The New Antiepileptic Drugs Scientific Review

SCIENTIFIC REVIEW CLINICIAN’S CORNER AND CLINICAL APPLICATIONS

Suzette M. LaRoche, MD Context The past decade has brought many advances to the treatment of epilepsy, Sandra L. Helmers, MD including many new pharmacological agents. Primary care physicians often care for patients with epilepsy and therefore should be familiar with the new options available. PILEPSY IS DEFINED AS A CHRONIC Objective To review data regarding the efficacy and tolerability of antiepileptic drugs neurological condition charac- introduced in the past decade. terized by recurrent, unpro- 1 Data Sources A search of the Cochrane Central Register of Controlled Trials was voked seizures. It is one of the performed to identify all published human and English-language randomized con- Emost common serious neurological dis- trolled trials evaluating the efficacy and tolerability of the antiepileptic drugs that have orders in the United States and often re- been approved for use in the United States since 1990. Additional reports evaluating quires long-term management. Each year pharmacokinetic properties were identified through a MEDLINE search as well as re- 150000 people in the United States are view of article bibliographies. newly diagnosed as having epilepsy, with Study Selection and Data Extraction Search terms included felbamate, gaba- the cumulative lifetime incidence ap- pentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonis- proaching 3%.2,3 The incidence is high- amide. Studies were selected if efficacy and tolerability were reported as major out- est during the first year of life and in el- come measures. Included studies (n=55) enrolled a minimum of 20 adult subjects and derly persons.2 Although most people had a treatment period of at least 6 weeks. with epilepsy become seizure-free with Data Synthesis Eight new antiepileptic drugs have been approved for use in the United appropriate therapy, 30% to 40% of pa- States in the past decade. Each new antiepileptic drug is well tolerated and demonstrates tients will continue to have seizures de- statistically significant reductions in seizure frequency over baseline. No randomized con- spite the use of antiepileptic drugs either trolled trials have compared the new antiepileptic drugs with each other or against the traditional antiepileptic drugs. Although there is no evidence to suggest that the newer alone or in combination.4 Patients with medications are more efficacious, several studies have demonstrated broader spectrum uncontrolled seizures experience signifi- of activity, fewer drug interactions, and overall better tolerability of the new agents. cant morbidity and mortality and face so- cial stigma and discrimination as well. Conclusions New antiepileptic drugs offer many options in the treatment of epilepsy, each with unique mechanisms of action as well as adverse effect profiles. The In the United States, only 17% of pa- new antiepileptic drugs are well tolerated with few adverse effects, minimal drug in- tients with new-onset epilepsy are ini- teractions, and a broad spectrum of activity. 5 tially seen by a neurologist. Further- JAMA. 2004;291:605-614 www.jama.com more, primary care physicians provide approximately 40% of the long-term that 45% had experienced a seizure well as intolerable adverse effects. Since management of epilepsy patients with or within the past year, 68% complained of 1993, 8 new medications have been ap- without initial consultation with a spe- drowsiness or difficulty in concentra- proved by the US Food and Drug Ad- 6 cialist. Unfortunately, a survey of gen- tion with their current medications, and ministration (FDA), expanding treat- eral practitioners revealed that only 40% 28% were prescribed polytherapy.8 ment options (TABLE 1). The newer of responders felt confident in their Therefore, general practitioners play a vi- antiepileptic drugs offer the potential ad- knowledge of epilepsy and two thirds tal role in the treatment of epilepsy pa- vantages of fewer drug interactions, were unfamiliar with the new antiepi- tients with ongoing seizures. unique mechanisms of action, and a 7 leptic drugs. A recent survey of 71 pa- Prior to 1993, the choice of an anti- broader spectrum of activity. With more tients with epilepsy who are treated ex- convulsant medication was limited to options, however, comes the challenge clusively by general practitioners showed phenobarbital, primidone, phenytoin, carbamazepine, and valproate. Al- Author Affiliations: Department of Neurology, Emory University (Drs LaRoche and Helmers), and Atlanta VA See also p 615 and Patient Page. though these “traditional” anticonvul- Medical Center (Dr LaRoche), Atlanta, Ga. sants have the advantage of familiarity Corresponding Author and Reprints: Suzette M. CME available online at as well as proven efficacy, many pa- LaRoche, MD, Emory Clinic, Bldg A, 1365 Clifton Rd, www.jama.com Atlanta, GA 30322 (e-mail: Suzette_LaRoche tients are left with refractory seizures as @emoryhealthcare.org).

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trials and fewer yet have been FDA ap- Table 1. Antiepileptic Drugs Approved Since 1993* proved for use as monotherapy. This pre- Approved Approved for Year Approved Approved for for Partial Generalized sents a dilemma that has led to frequent Antiepileptic Drug Approved Patient Age, y Monotherapy Seizures Seizures off-label use because monotherapy of- Felbamate (Felbatol)† 1993 Ն2 ߜߜߜfers many advantages over poly- Gabapentin (Neurontin) 1993 Ն3 ߜ therapy, including fewer adverse ef- Lamotrigine (Lamictal) 1994 Ն2 ߜߜߜfects, less drug interactions, lower cost, Topiramate (Topamax) 1996 Ն2 ߜߜand improved compliance. The reason Tiagabine (Gabatril) 1997 Ն12 ߜ for fewer monotherapy approvals stems Levetiracetam (Keppra) 1999 Ն16 ߜ from the difficulty in trial design. There Oxcarbazepine (Trileptal) 2000 Ն4 ߜߜ are 2 common approaches to mono- Zonisamide (Zonegran) 2000 Ն16 ߜ therapy trials. An active-control com- *Approved for use by the US Food and Drug Administration. †Not indicated as first-line antiepileptic treatment. parison typically randomly assigns patients with new-onset seizures to receive either the study drug or a well- of determining what role the new anti- either the study drug or placebo in addi- established antiepileptic drug at low epileptic drugs play in optimizing treat- tion to their original medication(s). therapeutic doses. Conversion to mono- ment in addition to understanding im- Patients were followed up for 6 to 8 therapy trials assigns patients to be con- portant adverse effects and drug weeks to establish a baseline seizure fre- verted from their current antiepileptic interactions of these increasingly pre- quency, then randomly assigned to drug(s) to either a subtherapeutic dose scribed medications. The purpose of this either placebo or study drug and fol- of the test drug (referred to as pseudo- article is to familiarize primary care cli- lowed up for 8 to 12 weeks while sei- placebo) or a higher dose of the test drug nicians with the efficacy, tolerability, and zure frequency and tolerability were that is thought to be efficacious. Effi- pharmacokinetic properties of the new monitored. The primary outcome mea- cacy is measured as completion rate or antiepileptic drugs. sure was a reduction in seizure fre- mean time to exiting the study. Exit cri- quency over baseline compared with teria consist of either an increase in sei- METHODS placebo. A “responder rate” is reported zure frequency above baseline, a pro- We searched the Cochrane Central Reg- as the number of patients who achieved longed generalized seizure, or status ister of Controlled Trials to identify all a 50% or greater reduction in seizure epilepticus. In addition, the percentage published human and English- frequency from baseline. of patients discontinuing due to ad- language randomized controlled clini- There are obvious limitations to this verse effects is reported. Agents that show cal trials evaluating the efficacy and tol- trial design. Efficacy is often underes- efficacy in placebo-controlled trials are erability of antiepileptic drugs that have timated and responder rates are typi- considered acceptable proof of efficacy been FDA approved since 1990. Addi- cally less than 50% because the study for FDA approval; however, this trial de- tional reports evaluating pharmacoki- population with refractory seizures has sign raises obvious ethical concerns. To netic properties were identified through typically not responded to multiple an- demonstrate efficacy in active-control a MEDLINE search as well as review of tiepileptic drugs and is therefore not comparison trials, the study drug must article bibliographies. Search terms in- comparable to patients in a typical clini- show superiority over the control and not cluded felbamate, gabapentin, la- cal practice. Toxicity is often overesti- merely equivalency.9 motrigine, topiramate, tiagabine, leveti- mated because adverse effects may be racetam, oxcarbazepine, and zonisamide. additive and not specifically due to the RESULTS Studies were selected if efficacy and tol- add-on therapy. In addition, many of Felbamate erability were reported as major out- the new antiepileptic drugs were ti- Felbamate was the first new antiepilep- come measures. Included studies trated more rapidly during clinical trials tic drug to gain FDA approval (in 1993) (n=55) enrolled a minimum of 20 adult than is currently recommended, fur- and its introduction was met with much subjects and had a treatment period of ther overestimating the risk of toxic- enthusiasm and initial success. It is a at least 6 weeks. ity and adverse effects. Finally, the vari- broad-spectrum agent approved for both The majority of the new antiepilep- ability in study groups and trial designs monotherapy and adjunctive treatment tic drugs gained initial FDA approval makes direct comparisons among trials of partial-onset seizures in adults as well based on randomized, double-blind, impossible. Despite these drawbacks, as partial- and generalized-onset sei- placebo-controlled clinical trials in adjunctive clinical trials are overall the zures associated with Lennox-Gastaut which the new antiepileptic drug was safest and most ethical means of test- syndrome (LGS) in children.10,11 Sev- used as adjunctive treatment. Typi- ing new antiepileptic compounds. eral mechanisms of action have been cally, trials enrolled patients with refrac- Few of the new antiepileptic drugs identified, including sodium channel tory partial-onset seizures to receive have been evaluated in monotherapy blockade, calcium channel blockade, and

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antagonism of N-methyl-D-aspartate Figure. Principal Mechanisms of Action of the New Antiepileptic Drugs (NMDA) and ␣-amino-3-hydroxy-5- methyl-4-isoxazole propionic acid (AMPA) receptors (FIGURE).12-15 The ef- EXCITATORY ficacy of felbamate as adjunctive therapy NEURON for partial seizures has been evaluated in 16,17 2 outpatient crossover trials. The INHIBITORY smaller trial enrolled 30 patients and Sodium Channel Potentiation of NEURON GABA Activity found no significant decrease in seizure Blockade Tiagabine frequency during the felbamate treat- Felbamate Lamotrigine Voltage-Gated Topiramate ment period, while there was a 23% de- Sodium Channel crease in seizure frequency in a larger trial Oxcarbazepine of 67 patients (P=.02). Topiramate Zonisamide GABA GABA Reuptake Felbamate has also shown efficacy as Transporter monotherapy in 2 trials that com- GABAA pared felbamate, 3600 mg/d, with low- PRESYNAPTIC Receptor MEMBRANE dose valproate.18,19 A total of 138 pa-

tients were randomized, and there were SYNAPTIC ASTROCYTE significantly higher completion rates in CLEFT Voltage-Gated Calcium Channel both felbamate groups (60% vs 22% and Glutamate 86% vs 10%, PϽ.01). More impor- POSTSYNAPTIC tantly, felbamate has shown great suc- MEMBRANE Calcium Channel cess in the treatment of LGS, a child- Blockade hood-onset epilepsy consisting of severe Antagonism of Felbamate Glutamate cognitive dysfunction accompanied by Lamotrigine Felbamate seizures of many types, including atonic Topiramate Topiramate seizures (drop attacks), which are no- Zonisamide toriously treatment resistant. Two stud- NMDA AMPA ies support the efficacy of felbamate as Receptor Receptor Exact Mechanism Unknown add-on therapy in adults with LGS, with Gabapentin responder rates up to 50% and a de- Levetiracetam crease in drop attacks of 30%.20,21 The most commonly documented adverse effects with felbamate include gas- Principal mechanisms of action of the newer antiepileptic drugs include voltage-dependent ion channel block- trointestinal disturbances, anorexia, and ade, enhancement of inhibitory neurotransmission, and reduction of excitatory neurotransmission. Mecha- insomnia.18,19 Unfortunately, a year af- 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) ter FDA approval, reports of rare idio- receptors (felbamate, topiramate) and inhibition of ␥-aminobutyric acid (GABA) reuptake in neurons and as- syncratic reactions began to emerge. trocytes (tiagabine). Aplastic anemia has been reported in 34 cases with an incidence of approximately 1 in 8000 patient exposures.22,23 Gabapentin onset epilepsy led to the FDA approval Hepatotoxicity was also reported at a Gabapentin was approved for use in 1993 of gabapentin.26-29 Dosages ranged from slightly lower incidence of 1 in 10000, and is currently indicated as adjunctive 1200 to 1800 mg/d with 25% to 33% which parallels the risk with valproate therapy for partial seizures with and demonstrating a greater than 50% re- therapy.22 Felbamate remains on the mar- without secondary generalization in per- duction in seizure frequency from base- ket but with a black box warning for sons 3 years and older.10 Interestingly, line (TABLE 2). aplastic anemia and hepatic failure and more than 80% of prescriptions for gaba- Gabapentin has also been evaluated in is currently not considered a first-line an- pentin are for off-label uses such as neu- 2 large monotherapy trials (TABLE 3). ticonvulsant medication. However, fel- ropathic pain, migraine headache, spas- The first study, a dose-response, pseu- bamate can still be useful for patients ticity, and bipolar disorder.24 Although doplacebo-controlled trial (n=275), ran- with LGS or partial-onset seizures re- structurally related to ␥-aminobutyric domly assigned patients to 1 of 3 daily fractory to other antiepileptic drugs, but acid (GABA), its precise mechanism of doses (600 mg, 1200 mg, and 2400 mg) it is recommended to obtain informed action in humans is unknown (Figure).25 and found no significant difference in consent and monitor hematologic func- Four initial add-on trials enrolling more completion rates, which were meager and tion frequently. than 700 patients with refractory partial- ranged from 15% to 26%.30 The second

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study compared gabapentin at 3 differ- was an increase in seizure frequency Modest weight gain has also been ob- ent daily doses (300 mg, 900 mg, and above baseline. Although gabapentin had served in postmarketing studies but no 1800 mg) with an active control (carba- modest efficacy as monotherapy in this serious idiosyncratic reactions or organ mazepine, 600 mg/d). There was no sig- single study, it is not FDA approved as toxicities have been identified.33 Gaba- nificant difference in completion rates such. A single study evaluated the effi- pentin possesses several desirable phar- (38% vs 37%), suggesting equivalent but cacy of gabapentin for generalized- macokinetic properties: it does not un- not superior efficacy of gabapentin to car- onset seizures and showed no change in dergo hepatic metabolism and is excreted bamazepine. In addition, the time to seizure frequency from baseline.32 unchanged in urine.34 In addition, gaba- study exit was significantly longer for the Adverse effects that were reported pentin does not affect plasma concen- patients in the gabapentin group admin- more often in patients taking gabapen- trations of other antiepileptic drugs, oral istered 900 or 1800 mg/d compared with tin than placebo included somnolence, contraceptives, or probenecid.35,36 Coad- those in the 300-mg/d group.31 The most dizziness, and fatigue, which usually re- ministration with antacids causes a de- common reason for exit from the study solved within the first 2 weeks of therapy. crease in bioavailability of gabapentin,

Table 2. Randomized, Placebo-Controlled Trials of the New Antiepileptic Drugs as Adjunctive Treatment for Partial-Onset Seizures* Study No. of Study Daily Responder % Decrease Source Design Patients Duration, wk Dosage, mg† Rate, %‡ in Seizures‡ Gabapentin Andrews 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) 31.9 Anhut et al,28 1994 Parallel 272 12 1200 28 (P = .008) 17.8 (P = .005) Lamotrigine Binnie et al,45 1989 Crossover 34 12 75-200 6.7 17 (PϽ.05) Jawad et al,38 1989 Crossover 24 12 75-400 66.7 59 (PϽ.002) Loiseau et al,39 1990 Crossover 23 8 300 34.8 23 (PϽ.05) Sander et al,46 1990 Crossover 21 12 150-300 NS NS Matsuo et al,40 1993 Parallel 216 24 300-500 33 (PϽ.05) 36 (P = .007) Schapel et al,42 1993 Crossover 41 12 150-300 22 26 (PϽ.01) Smith et al,41 1993 Crossover 81 16 400 17.7 29.7 (PϽ.05) Messenheimer et al,43 1994 Crossover 98 14 400 20 25 (PϽ.001) Boas et al,44 1996 Crossover 56 12 75-400 24 30.3 (P = .01) Topiramate Ben-Menachem et al,66 1996 Parallel 56 13 800 43 (P = .001) 54 (PϽ.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 (PϽ.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 Tiagabine Sachdeo et al,79 1997 Parallel 318 12 32 31 (PϽ.001) Not reported Kalviainen et al,78 1998 Parallel 154 16 12-30 14 (P = .17) 12.6 (PϽ.05) Uthman et al,80 1998 Parallel 297 20 56 29 (PϽ.001) Not reported Levetiracetam Ben-Menachem and Falter,90 2000 Parallel 286 12 3000 42.1 (PϽ.001) 39.9 (PϽ.001) Betts et al,91 2000 Parallel 119 24 2000 48.1 (PϽ.05) Not reported Cereghino et al,88 2000 Parallel 294 18 3000 39.8 (PϽ.001) 37.1 (PϽ.001) Shorvon et al,89 2000 Parallel 324 16 2000 31.6 (PϽ.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 (PϽ.001) 50 (PϽ.001) Zonisamide Schmidt et al,112 1993 Parallel 139 12 7/kg 29.9 (PϽ.05) 22.5 (PϽ.05) Faught et al,113 2001 Parallel 203 12 400 43 (P = .01) 40.5 (PϽ.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 tolerability. ‡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- ily by blockade of sodium channels and, pleted the study vs 31% in the valproate ance by 14%, which is of unknown clini- to a lesser extent, calcium channels (Fig- group (P=.001). In addition, active con- cal significance.10 Gabapentin offers the ure).37 Seven clinical trials have shown trol monotherapy trials have compared unique advantages of a wide margin of lamotrigine’s efficacy as an adjunctive lamotrigine to phenytoin as well as car- safety with good tolerability in the ab- agent in partial seizures with responder bamazepine and found lamotrigine to sence of any significant drug interac- rates ranging from 17% to 67% in dos- have similar efficacy but fewer adverse tions but with modest efficacy. ages up to 500 mg/d (Table 2).38-44 In ad- effects and lower withdrawal rates (Table dition, 2 smaller trials evaluating the ef- 3).48-50 Two studies have evaluated the Lamotrigine ficacy of lamotrigine as adjunctive efficacy of lamotrigine in generalized sei- Lamotrigine is a broad-spectrum agent therapy in partial seizures failed to show zures associated with LGS.51,52 The larg- that was approved for use in 1994 as an statistically significant reductions in sei- est study enrolled 169 patients and dem- adjunctive treatment in adults with par- zure frequency from baseline.45,46 The ef- onstrated a 33% responder rate (P=.01) tial-onset seizures.10 Later approval was ficacy of lamotrigine as monotherapy was and a 34% decrease in drop attacks. granted for use in adults and children established in a multicenter study of 156 Pooled clinical trial data showed that aged 2 years and older with generalized patients comparing lamotrigine (500 adverse effects necessitated withdrawal seizures associated with LGS and for con- mg/d) with low-dose valproate (1000 of lamotrigine therapy in 10.2% of version to monotherapy.10 Lamotrigine mg/d).47 Fifty-eight percent of the pa- patients (n=3501), with rash being the exhibits its antiepileptic effect primar- tients in the lamotrigine group com- most 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 Gabapentin Beydoun et al,30 1997 Pseudoplacebo control 275 No significant difference between 600, 1200, and 2400 mg/d; completion rates were 15%, 26%, and 19%, respectively Chadwick et al,31 1998 Active control 292 No significant difference between gabapentin, 1800 mg/d (carbamazepine) (completion rate, 38%), and carbamazepine, 600 mg/d (completion rate, 37%); time to exit longer for 900 and 1800 mg/d vs 300 mg/d (P = .04, P = .02); 14% withdrawn due to adverse events vs 24% carbamazepine Lamotrigine† Brodie et al,48 1995 Active control 260 Completion rate 65% vs 51% (carbamazepine), P = .02; 15% (carbamazepine) discontinued due to adverse events vs 27% carbamazepine Gilliam et al,47 1998 Active control (valproate 156 58% Completion rate for 500 mg/d vs 31% with valproate, low dose) 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 618 No significant difference in completion rates (81% vs 77%); (carbamazepine) 8% discontinued due to adverse events vs 13% carbamazepine Topiramate Sachdeo et al,72 1997 Pseudoplacebo control 48 54% Completion rate for 1000 mg/d vs 17% for 100 mg/d (P = .002) Oxcarbazepine† Reinikainen et al,98 1987 Active control 40 No significant difference in efficacy, 80% vs 90% completion (carbamazepine) rates; significantly fewer adverse effects with oxcarbazepine (PϽ.05) Dam et al,99 1989 Active control 235 Responder rates Ͼ80% for both oxcarbazepine and (carbamazepine) carbamazepine; significantly fewer adverse effects with oxcarbazepine (P = .04) Bill et al,100 1997 Active control (phenytoin) 287 No significant difference in completion rates (61% vs 58%); significantly fewer adverse effects with oxcarbazepine (P = .02) Christe et al,101 1997 Active control (valproate) 249 No significant difference in completion rates (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 (PϽ.001) Sachdeo et al,102 2001 Pseudoplacebo control 143 32% Completion rate for 2400 mg/d vs 0% for 300 mg/d (PϽ.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 In addition, there have been randomly assigned patients to multiple patients and showed a responder rate reports of lamotrigine-associated rash doses and found no significant increase of 14%, which was not significantly requiring hospitalization, some progress- in efficacy for dosages higher 400 mg/ greater than placebo. However, more ing to Stevens-Johnson syndrome.54 d.64,65 Topiramate has also shown effi- than 600 patients enrolled in 2 addi- However, a recent review of 73 cases of cacy against generalized-onset seizures tional trials showed modest but signifi- antiepileptic drug–related Stevens- including refractory seizures seen in cant responder rates of 29% and 31% Johnson syndrome and toxic epidermal LGS.70,71 In a study of 98 patients with at doses of 56 and 32 mg/d. The most necrolysis found lamotrigine to be asso- LGS, 33% had a 50% reduction in tonic- common adverse effects included diz- ciated with a lower relative risk com- clonic seizures as well as drop attacks ziness, tremor, and impaired concen- pared with phenobarbital, phenytoin, and (P=.002).71 A single pseudoplacebo- tration, most often seen with twice- carbamazepine.55 Subsequent review of controlled monotherapy trial in 48 pa- daily dosing and much less frequently published and unpublished clinical trial tients demonstrated a 54% completion with either 3- or 4-times daily dosing. data showed that severe rashes occur rate for patients taking 1000 mg/d vs 17% Tiagabine undergoes extensive he- more often with rapid titration and in completion rate for those taking 100 patic oxidation via the cytochrome pediatric patients as opposed to adults mg/d (P=.002).72 However, topiramate P450 system but has not been shown (1% vs 0.3%).56 It has also been recog- is not FDA approved for monotherapy. to induce or inhibit hepatic enzyme nized that the risk of skin rash is signifi- Adverse effects that were seen more function and thus has negligible ef- cantly higher when lamotrigine is coad- commonly for patients taking topira- fects on other drugs, including other an- ministered with valproate because mate than placebo in clinical trials in- tiepileptic drugs, warfarin, digoxin, ci- valproate markedly slows the metabo- cluded ataxia, decreased concentration, metidine, triazolam, antipyrine, and lism of lamotrigine. This risk can be confusion, dizziness, and fatigue, most theophylline.80-83 At low doses of 8 reduced with lower initial doses and of which occurred in patients taking mg/d, tiagabine demonstrated no effect slower titration schedules.57 Lamotrigine more than 600 mg/d or with relatively on oral contraceptive metabolism but undergoes hepatic metabolism through rapid titration to maintenance dose in 3 patients taking higher doses were not glucuronidation but does not induce or to 4 weeks.73 No idiosyncratic reactions evaluated.84 Concurrent use of tiagab- inhibit hepatic enzymes and thus has no or organ toxicities have been reported to ine and hepatic enzyme–inducing an- significant effects on the metabolism of date. Other clinically relevant adverse ef- tiepileptic drugs (phenobarbital, phe- other antiepileptic drugs or oral contra- fects include nephrolithiasis, with a re- nytoin, and carbamazepine) reduces the ceptives.58-60 Lamotrigine provides the ported incidence of 1.5%, and mild half-life of tiagabine while coadminis- advantage of a broad-spectrum agent with weight loss averaging 1 to 6 kg predomi- tration of cimetidine and tiagabine has minimal sedation or drug interactions, nantly in the first 3 months of therapy.73,74 no effect on tiagabine pharmacokinet- but its most significant drawback is a slow Topiramate exerts no significant effects ics.83 The effects of other drugs that im- titration schedule requiring 8 to 12 weeks on other antiepileptic drugs or on se- pact the cytochrome P450 system have to reach therapeutic maintenance doses rum norethindrone levels but de- not been extensively evaluated. Of some and even longer when used in conjunc- creases serum estradiol levels by 30% and concern are rare reports of tiagabine tion with valproate. serum digoxin levels by 12%.75,76 Topi- precipitating nonconvulsive status epi- ramate offers the advantage of a broad- lepticus, in particular, absence status Topiramate spectrum agent with minimal drug in- epilepticus.85,86 Tiagabine offers a novel Topiramate is another broad-spectrum teractions, the absence of serious adverse mechanism of action with modest ef- agent approved as adjunctive treatment effects, and the potential for weight loss ficacy in partial-onset seizures. in adults and children 2 years or older but with the slight risk of kidney stones with partial seizures, primary general- and a slow titration schedule (8-12 Levetiracetam ized seizures, and seizures associated weeks). Levetiracetam was approved in 1999 for with LGS.10 Multiple mechanisms of the adjunctive treatment of adults with action have been shown in preclinical Tiagabine partial-onset seizures.10 Its exact mecha- studies including sodium and calcium Tiagabine was FDA approved for use in nism of action is unknown but it does channel blockade, GABA potentiation, 1997 for the adjunctive treatment of not appear to have activity against tra- and glutamate receptor antagonism partial-onset seizures in persons 12 ditional drug targets.87 Four multi- (Figure).61-63 The efficacy of topiramate years or older.10 It has a novel mecha- center trials with levetiracetam as add-on as adjunctive therapy is supported by 6 nism of action, blocking reuptake of therapy enrolled more than a thousand multicenter trials that enrolled 580 pa- GABA into neurons and glial cells (Fig- patients and showed a responder rate of tients with refractory partial-onset sei- ure).77 Three multicenter studies evalu- between 32% and 48% with doses rang- zures (Table 2).64-69 Responder rates were ated the efficacy and tolerability of ti- ing from 2000 to 3000 mg/d (Table 35% to 48% with daily doses ranging agabine as adjunctive therapy (Table 2).88-91 In the US trial, patients were ti- from 300 to 800 mg. The 2 largest trials 2).78-80 The smallest trial enrolled 154 trated to maintenance dose over a 4-week

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period with minimal adverse effects and (PϽ.001).97 However, a similar but widespread clinical use in Japan since a median reduction in seizure fre- much smaller and shorter study enroll- 1989. It is a sulfonamide derivative that quency of 26% to 30% within the first 2 ing 48 patients failed to show a signifi- acts by blocking sodium as well as T- weeks.88 Betts et al91 evaluated the tol- cant decrease in seizure frequency.96 Ox- type calcium channels (Figure).110,111 erability and efficacy of 2000 and 4000 carbazepine was also evaluated in 6 Two multicenter trials carried out in the mg/d started without titration and found monotherapy trials (Table 3).98-103 Four United States and Europe in 342 pa- both to be well tolerated but, interest- active-control trials compared oxcar- tients evaluated the efficacy and toler- ingly, higher responder rates were seen bazepine with carbamazepine, phe- ability of zonisamide for partial-onset sei- in patients receiving 2000 mg/d. nytoin, or valproate and found similar zures.112,113 The patients randomly Common adverse effects of leveti- efficacy but a statistically significant de- assigned to receive zonisamide were ti- racetam in clinical trials included som- crease in adverse effects in the oxcar- trated up to a dose of 400 to 500 mg/d nolence, asthenia, headache, and infec- bazepine group in 3 of the trials. In ad- and had a responder rate of 30% to 43% tion. The majority of adverse effects dition, 2 pseudoplacebo-controlled trials (Table 2). Although FDA approved for occurred in the first 4 weeks of therapy in 230 patients compared the efficacy of use only in partial-onset seizures, case and did not appear to be dose related. In 300 mg/d vs 2400 mg/d of oxcarbaz- studies have demonstrated dramatic im- addition, behavioral disturbances such epine and demonstrated a significantly provement with zonisamide in patients as agitation and anxiety were reported higher completion rate in the high- with generalized-onset seizures, particu- in up to 13% of the study cohort.88-91 The dose group (PϽ.001).102,103 larly myoclonus.114,115 pharmacokinetic profile of leveti- Common adverse effects of oxcarbaz- Statistically significant adverse ef- racetam is favorable, with absence of he- epine in clinical trials were dose related fects were reported in up to 59% of patic metabolism and low protein bind- and included dizziness, diplopia, som- study patients compared with 28% in ing.92 No significant interaction was nolence, nausea, and ataxia, particu- the placebo group and included fa- reported with coadministration of other larly in patients receiving 2400 mg/d. Al- tigue, dizziness, ataxia, and anorexia. antiepileptic drugs, oral contraceptives, lergic skin reactions occurred less An earlier open-label study reported a digoxin, warfarin, or probenecid.92 Ad- frequently than with carbamazepine, al- 3.5% incidence of renal calculi that ini- ditionally, levetiracetam has the high- though a cross-sensitivity of approxi- tially halted the drug’s development, but est safety margin in animal models com- mately 30% has been demonstrated in this finding was not reproduced in sub- pared with all other antiepileptic drugs.93 patients with hypersensitivity to carba- sequent studies.116 In the pediatric Levetiracetam offers the advantage of a mazepine.104 Hyponatremia has also been population there have been rare re- favorable pharmacokinetic profile and reported, particularly in elderly per- ports of high fever secondary to hyper- high safety margin with the capability of sons. In a large postmarketing study, 23% hidrosis.117 Zonisamide has the advan- rapid dosage titration. of 350 patients receiving oxcarbaz- tage of a long half-life, averaging 63 to epine were found to have a serum so- 69 hours in healthy volunteers, mak- Oxcarbazepine dium level lower than 135 mEq/L, al- ing once-daily dosing possible.118 Low Oxcarbazepine, an analogue of carba- though only 1% required discontinuation protein binding as well as partial liver mazepine, is available for use as mono- of the drug.105 Oxcarbazepine does not metabolism via conjugation contrib- therapy or adjunctive therapy in the induce its own metabolism or hepatic mi- utes to its minimal interaction with treatment of partial-onset seizures in per- crosomal enzymes and is not affected by other medications, including other an- sons aged 4 years and older.10 It was de- concurrent administration of erythro- tiepileptic drugs and cimetidine.10 Be- signed to have similar efficacy to carba- mycin, as seen with carbamaze- cause zonisamide is a sulfonamide de- mazepine but fewer adverse effects, pine.106,107 In addition, oxcarbazepine has rivative its use is contraindicated in largely due to its lack of formation of the not been shown to interact with other an- patients with a known sulfonamide al- toxic metabolite carbamazepine10, 11 tiepileptic drugs, cimetidine, warfarin, or lergy. Zonisamide is efficacious as ad- epoxide.94 Like carbamazepine, its prin- dextropropoxyphene.10 However, oxcar- junctive therapy for many seizure types, cipal mechanism of action is via so- bazepine decreases serum levels of oral particularly myoclonus, with the ad- dium channel blockade (Figure).95 Ox- contraceptives and felodipine.108,109 Ox- vantage of once-daily dosing. carbazepine has been evaluated as carbazepine offers similar efficacy to car- adjunctive therapy for partial seizures in bamazepine but with fewer drug inter- COMMENT 2 clinical trials (Table 2).96,97 The larger actions and overall fewer adverse effects, Is There a Superior New trial enrolled 694 patients who were ran- with the exception of hyponatremia. Antiepileptic Drug? domly assigned to receive placebo or ox- Unfortunately, to our knowledge there carbazepine in dosages of 600 mg/d, Zonisamide have been no randomized controlled 1200 mg/d, or 2400 mg/d. Responder Zonisamide is a broad-spectrum anti- clinical trials comparing the efficacy and rates were 27%, 42%, and 50%, respec- convulsant that has been available in the tolerability of the new antiepileptic tively, for the oxcarbazepine groups United States since 2000 but has had drugs. Although most of the individual

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they do highlight some potential differ- that “therapeutic ranges” in the litera- Table 4. Dosing Adjustment for Patients With Impaired Renal Function* ences among these drugs that future ture often do not correlate with a given Creatinine studies may further differentiate. individual’s response. Therefore, titra- Clearance, mL/min Dosage, mg tion to clinical efficacy is recom- Gabapentin Are the New Antiepileptic Drugs mended not only for the traditional an- Ͼ60 400 3 times daily Superior to the Traditional 30-60 300 twice daily tiepileptic drugs but for the newer agents 15-30 300 daily Antiepileptic Drugs? as well. However, if a patient does not Ͻ15 300 every other day There was much enthusiasm with the ar- respond to a particular therapy as ex- Hemodialysis 200-300† Levetiracetam rival of the new antiepileptic drugs, es- pected, checking the serum drug con- Ͼ80 500-1500 twice daily pecially considering the number of pa- centration may aid in determining com- 50-80 500-1000 twice daily 30-50 250-750 twice daily tients who were taking combinations of pliance and identifying potential Ͻ30 250-500 twice daily the traditional antiepileptic drugs and pharmacokinetic interactions. Serum Hemodialysis 500-1000† continuing to have frequent break- drug level tests are commercially avail- *Recommendations based on package insert. †Supplemental dose following dialysis. through seizures coupled with intolerable, although there are not sufficient able adverse effects. Despite the lack of data available to determine the opti- comprehensive clinical trials compar- mum serum concentrations of many of drugs were approved based on add-on ing the new and traditional antiepilep- the new antiepileptic drugs. trials with similar study designs, vary- tic drugs, there is evidence to suggest Since many of the traditional antiepi- ing study populations and titration some advantages of the new agents. leptic drugs are associated with rare but schedules make direct comparisons dif- Gabapentin, lamotrigine, and oxcarbaz- potentially serious bone marrow sup- ficult. Nevertheless, Marson et al118 per- epine have each been compared with pression as well as hepatotoxicity, base- formed a meta-analysis of published and carbamazepine as monotherapy in par- line as well as routine monitoring of unpublished randomized controlled tial-onset seizures and found to have bet- hematological and liver functions is rec- trials in which gabapentin, lamotrigine, ter tolerability, although there was no ommended. Of the new antiepileptic tiagabine, topiramate, vigabatrin, and difference in efficacy.48,96,99,119 La- drugs, the only medication that has been zonisamide were compared with pla- motrigine, topiramate, and zonisamide associated with serious organ toxicity is cebo as add-on therapy in patients with have been shown to have broad- felbamate, with rare but potentially fatal refractory partial-onset seizures. The spectrum activity with efficacy against cases of aplastic anemia and hepatotox- odds ratio for a 50% or greater reduc- generalized- as well as partial-onset sei- icity.22,23 Therefore, felbamate is the only tion in seizure frequency was calcu- zures while valproate is the only tradi- new antiepileptic drug that requires rou- lated for each individual drug. There was tional antiepileptic drug with this spec- tine monitoring of complete blood cell no conclusive evidence for a difference trum of activity.51,52,70,71,114,115 counts and liver function.10 in efficacy or tolerability among the Most of the new antiepileptic drugs drugs because the 95% confidence in- lack hepatic enzyme induction and have What Dosage Adjustments Are tervals (CIs) overlapped. However, topi- not been shown to interact with other Required in the Setting of Hepatic ramate had the highest odds ratio for hepatically metabolized medications Disease or Renal Insufficiency? 50% responders (4.22; 95% CI, unlike phenobarbital, phenytoin, and Studies have been performed evaluat- 2.80-6.35), which was almost twice that carbamazepine.34,35,92 Finally, only fel- ing the pharmacokinetic effects of he- of the lowest odds ratio (2.29; 95% CI, bamate and lamotrigine have demon- patic and renal disease on most of the 1.53-3.43) for patients taking gabapen- strated potentially life-threatening ad- newer antiepileptic drugs. However, few tin. In addition, the odds ratios for with- verse effects, which have been well data are available regarding the clini- drawal from treatment for patients tak- documented with phenytoin, carba- cal significance of these effects. For pa- ing lamotrigine or gabapentin were no mazepine, and valproate.22,54 How- tients with hepatic disease, there is in- higher than placebo. ever, the new anticonvulsant medica- sufficient information available to make In addition to differences in study tions are significantly more expensive any recommendations on the neces- populations and nonrandomized com- than the traditional drugs, and ad hoc sity of dosage adjustments. However, parisons, shortcomings of this analysis studies have not shown evidence of su- since gabapentin and levetiracetam both include the absence of comparative data perior cost-effectiveness.120 lack significant hepatic metabolism, in patients taking felbamate, oxcarbaz- both of these drugs theoretically should epine, or levetiracetam as well as exclu- Is Routine Serum Monitoring be safe choices in patients with he- sion of monotherapy studies and stud- Required? patic dysfunction. ies evaluating generalized-onset seizures. Routine monitoring of serum drug con- Since gabapentin and levetiracetam are Although these results do not allow the centrations has traditionally been used primarily nonmetabolized and ex- physician to make an evidence-based de- to guide dosage adjustments in patients creted through the kidneys, the dosage cision in choosing an antiepileptic drug, taking antiepileptic drugs, despite the fact should be decreased for patients with re-

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