SCIENTIFIC REVIEW

AND CLINICAL APPLICATIONS

CLINICIANS CORNER

The New Antiepileptic Drugs

Scientific Review
Suzette M. LaRoche, MD
Sandra L. Helmers, MD

PILEPSY 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
150000 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
See also p 615 and Patient Page.
CME available online at
www.jama.com

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.
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JAMA. 2004;291:605-614

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

2004 American Medical Association. All rights reserved.

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
Author Affiliations: Department of Neurology, Emory
University (Drs LaRoche and Helmers), and Atlanta VA
Medical Center (Dr LaRoche), Atlanta, Ga.
Corresponding Author and Reprints: Suzette M.
LaRoche, MD, Emory Clinic, Bldg A, 1365 Clifton Rd,
Atlanta, GA 30322 (e-mail: Suzette_LaRoche
@emoryhealthcare.org).

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ANTIEPILEPTIC DRUGS

Table 1. Antiepileptic Drugs Approved Since 1993*

Antiepileptic Drug

Year
Approved
Approved for
Approved Patient Age, y Monotherapy

Felbamate (Felbatol)
Gabapentin (Neurontin)
Lamotrigine (Lamictal)

1993
1993
1994

2
3
2

Topiramate (Topamax)
Tiagabine (Gabatril)

1996
1997

2
12

Levetiracetam (Keppra)
Oxcarbazepine (Trileptal)
Zonisamide (Zonegran)

1999
2000
2000

16
4
16

Approved Approved for

for Partial Generalized
Seizures
Seizures

*Approved for use by the US Food and Drug Administration.

Not indicated as first-line antiepileptic treatment.

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 Englishlanguage 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.
The 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
606

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

JAMA, February 4, 2004Vol 291, No. 5 (Reprinted)

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 wellestablished 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

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ANTIEPILEPTIC DRUGS

antagonism of N-methyl-D-aspartate
(NMDA) and -amino-3-hydroxy-5methyl-4-isoxazole propionic acid
(AMPA) receptors (FIGURE).12-15 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 lowdose 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 10000,
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.

Figure. Principal Mechanisms of Action of the New Antiepileptic Drugs

E X C I TAT O R Y
NEURON

I N H I B I T O RY
NEURON

Potentiation of
GABA Activity

Sodium Channel
Blockade

Tiagabine

Felbamate
Lamotrigine
Oxcarbazepine

Topiramate

Voltage-Gated
Sodium Channel

Topiramate
GABA

Zonisamide
PRESYNAPTIC
MEMBRANE

GABA Reuptake
Transporter

GABAA
Receptor

SYNAPTIC
CLEFT

ASTROCYTE

Voltage-Gated
Calcium Channel

POSTSYNAPTIC
MEMBRANE

Glutamate
Calcium Channel
Blockade
Felbamate

Antagonism of
Glutamate

Lamotrigine

Felbamate

Topiramate

Topiramate

Zonisamide
NMDA
Receptor

AMPA
Receptor

Exact Mechanism Unknown

Gabapentin
Levetiracetam

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-Daspartate (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 astrocytes (tiagabine).

Gabapentin

Gabapentin 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 -aminobutyric
acid (GABA), its precise mechanism of
action in humans is unknown (Figure).25
Four initial add-on trials enrolling more
than 700 patients with refractory partial-

2004 American Medical Association. All rights reserved.

onset epilepsy led to the FDA approval

of gabapentin.26-29 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

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ANTIEPILEPTIC DRUGS

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 generalizedonset 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,

Table 2. Randomized, Placebo-Controlled Trials of the New Antiepileptic Drugs as Adjunctive Treatment for Partial-Onset Seizures*
Source
Gabapentin
Andrews et al,26 1990
Sivenius et al,29 1991
McLean et al,27 1993
Anhut et al,28 1994
Lamotrigine
Binnie et al,45 1989
Jawad et al,38 1989
Loiseau et al,39 1990
Sander et al,46 1990
Matsuo et al,40 1993
Schapel et al,42 1993
Smith et al,41 1993
Messenheimer et al,43 1994
Boas et al,44 1996
Topiramate
Ben-Menachem et al,66 1996
Faught et al,64 1996
Privetera et al,65 1996
Sharief et al,68 1996
Tassinari et al,67 1996
Yen et al,69 2000
Tiagabine
Sachdeo et al,79 1997
Kalviainen et al,78 1998
Uthman et al,80 1998
Levetiracetam
Ben-Menachem and Falter,90 2000
Betts et al,91 2000
Cereghino et al,88 2000
Shorvon et al,89 2000
Oxcarbazepine
Houtkooper et al,96 1987
Barcs et al,97 2000
Zonisamide
Schmidt et al,112 1993
Faught et al,113 2001

Study
Design

No. of
Patients

Study
Duration, wk

Daily
Dosage, mg

Responder
Rate, %

% Decrease
in Seizures

Parallel
Parallel
Parallel
Parallel

127
43
306
272

12
12
12
12

1200
1200
1800
1200

25 (P = .04)
33 (P = .02)
26.4 (P = .007)
28 (P = .008)

29.2
57 (P = .02)
31.9
17.8 (P = .005)

Crossover
Crossover
Crossover
Crossover
Parallel
Crossover

34
24
23
21
216
41

12
12
8
12
24
12

75-200
75-400
300
150-300
300-500
150-300

6.7
66.7
34.8

Crossover
Crossover
Crossover

81
98
56

16
14
12

400
400
75-400

17.7
20
24

Parallel
Parallel
Parallel
Parallel
Parallel
Parallel

56
181
190
47
60
46

13
12
18
11
12
14

800
400
600
400
600
300

43 (P = .001)
47 (P = .01)
44 (P.001)
35 (P = .03)
47 (P = .001)
47.8 (P = .01)

Parallel
Parallel

318
154

12
16

32
12-30

31 (P.001)
14 (P = .17)

Not reported
12.6 (P.05)

Parallel

297

20

56

29 (P.001)

Not reported

Parallel
Parallel
Parallel
Parallel

286
119
294
324

12
24
18
16

3000
2000
3000
2000

42.1 (P.001)
48.1 (P.05)
39.8 (P.001)
31.6 (P.001)

39.9 (P.001)
Not reported
37.1 (P.001)
26.5 (P = .003)

Crossover
Parallel

48
694

12
28

900-3600
2400

Not reported
50 (P.001)

NS
50 (P.001)

Parallel
Parallel

139
203

12
12

7/kg
400

29.9 (P.05)
43 (P = .01)

22.5 (P.05)
40.5 (P.001)

NS
33 (P.05)
22

17 (P.05)
59 (P.002)
23 (P.05)
NS
36 (P = .007)
26 (P.01)
29.7 (P.05)
25 (P.001)
30.3 (P = .01)
54 (P.001)
48 (P = .007)
41
41 (P = .06)
46 (P = .004)
Not reported

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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ANTIEPILEPTIC DRUGS

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 primar-

ily by blockade of sodium channels and,

to a lesser extent, calcium channels (Figure).37 Seven clinical trials have shown
lamotrigines 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).38-44 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 com-

pleted 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).48-50 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 discontinua-

Table 3. Randomized Monotherapy Trials of the New Antiepileptic Drugs in Partial-Onset Seizures*
Source
Gabapentin
Beydoun et al,30 1997

Chadwick et al,31 1998

Lamotrigine
Brodie et al,48 1995

Gilliam et al,47 1998

Steiner et al,49 1999
Nieto-Barrera et al,50 2001

Topiramate
Sachdeo et al,72 1997

Study Design

No. of Patients

Summary

Pseudoplacebo control

275

Active control
(carbamazepine)

292

No significant difference between 600, 1200, and 2400

mg/d; completion rates were 15%, 26%, and 19%,
respectively
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 and
1800 mg/d vs 300 mg/d (P = .04, P = .02); 14%
withdrawn due to adverse events vs 24% carbamazepine

Active control
(carbamazepine)

260

Active control (valproate

low dose)
Active control (phenytoin)

156

Active control
(carbamazepine)

181
618

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

discontinued due to adverse events vs 27%
carbamazepine
58% Completion rate for 500 mg/d vs 31% with valproate,
1000 mg/d (subtherapeutic), P = .001
Equivalent completion rates (48% vs 47%); 15%
discontinued due to adverse events vs 19% phenytoin
No significant difference in completion rates (81% vs 77%);
8% discontinued due to adverse events vs 13%
carbamazepine

Pseudoplacebo control

48

54% Completion rate for 1000 mg/d vs 17% for 100 mg/d
(P = .002)

Active control
(carbamazepine)

40

Dam et al,99 1989

Active control
(carbamazepine)

235

Bill et al,100 1997

Active control (phenytoin)

287

Christe et al,101 1997

Active control (valproate)

249

Beydoun et al,103 2000

Pseudoplacebo control

87

Sachdeo et al,102 2001

Pseudoplacebo control

143

No significant difference in efficacy, 80% vs 90% completion

rates; significantly fewer adverse effects with
oxcarbazepine (P.05)
Responder rates 80% for both oxcarbazepine and
carbamazepine; significantly fewer adverse effects with
oxcarbazepine (P = .04)
No significant difference in completion rates (61% vs 58%);
significantly fewer adverse effects with oxcarbazepine
(P = .02)
No significant difference in completion rates (59% vs 64%);
no significant difference in adverse effects
59% Completion rate for 2400 mg/d vs 7% for 300 mg/d
(P.001)
32% Completion rate for 2400 mg/d vs 0% for 300 mg/d
(P.001).

Oxcarbazepine
Reinikainen et al,98 1987

*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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ANTIEPILEPTIC DRUGS

tion (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 drugrelated StevensJohnson 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.58-60 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).61-63 The efficacy of topiramate
as adjunctive therapy is supported by 6
multicenter trials that enrolled 580 patients with refractory partial-onset seizures (Table 2).64-69 Responder rates were
35% to 48% with daily doses ranging
from 300 to 800 mg. The 2 largest trials
610

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 tonicclonic seizures as well as drop attacks
(P = .002).71 A single pseudoplacebocontrolled 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 broadspectrum 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).77 Three multicenter studies evaluated the efficacy and tolerability of tiagabine as adjunctive therapy (Table
2).78-80 The smallest trial enrolled 154

JAMA, February 4, 2004Vol 291, No. 5 (Reprinted)

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 twicedaily 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.80-83 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 enzymeinducing 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).88-91 In the US trial, patients were titrated to maintenance dose over a 4-week

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ANTIEPILEPTIC DRUGS

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.88-91 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).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).98-103 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 highdose 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

2004 American Medical Association. All rights reserved.

widespread clinical use in Japan since

1989. It is a sulfonamide derivative that
acts by blocking sodium as well as Ttype calcium channels (Figure).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 drugs 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

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ANTIEPILEPTIC DRUGS

Table 4. Dosing Adjustment for Patients

With Impaired Renal Function*
Creatinine
Clearance, mL/min
Gabapentin
60
30-60
15-30
15
Hemodialysis
Levetiracetam
80
50-80
30-50
30
Hemodialysis

Dosage, mg
400 3 times daily
300 twice daily
300 daily
300 every other day
200-300
500-1500 twice daily
500-1000 twice daily
250-750 twice daily
250-500 twice daily
500-1000

*Recommendations based on package insert.

Supplemental dose following dialysis.

drugs were approved based on add-on

trials with similar study designs, varying study populations and titration
schedules make direct comparisons difficult. Nevertheless, 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,
612

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 broadspectrum 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?

Routine monitoring of serum drug concentrations has traditionally been used

to guide dosage adjustments in patients
taking antiepileptic drugs, despite the fact

JAMA, February 4, 2004Vol 291, No. 5 (Reprinted)

that therapeutic ranges in the literature often do not correlate with a given
individuals 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 re-

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ANTIEPILEPTIC DRUGS

nal dysfunction. The manufacturers of

both drugs have established specific dosing guidelines based on creatinine clearance (TABLE 4). The elimination halflives 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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