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Figure. Principal Mechanisms of Action of the New Antiepileptic Drugs
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Principal mechanisms of action of the newer antiepileptic drugs include voltage-dependent ion channel blockade, enhancement of inhibitory neurotransmission, and reduction of excitatory neurotransmission. Mechanisms unique from those for traditional antiepileptic drugs include glutamate antagonism at N-methyl-D-aspartate (NMDA) receptors (felbamate) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (felbamate, topiramate) and inhibition of γ-aminobutyric acid (GABA) reuptake in neurons and astrocytes (tiagabine).
Table 1. Antiepileptic Drugs Approved Since 1993*
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Table 2. Randomized, Placebo-Controlled Trials of the New Antiepileptic Drugs as Adjunctive Treatment for Partial-Onset Seizures*
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Table 3. Randomized Monotherapy Trials of the New Antiepileptic Drugs in Partial-Onset Seizures*
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Table 4. Dosing Adjustment for Patients With Impaired Renal Function*
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Scientific Review and Clinical Applications
Clinician's Corner
February 4, 2004

The New Antiepileptic DrugsScientific Review

Author Affiliations

Author Affiliations: Department of Neurology, Emory University (Drs LaRoche and Helmers), and Atlanta VA Medical Center (Dr LaRoche), Atlanta, Ga.

JAMA. 2004;291(5):605-614. doi:10.1001/jama.291.5.605
Context

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

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

Data Sources A search of the Cochrane Central Register of Controlled Trials was performed to identify all published human and English-language randomized controlled trials evaluating the efficacy and tolerability of the antiepileptic drugs that have been approved for use in the United States since 1990. Additional reports evaluating pharmacokinetic properties were identified through a MEDLINE search as well as review of article bibliographies.

Study Selection and Data Extraction Search terms included felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Studies were selected if efficacy and tolerability were reported as major outcome measures. Included studies (n = 55) enrolled a minimum of 20 adult subjects and had a treatment period of at least 6 weeks.

Data Synthesis Eight new antiepileptic drugs have been approved for use in the United States in the past decade. Each new antiepileptic drug is well tolerated and demonstrates statistically significant reductions in seizure frequency over baseline. No randomized controlled 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 medications are more efficacious, several studies have demonstrated broader spectrum of activity, fewer drug interactions, and overall better tolerability of the new agents.

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 new antiepileptic drugs are well tolerated with few adverse effects, minimal drug interactions, and a broad spectrum of activity.

Quiz Ref IDEpilepsy is defined as a chronic neurological condition characterized by recurrent, unprovoked seizures.1 It is one of the most common serious neurological disorders in the United States and often requires long-term management. Each year 150 000 people in the United States are newly diagnosed as having epilepsy, with the cumulative lifetime incidence approaching 3%.2,3 The incidence is highest during the first year of life and in elderly persons.2 Although most people with epilepsy become seizure-free with appropriate therapy, 30% to 40% of patients will continue to have seizures despite the use of antiepileptic drugs either alone or in combination.4 Patients with uncontrolled seizures experience significant morbidity and mortality and face social stigma and discrimination as well.

In the United States, only 17% of patients with new-onset epilepsy are initially seen by a neurologist.5 Furthermore, primary care physicians provide approximately 40% of the long-term management of epilepsy patients with or without initial consultation with a specialist.6 Unfortunately, a survey of general practitioners revealed that only 40% of responders felt confident in their knowledge of epilepsy and two thirds were unfamiliar with the new antiepileptic drugs.7 A recent survey of 71 patients with epilepsy who are treated exclusively by general practitioners showed that 45% had experienced a seizure within the past year, 68% complained of drowsiness or difficulty in concentration with their current medications, and 28% were prescribed polytherapy.8 Therefore, general practitioners play a vital role in the treatment of epilepsy patients with ongoing seizures.

Prior to 1993, the choice of an anticonvulsant medication was limited to phenobarbital, primidone, phenytoin, carbamazepine, and valproate. Although these "traditional" anticonvulsants have the advantage of familiarity as well as proven efficacy, many patients are left with refractory seizures as well as intolerable adverse effects. Since 1993, 8 new medications have been approved by the US Food and Drug Administration (FDA), expanding treatment options (Table 1). The newer antiepileptic drugs offer the potential advantages of fewer drug interactions, unique mechanisms of action, and a broader spectrum of activity. With more options, however, comes the challenge of determining what role the new antiepileptic drugs play in optimizing treatment in addition to understanding important adverse effects and drug interactions of these increasingly prescribed medications. The purpose of this article is to familiarize primary care clinicians with the efficacy, tolerability, and pharmacokinetic properties of the new antiepileptic drugs.

METHODS

We searched the Cochrane Central Register of Controlled Trials to identify all published human and English-language randomized controlled clinical trials evaluating the efficacy and tolerability of antiepileptic drugs that have been FDA approved since 1990. Additional reports evaluating pharmacokinetic properties were identified through a MEDLINE search as well as review of article bibliographies. Search terms included felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Studies were selected if efficacy and tolerability were reported as major outcome measures. Included studies (n = 55) enrolled a minimum of 20 adult subjects and had a treatment period of at least 6 weeks.

Quiz Ref IDThe majority of the new antiepileptic drugs gained initial FDA approval based on randomized, double-blind, placebo-controlled clinical trials in which the new antiepileptic drug was used as adjunctive treatment. Typically, trials enrolled patients with refractory partial-onset seizures to receive either the study drug or placebo in addition to their original medication(s). Patients were followed up for 6 to 8 weeks to establish a baseline seizure frequency, then randomly assigned to either placebo or study drug and followed up for 8 to 12 weeks while seizure frequency and tolerability were monitored. The primary outcome measure was a reduction in seizure frequency over baseline compared with placebo. A "responder rate" is reported as the number of patients who achieved a 50% or greater reduction in seizure frequency from baseline.

There are obvious limitations to this trial design. Efficacy is often underestimated and responder rates are typically less than 50% because the study population with refractory seizures has typically not responded to multiple antiepileptic drugs and is therefore not comparable to patients in a typical clinical practice. Toxicity is often overestimated because adverse effects may be additive and not specifically due to the add-on therapy. In addition, many of the new antiepileptic drugs were titrated more rapidly during clinical trials than is currently recommended, further overestimating the risk of toxicity and adverse effects. Finally, the variability in study groups and trial designs makes direct comparisons among trials impossible. Despite these drawbacks, adjunctive clinical trials are overall the safest and most ethical means of testing new antiepileptic compounds.

Few of the new antiepileptic drugs have been evaluated in monotherapy trials and fewer yet have been FDA approved for use as monotherapy. This presents a dilemma that has led to frequent off-label use because monotherapy offers many advantages over polytherapy, including fewer adverse effects, less drug interactions, lower cost, and improved compliance. The reason for fewer monotherapy approvals stems from the difficulty in trial design. There are 2 common approaches to monotherapy trials. An active-control comparison typically randomly assigns patients with new-onset seizures to receive either the study drug or a well-established antiepileptic drug at low therapeutic doses. Conversion to monotherapy trials assigns patients to be converted from their current antiepileptic drug(s) to either a subtherapeutic dose of the test drug (referred to as pseudoplacebo) or a higher dose of the test drug that is thought to be efficacious. Efficacy is measured as completion rate or mean time to exiting the study. Exit criteria consist of either an increase in seizure frequency above baseline, a prolonged generalized seizure, or status epilepticus. In addition, the percentage of patients discontinuing due to adverse effects is reported. Agents that show efficacy in placebo-controlled trials are considered acceptable proof of efficacy for FDA approval; however, this trial design raises obvious ethical concerns. To demonstrate efficacy in active-control comparison trials, the study drug must show superiority over the control and not merely equivalency.9

RESULTS
Felbamate

Felbamate was the first new antiepileptic drug to gain FDA approval (in 1993) and its introduction was met with much enthusiasm and initial success. It is a broad-spectrum agent approved for both monotherapy and adjunctive treatment of partial-onset seizures in adults as well as partial- and generalized-onset seizures associated with Lennox-Gastaut syndrome (LGS) in children.10,11 Several mechanisms of action have been identified, including sodium channel blockade, calcium channel blockade, and antagonism of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (Figure 1).1215 The efficacy of felbamate as adjunctive therapy for partial seizures has been evaluated in 2 outpatient crossover trials.16,17 The smaller trial enrolled 30 patients and found no significant decrease in seizure frequency during the felbamate treatment period, while there was a 23% decrease in seizure frequency in a larger trial of 67 patients (P = .02).

Felbamate has also shown efficacy as monotherapy in 2 trials that compared felbamate, 3600 mg/d, with low-dose valproate.18,19 A total of 138 patients were randomized, and there were significantly higher completion rates in both felbamate groups (60% vs 22% and 86% vs 10%, P<.01). More importantly, felbamate has shown great success in the treatment of LGS, a childhood-onset epilepsy consisting of severe cognitive dysfunction accompanied by seizures of many types, including atonic seizures (drop attacks), which are notoriously treatment resistant. Two studies support the efficacy of felbamate as add-on therapy in adults with LGS, with responder rates up to 50% and a decrease in drop attacks of 30%.20,21

The most commonly documented adverse effects with felbamate include gastrointestinal disturbances, anorexia, and insomnia.18,19 Unfortunately, a year after FDA approval, reports of rare idiosyncratic reactions began to emerge. Aplastic anemia has been reported in 34 cases with an incidence of approximately 1 in 8000 patient exposures.22,23 Hepatotoxicity was also reported at a slightly lower incidence of 1 in 10 000, which parallels the risk with valproate therapy.22 Felbamate remains on the market but with a black box warning for aplastic anemia and hepatic failure and is currently not considered a first-line anticonvulsant medication. However, felbamate can still be useful for patients with LGS or partial-onset seizures refractory to other antiepileptic drugs, but it is recommended to obtain informed consent and monitor hematologic function frequently.

Gabapentin

Quiz Ref IDGabapentin was approved for use in 1993 and is currently indicated as adjunctive therapy for partial seizures with and without secondary generalization in persons 3 years and older.10 Interestingly, more than 80% of prescriptions for gabapentin are for off-label uses such as neuropathic pain, migraine headache, spasticity, and bipolar disorder.24 Although structurally related to γ-aminobutyric acid (GABA), its precise mechanism of action in humans is unknown (Figure 1).25 Four initial add-on trials enrolling more than 700 patients with refractory partial-onset epilepsy led to the FDA approval of gabapentin.2629 Dosages ranged from 1200 to 1800 mg/d with 25% to 33% demonstrating a greater than 50% reduction in seizure frequency from baseline (Table 2).

Gabapentin has also been evaluated in 2 large monotherapy trials (Table 3). The first study, a dose-response, pseudoplacebo-controlled trial (n = 275), randomly assigned patients to 1 of 3 daily doses (600 mg, 1200 mg, and 2400 mg) and found no significant difference in completion rates, which were meager and ranged from 15% to 26%.30 The second study compared gabapentin at 3 different daily doses (300 mg, 900 mg, and 1800 mg) with an active control (carbamazepine, 600 mg/d). There was no significant difference in completion rates (38% vs 37%), suggesting equivalent but not superior efficacy of gabapentin to carbamazepine. In addition, the time to study exit was significantly longer for the patients in the gabapentin group administered 900 or 1800 mg/d compared with those in the 300-mg/d group.31 The most common reason for exit from the study was an increase in seizure frequency above baseline. Although gabapentin had modest efficacy as monotherapy in this single study, it is not FDA approved as such. A single study evaluated the efficacy of gabapentin for generalized-onset seizures and showed no change in seizure frequency from baseline.32

Adverse effects that were reported more often in patients taking gabapentin than placebo included somnolence, dizziness, and fatigue, which usually resolved within the first 2 weeks of therapy. Modest weight gain has also been observed in postmarketing studies but no serious idiosyncratic reactions or organ toxicities have been identified.33 Gabapentin possesses several desirable pharmacokinetic properties: it does not undergo hepatic metabolism and is excreted unchanged in urine.34 In addition, gabapentin does not affect plasma concentrations of other antiepileptic drugs, oral contraceptives, or probenecid.35,36 Coadministration with antacids causes a decrease in bioavailability of gabapentin, while cimetidine decreases oral clearance by 14%, which is of unknown clinical significance.10 Gabapentin offers the unique advantages of a wide margin of safety with good tolerability in the absence of any significant drug interactions but with modest efficacy.

Lamotrigine

Lamotrigine is a broad-spectrum agent that was approved for use in 1994 as an adjunctive treatment in adults with partial-onset seizures.10 Later approval was granted for use in adults and children aged 2 years and older with generalized seizures associated with LGS and for conversion to monotherapy.10 Lamotrigine exhibits its antiepileptic effect primarily by blockade of sodium channels and, to a lesser extent, calcium channels (Figure 1).37 Seven clinical trials have shown lamotrigine's efficacy as an adjunctive agent in partial seizures with responder rates ranging from 17% to 67% in dosages up to 500 mg/d (Table 2).3844 In addition, 2 smaller trials evaluating the efficacy of lamotrigine as adjunctive therapy in partial seizures failed to show statistically significant reductions in seizure frequency from baseline.45,46 The efficacy of lamotrigine as monotherapy was established in a multicenter study of 156 patients comparing lamotrigine (500 mg/d) with low-dose valproate (1000 mg/d).47 Fifty-eight percent of the patients in the lamotrigine group completed the study vs 31% in the valproate group (P = .001). In addition, active control monotherapy trials have compared lamotrigine to phenytoin as well as carbamazepine and found lamotrigine to have similar efficacy but fewer adverse effects and lower withdrawal rates (Table 3).4850 Two studies have evaluated the efficacy of lamotrigine in generalized seizures associated with LGS.51,52 The largest study enrolled 169 patients and demonstrated a 33% responder rate (P = .01) and a 34% decrease in drop attacks.

Pooled clinical trial data showed that adverse effects necessitated withdrawal of lamotrigine therapy in 10.2% of patients (n = 3501), with rash being the most common cause for discontinuation (3.8%).53 In addition, there have been reports of lamotrigine-associated rash requiring hospitalization, some progressing to Stevens-Johnson syndrome.54 However, a recent review of 73 cases of antiepileptic drug–related Stevens-Johnson syndrome and toxic epidermal necrolysis found lamotrigine to be associated with a lower relative risk compared with phenobarbital, phenytoin, and carbamazepine.55 Subsequent review of published and unpublished clinical trial data showed that severe rashes occur more often with rapid titration and in pediatric patients as opposed to adults (1% vs 0.3%).56 It has also been recognized that the risk of skin rash is significantly higher when lamotrigine is coadministered with valproate because valproate markedly slows the metabolism of lamotrigine. This risk can be reduced with lower initial doses and slower titration schedules.57 Lamotrigine undergoes hepatic metabolism through glucuronidation but does not induce or inhibit hepatic enzymes and thus has no significant effects on the metabolism of other antiepileptic drugs or oral contraceptives.5860 Lamotrigine provides the advantage of a broad-spectrum agent with minimal sedation or drug interactions, but its most significant drawback is a slow titration schedule requiring 8 to 12 weeks to reach therapeutic maintenance doses and even longer when used in conjunction with valproate.

Topiramate

Topiramate is another broad-spectrum agent approved as adjunctive treatment in adults and children 2 years or older with partial seizures, primary generalized seizures, and seizures associated with LGS.10 Multiple mechanisms of action have been shown in preclinical studies including sodium and calcium channel blockade, GABA potentiation, and glutamate receptor antagonism (Figure 1).6163 The efficacy of topiramate as adjunctive therapy is supported by 6 multicenter trials that enrolled 580 patients with refractory partial-onset seizures (Table 2).6469 Responder rates were 35% to 48% with daily doses ranging from 300 to 800 mg. The 2 largest trials randomly assigned patients to multiple doses and found no significant increase in efficacy for dosages higher 400 mg/d.64,65 Topiramate has also shown efficacy against generalized-onset seizures including refractory seizures seen in LGS.70,71 In a study of 98 patients with LGS, 33% had a 50% reduction in tonic-clonic seizures as well as drop attacks (P = .002).71 A single pseudoplacebo-controlled monotherapy trial in 48 patients demonstrated a 54% completion rate for patients taking 1000 mg/d vs 17% completion rate for those taking 100 mg/d (P = .002).72 However, topiramate is not FDA approved for monotherapy.

Adverse effects that were seen more commonly for patients taking topiramate than placebo in clinical trials included ataxia, decreased concentration, confusion, dizziness, and fatigue, most of which occurred in patients taking more than 600 mg/d or with relatively rapid titration to maintenance dose in 3 to 4 weeks.73 No idiosyncratic reactions or organ toxicities have been reported to date. Other clinically relevant adverse effects include nephrolithiasis, with a reported incidence of 1.5%, and mild weight loss averaging 1 to 6 kg predominantly in the first 3 months of therapy.73,74 Topiramate exerts no significant effects on other antiepileptic drugs or on serum norethindrone levels but decreases serum estradiol levels by 30% and serum digoxin levels by 12%.75,76 Topiramate offers the advantage of a broad-spectrum agent with minimal drug interactions, the absence of serious adverse effects, and the potential for weight loss but with the slight risk of kidney stones and a slow titration schedule (8-12 weeks).

Tiagabine

Tiagabine was FDA approved for use in 1997 for the adjunctive treatment of partial-onset seizures in persons 12 years or older.10 It has a novel mechanism of action, blocking reuptake of GABA into neurons and glial cells (Figure 1).77 Three multicenter studies evaluated the efficacy and tolerability of tiagabine as adjunctive therapy (Table 2).7880 The smallest trial enrolled 154 patients and showed a responder rate of 14%, which was not significantly greater than placebo. However, more than 600 patients enrolled in 2 additional trials showed modest but significant responder rates of 29% and 31% at doses of 56 and 32 mg/d. The most common adverse effects included dizziness, tremor, and impaired concentration, most often seen with twice-daily dosing and much less frequently with either 3- or 4-times daily dosing.

Tiagabine undergoes extensive hepatic oxidation via the cytochrome P450 system but has not been shown to induce or inhibit hepatic enzyme function and thus has negligible effects on other drugs, including other antiepileptic drugs, warfarin, digoxin, cimetidine, triazolam, antipyrine, and theophylline.8083 At low doses of 8 mg/d, tiagabine demonstrated no effect on oral contraceptive metabolism but patients taking higher doses were not evaluated.84 Concurrent use of tiagabine and hepatic enzyme–inducing antiepileptic drugs (phenobarbital, phenytoin, and carbamazepine) reduces the half-life of tiagabine while coadministration of cimetidine and tiagabine has no effect on tiagabine pharmacokinetics.83 The effects of other drugs that impact the cytochrome P450 system have not been extensively evaluated. Of some concern are rare reports of tiagabine precipitating nonconvulsive status epilepticus, in particular, absence status epilepticus.85,86 Tiagabine offers a novel mechanism of action with modest efficacy in partial-onset seizures.

Levetiracetam

Levetiracetam was approved in 1999 for the adjunctive treatment of adults with partial-onset seizures.10 Its exact mechanism of action is unknown but it does not appear to have activity against traditional drug targets.87 Four multicenter trials with levetiracetam as add-on therapy enrolled more than a thousand patients and showed a responder rate of between 32% and 48% with doses ranging from 2000 to 3000 mg/d (Table 2).8891 In the US trial, patients were titrated to maintenance dose over a 4-week period with minimal adverse effects and a median reduction in seizure frequency of 26% to 30% within the first 2 weeks.88 Betts et al91 evaluated the tolerability and efficacy of 2000 and 4000 mg/d started without titration and found both to be well tolerated but, interestingly, higher responder rates were seen in patients receiving 2000 mg/d.

Common adverse effects of levetiracetam in clinical trials included somnolence, asthenia, headache, and infection. The majority of adverse effects occurred in the first 4 weeks of therapy and did not appear to be dose related. In addition, behavioral disturbances such as agitation and anxiety were reported in up to 13% of the study cohort.8891 The pharmacokinetic profile of levetiracetam is favorable, with absence of hepatic metabolism and low protein binding.92 No significant interaction was reported with coadministration of other antiepileptic drugs, oral contraceptives, digoxin, warfarin, or probenecid.92 Additionally, levetiracetam has the highest safety margin in animal models compared with all other antiepileptic drugs.93 Levetiracetam offers the advantage of a favorable pharmacokinetic profile and high safety margin with the capability of rapid dosage titration.

Oxcarbazepine

Oxcarbazepine, an analogue of carbamazepine, is available for use as monotherapy or adjunctive therapy in the treatment of partial-onset seizures in persons aged 4 years and older.10 It was designed to have similar efficacy to carbamazepine but fewer adverse effects, largely due to its lack of formation of the toxic metabolite carbamazepine10, 11 epoxide.94 Like carbamazepine, its principal mechanism of action is via sodium channel blockade (Figure 1).95 Oxcarbazepine has been evaluated as adjunctive therapy for partial seizures in 2 clinical trials (Table 2).96,97 The larger trial enrolled 694 patients who were randomly assigned to receive placebo or oxcarbazepine in dosages of 600 mg/d, 1200 mg/d, or 2400 mg/d. Responder rates were 27%, 42%, and 50%, respectively, for the oxcarbazepine groups (P<.001).97 However, a similar but much smaller and shorter study enrolling 48 patients failed to show a significant decrease in seizure frequency.96 Oxcarbazepine was also evaluated in 6 monotherapy trials (Table 3).98103 Four active-control trials compared oxcarbazepine with carbamazepine, phenytoin, or valproate and found similar efficacy but a statistically significant decrease in adverse effects in the oxcarbazepine group in 3 of the trials. In addition, 2 pseudoplacebo-controlled trials in 230 patients compared the efficacy of 300 mg/d vs 2400 mg/d of oxcarbazepine and demonstrated a significantly higher completion rate in the high-dose group (P<.001).102,103

Common adverse effects of oxcarbazepine in clinical trials were dose related and included dizziness, diplopia, somnolence, nausea, and ataxia, particularly in patients receiving 2400 mg/d. Allergic skin reactions occurred less frequently than with carbamazepine, although a cross-sensitivity of approximately 30% has been demonstrated in patients with hypersensitivity to carbamazepine.104 Hyponatremia has also been reported, particularly in elderly persons. In a large postmarketing study, 23% of 350 patients receiving oxcarbazepine were found to have a serum sodium level lower than 135 mEq/L, although only 1% required discontinuation of the drug.105 Oxcarbazepine does not induce its own metabolism or hepatic microsomal enzymes and is not affected by concurrent administration of erythromycin, as seen with carbamazepine.106,107 In addition, oxcarbazepine has not been shown to interact with other antiepileptic drugs, cimetidine, warfarin, or dextropropoxyphene.10 However, oxcarbazepine decreases serum levels of oral contraceptives and felodipine.108,109 Oxcarbazepine offers similar efficacy to carbamazepine but with fewer drug interactions and overall fewer adverse effects, with the exception of hyponatremia.

Zonisamide

Zonisamide is a broad-spectrum anticonvulsant that has been available in the United States since 2000 but has had widespread clinical use in Japan since 1989. It is a sulfonamide derivative that acts by blocking sodium as well as T-type calcium channels (Figure 1).110,111 Two multicenter trials carried out in the United States and Europe in 342 patients evaluated the efficacy and tolerability of zonisamide for partial-onset seizures.112,113 The patients randomly assigned to receive zonisamide were titrated up to a dose of 400 to 500 mg/d and had a responder rate of 30% to 43% (Table 2). Although FDA approved for use only in partial-onset seizures, case studies have demonstrated dramatic improvement with zonisamide in patients with generalized-onset seizures, particularly myoclonus.114,115

Statistically significant adverse effects were reported in up to 59% of study patients compared with 28% in the placebo group and included fatigue, dizziness, ataxia, and anorexia. An earlier open-label study reported a 3.5% incidence of renal calculi that initially halted the drug's development, but this finding was not reproduced in subsequent studies.116 In the pediatric population there have been rare reports of high fever secondary to hyperhidrosis.117 Zonisamide has the advantage of a long half-life, averaging 63 to 69 hours in healthy volunteers, making once-daily dosing possible.118 Low protein binding as well as partial liver metabolism via conjugation contributes to its minimal interaction with other medications, including other antiepileptic drugs and cimetidine.10 Because zonisamide is a sulfonamide derivative its use is contraindicated in patients with a known sulfonamide allergy. Zonisamide is efficacious as adjunctive therapy for many seizure types, particularly myoclonus, with the advantage of once-daily dosing.

COMMENT
Is There a Superior New Antiepileptic Drug?

Unfortunately, to our knowledge there have been no randomized controlled clinical trials comparing the efficacy and tolerability of the new antiepileptic drugs. Although most of the individual drugs were approved based on add-on trials with similar study designs, varying study populations and titration schedules make direct comparisons difficult. Quiz Ref IDNevertheless, Marson et al118 performed a meta-analysis of published and unpublished randomized controlled trials in which gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide were compared with placebo as add-on therapy in patients with refractory partial-onset seizures. The odds ratio for a 50% or greater reduction in seizure frequency was calculated for each individual drug. There was no conclusive evidence for a difference in efficacy or tolerability among the drugs because the 95% confidence intervals (CIs) overlapped. However, topiramate had the highest odds ratio for 50% responders (4.22; 95% CI, 2.80-6.35), which was almost twice that of the lowest odds ratio (2.29; 95% CI, 1.53-3.43) for patients taking gabapentin. In addition, the odds ratios for withdrawal from treatment for patients taking lamotrigine or gabapentin were no higher than placebo.
 In addition to differences in study populations and nonrandomized comparisons, shortcomings of this analysis include the absence of comparative data in patients taking felbamate, oxcarbazepine, or levetiracetam as well as exclusion of monotherapy studies and studies evaluating generalized-onset seizures.
Although these results do not allow the physician to make an evidence-based decision in choosing an antiepileptic drug, they do highlight some potential differences among these drugs that future studies may further differentiate.

Are the New Antiepileptic Drugs Superior to the Traditional Antiepileptic Drugs?

There was much enthusiasm with the arrival of the new antiepileptic drugs, especially considering the number of patients who were taking combinations of the traditional antiepileptic drugs and continuing to have frequent breakthrough seizures coupled with intolerable adverse effects. Despite the lack of comprehensive clinical trials comparing the new and traditional antiepileptic drugs, there is evidence to suggest some advantages of the new agents. Gabapentin, lamotrigine, and oxcarbazepine have each been compared with carbamazepine as monotherapy in partial-onset seizures and found to have better tolerability, although there was no difference in efficacy.48,96,99,119 Lamotrigine, topiramate, and zonisamide have been shown to have broad-spectrum activity with efficacy against generalized as well as partial-onset seizures while valproate is the only traditional antiepileptic drug with this spectrum of activity.51,52,70,71,114,115

Most of the new antiepileptic drugs lack hepatic enzyme induction and have not been shown to interact with other hepatically metabolized medications unlike phenobarbital, phenytoin, and carbamazepine.34,35,92 Finally, only felbamate and lamotrigine have demonstrated potentially life-threatening adverse effects, which have been well documented with phenytoin, carbamazepine, and valproate.22,54 However, the new anticonvulsant medications are significantly more expensive than the traditional drugs, and ad hoc studies have not shown evidence of superior cost-effectiveness.120

Is Routine Serum Monitoring Required?

Quiz Ref IDRoutine monitoring of serum drug concentrations has traditionally been used to guide dosage adjustments in patients taking antiepileptic drugs, despite the fact that "therapeutic ranges" in the literature often do not correlate with a given individual's response. Therefore, titration to clinical efficacy is recommended not only for the traditional antiepileptic drugs but for the newer agents as well. However, if a patient does not respond to a particular therapy as expected, checking the serum drug concentration may aid in determining compliance and identifying potential pharmacokinetic interactions. Serum drug level tests are commercially available, although there are not sufficient data available to determine the optimum serum concentrations of many of the new antiepileptic drugs.

Since many of the traditional antiepileptic drugs are associated with rare but potentially serious bone marrow suppression as well as hepatotoxicity, baseline as well as routine monitoring of hematological and liver functions is recommended. Of the new antiepileptic drugs, the only medication that has been associated with serious organ toxicity is felbamate, with rare but potentially fatal cases of aplastic anemia and hepatotoxicity.22,23 Therefore, felbamate is the only new antiepileptic drug that requires routine monitoring of complete blood cell counts and liver function.10

What Dosage Adjustments Are Required in the Setting of Hepatic Disease or Renal Insufficiency?

Studies have been performed evaluating the pharmacokinetic effects of hepatic and renal disease on most of the newer antiepileptic drugs. However, few data are available regarding the clinical significance of these effects. For patients with hepatic disease, there is insufficient information available to make any recommendations on the necessity of dosage adjustments. However, since gabapentin and levetiracetam both lack significant hepatic metabolism, both of these drugs theoretically should be safe choices in patients with hepatic dysfunction.

Since gabapentin and levetiracetam are primarily nonmetabolized and excreted through the kidneys, the dosage should be decreased for patients with renal dysfunction. The manufacturers of both drugs have established specific dosing guidelines based on creatinine clearance (Table 4). The elimination half-lives of topiramate, oxcarbazepine, and zonisamide are prolonged in the setting of moderate to severe renal disease and therefore dosage adjustment is recommended in patients with renal dysfunction, although no specific guidelines have been published. There are insufficient data available on the use of felbamate, lamotrigine, or tiagabine in patients with renal dysfunction.

CONCLUSION

Epilepsy is a prevalent, serious medical condition that is treated largely by general practitioners. The development of new antiepileptic drugs has expanded treatment options and offered significant advantages to patients, particularly those with adverse effects or frequent breakthrough seizures with traditional antiepileptic drugs. Randomized controlled clinical trial data support the efficacy as well as tolerability of each of the new antiepileptic drugs. Although there is no evidence to suggest that the newer medications are more efficacious, several studies have demonstrated broader spectrum of activity, fewer drug interactions, and overall better tolerability of the new agents. As experience with these medications increases and further studies are performed, additional advantages may become evident.

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