years of age: 3040 mg/kg/day

Available formulations:Tablets: 100 mg, 200 mg, 400 mg

Chewable tablets: 100 mg, 200 mgLiquid (oral suspension): 300 mL, 450 mL (100 mg/5 mL)

Suppositories: 125 mg, 250 mgExtended release tablets: 100 mg, 200 mg, 400 mgExtended release capsules: 200 mg, 300 mg

How to dose:

When initiating carbamazepine treatment start with a low doseand titrate slowly so as to minimize adverse effects. For adults and children over 12 years of age: start treatment with 200mg twice daily (tablet) or 1 teaspoon (100 mg) four times a day(suspension); each week increase by up to 200 mg/day in divideddoses (two doses for extended release formulation, threefourdoses for other tablets); maintenance dose generally 8001200 mg/day for adults; some patients may require up to 1600 mg/day.

Children 612 years old: start treatment with 100 mg/day twicedaily or 0.5 teaspoon (50 mg) four times a day (suspension) andincrease at weekly intervals in increments of 100 mg/day individed doses (two doses for extended release formulation, threefour doses for all other formulations); maximum dose generally1000 mg/day; maintenance dose generally 6001000 mg/day

Children under 6 years: start treatment with 510 mg/kg/day intwo or three divided doses for tablet formulations (four dosesfor suspension) and increase at weekly intervals in increments of510 mg/kg/day; maintenance dose of 30 mg/kg/day or moreis often required and dosage requirement increase two-fold in

children co-prescribed enzyme-inducing antiepileptic drugs

Dosing tips:Higher peak plasma levels occur with the suspension formulationthan with the same dose of the tablet formulation, so suspensionshould generally be started at a lower dose and titrated slowly


25

C

DOSING

AND

USE

Take carbamazepine with food to avoid gastrointestinal effectsSlow dose titration may delay onset of therapeutic action but

enhance tolerability to sedating effects

Should titrate slowly in the presence of other sedating agents,such as other antiepileptic drugs to best tolerate additive sedativeadverse effectsCan sometimes minimize the impact of carbamazepine upon the

bone marrow by dosing slowly and monitoring closely when ini-tiating treatment; initial trend to leukopenia/neutropenia mayreverse with continued conservative dosing over time and allowsubsequent dosage increases with careful monitoringCarbamazepine often requires a dosage adjustment upward with

time, as the drug induces its own metabolism, thus loweringits own plasma levels over the first several weeks to months oftreatmentDo not break or chew carbamazepine extended release tablets asthis will alter the controlled release propertiesGenerally higher doses of the extended release formulations arepossible (because of the reduction in diurnal changes in plasmacarbamazepine blood levels) resulting in better seizure control andreduced intermittent diurnal adverse effects

How to withdraw drug:May need to adjust dosage of concurrent medications as carba-mazepine is being discontinued, because plasma levels of otherdrugs may change (see Pharmacokinetic drug interactionssection)Rapid discontinuation may increase the risk of seizures

Overdose:

Can be fatal (lowest known fatal dose in adults is 3.2 g, inadolescents is 4 g, and in children is 1.6 g): symptoms include

nausea, vomiting, involuntary movements, urinary retention,trouble breathing, sedation, comaThe stomach should be emptied immediately by lavage or by

induction of emesisHemodialysis removes carbamazepine from blood and, therefore,serves as a useful procedure in cases of overdose


Before starting: blood count, liver, kidney, and thyroid function

testsDuring treatment: blood count every 2 weeks for 2 months, then

every 3 months throughout treatmentDuring treatment: liver, kidney, and thyroid function tests every612 months. Consider monitoring sodium levels because of pos-sibility of hyponatremia


26

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CARBAMAZEPINE

Therapeutic drug monitoring:Optimum seizure control in patients on monotherapy is mostlikely to occur at carbamazepine plasma concentrations of 412

mg/L (1751 mol/L)The conversion factor from mg/L to mol/L is 4.23 (i.e.,1 mg/L = 4.23 mol/L)Because children metabolize carbamazepine more rapidly,resulting in carbamazepine-10,11-epoxide levels approachingthose of carbamazepine, carbamazepine-10,11-epoxide makes agreater contribution to the pharmacological effects (both ben-eficial and toxic) of carbamazepine in children than in adultsThe upper boundary of the reference range for carbamazepine-10,11-epoxide is 9 mol/LThe conversion factor from mg to mol is 3.96 (i.e., 1 mg/L =3.96 mol/L)The reference range of carbamazepine in plasma is considered tobe the same for children and adults although no data are avail-able to support this clinical practiceCarbamazepine can be monitored by use of saliva, which is ameasure of the free nonprotein bound plasma concentration andthat is pharmacologically relevant

Other warnings/precautions:Patients should be monitored carefully for signs of unusual bleeding

or bruising, mouth sores, infections, fever, or sore throat, as the risk ofaplastic anemia and agranulocytosis with carbamazepine use is fiveeight times greater than in the general population (risk in the untreatedgeneral population is 6 patients per 1 million per year for agranulocy-tosis and 2 patients per 1 million per year for aplastic anemia)Because carbamazepine has a tr icyclic chemical structure, it is notrecommended to be taken with MAOIs, including 14 days afterMAOIs are stopped; do not start an MAOI until 2 weeks after

discontinuing carbamazepineMay exacerbate narrow angle-closure glaucoma

May need to restrict fluid intake because of risk of develop-ing syndrome of inappropriate antidiuretic hormone secretion,hyponatremia and its complicationsUse with caution in patients with mixed seizure disorders thatinclude atypical absence seizures because carbamazepine has beenassociated with increased frequency of generalized convulsions insuch patients

Do not use:If patient has a proven allergy to tricyclic compoundsIf patient has a proven allergy to carbamazepine, oxcarbazepine oreslicarbazepine acetateIf a patient has bone marrow suppressionIf a patient is taking an MAOI


27

C

SPECIALPOPULATIONS


Carbamazepine is renally secreted, therefore, the dose may need

to be loweredBecause carbamazepine can be removed by hemodialysis, patientsreceiving hemodialysis may require supplemental doses ofcarbamazepine

Hepatic impairment:

Carbamazepine is extensively metabolized in the liver and conse-quently lower doses may be required

Children:

Children have an increased metabolic capacity and consequentlyhigher doses on a mg/kg basis are usual ly required to achieve theequivalent therapeutic plasma levels seen in adultsPharmacokinetic interactions in children are usually of a greater

magnitude than that seen in adults

Elderly:

Elderly patients are more susceptible to adverse effects and, there-fore, tolerate lower doses betterBecause of an age-related reduction in renal and hepatic function,

lower carbamazepine doses are appropriateInvariably the elderly are prescribed drug therapies for concurrent

comorbidities and, therefore, the risk of pharmacokinetic interac-tions with carbamazepine is substantial

Pregnancy:Specialist advice should be given to women who are of childbearingpotential; they should be informed about the teratogenicity of allantiepileptic drugs and the importance of avoiding an unplanned

pregnancy; the antiepileptic drug treatment regimen should bereviewed when a woman is planning to become pregnantRapid discontinuation of antiepileptic drugs should be avoided asthis may lead to breakthrough seizures, which could have seriousconsequences for the woman and the unborn childCarbamazepine is classified by the US Food and Drug Administration

as risk category D [positive evidence of risk to human fetus; poten-tial benefits may still justify its use during pregnancy]Use during first trimester may raise risk of neural tube defects (e.g.,

spina bifida) or other congenital anomalies

Use in women of childbearing potential requires weighing poten-tial benefits to the mother against the risks to the fetusIf drug is continued, start on folate 1 mg/day early in pregnancy toreduce risk of neural tube defectsUse with other antiepileptic drugs in combination may cause a higherprevalence of teratogenic effects than carbamazepine monotherapy


28

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CARBAMAZEPINE

Taper drug if discontinuingVitamin K-deficient hemorrhagic disease in newborns of mothers

treated with carbamazepine; can be prevented by administration of

vitamin K to the mother before deliverySeizures, even mild seizures, may cause harm to the embryo/fetusData on the pharmacokinetic changes of carbamazepine during

pregnancy are conflicting; carbamazepine clearance can increaseby up to 20% during pregnancy, accompanied by a decrease inthe total plasma concentration of up to 42% and a 22% decreasein the free (nonprotein bound) concentration

Breast feedingBreast milk: carbamazepine: 1030% of maternal plasma levels;carbamazepine-10,11-epoxide: 50% of maternal plasma levelsBreastfed infants: carbamazepine plasma levels are 1020% ofmaternal plasma levelsIf drug is continued while breast feeding, infant should be moni-tored for possible adverse effects, including hematological effectsRecommend bottle feed particularly if infant shows signs of irri-

tability or sedationSome cases of neonatal seizures, respiratory depression, vomiting,

and diarrhea have been reported in infants whose mothers receivedcarbamazepine during pregnancy

The overall place of carbamazepine in the treatmentof epilepsyCarbamazepine is particularly effective for the treatment of focalepilepsies (idiopathic or symptomatic) with or without secondar-ily generalized tonicclonic seizures. It is also effective in primary

generalized tonicclonic seizures. Comparative studies show thatcarbamazepine is superior to other antiepileptic drugs (e.g., pheny-toin, phenobarbital and primidone) and of the newer antiepilepticdrugs only levetiracetam may have similar efficacy. However, car-bamazepine is ineffective in neonatal or febrile seizures and is con-traindicated and ineffective in idiopathic generalized epilepsies andepileptic encephalopathies.

Primary seizure types:

Focal epilepsies of any type (idiopathic or symptomatic) with orwithout secondarily generalized tonicclonic seizuresPrimary generalized tonicclonic seizures

Secondary seizure types:

None


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CARBAMA

ZEPINE,OVERALLROLE

Potential advantages:Carbamazepine is a particularly good antiepileptic drug for the

treatment of focal epilepsies of any type (idiopathic or symptomatic)

with or without secondarily generalized tonicclonic seizuresAlso effective in primary generalized tonicclonic seizuresIn numerous comparative studies, no other antiepileptic drugshowed better efficacy than carbamazepine in focal seizuresalthough some of the new antiepileptic drugs are better toleratedContrary to previous studies, a recent pregnancy register found

that the risk of teratogenicity is smal l monotherapy serious mal-formation rates are 2.3% versus 2.4% for no antiepileptic drug

Potential disadvantages:Idiosyncratic and other adverse effectsRequires frequent blood testing and close monitoring

Pharmacokinetics are not linear due to autoinductionAssociated with significant pharmacokinetic interactions and usu-

ally acts as an inducer of drug metabolismPotential teratogen, but not more than most other antiepilepticdrugs

Suggested readingCallaghan N, Kenny RA, ONeil B, Crowley M, Goggin T.

A prospective study between carbamazepine, phenytoin and sodiumvalproate as monotherapy in previously untreated and recentlydiagnosed patients with epilepsy.Journal of Neurology, Neurosurgery,and Psychiatry1985; 48: 639644.

Johannessen Landmark C, Patsalos PN. Drug interactions involving

the new second- and third-generation antiepileptic drugs. ExpertReviews in Neurotheropeutics2010; 10: 119140.

Mattson RH, Cramer JA, Collins JF. A comparison of valproatewith carbamazepine for the treatment of complex partia l seizuresand secondarily generalized tonic-clonic seizures in adults. TheDepartment of Veterans Affairs Epilepsy Cooperative Study. NewEngland Journal of Medicine1992; 327: 765771.

Patsalos PN, Berry DJ, Bourgeois BFD, Cloyd JC, Glauser TA,Johannessen SI, Leppik IE, Tomson T, Perucca E. Antiepilepticdrugs Best practice guidelines for therapeutic drug monitor-ing: a position paper by the Subcommission on TherapeuticDrug Monitoring, ILAE Commission on Therapeutic Strategies.Epilepsia2008; 49: 12391276.

Patsalos PN, Froscher W, Pisani F, van Rijn CM. The impor-tance of drug interactions in epilepsy therapy. Epilepsia 2002;43: 365385.


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CARBAMAZEPINE

Patsalos PN, Krishna S, Elyas AA, Lascelles PT. Carbamazepine andcarbamazepine-10,11-epoxide pharmacokinetics in an overdosepatient. Human Toxicology1987; 6: 241244.

Patsalos PN, Perucca E. Clinically important interactions in epi-lepsy: general features and interactions between antiepilepticdrugs. Lancet Neurology2003; 2: 347356.

Patsalos PN, Perucca E. Clinically important interactions in epi-lepsy: interactions between antiepileptic drugs and other drugs.Lancet Neurology2003; 2: 473481.

Rambeck B, Salke-Treumann A, May T, Boenigh HE. Valproic acidinduced carbamazepine-10,11-epoxide toxicity in children andadolescents. European Neurology1990; 30: 7983.

Sisodiya SM, Sander JWAS, Patsalos PN. Carbamazepine toxicityduring combination therapy with levetiracetam: a pharmacody-namic interaction. Epilepsy Research2002; 48: 217219.


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THERAPEUTICS

CLOBAZAM

Therapeutics

Chemical name and structure:Clobazam, 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione, is a white crystalline powder, with a molecular weight of300.74 and an empirical formula of C

16H

13Cl

2O

2.

Brand names:

AsabiumCastilium; Clarmyl; Clobamax; Clobazan; ClopaxFrisium

GrifoclobamKaridiumLucium

NoiafrenSederlona

Urbadan; Urbanil; Urbanol; Urbanyl

Generics available:

Yes


Adjunctive intermittent therapy of partial or generalized seizuresin patients > 3 years of age (UK-SPC)Nonconvulsive status epilepticus (UK-SPC)

Licensed indications for non-epilepsy conditions:

Anxiolytic (UK-SPC)

Nonlicensed use for epilepsy:Reading epilepsyFebrile seizures

Catamenial epilepsy

O

O

N

H

NCl


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CLOBAZAM

Lennox-Gastaut syndromeStartle epilepsy

Alcohol withdrawal seizures

Benign childhood partial epilepsies


Ineffective (contraindicated):Data on seizure contraindications are not available

Mechanism of action:Binds to benzodiazepine receptors at the GABA-A ligand-gated

chloride channel complexEnhances the inhibitory effects of GABABoosts chloride conductance through GABA-regulated channels

Efficacy profile:Clobazam is commonly combined with other antiepileptic drugs

for the treatment of seizuresThe goal of treatment is complete remission of seizures

Onset of action may occur within the first few daysContinue treatment until all symptoms are gone or until improve-ment is stable and then continue treating indefinitely as long asimprovement persistsContinue treatment indefinitely to avoid recurrence of seizures

If clobazam is ineffective or only partially effective, it can bereplaced by or combined with another antiepileptic drug that isappropriate for the patients seizure type or epilepsy syndrome


Oral bioavailability: > 95%Food co-ingestion: does not affect the extent of absorption butdoes slow the rate of absorptionTmax: 13 hoursTime to steady state: 27 days (710 days if the pharmacologically

active N-desmethylclobazam metabolite is included)Pharmacokinetics: linearProtein binding: 85%

Volume of distribution: 0.871.83 L/kgSalivary concentrations: clobazam and N-desmethylclobazam are

secreted into saliva and concentrations are similar to the unboundlevels seen in plasma

Metabolism:Metabolized in the liver, primarily by desmethylation, toN-desmethylclobazam which is pharmacologically active


33

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DRU

GINTERACTIONPROFILE

Clobazam also undergoes metabolism by hydroxylation to formother metabolites, namely 4-hydroxyclobazam and 4-hydroxydesmethylclobazam

The N-desmethylclobazam metabolite contributes significantly tothe efficacy of clobazamAutoinduction is not a feature of clobazam metabolism

Elimination:Elimination half-life values for clobazam in adults are 1030 hoursElimination half-life values for N-desmethylclobazam in adults are

3646 hoursIn children clobazam half-life values are ~16 hours

In the elderly clobazam half-li fe values are 3048 hours

Renal excretion: the excreted unchanged clobazam in urine isinsignificant


Interactions between AEDs: effects on clobazam:

Carbamazepine, phenobarbital, phenytoin, and primidone can

increase the clearance of clobazam and decreaseclobazam plasmalevels; concurrently N-desmethylclobazam plasma levels are alsoincreasedFelbamate can decrease the clearance of clobazam and increaseclobazam plasma levels; concurrently N-desmethylclobazamplasma levels are also increasedStiripentol can decrease the clearance of clobazam and, morepotently, of N-desmethylclobazam and it increases clobazamplasma levels and N-desmethylclobazam plasma levels several-fold

Interactions between AEDs: effects by clobazam:Clobazam can increaseplasma levels of phenytoin, primidone,and valproic acid

Interactions between AEDs and non-AED drugs: effects onclobazam:

Cimetidine can increaseclobazam plasma levels but has no effecton N-desmethylclobazam plasma levels

Interactions between AEDs and non-AED drugs: effects byclobazam:

To date, there have been no reports of clobazam affecting the clearance of other non-AED drugs and affecting their plasmalevels

Pharmacodynamic drug interactions:

Clobazam can potentiate the effects of CNS depressants such asalcohol, barbiturates, and neuroleptics


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CLOBAZAM

Hormonal contraception:Clobazam does not enhance the metabolism of oral contraceptives

so as to decrease plasma levels of hormonal contraceptives and,

therefore, does not compromise contraception control


Same mechanism for adverse effects as for therapeutic effects namely due to excessive actions at benzodiazepine receptorsLong-term adaptations in benzodiazepine receptors may explainthe development of dependence, tolerance, and withdrawalAdverse effects are generally immediate, but immediate adverseeffects often disappear in timeMajor metabolite (N-desmethylclobazam) may contribute to the

observed adverse effects

Common adverse effects:

Sedation (sometimes intolerably severe)Drowsiness, fatigue

Hyposalivation, dryness of mouthLoss of appetite, constipationBehavioral and cognitive impairment

Restlessness, aggressiveness, coordination disturbancesSevere aggressive outbursts, hyperactivit y, insomnia, and depres-sion with suicidal ideation may occur, particularly in childrenPhysical dependence characterized by a withdrawal syndromewhen the drug is withdrawn physical dependence develops morerapidly with larger doses

Life-threatening or dangerous adverse effects:

Withdrawal syndrome in chronic use

Respiratory depression, especially at high doses and when taken

with CNS depressants in overdose

Rare and not life-threatening adverse effects:Amnesia accompanied by inappropriate behavior

Hallucination, nightmareUnsteadiness of gait

NystagmusLoss of libido

Weight change:Not common

What to do about adverse effects:Discuss common and severe adverse effects with patients or par-

ents before starting medication, including symptoms that shouldbe reported to the physician


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DOSING

AND

USE

Lower the doseSomnolence may be partly prevented by administering the drug in

small doses 1 hour before sleep



Children under 12 years of age: 0.40.8 mg/kg/day

Available formulations:

Tablets: 10 mgCapsules: 10 mg

How to dose:When initiating clobazam treatment start with a low dose and

titrate slowly so as to minimize adverse effects. For adults and children over 12 years of age: start treatment with510 mg/day at night and increase at weekly intervals in incre-ments of 5 mg/day up to a total of 40 mg/day

Children under 12 years of age: start treatment with 0.10.2 mg/kg/day and slowly increase in weekly intervals in increments of

0.1 mg/kg/day up to a total of 0.8 mg/kg/day

Dosing tips:Administer as adjunctive therapy in all drug-resistant epilepsies at a

dose of 2030 mg nocte half this dose in children < 5 years oldTwice a day dosing is fine smaller dose should be ingested in theday with the larger dose just before sleepTolerance may develop but more than a third of patients do notdevelop tolerance

When clobazam is effective, most patients continue to benefit for

years without drug dependence or unwanted adverse effects

How to withdraw drug:May need to adjust dosage of concurrent medications as clobazam

is being discontinued, because plasma levels of other drugs maychange (see Pharmacokinetic drug interactions section)Withdrawal should be very slow, occurring over 46 months

Rapid discontinuation often leads to withdrawal symptoms,seizures and status epilepticus

Overdose:To date, there have been no cases of overdose reported with

clobazamThe stomach should be emptied immediately by lavage or byinduction of emesis


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CLOBAZAM

Treatment of overdose consists of supportive care and the adminis-tration of the benzodiazepine receptor antagonist flumazenilIt is not known whether hemodialysis removes clobazam from

blood and, therefore, would serve as a useful procedure in casesof overdose


During treatment: periodic liver tests and blood counts may beprudentTherapeutic drug monitoring:

Optimum seizure control in patients on monotherapy ismost likely to occur at clobazam plasma concentrations of

0.030.30 mg/L (0.11.0 mol/L)The conversion factor from mg/L to mol/L is 3.33 (i.e.,1 mg/L = 3.33 mol/L)The reference range for N-desmethylclobazam is 0.303.00mg/L (110 mol/L)The conversion factor from mg/L to mol/L is 3.49 (i.e., 1 mg/L= 3.49 mol/L)The reference ranges of clobazam and N-desmethylclobazam inplasma are considered to be the same for children and adultsalthough no data are available to support this clinical practice

Clobazam and N-desmethylclobazam can be monitored by useof saliva which is a measure of the free nonprotein bound plasmaconcentration and that is pharmacological ly relevant

Other warnings/precautions:

Use with caution in patients with pulmonary disease; rare reportsof death after initiation of benzodiazepines in patients with severepulmonary impairmentUse only with extreme caution if patient has obstructive sleep apnea

Some depressed patients may experience a worsening of suicidal

ideationSome patients may exhibit abnormal thinking or behavioralchanges similar to those caused by other CNS depressants (i.e.,either depressant actions or disinhibiting actions)Clobazam is a Schedule IV drug and the risk of dependence mayincrease with dose and duration of treatment

Do not use:

If patient has respiratory depression

If patient has acute pulmonary insufficiencyIf patient has sleep apnea syndromeIf patient has marked neuromuscular respiratory weakness, includ-ing unstable myasthenia gravisIf patient has severe liver diseaseIf there is a proven allergy to clobazam or any other benzodiazepine


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SPECIALPOPULATIONS


Clobazam is renally secreted, so the dose may need to be lowered

Hepatic impairment:Clobazam is extensively metabolized in the liver and consequentlylower doses may be required

Children:

Children have an increased metabolic capacity and consequentlyhigher doses on a mg/kg basis are usual ly required to achieve theequivalent therapeutic plasma levels seen in adults

Pharmacokinetic interactions in children are usually of a greater

magnitude than that seen in adults

Elderly:Elderly patients are more susceptible to adverse effects and, there-

fore, tolerate lower doses betterBecause of an age-related reduction in renal and hepatic function,

lower clobazam doses are appropriateInvariably the elderly are prescribed drug therapies for concurrentcomorbidities and, therefore, the risk of pharmacokinetic interac-

tions with clobazam is moderate

Pregnancy:

Specialist advice should be given to women who are of childbearingpotential; they should be informed about the teratogenicity of allantiepileptic drugs and the importance of avoiding an unplannedpregnancy; the antiepileptic drug treatment regimen should bereviewed when a woman is planning to become pregnantRapid discontinuation of antiepileptic drugs should be avoided as

this may lead to breakthrough seizures, which could have seriousconsequences for the woman and the unborn childThe risk category for clobazam has yet to be classified by the USFood and Drug Administration. However, it is likely to be in riskcategory D [positive evidence of risk to human fetus; potentialbenefits may stil l justify its use during pregnancy]Possible increased risk of birth defects when benzodiazepines aretaken during pregnancyInfants whose mothers received a benzodiazepine late in preg-

nancy may experience withdrawal effects

Neonatal flaccidity has been reported in infants whose motherstook a benzodiazepine during pregnancyUse in women of childbearing potential requires weighing poten-tial benefits to the mother against the risks to the fetusIf drug is continued, start on folate 1 mg/day early in pregnancy toreduce risk of neural tube defects


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CLOBAZAM

Use with other antiepileptic drugs in combination may cause a higherprevalence of teratogenic effects than clobazam monotherapyTaper drug if discontinuing

Seizures, even mild seizures, may cause harm to the embryo/fetusData on the pharmacokinetic changes of clobazam during preg-nancy have not been identified

Breast feedingBreast milk: clobazam plus N-desmethylclobazam: 1336% ofmaternal plasma levelsBreastfed infants: it is not known what plasma clobazam andN-desmethylclobazam concentrations are achieved in breastfedinfants compared with the levels of their mothers

If drug is continued while breast feeding, infant should be moni-tored for possible adverse effects, including sedation and poorsucklingRecommend bottle feed particularly if infant shows signs of

sedation

The overall place of clobazam in the treatmentof epilepsyClobazam should be tried as adjunctive medication in all drug-resist-ant epilepsies although it is less effective in symptomatic than in focalepilepsies. It is much less effective than clonazepam in myoclonicjerks and absences. Probably only 1 of 10 patients wil l have a clini-cally significant improvement, but this may be very dramatic andrender the patient seizure-free. Clobazam has comparable effective-ness to carbamazepine and phenytoin as first-line monotherapy inchildren with newly diagnosed partial epilepsy.

Primary seizure types:

All drug-resistant epilepsies

Secondary seizure types:Reading epilepsy

Febrile seizuresCatamenial epilepsyLennox-Gastaut syndrome

Startle epilepsyAlcohol withdrawal seizures

Benign childhood partial epilepsies

Potential advantages:

Although tolerance may develop, more than 30% of patients donot develop toleranceWhen clobazam is effective, most patients continue to benefit foryears without drug dependence or unwanted adverse effects


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CLO

BAZAM,OVERALLROLE

Some patients (20%) experience dramatic seizure reduction andeven become seizure-free

Potential disadvantages:SedationDevelopment of toleranceAssociated with significant pharmacokinetic interactions and usu-

ally its metabolism is induced or inhibitedPotential teratogen, but not more than most other antiepileptic drugs

Suggested readingAnonymous. Clobazam has equivalent efficacy to carbamazepine and

phenytoin as monotherapy for childhood epilepsy: Canadian StudyGroup for Childhood Epilepsy. Epilepsia1998; 39: 952959.

Conry JA, Ng YT, Paolicchi JM, Kernitsky L, Mitchell WG, RitterFJ, Collins SD, Tracy K, Kormany WN, Abdulnabi R, Riley B,Stolle J. Clobazam in the treatment of Lennox-Gastaut syn-drome. Epilepsia2009; 50: 11581166.

Feely M, Gibson J. Intermittent clobazam for catamenial epi-lepsy: tolerance avoided. Journal of Neurology, Neurosurgery, andPsychiatry1984; 47: 12791282.

Kinoshita M, Ikeda A, Begum T, Terada K, Shibashaki H. Efficacyof low-dose, add-on therapy of clobazam (CLB) is produced byits major metabolite, N-desmethyl-CLB. Journal of NeurologicalSciences2007; 263: 4448.

Mechndiratta MM, Krishnamurthy M, Rajesh KN, Singh G.Clobazam monotherapy in drug nave adult patients with epi-lepsy. Seizure2003; 12: 226228.

Ng YT, Collins SD. Clobazam. Neurotherapeutics2007; 4: 138144.Patsalos PN. Anti-epileptic drug interactions. A clinical guide. Clarius

Press, Guildford, UK; 2005.

Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: phar-macology and pharmacokinetics. Acta Neurologica Scandinavica2008; 118: 6986.

Sennoune S, Mesdjian E, Bonneton J, Genton P, Dravet C, Roger J.Interactions between clobazam and standard antiepileptic drugsin patients with epilepsy. Therapeutic Drug Monitoring 1992;14: 269274.

Silva RC, Montenegro MA, Guerreiro CA, Guerreiro MM. Clobazamas add-on therapy in children with epileptic encephalopathy.

Canadian Journal of Neurological Sciences2006; 33: 209213.


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CLONAZEPAM

CLONAZEPAM

Therapeutics

Chemical name and structure:Clonazepam, 5-(2-chlorophenol)-1,3-dihydro-7-nitro-2H-1,4 benzo-diazepin-2-one, is a light yellow crystalline powder, with a molecularweight of 315.71 and an empirical formula of C

15H

10ClN

3O

3.

Brand names:Amotril; Antelepsin

Clonapilep; Clonatryl; Clonazepamum; Clonex; Clonopam; Clozer;CoquanIktorivil

Kenoket; Klonopin; KriadexLansden; LonazepNeuryl

Paxam; PovanilRavotril; Riklona; Rivatril; Rivotril

Zepanc; Zymanta



Absence seizures (UK-SPC, FDA-PI)Akinetic seizures (UK-SPC, FDA-PI)

Atonic seizures (UK-SPC)Lennox-Gastaut syndrome (UK-SPC, FDA-PI)Myoclonic seizures (UK-SPC, FDA-PI)

Status epilepticus (UK-SPC)

Licensed indications for non-epilepsy conditions:

There are none

Nonlicensed use for epilepsy:

Acquired epileptic aphasia (Landau-Kleffner syndrome)

NO2

O

Cl

N

N

H


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PHARMACOKINETICS

Infantile spasms (West syndrome)Neonatal seizures



Because of its sedation, problems during withdrawal, and hyper-salivation, clonazepam is not indicated as first-line therapy for anytype of seizuresTonic status epilepticus can be worsened by clonazepamGeneralized tonicclonic seizures can be exacerbated by clonazepam

Mechanism of action:Binds to benzodiazepine receptors at the GABA

A ligand-gated

chloride channel complexEnhances the inhibitory effects of GABABoosts chloride conductance through GABA-regulated channels

Efficacy profile:

Clonazepam is commonly combined with other antiepilepticdrugs for the treatment of seizures and usually only when better-tolerated adjunctive antiepileptic drugs have not been helpfulThe goal of treatment is complete remission of seizuresOnset of action may occur within the first few days

Effective against partial and generalized seizures: especial ly absenceand myoclonic seizuresEffective in the treatment of convulsive or nonconvulsive status

epilepticus, although its use as a second-line drug has been super-seded in many centers by diazepam, midazolam, and lorazepamContinue treatment until all symptoms are gone or until improve-

ment is stable and then continue treating indefinitely as long as

improvement persistsContinue treatment indefinitely to avoid recurrence of seizuresIf clonazepam is ineffective or only partially effective, it can bereplaced by or combined with another antiepileptic drug that isappropriate for the patients seizure type or epilepsy syndrome


Oral bioavailability: > 80%

Food co-ingestion: it is not known whether food co-ingestiondelays the rate of absorption or the extent of absorptionTmax: 14 hours (adults); 23 hours (children)Time to steady state: 210 days (adults); 57 days (children)Pharmacokinetics: linear

Protein binding: 86%

5/24/2018 The Epilepsy Prescriber's Guide to

the epilepsy prescriber's guide to antiepileptic drugs 2010

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