JAMA-Thenewantiepilepticdrugs

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CLINICIANS CORNERSCIENTIFIC REVIEW

AND CLINICAL APPLICATIONS

The New Antiepileptic DrugsScientific ReviewSuzette M. LaRoche, MD

Sandra L. Helmers, MD

EPILEPSY IS DEFINED AS A CHRONIC

neurological condition charac-terized by recurrent, unpro-voked seizures.1 It is one of the

mostcommon serious neurological dis-orders in the United States and often re-

quires long-term management.Eachyear150000 people in the United States arenewly diagnosed as having epilepsy, withthe cumulative lifetime incidence ap-proaching 3%.2,3 The incidence is high-est during the first year of life and in el-derly persons.2 Although most peoplewith epilepsy become seizure-free withappropriate therapy, 30% to 40% of pa-tients will continue to have seizures de-spite the useof antiepilepticdrugs eitheralone or in combination.4 Patients withuncontrolled seizures experiencesignifi-

cant morbidity andmortality andfaceso-cial stigma and discrimination as well.In the United States, only 17% of pa-

tients with new-onset epilepsy are ini-tially seen by a neurologist.5 Further-more, primary care physicians provideapproximately 40% of the long-termmanagement of epilepsy patients with orwithout initial consultation with a spe-cialist.6 Unfortunately, a survey of gen-eralpractitionersrevealed thatonly 40%of responders felt confident in theirknowledge of epilepsy and two thirdswere unfamiliar with the new antiepi-leptic drugs.7 A recent survey of 71 pa-tients with epilepsy who are treated ex-clusively by general practitioners showed

that 45% had experienced a seizurewithin thepast year,68% complained ofdrowsiness or difficulty in concentra-tion with their current medications, and28% were prescribed polytherapy.8

Therefore, general practitionersplaya vi-tal role in the treatment of epilepsy pa-

tients with ongoing seizures.Prior to 1993, the choice of an anti-convulsant medication was limited tophenobarbital, primidone, phenytoin,carbamazepine, and valproate. Al-though these traditional anticonvul-sants have the advantage of familiarityas well as proven efficacy, many pa-tients are left with refractory seizures as

well as intolerable adverse effects. Since1993, 8 new medications have been ap-proved by the US Food and Drug Ad-ministration (FDA), expanding treat-ment options (TABLE 1). The newerantiepilepticdrugsofferthe potentialad-vantages of fewer drug interactions,

unique mechanisms of action, and abroader spectrum of activity. With moreoptions, however, comes the challenge

AuthorAffiliations: Department of Neurology, EmoryUniversity (DrsLaRoche andHelmers), andAtlantaVAMedical Center (Dr LaRoche), Atlanta, Ga.Corresponding Author and Reprints: Suzette M.LaRoche, MD,EmoryClinic, Bldg A, 1365 CliftonRd,Atlanta, GA 30322 (e-mail: [email protected]).

Context The past decade has brought many advances to the treatment of epilepsy,including many new pharmacological agents. Primary care physicians often care for pa-tients with epilepsy and therefore should be familiar with the new options available.

Objective To review data regarding the efficacy and tolerability of antiepileptic drugsintroduced in the past decade.

Data Sources A search of the Cochrane Central Register of Controlled Trials wasperformed to identify all published human and English-language randomized con-trolled trials evaluating the efficacy and tolerability of the antiepileptic drugs that havebeen approved for use in the United States since 1990. Additional reports evaluating

pharmacokinetic properties were identified through a MEDLINE search as well as re-view of article bibliographies.

Study Selection and Data Extraction Search terms included felbamate, gaba-pentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonis-amide. Studies were selected if efficacy and tolerability were reported as major out-come measures. Included studies (n=55) enrolled a minimum of 20 adult subjects andhad a treatment period of at least 6 weeks.

Data Synthesis Eight newantiepileptic drugs have been approved foruse in theUnitedStates in the past decade. Each new antiepileptic drug is well tolerated and demonstratesstatistically significant reductions in seizure frequency over baseline. No randomized con-trolled trials have compared the new antiepileptic drugs with each other or against thetraditional antiepileptic drugs. Although there is no evidence to suggest that the newermedications are more efficacious, several studies have demonstrated broader spectrumof activity, fewer drug interactions, and overall better tolerability of the new agents.

Conclusions New antiepileptic drugs offer many options in the treatment of epi-lepsy, each with unique mechanisms of action as well as adverse effect profiles. Thenew antiepileptic drugs are well tolerated with few adverse effects, minimal drug in-teractions, and a broad spectrum of activity.

JAMA. 2004;291:605-614 www.jama.com

See also p 615 and Patient Page.

CME available online atwww.jama.com

2004 American Medical Association. All rights reserved. (Reprinted) JAMA, February 4, 2004Vol 291, No. 5 605


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of determining what role the new anti-epileptic drugs play in optimizing treat-ment in addition to understanding im-portant adverse effects and druginteractions of these increasingly pre-

scribed medications.Thepurpose of thisarticle is to familiarize primary care cli-nicians withtheefficacy,tolerability,andpharmacokinetic properties of the newantiepileptic drugs.

METHODS

We searched the Cochrane Central Reg-ister of Controlled Trials to identify allpub l i shed hum an and Eng l i sh-language randomized controlled clini-cal trials evaluating the efficacy and tol-erability of antiepileptic drugsthat have

been FDA approved since 1990. Addi-tional reports evaluating pharmacoki-netic properties wereidentified througha MEDLINE search as well as review ofarticle bibliographies. Search terms in-cluded felbamate , gabapentin , la -motrigine, topiramate, tiagabine, leveti-racetam, oxcarbazepine,and zonisamide.Studies were selected if efficacy andtol-erability were reported as major out-come measures. Included studies(n= 55) enrolleda minimum of 20 adultsubjects and had a treatment period of

at least 6 weeks.The majority of the new antiepilep-tic drugs gained initial FDA approvalbased on randomized, double-blind,placebo-controlled clinical trials inwhich the new antiepileptic drug wasused as adjunctive treatment. Typi-cally, trials enrolledpatients with refrac-tory partial-onset seizures to receive

eitherthe study drug or placebo in addi-tion to their original medication(s).Patients were followed up for 6 to 8weeksto establisha baselineseizure fre-quency, then randomly assigned to

either placebo or study drug and fol-lowed up for 8 to 12 weeks while sei-zure frequency and tolerability weremonitored.The primary outcomemea-sure was a reduction in seizure fre-quency over baseline compared withplacebo. A responder rateis reportedas the numberof patients whoachieveda 50% or greater reduction in seizurefrequency from baseline.

There are obvious limitations to thistrial design. Efficacy is often underes-timated and responder rates are typi-

cally less than 50% because the studypopulation with refractory seizures hastypically not responded to multiple an-tiepileptic drugs and is therefore notcomparableto patientsin a typical clini-cal practice. Toxicity is often overesti-mated because adverse effects may beadditive and not specifically due to theadd-on therapy. In addition, many ofthe new antiepileptic drugs were ti-trated morerapidly during clinical trialsthan is currently recommended, fur-ther overestimating the risk of toxic-

ity and adverse effects. Finally, the vari-ability in study groups and trial designsmakes direct comparisons among trialsimpossible. Despite these drawbacks,adjunctive clinical trials are overall thesafest and most ethical means of test-ing new antiepileptic compounds.

Few of the new antiepileptic drugshave been evaluated in monotherapy

trials and fewer yet have been FDA ap-proved for useas monotherapy.This pre-sents a dilemma that has led to frequentoff-label use because monotherapy of-fers many advantages over poly-therapy, including fewer adverse ef-

fects, less drug interactions, lower cost,and improved compliance. The reasonfor fewer monotherapy approvals stemsfrom the difficulty in trial design. Thereare 2 common approaches to mono-therapy trials. An active-control com-parison typically randomly assignspatients with new-onset seizures to re-ceive either the study drug or a well-established antiepileptic drug at lowtherapeuticdoses.Conversion to mono-therapy trials assigns patients to be con-verted from their current antiepilepticdrug(s) to either a subtherapeutic dose

of the test drug (referred to as pseudo-placebo)or a higher doseof the test drugthat is thought to be efficacious. Effi-cacy is measured as completion rate ormean time to exiting the study.Exit cri-teria consist of either an increase in sei-zure frequency above baseline, a pro-longed generalized seizure, or statusepilepticus. In addition, the percentageof patients discontinuing due to ad-verse effectsis reported. Agentsthatshowefficacy in placebo-controlled trials areconsidered acceptable proof of efficacy

for FDAapproval;however, thistrial de-sign raises obvious ethical concerns. Todemonstrate efficacy in active-controlcomparison trials, the study drug mustshow superiorityover thecontroland notmerely equivalency.9

RESULTS

Felbamate

Felbamate was the first new antiepilep-ticdrug to gain FDAapproval (in1993)andits introduction was met with muchenthusiasm and initial success. It is a

broad-spectrumagentapprovedfor bothmonotherapy and adjunctive treatmentof partial-onset seizures in adults as wellas partial- and generalized-onset sei-zures associated with Lennox-Gastautsyndrome (LGS) in children.10,11 Sev-eral mechanisms of action have beenidentified, including sodium channelblockade,calciumchannelblockade, and

Table 1. Antiepileptic Drugs Approved Since 1993*

Antiepileptic DrugYear

ApprovedApproved

Patient Age, yApproved forMonotherapy

Approvedfor PartialSeizures

Approved forGeneralized

Seizures

Felbamate (Felbatol) 1993 2

Gabapentin (Neurontin) 1993 3

Lamotrigine (Lamictal) 1994 2

Topiramate (Topamax) 1996 2

Tiaga bine (Gabatri l) 1997 12

Levetiracetam (Keppra) 1999 16

Oxcarbazepine (Trileptal) 2000 4

Zonisamide (Zonegran) 2000 16

*Approved for use by the US Food and Drug Administration.Not indicated as first-line antiepileptic treatment.

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antagonism ofN-methyl-D-aspartate(NMDA) and -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA) receptors (FIGURE).12-15 Theef-ficacy of felbamateas adjunctive therapyfor partialseizures hasbeen evaluated in

2 outpatient crossover trials.

16,17

Thesmaller trial enrolled 30 patients andfound no significant decrease in seizurefrequency during the felbamate treat-ment period, while there was a 23% de-creasein seizurefrequencyina larger trialof 67 patients (P=.02).

Felbamate has also shown efficacy asmonotherapy in 2 trials that com-pared felbamate, 3600 mg/d, with low-dose valproate.18,19 A total of 138 pa-tients were randomized, andthere weresignificantly higher completion rates inboth felbamategroups (60% vs 22% and

86% vs 10%, P.01). More impor-tantly, felbamate has shown great suc-cess in the treatment of LGS, a child-hood-onset epilepsy consisting of severecognitive dysfunction accompanied byseizuresof many types, including atonicseizures (drop attacks), which are no-toriously treatmentresistant. Two stud-ies support the efficacy of felbamate asadd-on therapy in adultswith LGS, withresponder rates up to 50% and a de-crease in drop attacks of 30%.20,21

Themost commonly documented ad-

verse effects withfelbamate include gas-trointestinaldisturbances,anorexia, andinsomnia.18,19 Unfortunately, a year af-ter FDA approval, reports of rare idio-syncratic reactions began to emerge.Aplastic anemia hasbeen reported in 34cases with an incidence of approxi-mately 1 in 8000 patient exposures.22,23

Hepatotoxicity was also reported at aslightly lower incidence of 1 in 10000,which parallels the risk with valproatetherapy.22 Felbamateremains onthemar-ket but with a black box warning for

aplastic anemia and hepatic failure andiscurrentlynot considered a first-linean-ticonvulsant medication. However, fel-bamate can still be useful for patientswith LGS or partial-onset seizures re-fractoryto other antiepileptic drugs, butit is recommended to obtain informedconsent and monitor hematologic func-tion frequently.

Gabapentin

Gabapentinwasapprovedforusein1993and is currently indicated as adjunctivetherapy for partial seizures with andwithout secondarygeneralization in per-sons 3 years and older.10 Interestingly,

more than 80%of prescriptions forgaba-pentin arefor off-label uses such as neu-ropathic pain, migraineheadache, spas-ticity, and bipolar disorder.24 Althoughstructurally related to -aminobutyricacid (GABA), its precise mechanism ofaction in humans is unknown (Figure).25

Four initial add-on trials enrolling morethan 700 patients with refractory partial-

onset epilepsy led to the FDA approvalof gabapentin.26-29 Dosages ranged from1200 to 1800 mg/d with 25% to 33%demonstrating a greater than 50% re-duction in seizure frequencyfrom base-line (TABLE 2).

Gabapentinhasalso been evaluatedin2 large monotherapy trials (TABLE 3).The first study, a dose-response, pseu-doplacebo-controlledtrial(n= 275), ran-domly assigned patients to 1 of 3 dailydoses (600 mg, 1200 mg, and 2400 mg)and found no significant difference incompletion rates,whichwere meagerandranged from 15% to 26%.30 The second

Figure. Principal Mechanisms of Action of the New Antiepileptic Drugs

EXCITATORY

NEURON

INHIB ITORY

NEURON

ASTROCYTESYNAPTIC

CLEFT Voltage-GatedCalcium Channel

Voltage-GatedSodium Channel

GABAAReceptor

GABA

Glutamate

Exact Mechanism Unknown

Gabapentin

Levetiracetam

Calcium ChannelBlockade

Felbamate

Lamotrigine

Topiramate

Zonisamide

GABA ReuptakeTransporter

PRESYNAPTIC

MEMBRANE

POSTSYNAPTIC

MEMBRANE

Sodium ChannelBlockade

Felbamate

Lamotrigine

Oxcarbazepine

Topiramate

Zonisamide

AMPAReceptor

NMDAReceptor

Antagonism ofGlutamate

Felbamate

Topiramate

Potentiation ofGABA Activity

Tiagabine

Topiramate

Principal mechanisms of action of the newer antiepileptic drugs include voltage-dependent ion channel block-ade, enhancement of inhibitory neurotransmission, and reduction of excitatory neurotransmission. Mecha-nisms unique from those for traditional antiepileptic drugs include glutamate antagonism at N-methyl-D-aspartate(NMDA) receptors (felbamate) and-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)receptors (felbamate, topiramate) and inhibition of -aminobutyric acid (GABA) reuptake in neurons and as-trocytes (tiagabine).

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study compared gabapentin at 3 differ-ent daily doses (300 mg, 900 mg, and1800 mg) with an active control (carba-mazepine, 600 mg/d). There wasno sig-nificant difference in completion rates(38% vs 37%), suggesting equivalent but

notsuperiorefficacyof gabapentinto car-bamazepine. In addition, the time tostudy exit wassignificantly longer for thepatientsin the gabapentingroup admin-istered 900 or 1800 mg/d compared withthose in the300-mg/d group.31 Themostcommon reason for exit from the study

was an increase in seizure frequencyabove baseline. Although gabapentinhadmodest efficacy as monotherapy in thissingle study, it is not FDA approved assuch. A single study evaluated the effi-cacy of gabapentin for generalized-

onsetseizuresand showedno changeinseizure frequency from baseline.32

Adverse effects that were reportedmore often in patients taking gabapen-tin than placebo included somnolence,dizziness, and fatigue,which usually re-solvedwithin thefirst 2 weeks oftherapy.

Modest weight gain has also been ob-served in postmarketing studies but noserious idiosyncratic reactions or organtoxicities have been identified.33 Gaba-pentin possesses several desirable phar-macokinetic properties: it does not un-

dergo hepaticmetabolism andisexcretedunchanged in urine.34 In addition, gaba-pentin does not affect plasma concen-trations of other antiepileptic drugs,oralcontraceptives, or probenecid.35,36 Coad-ministration with antacids causes a de-crease in bioavailability of gabapentin,

Table 2. Randomized, Placebo-Controlled Trials of the New Antiepileptic Drugs as Adjunctive Treatment for Partial-Onset Seizures*

SourceStudy

DesignNo. of

PatientsStudy

Duration, wkDaily

Dosage, mgResponder

Rate, %% Decreasein Seizures

GabapentinAndrews et al,26 1990 Parallel 127 12 1200 25 (P = .04) 29.2

Sivenius et al,29 1991 Parallel 43 12 1200 33 (P = .02) 57 (P = .02)

McLean et al,27

1993 Parallel 306 12 1800 26.4 (P = .007) 31.9Anhut et al,28 1994 Parallel 272 12 1200 28 (P = .008) 17.8 (P = .005)

LamotrigineBinnie et al,45 1989 Crossover 34 12 75-200 6.7 17 (P.05)

Jawad et al,38 1989 Crossover 24 12 75-400 66.7 59 (P.002)

Loiseau et al,39 1990 Crossover 23 8 300 34.8 23 (P.05)

Sander et al,46 1990 Crossover 21 12 150-300 NS NS

Matsuo et al,40 1993 Parallel 216 24 300-500 33 (P.05) 36 (P = .007)

Schapel et al,42 1993 Crossover 41 12 150-300 22 26 (P.01)

Smith et al,41 1993 Crossover 81 16 400 17.7 29.7 (P.05)

Messenheimer et al,43 1994 Crossover 98 14 400 20 25 (P.001)

Boas et al,44 1996 Crossover 56 12 75-400 24 30.3 (P = .01)

TopiramateBen-Menachem et al,66 1996 Parallel 56 13 800 43 (P = .001) 54 (P.001)

Faught et al,64 1996 Parallel 181 12 400 47 (P = .01) 48 (P = .007)

Privetera et al,65 1996 Parallel 190 18 600 44 (P.001) 41

Sharief et al,68 1996 Parallel 47 11 400 35 (P = .03) 41 (P = .06)

Tassinari et al,67 1996 Parallel 60 12 600 47 (P = .001) 46 (P = .004)

Yen et al,69 2000 Parallel 46 14 300 47.8 (P = .01) Not reported

TiagabineSachdeo et al,79 1997 Parallel 318 12 32 31 (P. 001) Not reported

Kalviainen et al,78 1998 Parallel 154 16 12-30 14 (P = .17) 12.6 (P.05)

Uthman et al,80 1998 Parallel 297 20 56 29 (P. 001) Not reported

LevetiracetamBen-Menachem and Falter,90 2000 Parallel 286 12 3000 42.1 (P.001) 39.9 (P.001)

Betts et al,91 2000 Parallel 119 24 2000 48.1 (P.05) Not reported

Cereghino et al,88 2000 Parallel 294 18 3000 39.8 (P.001) 37.1 (P.001)

Shorvon et al,89 2000 Parallel 324 16 2000 31.6 (P.001) 26.5 (P = .003)

Oxcarbazepine

Houtkooper et al,96 1987 Crossover 48 12 900-3600 Not reported NS

Barcs et al,97 2000 Parallel 694 28 2400 50 (P.001) 50 (P.001)

ZonisamideSchmidt et al,112 1993 Parallel 139 12 7/kg 29.9 (P.05) 22.5 (P.05)

Faught et al,113 2001 Parallel 203 12 400 43 (P = .01) 40.5 (P.001)

Abbreviation: NS, not significant and P value not reported in source.

*Felbamate is excluded because it is not considered first-line therapy due to risk of aplastic anemia and hepatotoxicity.If patients were randomized to multiple doses, the most effective dose is listed. A dose range is listed when study allowed titration to various doses based on efficacy and toler-

ability.Responder rate indicates patients who achieved a 50% or greater reduction in seizure frequency from baseline. P values are included when they were reported.

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while cimetidine decreases oral clear-ance by14%,which isofunknown clini-cal significance.10 Gabapentin offers theunique advantages of a wide margin ofsafety with good tolerability in the ab-sence of any significant drug interac-

tions but with modest efficacy.Lamotrigine

Lamotrigine is a broad-spectrum agentthat was approved for use in 1994 as anadjunctive treatmentin adults with par-tial-onset seizures.10 Later approval wasgranted for use in adults and childrenaged 2 years and older with generalizedseizuresassociatedwithLGSandforcon-version to monotherapy.10 Lamotrigineexhibits its antiepileptic effect primar-

ily by blockade of sodium channels and,to a lesser extent,calcium channels (Fig-ure).37 Seven clinical trials have shownlamotrigines efficacy as an adjunctiveagent in partial seizures with responderrates ranging from 17% to 67% in dos-

ages up to 500 mg/d (Table 2).

38-44

In ad-dition, 2 smaller trials evaluating the ef-ficacy of lamotrigine as adjunctivetherapy in partial seizures failedto showstatistically significantreductions in sei-zurefrequency frombaseline.45,46 Theef-ficacyoflamotrigine asmonotherapywasestablished in a multicenter study of 156patients comparing lamotrigine (500mg/d) with low-dose valproate (1000mg/d).47 Fifty-eight percent of the pa-tients in the lamotrigine group com-

pleted the study vs 31% in the valproategroup (P=.001). In addition, activecon-trol monotherapy trials have comparedlamotrigine to phenytoin as well as car-bamazepine and found lamotrigine tohave similar efficacy but fewer adverse

effectsandlower withdrawal rates(Table3).48-50 Two studies have evaluated theefficacy of lamotrigine in generalized sei-zuresassociated withLGS.51,52 The larg-eststudy enrolled 169patients anddem-onstrateda 33% responder rate (P=.01)and a 34% decrease in drop attacks.

Pooled clinical trial data showed thatadverse effects necessitated withdrawalof lamotrigine therapy in 10.2% ofpatients (n=3501), with rash being themost common cause for discontinua-

Table 3. Randomized Monotherapy Trials of the New Antiepileptic Drugs in Partial-Onset Seizures*

Source Study Design No. of Patients Summary

GabapentinBeydoun et al,30 1997 Pseudoplacebo control 275 No si gnificant difference bet ween 600, 1200, and 2400

mg/d; completion rates were 15%, 26%, and 19%,respectively

Chadwick et al,31 1998 Active control(carbamazepine)

292 No significant difference between gabapentin, 1800 mg/d(completion rate, 38%), and carbamazepine, 600 mg/d(completion rate, 37%); time to exit longer for 900 and1800 mg/d vs 300 mg/d (P = .04, P = .02); 14%withdrawn due to adverse events vs 24% carbamazepine

LamotrigineBrodie et al,48 1995 Active control

(carbamazepine)260 Completion rate 65% vs 51% (carbamazepine), P = .02; 15%

discontinued due to adverse events vs 27%carbamazepine

Gilliam et al,47 1998 Act ive cont rol ( valproat elow dose)

156 58% Completion rate for 500 mg/d vs 31% with valproate,1000 mg/d (subtherapeutic), P = .001

Steiner et al,49 1999 Active control (phenytoin) 181 Equivalent completion rates (48% vs 47%); 15%discontinued due to adverse events vs 19% phenytoin

Nieto-Barrera et al,50 2001 Active control(carbamazepine)

618 No significant difference in completion rates (81% vs 77%);8% discontinued due to adverse events vs 13%carbamazepine

TopiramateSachdeo et al,72 1997 Pseudoplacebo control 48 54% Completion rate for 1000 mg/d vs 17% for 100 mg/d

(P = .002)

OxcarbazepineReinikainen et al,98 1987 Act ive cont rol

(carbamazepine)40 No significant difference in efficacy, 80% vs 90% completion

rates; significantly fewer adverse effects withoxcarbazepine (P.05)

Dam et al,99 1989 Active control(carbamazepine)

235 Responder rates 80% for both oxcarbazepine andcarbamazepine; significantly fewer adverse effects withoxcarbazepine (P = .04)

Bill et al,100 1997 Act ive cont rol ( phenytoin) 287 No si gnificant difference in completi on rat es (61% vs 58%);

significantly fewer adverse effects with oxcarbazepine(P = .02)

Christe et al,101 1997 Act ive cont rol ( valproat e) 249 No si gnificant difference in completi on rat es (59% vs 64%);no significant difference in adverse effects

Beydoun et al,103 2000 Pseudoplacebo control 87 59% Completion rate for 2400 mg/d vs 7% for 300 mg/d(P.001)

Sachdeo et al,102 2001 Pseudoplacebo control 143 32% Completion rate for 2400 mg/d vs 0% for 300 mg/d(P.001).

*Felbamate is excluded because it is not considered first-line therapy due to risk of aplastic anemia and hepatotoxicity.Approved for monotherapy.

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tion(3.8%).53 Inaddition,therehavebeenreports of lamotrigine-associated rashrequiringhospitalization,someprogress-ing to Stevens-Johnson syndrome.54

However, a recent review of 73 cases ofantiepileptic drugrelated Stevens-

Johnson syndromeand toxic epidermalnecrolysis found lamotrigine to be asso-ciated with a lower relative risk com-paredwithphenobarbital, phenytoin,andcarbamazepine.55 Subsequent review ofpublished andunpublished clinicaltrialdata showed that severe rashes occurmore often with rapid titration and inpediatric patients as opposed to adults(1% vs 0.3%).56 It has also been recog-nized that the risk of skin rash is signifi-cantly higher when lamotrigine is coad-ministered with valproate becausevalproate markedly slows the metabo-

lism of lamotrigine. This risk can bereduced with lower initial doses andslower titration schedules.57 Lamotrigineundergoes hepatic metabolism throughglucuronidation but does not induce orinhibit hepatic enzymes andthushasnosignificant effects on the metabolism ofother antiepileptic drugs or oral contra-ceptives.58-60 Lamotrigine provides theadvantageofabroad-spectrumagentwithminimal sedation or drug interactions,butitsmostsignificantdrawbackis a slowtitrationschedulerequiring 8 to12weeks

to reach therapeuticmaintenance dosesand even longer when used in conjunc-tion with valproate.

Topiramate

Topiramate is another broad-spectrumagent approved as adjunctive treatmentin adults and children 2 years or olderwith partial seizures, primary general-ized seizures, and seizures associatedwith LGS.10 Multiple mechanisms ofaction have been shown in preclinicalstudies including sodium and calcium

channel blockade, GABA potentiation,and glutamate receptor antagonism(Figure).61-63 The efficacy of topiramateas adjunctive therapy is supported by 6multicenter trials that enrolled 580 pa-tients with refractory partial-onset sei-zures(Table2).64-69 Responder rateswere35% to 48% with daily doses rangingfrom 300 to 800 mg. The 2 largest trials

randomly assigned patients to multipledoses and found no significant increasein efficacy for dosages higher 400 mg/d.64,65 Topiramate has also shown effi-cacy against generalized-onset seizuresincluding refractory seizures seen in

LGS.

70,71

In a study of 98 patients withLGS, 33% hada 50% reduction in tonic-clonic seizures as well as drop attacks(P=.002).71 A single pseudoplacebo-controlled monotherapy trial in 48 pa-tients demonstrated a 54% completionrate for patientstaking 1000mg/dvs17%completion rate for those taking 100mg/d (P=.002).72 However, topiramateis not FDA approved for monotherapy.

Adverse effects that were seen morecommonly for patients taking topira-mate than placebo in clinical trials in-cluded ataxia, decreased concentration,

confusion, dizziness, and fatigue, mostof which occurred in patients takingmore than 600 mg/d or with relativelyrapid titration to maintenance dose in 3to 4 weeks.73 No idiosyncratic reactionsor organ toxicitieshave been reportedtodate. Other clinically relevant adverse ef-fects include nephrolithiasis, with a re-ported incidence of 1.5%, and mildweight loss averaging 1 to 6 kg predomi-nantly inthefirst 3 months oftherapy.73,74

Topiramate exerts no significant effectson other antiepileptic drugs or on se-

rum norethindrone levels but de-creasesserum estradiol levelsby 30%andserum digoxin levels by 12%.75,76 Topi-ramate offers the advantage of a broad-spectrum agent with minimal drug in-teractions, the absence of serious adverseeffects, and the potential for weight lossbut with the slight risk of kidney stonesand a slow titration schedule (8-12weeks).

Tiagabine

Tiagabine was FDA approved for use in

1997 for the adjunctive treatment ofpartial-onset seizures in persons 12years or older.10 It has a novel mecha-nism of action, blocking reuptake ofGABA into neurons and glial cells (Fig-ure).77 Three multicenter studies evalu-ated the efficacy and tolerability of ti-agabine as adjunctive therapy (Table2).78-80 The smallest trial enrolled 154

patients and showed a responder rateof 14%, which was not significantlygreater than placebo. However, morethan 600 patients enrolled in 2 addi-tional trials showed modest but signifi-cant responder rates of 29% and 31%

at doses of 56 and 32 mg/d. The mostcommon adverse effects included diz-ziness, tremor, and impaired concen-tration, most often seen with twice-daily dosing and much less frequentlywith either 3- or 4-times daily dosing.

Tiagabine undergoes extensive he-patic oxidation via the cytochromeP450 system but has not been shownto induce or inhibit hepatic enzymefunction and thus has negligible ef-fects on other drugs, including other an-tiepileptic drugs, warfarin, digoxin, ci-metidine, triazolam, antipyrine, and

theophylline.80-83 At low doses of 8mg/d, tiagabine demonstrated no effecton oral contraceptive metabolism butpatients taking higher doses were notevaluated.84 Concurrent use of tiagab-ine and hepatic enzymeinducing an-tiepileptic drugs (phenobarbital, phe-nytoin,and carbamazepine)reducesthehalf-life of tiagabine while coadminis-tration of cimetidine and tiagabine hasno effect on tiagabine pharmacokinet-ics.83 The effects of other drugs that im-pact the cytochrome P450 system have

not been extensivelyevaluated.Of someconcern are rare reports of tiagabineprecipitating nonconvulsive status epi-lepticus, in particular, absence statusepilepticus.85,86 Tiagabine offers a novelmechanism of action with modest ef-ficacy in partial-onset seizures.

Levetiracetam

Levetiracetam wasapproved in 1999 forthe adjunctive treatment of adults withpartial-onsetseizures.10 Itsexact mecha-nism of action is unknown but it does

not appear to have activity against tra-ditional drug targets.87 Four multi-center trials withlevetiracetamas add-ontherapy enrolled more than a thousandpatients andshoweda responder rate ofbetween 32% and48%with doses rang-ing from 2000 to 3000 mg/d (Table2).88-91 In the US trial, patients were ti-trated to maintenancedose over a 4-week

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period withminimal adverseeffects anda median reduction in seizure fre-quency of 26% to 30% within the first 2weeks.88 Betts et al91 evaluated the tol-erability and efficacy of 2000 and 4000mg/d startedwithout titration andfound

both to be well tolerated but, interest-ingly, higher responder rates were seenin patients receiving 2000 mg/d.

Common adverse effects of leveti-racetam in clinical trials included som-nolence, asthenia, headache, and infec-tion. The majority of adverse effectsoccurred in the first 4 weeks of therapyand did not appear to bedose related. Inaddition, behavioral disturbances suchas agitation and anxiety were reportedin upto 13% ofthestudy cohort.88-91 Thepharmacokinetic profile of leveti-racetam is favorable, with absence of he-

patic metabolism and low protein bind-ing.92 No significant interaction wasreportedwithcoadministration of otherantiepileptic drugs, oral contraceptives,digoxin, warfarin, or probenecid.92 Ad-ditionally, levetiracetam has the high-est safety margin in animal models com-paredwithall otherantiepilepticdrugs.93

Levetiracetam offers the advantage of afavorable pharmacokinetic profile andhigh safetymargin with thecapability ofrapid dosage titration.

OxcarbazepineOxcarbazepine, an analogue of carba-mazepine, is available for use as mono-therapy or adjunctive therapy in thetreatmentof partial-onsetseizuresin per-sons aged 4 yearsand older.10 It was de-signed to have similar efficacy to carba-mazepine but fewer adverse effects,largely due to its lack of formation of thetoxic metabolite carbamazepine10, 11epoxide.94 Likecarbamazepine, its prin-cipal mechanism of action is via so-dium channel blockade (Figure).95 Ox-

carbazepine has been evaluated asadjunctivetherapy for partial seizures in2 clinical trials (Table2).96,97 The largertrial enrolled 694patientswhowere ran-domly assigned to receiveplacebo or ox-carbazepine in dosages of 600 mg/d,1200 mg/d, or 2400 mg/d. Responderrates were 27%, 42%, and 50%, respec-tively, for the oxcarbazepine groups

(P.001).97 However, a similar butmuch smaller and shorter study enroll-ing 48 patients failed to show a signifi-cant decrease in seizure frequency.96 Ox-carbazepine was also evaluated in 6monotherapy trials(Table 3).98-103 Four

active-control trials compared oxcar-bazepine with carbamazepine, phe-nytoin, or valproate and found similarefficacy but a statistically significant de-crease in adverse effects in the oxcar-bazepine group in 3 of the trials. In ad-dition, 2 pseudoplacebo-controlled trialsin 230 patients compared theefficacy of300 mg/d vs 2400 mg/d of oxcarbaz-epine and demonstrated a significantlyhigher completion rate in the high-dose group (P.001).102,103

Common adverse effects of oxcarbaz-epine in clinical trials were dose related

and included dizziness, diplopia, som-nolence, nausea, and ataxia, particu-larly in patients receiving2400 mg/d. Al-lergic skin reactions occurred lessfrequently thanwithcarbamazepine, al-though a cross-sensitivity of approxi-mately 30% has been demonstrated inpatients with hypersensitivity to carba-mazepine.104 Hyponatremia hasalso beenreported, particularly in elderly per-sons.In a largepostmarketingstudy,23%of 350 patients receiving oxcarbaz-epine were found to have a serum so-

dium level lower than 135 mEq/L, al-thoughonly1% required discontinuationof the drug.105 Oxcarbazepine does notinduceitsownmetabolism or hepaticmi-crosomal enzymes and is not affectedbyconcurrent administration of erythro-mycin, as seen with carbamaze-pine.106,107 In addition, oxcarbazepine hasnot beenshownto interactwith otheran-tiepilepticdrugs, cimetidine, warfarin,ordextropropoxyphene.10 However,oxcar-bazepine decreases serum levels of oralcontraceptives and felodipine.108,109 Ox-

carbazepine offerssimilar efficacy to car-bamazepine but with fewer drug inter-actions andoverall fewer adverse effects,with the exception of hyponatremia.

Zonisamide

Zonisamide is a broad-spectrum anti-convulsant thathasbeen availablein theUnited States since 2000 but has had

widespread clinical use in Japan since1989. It is a sulfonamide derivative thatacts by blocking sodium as well as T-type calcium channels (Figure).110,111

Two multicenter trials carried out in theUnited States and Europe in 342 pa-

tients evaluated the efficacy and toler-abilityofzonisamidefor partial-onset sei-zures.112,113 The patients randomlyassigned to receive zonisamide were ti-trated up to a dose of 400 to 500 mg/dand had a responder rate of 30% to 43%(Table 2). Although FDA approved foruse only in partial-onset seizures, casestudieshave demonstrated dramaticim-provement with zonisamide in patientswithgeneralized-onset seizures, particu-larly myoclonus.114,115

Statistically significant adverse ef-fects were reported in up to 59% of

study patients compared with 28% inthe placebo group and included fa-tigue, dizziness, ataxia, and anorexia.An earlier open-label study reported a3.5% incidence of renalcalculi that ini-tiallyhalted the drugsdevelopment, butthis finding was not reproduced in sub-sequent studies.116 In the pediatricpopulation there have been rare re-ports of high fever secondary to hyper-hidrosis.117 Zonisamide has the advan-tage of a long half-life, averaging 63 to69 hours in healthy volunteers, mak-

ing once-daily dosing possible.118

Lowprotein binding as well as partial livermetabolism via conjugation contrib-utes to its minimal interaction withother medications, including other an-tiepileptic drugs and cimetidine.10 Be-cause zonisamide is a sulfonamide de-rivative its use is contraindicated inpatients with a known sulfonamide al-lergy. Zonisamide is efficacious as ad-junctivetherapy for manyseizure types,particularly myoclonus, with the ad-vantage of once-daily dosing.

COMMENTIs There a Superior New

Antiepileptic Drug?

Unfortunately, to our knowledge therehave been no randomized controlledclinical trials comparing the efficacyandtolerability of the new antiepilepticdrugs. Although most of the individual

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drugs were approved based on add-ontrials with similar study designs, vary-ing study populations and titrationschedules make direct comparisons dif-

ficult. Nevertheless, Marson et al118 per-formeda meta-analysis of publishedandunpublished randomized controlledtrials in which gabapentin, lamotrigine,tiagabine, topiramate, vigabatrin, andzonisamide were compared with pla-cebo as add-on therapy in patients withrefractory partial-onset seizures. Theodds ratio for a 50% or greater reduc-tion in seizure frequency was calcu-latedforeach individual drug. There wasno conclusive evidence for a differencein efficacy or tolerability among the

drugs because the 95% confidence in-tervals(CIs)overlapped.However, topi-ramate had the highest odds ratio for5 0 % r espo nder s (4 .2 2 ; 9 5 % CI ,2.80-6.35), which was almost twice thatof the lowest odds ratio (2.29; 95% CI,1.53-3.43) for patients taking gabapen-tin. In addition, theodds ratios for with-drawal from treatment for patients tak-ing lamotrigine or gabapentin were nohigher than placebo.

In addition to differences in studypopulations and nonrandomized com-

parisons, shortcomings of this analysisinclude the absenceof comparativedatain patients taking felbamate, oxcarbaz-epine, or levetiracetam as well as exclu-sion of monotherapy studies and stud-ies evaluatinggeneralized-onsetseizures.Although these results do not allow thephysicianto makean evidence-based de-cision in choosing an antiepileptic drug,

they do highlight some potential differ-ences among these drugs that futurestudies may further differentiate.

Are the New Antiepileptic Drugs

Superior to the Traditional

Antiepileptic Drugs?

There wasmuch enthusiasm with thear-rival of the new antiepileptic drugs, es-pecially considering the number of pa-tients whowere taking combinationsofthe traditional antiepileptic drugs andcontinuing to have frequent break-through seizures coupled with intoler-able adverse effects. Despite the lack ofcomprehensive clinical trials compar-ing the new and traditional antiepilep-tic drugs, there is evidence to suggestsome advantages of the new agents.Gabapentin, lamotrigine, and oxcarbaz-

epine have each been compared withcarbamazepine as monotherapy in par-tial-onset seizures andfoundto have bet-ter tolerability, although there was nodifference in efficacy.48,96,99,119 La-motrigine, topiramate, and zonisamidehave been shown to have broad-spectrum activity with efficacy againstgeneralized- as well as partial-onset sei-zures while valproate is the only tradi-tional antiepileptic drug with this spec-trum of activity.51,52,70,71,114,115

Most of the new antiepileptic drugs

lack hepaticenzyme induction andhavenot been shown to interact with otherhepatically metabolized medicationsunlike phenobarbital, phenytoin, andcarbamazepine.34,35,92 Finally, only fel-bamate and lamotrigine have demon-strated potentially life-threatening ad-verse effects, which have been welldocumented with phenytoin, carba-mazepine, and valproate.22,54 How-ever, the new anticonvulsant medica-tions are significantly more expensivethan the traditional drugs, and ad hoc

studies have not shown evidence of su-perior cost-effectiveness.120

Is Routine Serum Monitoring

Required?

Routine monitoring of serum drug con-centrations has traditionally been usedto guide dosage adjustments in patientstakingantiepilepticdrugs,despite thefact

that therapeutic ranges in the litera-ture often do not correlate with a givenindividuals response. Therefore, titra-tion to clinical efficacy is recom-mended not only for the traditional an-tiepileptic drugs butfor thenewer agents

as well. However, if a patient does notrespond to a particular therapy as ex-pected, checking the serum drug con-centration may aid in determining com-pliance and identifying potentialpharmacokinetic interactions. Serumdrug level tests are commercially avail-able, although there are not sufficientdata available to determine the opti-mum serum concentrations of many ofthe new antiepileptic drugs.

Since many of the traditional antiepi-leptic drugs are associated with rare butpotentially serious bone marrow sup-

pressionas wellas hepatotoxicity, base-line as well as routine monitoring ofhematological andliver functionsis rec-ommended. Of the new antiepilepticdrugs, theonly medicationthat hasbeenassociated with serious organ toxicity isfelbamate, withrarebutpotentially fatalcases of aplastic anemia and hepatotox-icity.22,23 Therefore,felbamate is theonlynewantiepileptic drugthat requires rou-tine monitoring of complete blood cellcounts and liver function.10

What Dosage Adjustments AreRequired in the Setting of Hepatic

Disease or Renal Insufficiency?

Studies have been performed evaluat-ing the pharmacokinetic effects of he-patic and renal disease on most of thenewer antiepileptic drugs.However, fewdata are available regarding the clini-cal significance of these effects. For pa-tients with hepatic disease, there is in-sufficient information available to makeany recommendations on the neces-sity of dosage adjustments. However,

since gabapentinandlevetiracetam bothlack significant hepatic metabolism,both of these drugs theoretically shouldbe safe choices in patients with he-patic dysfunction.

Since gabapentin andlevetiracetam areprimarily nonmetabolized and ex-creted through the kidneys, the dosageshouldbe decreased for patients with re-

Table 4. Dosing Adjustment for PatientsWith Impaired Renal Function*

CreatinineClearance, mL/min Dos age, mg

Gabapentin60 400 3 times daily30-60 300 twice daily

15-30 300 daily15 300 every other dayHemodialysis 200-300

Levetiracetam80 500-1500 twice daily50-80 500-1000 twice daily30-50 250-750 twice daily30 250-500 twice dailyHemodialysis 500-1000

*Recommendations based on package insert.Supplemental dose following dialysis.

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nal dysfunction. The manufacturers ofboth drugs have established specific dos-ing guidelinesbased on creatinine clear-ance (TABLE 4). The elimination half-lives of topiramate, oxcarbazepine, andzonisamide are prolonged in the setting

of moderate to severe renal disease andtherefore dosage adjustment is recom-mended in patients with renal dysfunc-tion, although no specific guidelineshavebeen published. There are insufficientdata availableon theuseof felbamate, la-motrigine, or tiagabine in patients withrenal dysfunction.

CONCLUSION

Epilepsy is a prevalent, serious medicalcondition that is treated largely by gen-eral practitioners. The development ofnew antiepileptic drugs has expanded

treatment options and offered signifi-cant advantages to patients, particularlythose with adverse effects or frequentbreakthrough seizures with traditionalantiepileptic drugs. Randomized con-trolledclinicaltrial datasupportthe effi-cacy as well as tolerability of each of thenew antiepilepticdrugs. Althoughthereis no evidence to suggest that the newermedications are more efficacious, sev-eral studies have demonstrated broaderspectrum of activity, fewer drug inter-actions, and overall better tolerability of

thenewagents. Asexperiencewith thesemedications increases and further stud-ies are performed, additional advan-tages may become evident.

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