Antiepileptic Drugs Continuum 2016

Review Article
Antiepileptic Drugs
Address correspondence to
Dr Bassel W. Abou-Khalil,
Vanderbilt University,
A-0118 Medical Center North,
Neurology Department, Bassel W. Abou-Khalil, MD, FAAN
Nashville, TN 37232, Bassel.
abou-khalil@vanderbilt.edu.
Relationship Disclosure:
Dr Abou-Khalil has served on ABSTRACT
the editorial boards of Clinical Purpose of Review: Treatment of epilepsy starts with antiepileptic drug (AED)
Neurophysiology and Epilepsy
Research and received monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and
royalties from Elsevier Inc. modes of use for individual AEDs is essential for optimal treatment for epilepsy. This
Unlabeled Use of article addresses AEDs individually, focusing on key pharmacokinetic characteristics,
Products/Investigational
Use Disclosure:
indications, and modes of use.
Dr Abou-Khalil discusses the Recent Findings: Older-generation AEDs are effective but have tolerability and
unlabeled/investigational use pharmacokinetic disadvantages. Several newer-generation AEDs have undergone
of primidone for the treatment
of essential tremor, valproate
comparative trials demonstrating efficacy equal to and tolerability at least equal to or
for the treatment of generalized better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarba-
myoclonic and generalized zepine, levetiracetam, topiramate, and, more recently, zonisamide. Pregabalin was
tonic-clonic seizures,
gabapentin for the treatment of
found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbaze-
headache and sleep disorders, pine have undergone successful trials of conversion to monotherapy. Other newer-
lamotrigine as a first-line generation AEDs with a variety of mechanisms of action are suitable for adjunctive
treatment for epilepsy, and
zonisamide as initial
therapy. Rational AED combinations should avoid AEDs with unfavorable pharma-
monotherapy for epilepsy. cokinetic interactions or pharmacodynamic interactions related to mechanism of action.
* 2016 American Academy Summary: Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles
of Neurology. facilitates the choice of appropriate AED therapy for patients with epilepsy.
Continuum (Minneap Minn) 2016;22(1):132156.
INTRODUCTION dren are highlighted throughout the

Antiepileptic drugs (AEDs) are the main- text, and Table 7-3 summarizes AED
stay of epilepsy therapy. Until 1993, the dosing in children. The order in which
choice of AED was limited to seven or AEDs are presented is roughly based on
eight major agents. However, 16 new the order in which AEDs were marketed,
AEDs have been approved and marketed although related AEDs will be discussed
since then. With such a large choice of together with their oldest relative.
AEDs, much guidance is needed in the
choice of AEDs for initial therapy, later PHENOBARBITAL
replacement monotherapy, or adjunctive Phenobarbital has been in clinical use
therapy. Considerations in AED choice since 1912, although initially used as a
must include the spectrum of efficacy sedative and sleep aid. Its main mecha-
of the AED (Table 7-1), its pharmaco- nism of action is through binding the
kinetic properties (Table 7-2), its safety ,-aminobutyric acid (GABA)-A receptor,
and tolerability profile, and its efficacy prolonging the opening of the associated
against comorbidities, as relevant to the chloride channel. It is available as an
patients specific circumstances. This oral preparation as well as a parenteral
article addresses each AED, focusing solution. It has excellent oral bioavail-
on indications, tolerability, and clinical ability and relatively low protein binding.
use. Relevant pharmacokinetic proper- It is mostly metabolized in the liver, but
ties are also discussed. This article approximately one-quarter of the dose
focuses on AED use in adults; however, is eliminated unchanged in the urine.
salient features related to use in chil- It has a long half-life of approximately
132 www.ContinuumJournal.com February 2016
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 7-1 Spectrum of Efficacy of Select Antiepileptic Drugs
Lennox-Gastaut
Generalized Generalized Generalized Syndrome (LGS)
Antiepileptic Focal Tonic-Clonic Absence Myoclonic or Infantile
Drug Seizures Seizures Seizures Seizures Spasms (IS)a
Phenobarbital Class I trials Suggested, Not effective Class IV
but not evidence
proven in
Class I trials
Phenytoin Class I trials Suggested, Not effective Not effective
but not
proven in
Class I trials
Carbamazepine Class I trials Suggested, Not effective Not effective
but not
proven in
Class I trials
Oxcarbazepine Class I trials Unknown Not effective Not effective
Eslicarbazepine Class I trials Unknown Not effective Not effective
acetate
Valproate Class I trials Suggested, Class I trials Suggested, Suggested,
but not but not but not
proven in proven in proven in
Class I trials Class I trials Class I trials
Ethosuximide Not effective Not effective Class I trials Not effective
Clobazam Suggested, Suggested, Suggested, Suggested, Class I trials LGS
but not but not but not but not
proven in proven in proven in proven in
Class I trials Class I trials Class I trials Class I trials
Felbamate Class I trials Suggested, Unknown Unknown Class I trials LGS
but not
proven in
Class I trials
Gabapentin Class I trials Not effective Not effective Not effective
Pregabalin Class I trials Not effective Not effective Not effective
Lamotrigine Class I trials Class I trials Suggested, Variable Class I trials LGS
but not
proven in
Class I trials
Topiramate Class I trials Class I trials Not effective in Unknown Class I trials LGS
one Class I trial
Tiagabine Class I trials Not effective Not effective Not effective
Levetiracetam Class I trials Class I trials Suggested, but Class I trials
not proven in
Class I trials
Continued on page 134
Continuum (Minneap Minn) 2016;22(1):132156 www.ContinuumJournal.com 133

Antiepileptic Drugs
TABLE 7-1 Spectrum of Efficacy of Select Antiepileptic Drugs Continued from page 133
Lennox-Gastaut
Generalized Generalized Generalized Syndrome (LGS)
Antiepileptic Focal Tonic-Clonic Absence Myoclonic or Infantile
Drug Seizures Seizures Seizures Seizures Spasms (IS)a
Zonisamide Class I trials Suggested, Suggested, but Suggested,
but not not proven in but not
proven in Class I trials proven in
Class I trials Class I trials
Lacosamide Class I trials Unknown Not effective Not effective
Vigabatrin Class I trials Not effective Not effective Not effective Class I trials IS
Rufinamide Class I trials, Suggested, Unknown Unknown Class I trials LGS
but not FDA but not
approved proven in
Class I trials
Ezogabine Class I trials Unknown Unknown Unknown
Perampanel Class I trials Class I trials Unknown
FDA = US Food and Drug Administration.

a
Blank cells in this column represent no convincing or Class I data.
KEY POINTS 80 to 100 hours. Phenobarbital is a Phenobarbitals main adverse effects

h Phenobarbital, potent hepatic P450 enzyme inducer, are sedation, decreased concentration,
primidone, phenytoin, accelerating the metabolism of medica- and mood changes, particularly depres-
and carbamazepine are
tions processed by this enzyme system sion. In children, it can cause hyperac-
potent inducers of liver
and reducing their plasma concentra- tivity. Long-term use is associated with
enzymes, reducing the
efficacy of drugs
tion. This affects its use in combination decreased bone density, Dupuytren con-
metabolized by the therapy, since it may render concomi- tractures, plantar fibromatosis, and fro-
P450 enzyme system. tant AEDs less effective if they are me- zen shoulder. It is assigned pregnancy
tabolized by the liver. Category D because of teratogenicity
h Phenobarbital has
long-term connective
Phenobarbital is effective against fo- with increased risk of cardiac malfor-
tissue adverse effects. cal seizures and generalized tonic-clonic mations in the exposed fetus. Evidence
seizures, but is not effective against also exists of decreased cognitive abili-
generalized absence seizures. The par- ties in males exposed in utero.
enteral solution has been used effectively
for status epilepticus. The suggested Place in Therapy
maintenance dose is 1 mg/kg/d to Because of its adverse effect on cogni-
2.5 mg/kg/d,1 but a much lower starting tive function and its enzyme induction,
dose is recommended, such as 30 mg to phenobarbital is used very infrequently
60 mg at bedtime. The dose can be in- as first-line therapy in developed coun-
creased by 30 mg to 60 mg every 2 weeks tries. However, its low cost and wide
as needed, depending on seizure con- availability make it the only affordable
trol and tolerability. A once-daily dose at AED in much of the developing world.
bedtime may reduce sedation and is In addition, there has been some
adequate because of its long half-life. debate about adverse cognitive effects;
The recommended serum concentra- one study in rural China reported no
tion is 15 mg/L to 40 mg/L. major negative cognitive effects, and

TABLE 7-2 Select Pharmacokinetic Parameters of Antiepileptic Drugs
Antiepileptic Oral Protein

Drug Bioavailability Bindinga Metabolism Half-lifeb Interactions
Phenobarbital Good Low 970% Long Present
Phenytoin Variable High Extensive, Intermediate Present
nonlinear (long with
toxicity)
Carbamazepine Good Intermediate Extensive Intermediate Present
Oxcarbazepine Good Low Extensive Short Present
Eslicarbazepine Good Low 40% Intermediate Present
acetate
Valproate Good High Extensive Intermediate Present
Ethosuximide Good Low Extensive Long Present
Clobazam Good High Extensive Intermediate Present
Felbamate Good Low 50% Intermediate Present
Gabapentin Low Low None Short Absent
Pregabalin Good Low None Short Absent
Lamotrigine Good Intermediate Extensive Intermediate Present
Topiramate Good Low 30% Intermediate Minimal
Tiagabine Good High Extensive Short Present
Levetiracetam Good Low 30% Short Absent
nonhepatic
Zonisamide Good Low 65% Long Present
Lacosamide Good Low 60% Intermediate Minimal
Vigabatrin Good Low None Intermediate Absent
Rufinamide Good Intermediate Extensive Short Present
Ezogabine Limited Intermediate Extensive Short to Present
intermediate
Perampanel Good High Extensive Long Present
a
Low: G50%; intermediate: 50Y85%; high: 985%.
b
Short: G10 hours; intermediate: 10Y30 hours; long: 930 hours.
some cognitive gains, likely related to about 25% of oral primidone is con-
improved seizure control.2 verted to phenobarbital. The half-life
of primidone is 10 to 15 hours in mon-
PRIMIDONE otherapy and 6.5 to 8.3 hours with
Primidone is converted in the liver to phe- enzyme inducers. Primidone is a potent
nobarbital and phenylethylmalonamide enzyme inducer.
(PEMA), which is also an active metabo- Primidone is effective against focal
lite. It is available only as an oral prepa- seizures and generalized tonic-clonic
ration. When used in monotherapy, seizures. Anecdotal evidence also

Antiepileptic Drugs
a
TABLE 7-3 Suggested Pediatric Antiepileptic Drug Dosing
Antiepileptic Target Dose; Usual

Drug Starting Dose Titration Maximal Effective Dose
Phenobarbital 1Y3 mg/kg/d 1 mg/kg/d every 3 mg/kg/d; up to 8 mg/kg/d
1Y2 weeks
Phenytoin 5Y7 mg/kg/d No titration 6Y8 mg/kg/d; up to 10 mg/kg/d
needed (may be guided by serum
concentration)
Carbamazepine 10Y20 mg/kg/d Increase weekly 20 mg/kg/d; usually
using 100-mg G35 mg/kg/d
increments
Oxcarbazepine 8Y10 mg/kg/d 5Y10 mg/kg/d 30Y50 mg/kg/d; usually
every 3Y7 days G60 mg/kg/d
as needed
Valproate 15 mg/kg/d 5Y10 mg/kg/d 30 mg/kg/d; up to 60 mg/kg/d
every week with enzyme-inducing
antiepileptic drugs
Ethosuximide 10Y15 mg/kg/d 5 mg/kg/d every 20Y30 mg/kg/d; up to
week as needed 40 mg/kg/d
Clobazam 0.1 mg/kg/d 0.1 mg/kg/d every 1.0 mg/kg/d
week as needed
Felbamate 15 mg/kg/d 15 mg/kg/d 45 mg/kg/d
every week
Gabapentin 10Y15 mg/kg/d 10 mg/kg/d 40 mg/kg/d; up to 70 mg/kg/d
every day
Lamotrigine Monotherapy for Monotherapy for Maintenance dose for
weeks 1 and 2: weeks 3 and 4: monotherapy: 4.5Y7.5 mg/kg/d
0.3 mg/kg/d 0.6 mg/kg/d;
week 5 and on:
increase by
0.6 mg/kg/d
every 1Y2 weeks
With valproate: With valproate for With valproate: 1Y5 mg/kg/d
0.15 mg/kg/d weeks 3 and 4:
0.3 mg/kg/d;
week 5 and on:
increase by
0.3 mg/kg/d
every 1Y2 weeks
With enzyme-inducer: With enzyme- With enzyme-inducers:
0.6 mg/kg/d inducer for 5Y15 mg/kg/d
weeks 3 and 4:
1.2 mg/kg/d;
week 5 and on:
increase by
1.2 mg/kg/d
every 1Y2 weeks
Continued on page 137

a
TABLE 7-3 Suggested Pediatric Antiepileptic Drug Dosing Continued from page 136
Antiepileptic Target Dose; Usual

Drug Starting Dose Titration Maximal Effective Dose
Topiramate 1Y3 mg/kg/d 1Y3 mg/kg/d every 5Y9 mg/kg/d
1Y2 weeks
Levetiracetam 20 mg/kg/d 20 mg/kg/d every 60 mg/kg/d
week as needed
Zonisamideb 1 mg/kg/d 2 mg/kg/d every 12 mg/kg/d
2 weeks as needed
Vigabatrin 20 mg/kg/d 20 mg/kg/d every 40Y60 mg/kg/d
week as needed
Infantile spasms: Infantile spasms: Infantile spasms: 100 mg/kg/d;
50 mg/kg/d; Increase to maximum dose is 150 mg/kg/d
titration to effect 100 mg/kg/d
over 1 week after 5 days
Rufinamide 10 mg/kg/d Increase by 45 mg/kg/d
10 mg/kg/d
every other day
In the presence In the presence In the presence of valproate,
of valproate, of valproate, target dose should be
the starting dose titration rate should 20Y30 mg/kg/d
should be be 5 mg/kg/d
5 mg/kg/d every other day
a
Generally applicable to children younger than 12 years. The dosing is provided for antiepileptic drugs that have at least been tested in
children.
b
Not US Food and Drug Administration approved for children.
exists of efficacy against myoclonic 125 mg at bedtime, then increased grad- KEY POINT
seizures. Primidone is also effective ually by 50 mg to 125 mg every 3 to h Primidone has acute
in controlling essential tremor. 7 days to 250 mg 3 times a day. toxicity not related to
its phenobarbital
In addition to sedation and other
PHENYTOIN metabolite. Slow
phenobarbital adverse effects, primidone
titration is required to
use is associated with an acute toxic Phenytoin has been in clinical use avoid this toxicity.
reaction unrelated to phenobarbital, since 1938 when its efficacy in the
with potentially debilitating drowsiness, maximum electroshock animal model
dizziness, ataxia, nausea, and vomiting. was discovered. Phenytoin binds to
the active state of the sodium channel
Place in Therapy to prolong its fast inactivated state,
Primidone was the least-tolerated agent thus reducing high-frequency firing as
in the large cooperative US Department might occur during a seizure, while
of Veterans Affairs trial comparing the allowing normal action potentials to
efficacy and tolerability of carbamaze- occur. It is available as an oral prepa-
pine, phenobarbital, phenytoin, and ration and a parenteral solution, and a
primidone.3 As a result, it is infrequently phenytoin prodrug, fosphenytoin, is
used. In view of the acute toxic adverse available for IV and IM administration.
effects, primidone should be started Phenytoin bioavailability is reduced
at a low dose, for example, 50 mg to with coadministration of calcium,

Antiepileptic Drugs
KEY POINTS
h Phenytoin has saturable antacids, and nasogastric feedings. It isoniazid, and azole antifungal agents.
nonlinear kinetics. is highly protein bound at approxi- The phenytoin protein-free fraction may
Beyond a certain mately 90%. It is metabolized in the increase with hepatic and renal failure, in
serum concentration, liver, mostly by cytochrome P450 (CYP) low-protein states, during pregnancy, in
usually within the 2C9 and, to a lesser extent, CYP 2C19. old age, and in the presence of highly
accepted therapeutic Phenytoins metabolism is saturable, protein-bound drugs, such as valproate,
range, phenytoin resulting in nonlinear kinetics. As the that compete for protein binding. This is
concentration increases serum concentration increases, it of clinical relevance when decisions are
disproportionately with reaches a point within the recom- made based on total phenytoin serum
an increase in the mended therapeutic range after which concentration (Case 7-1).
dose. Small increments
the half-life starts increasing. Beyond Phenytoin is effective against focal
are necessary when
that point, the phenytoin plasma level seizures and generalized tonic-clonic
increasing the dose at a
serum concentration in
increases disproportionately with an in- seizures. Phenytoin is not effective
the therapeutic range. crease in the dose (Figure 7-1). against generalized myoclonic or gen-
Phenytoin is a potent enzyme inducer eralized absence seizures and may
h The traditional sodium
that reduces the efficacy of drugs me- even exacerbate these seizures; hence,
channel blockers
phenytoin,
tabolized by the P450 enzyme system. it is not a drug of choice in idiopathic
carbamazepine, and Phenytoin is also affected by a number generalized epilepsy. The usual phe-
oxcarbazepine may of agents that reduce its metabolism and nytoin initiation dose is 200 mg/d to
exacerbate generalized cause it to accumulate. These include 400 mg/d, initially given as a bedtime
absence and myoclonic amiodarone, fluoxetine, fluvoxamine, dose. Titration is primarily based on
seizures and should be
avoided in idiopathic
generalized epilepsy.
Other antiepileptic
drugs that have similar
potential are
gabapentin, pregabalin,
tiagabine, and vigabatrin.
FIGURE 7-1 Example of the nonlinear kinetics of

phenytoin. An increase in the daily dose
beyond 300 mg is associated with a
disproportionate increase in serum concentration. At a
dose of 400 mg/d, the serum concentration is about
13 mg/L. If seizures are still not controlled at this dose,
an increment of 100 mg pushes the serum concentration
beyond 30 mg/L, with clinical toxicity. An increment of
30 mg would be more appropriate.

KEY POINT
Case 7-1 h Unlike phenytoin, the

phenytoin prodrug
A 26-year-old woman with chronic renal failure and focal seizures was
fosphenytoin may be
admitted to the hospital because of an exacerbation of seizures, with focal
administered
seizures recurring almost every hour. She had been receiving phenytoin
intramuscularly, with
100 mg 3 times a day. Her phenytoin plasma concentration was measured at
reliable absorption,
15 mg/L. The neurology service was consulted and requested a protein-free
in the absence of
phenytoin level. It was 4.5 mg/L, which represents a 30% protein-free
IV access.
fraction. In a subject with 10% protein-free fraction, the corresponding total
phenytoin concentration would be 45 mg/L. Holding phenytoin was
associated with resolution of the seizures, which had apparently worsened
paradoxically due to phenytoin toxicity.
Comment. Phenytoin protein binding is reduced with renal failure not only
because of lower serum albumin, but also because of accumulation of small
molecules that compete with phenytoin for protein binding. In this situation,
protein-free phenytoin levels are essential for management decisions.
clinical response, but also takes into may be associated with paresthesia,
consideration the serum concentration. most often in the groin region. IV
The recommended therapeutic serum administration of both phenytoin
concentration is 10 mg/L to 20 mg/L; the and fosphenytoin can be associated
protein-free recommended thera- with hypotension and arrhythmias,
peutic serum concentration is 1 mg/L so ECG and blood pressure monitor-
to 2 mg/L. Protein-free levels should ing are recommended and the rate
be checked where the protein-free of IV administration should not ex-
fraction is expected to be increased. In ceed 50 mg/min for phenytoin and
view of nonlinear kinetics, small incre- 150 mg/min for fosphenytoin.
ments (eg, 30 mg to 60 mg) should be Phenytoin is less sedating than
used when in the therapeutic range. phenobarbital but nevertheless may
Extended-release capsules are pre- have cognitive adverse effects in some
ferred. Twice daily dosing may be individuals, even within the therapeu-
needed when seizures are drug resis- tic range. Adverse effects that occur
tant. Phenytoin can be loaded orally at with high concentrations include ataxia,
18 mg/kg divided into three doses given incoordination, dysarthria, nystagmus,
2 to 3 hours apart (or even as a single and diplopia. A paradoxical increase in
dose if needed). The IV preparation of seizures has been documented with
phenytoin is associated with local re- concentrations exceeding 30 mg/L
actions, including burning pain, phlebi- (Case 7-1). Idiosyncratic reactions
tis, cellulitis, and, rarely, the purple include allergic rash (almost 6% in a
glove syndrome. IM administration is study based on clinical practice)4 and,
contraindicated because of erratic ab- rarely, Stevens-Johnson syndrome, toxic
sorption and sterile abscess formation. epidermal necrolysis, or hypersensitivity
The phenytoin water-soluble prodrug syndrome with fever, rash, lymphade-
fosphenytoin is preferred for parenteral nopathy, eosinophilia, and liver and
use. It has a lower incidence of local renal impairment. Adverse effects asso-
reactions with IV administration and ciated with long-term use include gin-
is also well absorbed after IM admin- gival hyperplasia, acne, hirsutism,
istration. When administered intra- cerebellar atrophy, decreased bone den-
venously in an awake individual, it sity, anemia, and peripheral neuropathy.

Antiepileptic Drugs
KEY POINTS
h Carbamazepine induces Place in Therapy the extended-release preparation. The
its own metabolism, Phenytoin was the most frequently used dose can be increased by 200 mg every
so it has to be titrated AED for many years, but its use has 3 days, up to 200 mg to 400 mg 2 times
gradually to the declined considerably since the appear- a day. This dose can be increased
target dose. ance of newer-generation AEDs with further, if needed, for persistent sei-
h The HLA-B1502 allele improved tolerability. zures. The extended-release prepara-
is predictive of a tion provides steadier levels with
carbamazepine-induced CARBAMAZEPINE evidence for improved tolerability as
severe rash in individuals Carbamazepines mechanism of action well as efficacy. The recommended ther-
of Asian descent. is similar to that of phenytoin. It blocks apeutic range is 4 mg/L to 12 mg/L.
the sodium channel in a voltage- and Adverse effects noted with carbamaz-
use-dependent fashion, reducing high- epine include nausea, headache, dizzi-
frequency neuronal firing. ness, sedation, and tiredness. Cognitive
Carbamazepine is only available as an impairment has been reported on neu-
oral preparation. It has good bioavailabil- ropsychological testing. With elevated
ity. Its protein binding of about 75% is levels, there may be blurred vision,
not of clinical importance. It is metabo- diplopia, nystagmus, unsteadiness, inco-
lized in the liver, mainly by CYP 3A4; ordination, and tremor. Hyponatremia
the most important metabolite is may occur. Weight gain and decreased
carbamazepine-10,11-epoxide. It is an bone density are reported with long-
active metabolite also responsible for term use. Mild leukopenia seen in 10%
some adverse effects. Carbamazepine is to 20% of patients is usually benign,
a potent enzyme inducer, reducing the even though it may be persistent; the
levels of drugs as well as endogenous more serious aplastic anemia is rare
substances metabolized by the P450 (estimated at 1 in 200,000).
enzyme system. Carbamazepine also Idiosyncratic adverse experiences in-
induces its own metabolism, a process clude rash, which may be less common
known as autoinduction, which results than with phenytoin. Stevens-Johnson
in increased clearance over 2 to 4 weeks, syndrome and toxic epidermal
with shortened half-life and lower serum necrolysis are rare, but more likely with
concentration. Carbamazepine may ac- the HLA-B1502 allele in individuals of
cumulate when coadministered with Asian descent, for whom genetic testing
inhibitors of CYP 3A4, such as erythro- of HLA-B polymorphisms is indicated
mycin and other macrolide antibiotics prior to initiation. Other rare idiosyn-
(except azithromycin), fluoxetine, pro- cratic adverse effects include lupuslike
poxyphene, and grapefruit juice. Carba- syndrome, hepatotoxicity, and hyper-
mazepine epoxide levels increase with sensitivity syndrome with fever, rash,
concomitant use of some inhibitors and organ involvement. Carbamazepine
such as valproate and felbamate. use in polytherapy has been associated
Carbamazepine is effective against with increased risk of spina bifida in
focal seizures and generalized tonic- infants exposed during gestation.
clonic seizures. However, it may exac- Abrupt withdrawal may be associated
erbate absence, myoclonic, and atonic with severe rebound seizures.
seizures. Hence, it is not a good choice
in idiopathic generalized epilepsy. It has Place in Therapy
indications for trigeminal neuralgia and Carbamazepine had the best balance of
for acute mania and bipolar disorder. efficacy and tolerability in the large
The starting dose is 100 mg 2 times a cooperative US Department of Veterans
day or 200 mg at bedtime when using Affairs study that also included phenytoin,

KEY POINT
phenobarbital, and primidone.3 As a metabolism. Unlike carbamazepine, it is h Oxcarbazepine is more
result, it became the standard treatment not affected by CYP 3A4 inhibitors such likely to cause
for focal seizures. No drug has been as erythromycin, fluoxetine, propoxy- hyponatremia than
demonstrated to be more effective than phene, and grapefruit juice. carbamazepine. Older
carbamazepine, but its use has declined Oxcarbazepine is effective against individuals taking a
with the marketing of new AEDs that focal seizures. It may exacerbate absence diuretic are at
had pharmacokinetic advantages. Lamo- and myoclonic seizures and should be particularly high risk.
trigine, oxcarbazepine, and gabapentin avoided in patients with generalized
had better tolerability than immediate- epilepsy. It can be started at the dose
release carbamazepine.5Y11 However, of 300 mg 2 times a day, but in the
comparative trials using extended- absence of urgency, it is better to start at
release carbamazepine have failed to 150 mg 2 times a day. The dose can be
show superior tolerability of lamotri- titrated by 300 mg per week as needed.
gine, levetiracetam, or zonisamide.12Y14 The highest dose used in clinical trials
Nevertheless, enzyme induction and was 1200 mg 2 times a day. An extended-
pharmacokinetic interactions have been release preparation is available, al-
issues favoring newer AEDs. On the lowing for once-daily dosing. The
other hand, economic considerations recommended therapeutic range for
favor the less-expensive carbamazepine. the monohydroxy derivative is 15 mg/L
to 35 mg/L. Conversion from carbamaz-
OXCARBAZEPINE epine can be made overnight using
Oxcarbazepine is a structural analogue 300 mg of oxcarbazepine for every
of carbamazepine, but the minor struc- 200 mg of carbamazepine when the
tural differences have resulted in major carbamazepine dose is 800 mg or less. A
differences in metabolism and induction slower conversion and lower ratio are
of metabolic pathways. Like carbamaze- advisable with higher carbamazepine
pine and phenytoin, oxcarbazepine doses. Conversion from carbamazepine
binds to the sodium channel, inhibiting may be accompanied by reduction in
high-frequency repetitive neuronal fir- sodium concentration and increased
ing. Oxcarbazepine is only available as levels of concomitant medications me-
an oral preparation. tabolized by the P450 enzyme system.
Oxcarbazepine has excellent oral bio- Oxcarbazepine may cause drowsi-
availability. It is very rapidly converted ness, headache, and fatigue. Higher
to an active metabolite, the monohy- doses can cause dizziness, blurred
droxy derivative, also referred to as vision, diplopia, nausea, vomiting, and
licarbazepine, which is responsible for ataxia. Rash may occur in 2% to 4% of
oxcarbazepine antiseizure activity. Its individuals. Oxcarbazepine has 25%
protein binding is not clinically impor- cross-reactivity with carbamazepine.
tant. The half-life of oxcarbazepine is Oxcarbazepine is more likely to cause
only 1 to 3.7 hours, and that of the hyponatremia than carbamazepine;
monohydroxy derivative is 8 to 10 hours. symptomatic hyponatremia is more
Oxcarbazepine is a weak inducer of CYP likely in older individuals and those
3A4, which is responsible for estrogen taking a diuretic (Case 7-2). Abrupt
metabolism, and reduces the efficacy of withdrawal may be associated with
the oral contraceptive pill at high doses, severe rebound seizures.15
usually greater than 900 mg/d. It is a
weak inhibitor of CYP 2C19, thus raising Place in Therapy
the phenytoin level when used at high Oxcarbazepine is approved as a first-
doses. It does not induce its own line monotherapy for focal seizures.

Antiepileptic Drugs
KEY POINT
h Eslicarbazepine has a
long half-life in CSF,
Case 7-2
A 66-year-old woman with a 3-year history of seizures presented to her
justifying once-daily
neurologist for follow-up of continued seizures despite treatment with
oral dosing.
carbamazepine. Her seizures included a rising epigastric sensation and then
flushing of the face, with or without feeling as if she were in another world,
and word-finding difficulties. Some seizures evolved to staring, then
extension of the legs, flexion of the right arm at the elbow, and right arm
jerking. She had postictal word-finding difficulty. She estimated that the
small seizures occurred 2 times a month, whereas the more involved seizures
occurred about once every 6 months. She was on extended-release
carbamazepine 600 mg 2 times a day. Lamotrigine had caused a rash. In
addition to seizures, she reported memory loss and cognitive slowing.
Her physician considered that carbamazepine could be responsible for her
cognitive difficulties, and she was offered a trial of oxcarbazepine to replace
carbamazepine. Her comprehensive metabolic panel was normal except for
slightly low sodium of 133 mEq/L. Her carbamazepine level was 14.9 mg/L.
She was switched to oxcarbazepine 600 mg 2 times a day. In the next 2 days,
she experienced dizziness and flushing of the face and had a generalized
tonic-clonic seizure, for which she presented to an emergency department
3 days after switching to oxcarbazepine. Her serum sodium was 119 mEq/L.
Oxcarbazepine was stopped and replaced with levetiracetam.
Comment. This patient demonstrates that oxcarbazepine has a greater
potential to produce hyponatremia than carbamazepine, particularly in older
individuals. In this particular patient, a mild hyponatremia already existed
with carbamazepine, which should have been a reason to avoid
oxcarbazepine. An overnight switch, as occurred in this patient, is not
advisable when the carbamazepine dose exceeds 800 mg/d.
Multiple comparative monotherapy tri- rivative of oxcarbazepine (after admin-

als for new-onset partial epilepsy have istration of oxcarbazepine, the ratio of
demonstrated that oxcarbazepine is S-licarbazepine to R-licarbazepine is
equal in efficacy to phenytoin and about 4:1). Eslicarbazepine acts by
immediate-release carbamazepine, but blocking sodium channels and stabiliz-
with superior tolerability.16 Combining ing the inactive state of the voltage-
oxcarbazepine with other classic sodium gated sodium channel. A 2015 study
channel blockers, such as carbamaze- suggested that, unlike carbamazepine,
pine, lamotrigine, and phenytoin, may it may enhance slow inactivation of
limit tolerability because of dizziness, voltage-gated sodium channels.17 It is
diplopia, and ataxia. available only as an oral preparation.
Eslicarbazepine is metabolized to in-
ESLICARBAZEPINE ACETATE active compounds, but more than 50%
Eslicarbazepine acetate was approved is excreted in the urine as unchanged
for marketing in the United States in eslicarbazepine. The half-life of
2014, but it is listed here as it repre- eslicarbazepine is 13 to 20 hours in plasma
sents a third-generation relative of and 20 to 24 hours in CSF, justifying
carbamazepine and oxcarbazepine. It once-daily dosing. Unlike oxcarbazepine,
is rapidly converted to the active eslicarbazepine acetate is not followed
metabolite S-licarbazepine, the active by a CSF spike, which is suspected to be
enantiomer of the monohydroxy de- responsible for acute adverse effects.18

KEY POINT
Eslicarbazepine is a weak inducer of VALPROIC ACID/DIVALPROEX
h Valproate has a wide
CYP 3A4, potentially decreasing plasma (VALPROATE)
spectrum of efficacy
concentrations of estrogen and other Valproate has multiple mechanisms of against all focal and
molecules metabolized by this enzyme, action, including GABA potentiation, generalized seizure types.
and a weak inhibitor of CYP 2C19, blocking of T-type calcium channels
potentially increasing plasma concentra- (predictive of efficacy against absence
tion of phenytoin and other drugs metab- seizures), and blocking of sodium chan-
olized by this enzyme. nels. It is available as oral preparations
Eslicarbazepine acetate is effective (mainly in the form of divalproex so-
against focal seizures. The recommended dium, a complex of valproate and so-
starting dose is 400 mg once daily, to be dium valproate) and parenteral valproate
increased to 800 mg once daily after sodium preparation. Oral bioavailability
1 week. If needed, the dose can be is almost complete, although slightly
increased again to 1200 mg daily less for the extended-release prepara-
after 1 week. In a 2015 successful tion. It is highly protein bound at about
conversion to monotherapy study, a 90%. The free fraction increases with in-
dose of 1600 mg daily was used.19 creasing total concentration and with
Eslicarbazepine acetate has adverse coadministration of phenytoin, with
effects similar to oxcarbazepine, al- which it competes for protein binding.
though less frequent. The most com- Valproate is extensively metabolized
mon dose-related adverse effects are by conjugation and oxidation. The half-
dizziness, somnolence, headache, dip- life in adults is 13 to 16 hours, but
lopia, nausea, vomiting, fatigue, and shorter at about 9 hours with enzyme-
ataxia. Hyponatremia was less com- inducing drugs. It is a potent inhibitor,
monly reported than in oxcarbazepine reducing the clearance of phenobarbi-
trials. Sodium levels of 125 mEq/L or tal, lamotrigine, rufinamide, and carba-
lower were reported in up to 1.5% of mazepine epoxide.
individuals taking 1200 mg/d. Rash Valproate has a wide spectrum of
occurs in up to 3% of individuals at efficacy against all focal and general-
1200 mg/d. ized seizures, including generalized
absence and myoclonic seizures. It
Place in Therapy also has FDA indications for migraine
Eslicarbazepine acetate was first ap- prophylaxis and bipolar disorder. It
proved by the US Food and Drug should be started at a low dose to im-
Administration (FDA) as adjunctive prove tolerability. The extended-release
treatment for focal seizures. A divalproex sodium preparation, which
monotherapy indication followed after can be administered once daily, is pre-
successful completion of a conversion ferred. The recommended starting dose
to monotherapy trial.19 Like oxcar- is 500 mg at bedtime for the extended-
bazepine, it should be avoided in release divalproex sodium preparation
idiopathic generalized epilepsy. Theo- or 250 mg 2 times a day for the delayed-
retical considerations suggest eslicar- release and immediate-release prepara-
bazepine acetate could be considered tions. The dose can be increased gradually
as first-line monotherapy for focal as needed to achieve seizure control,
seizures, with tolerability advantages up to 1000 mg/d to 2000 mg/d. A dose
o v e r i mm e d i a t e - r e l e a s e o x c a r - greater than 1000 mg should be avoided
bazepine. However, financial consid- in women of childbearing potential.
erations may be an obstacle to this The recommended therapeutic range
practice. is 50 mg/L to 100 mg/L. A protein-free

Antiepileptic Drugs
KEY POINTS
h Valproate has the concentration should be checked at bioavailability (greater than 90%). Pro-
highest rate of high levels and in other circumstances tein binding is very low. Ethosuximide is
teratogenicity among in which the protein-free fraction is extensively metabolized in the liver. It
antiepileptic drugs expected to rise. has a long half-life of 30 to 60 hours.
and should be avoided Valproate adverse effects include gas- Ethosuximide is a narrow-spectrum
in women of tric irritation with nausea, vomiting, and AED, selective for generalized absence
childbearing potential. anorexia, all of which are least likely with seizures. The starting dose is 250 mg/d
h Ethosuximide is the the extended-release divalproex sodium for patients between 3 and 6 years of
drug of choice for pure formulation. It may cause fatigue, drows- age and 250 mg 2 times a day for those
absence seizures. While iness, tremor, weight gain, hair loss, older than 6 years of age. The dose can
valproate is equally peripheral edema, thrombocytopenia, be increased by 250 mg every week as
effective, it is associated and confusion. Reversible parkinsonism, needed for persistent seizures, not to
with more cognitive gait disorder, dementia, and brain atro- exceed 500 mg 3 times a day. The
adverse effects. phy have been described with chronic recommended therapeutic range is
use in seniors. Encephalopathy and hy- 40 mg/L to 100 mg/L.
perammonemia may occur in polytherapy. Adverse effects include nausea, ab-
The idiosyncratic hepatotoxicity and dominal discomfort, anorexia, vomiting,
pancreatitis are potentially life threat- diarrhea, drowsiness, insomnia, ner-
ening, but rare. Risk factors are vousness, dizziness, fatigue, ataxia, and
polytherapy and young age. Valproate behavior changes. Most adverse effects
is associated with a dose-related terato- are dose related and are helped by
genicity rate higher than any other administration of divided doses with
marketed AED, with risk of major meals. Headaches, psychosis, depres-
malformations higher than 30% at sion, and hallucinations are not clearly
doses greater than 1100 mg/d.20 In dose related. Idiosyncratic adverse ex-
utero exposure is also associated with periences include rash, Stevens-Johnson
dose-dependent reduced verbal IQ syndrome, systemic lupus erythema-
and autism.21,22 tosus, rare aplastic anemia, thrombocy-
topenia, agranulocytosis, and rare
Place in Therapy autoimmune thyroiditis.
Valproate remains the most effective AED
for idiopathic generalized epilepsy with Place in Therapy
generalized tonic-clonic seizures, and Ethosuximide is the AED of choice for
should remain a drug of first choice for absence epilepsy with generalized ab-
men with generalized epilepsy.23 Al- sence seizures as the only seizure type,
though equally effective to ethosuximide a status supported by the large multi-
for generalized absence seizures, it has center double-blind randomized con-
more cognitive adverse effects.24 A large trolled trial comparing ethosuximide,
cooperative US Department of Veterans valproic acid, and lamotrigine.26
Affairs study found it less well tolerated
and less effective than carbamazepine BENZODIAZEPINES
for complex partial seizures, although Benzodiazepines act mainly on the
equally effective for secondarily general- GABA-A receptor, increasing the fre-
ized tonic-clonic seizures.25 quency of GABA-mediated chloride
channel openings. Clobazam is the only
ETHOSUXIMIDE 1,5-benzodiazepine, referring to the
Ethosuximide blocks T-type calcium cur- position of nitrogen atoms in the
rents, which predicts efficacy against heterocyclic ring; other benzodiaze-
absence seizures. It has an excellent oral pines are 1,4-benzodiazepines. Only

KEY POINTS
clonazepam and clobazam, used for inhibiting the metabolism of phenobar- h Tolerance may develop
chronic epilepsy management, are dis- bital, phenytoin, valproate, carbamaze- to the therapeutic effect
cussed here. In the United States, they pine epoxide, and warfarin, and it is a of benzodiazepines;
are available only as oral preparations. weak inducer of CYP 3A4, decreasing this appears less likely
Both have good oral bioavailability. carbamazepine levels and reducing oral with clobazam
Both are highly protein bound. How- contraceptive efficacy. than clonazepam.
ever, they differ in their metabolism.27 Felbamate is a broad-spectrum agent h Felbamate-related
Clonazepam is converted to inactive effective against focal seizures as well as aplastic anemia and
metabolites, while clobazam is meta- generalized seizures in the setting of liver failure are unlikely
bolized in the liver to the active Lennox-Gastaut syndrome. The to start after 1 year
N-desmethylclobazam. They both recommended starting dose is 600 mg of treatment.
have long half-lives, justifying once- 2 times a day, with subsequent titration
daily dosing. Both clonazepam and by 600 mg to 1200 mg per week up to
clobazam are broad-spectrum agents, 1200 mg 3 times a day.
although their FDA indication is limited The most common adverse effect of
to generalized seizure types. felbamate is gastrointestinal irritation
Drowsiness is a common adverse with anorexia, nausea, and vomiting,
effect that improves over time. It is less which can be helped by administration
likely with clobazam. With increasing with food. Felbamate may also cause
doses, nystagmus, incoordination, un- insomnia, irritability, headache, and
steadiness, and dysarthria may occur. weight loss. The most concerning tox-
Tolerance may develop to the thera- icity is the potentially lethal aplastic
peutic effect of benzodiazepines, but anemia, with an estimated risk of 1 in
this appears less likely with clobazam. 5000 to 1 in 8000 patients, and hepatic
Withdrawal seizures may occur with failure, with an estimated risk of 1 in
abrupt discontinuation. 26,000 to 1 in 54,000 patients. Both are
unlikely after 1 year of treatment. It is
Place in Therapy recommended to check a complete
blood count and liver function tests
Both clonazepam and clobazam are
prior to starting felbamate and to repeat
typically used as adjunctive therapy
the tests every 2 weeks in the first
and have limited data to support 6 months of treatment. The frequency
monotherapy use. of monitoring can be reduced consid-
erably after 1 year of treatment.
FELBAMATE
Felbamate was the first second-gener- Place in Therapy
ation AED approved in the United Although felbamate was approved for
States in 1993. It has multiple mecha- monotherapy, it is not indicated as a
nisms of action, including N-methyl-D- first-line treatment because of its poten-
aspartate (NMDA) receptor antagonism, tial serious idiosyncratic toxicity. Adjunc-
GABA enhancement, and sodium chan- tive therapy or alternative monotherapy
nel blocking. It is available as an oral can be considered when other appro-
preparation. priate and safer options have failed.
Felbamate has excellent oral bioavail-
ability; its protein binding is not clini- GABAPENTIN
cally significant. It is metabolized in the Gabapentin binds to the alpha-2-delta
liver to inactive metabolites, with a half- subunit of voltage-gated calcium chan-
life of 20 to 23 hours. It is an inhibitor nels, reducing the influx of calcium and
of CYP 2C19, CYP 1A2, and $-oxidation, associated neurotransmitter release

Antiepileptic Drugs
KEY POINTS
h Gabapentin under hyperexcitable conditions. It is of action. It is also available only as an
bioavailability is low available as an oral preparation only. oral preparation. Unlike gabapentin,
and decreases with Gabapentin bioavailability is low and pregabalin has very good oral bioavail-
increasing doses. variable between subjects and even in ability, which is independent of dose.
h Pregabalin bioavailability the same subject. Because of its active Like gabapentin, it has no protein bind-
is very good and saturable transport system from the gut, ing and is not metabolized in humans,
independent of dose. its bioavailability decreases with increas- and it has no known interactions. It is
ing doses, from 60% after a single 300-mg excreted unchanged in the urine. Its
dose to 29% for 1600 mg 3 times a day.28 half-life is about 6 hours.
Protein binding is negligible. It is elimi- Pregabalin is a narrow-spectrum drug
nated unchanged in the urine. Its half- against focal seizures. The official FDA
life is 5 to 7 hours. It has no known inter- epilepsy indication is adjunctive therapy
actions, other than potential antacid inter- for adult patients with partial-onset
ference with its absorption. seizures. Like gabapentin, pregabalin
Gabapentin is a narrow-spectrum has a narrow spectrum of efficacy
agent against focal seizures. It may cause against focal seizures and may exacer-
exacerbation of myoclonus.29 It is also bate generalized myoclonic and ab-
approved for the treatment of post- sence seizures. It also has an indication
herpetic neuralgia. An extended-release for neuropathic pain associated with
preparation (gabapentin enacarbil) has diabetic peripheral neuropathy,
been approved for the treatment of postherpetic neuralgia, and fibromyal-
restless legs syndrome. The recom- gia. The starting dose is 75 mg 1 time (at
mended starting dose of gabapentin is bedtime) or 2 times a day. The dose can
300 mg/d to 400 mg/d, to be increased then be increased by 75 mg to 150 mg
by 300 mg to 400 mg every day up to every week as needed, until seizure
300 mg to 400 mg 3 times a day. The control, appearance of adverse effects,
dose can be increased as needed up to or reaching a maximum dose of 300 mg
4800 mg/d in three divided doses. 2 times a day.
Adverse effects include drowsiness, Pregabalin adverse effects include
dizziness, ataxia, tiredness, and weight dizziness, somnolence, increased appe-
gain. It may cause myoclonus. It may tite, weight gain, and peripheral edema.
cause cognitive slowing in the elderly Myoclonus may occur with higher doses
and emotional lability in children. Pe- in some individuals.
ripheral edema is more likely with
increasing age. Place in Therapy
Pregabalin is indicated as adjunctive
Place in Therapy therapy for focal seizures. It was in-
Gabapentin can be used as adjunctive ferior to lamotrigine as first-line ther-
treatment for focal seizures. It is often apy31 and should probably not be
chosen for its anecdotal benefit in the used as a first-line treatment. How-
treatment of headache and other pain and ever, a conversion-to-monotherapy
its benefit for sleep. Although approved in study was successful.32
Europe for initial monotherapy, a large
randomized comparative trial found it less LAMOTRIGINE
effective than lamotrigine.30 Lamotrigine blocks sodium channels, like
phenytoin and carbamazepine, but must
PREGABALIN have other unrecognized actions to ex-
Pregabalin is structurally related to plain efficacy against absence seizures. It
gabapentin and has a similar mechanism is available as an oral preparation only.

KEY POINTS
Lamotrigine has an excellent oral 3% of patients, with a higher incidence in h Lamotrigine clearance
bioavailability. Its protein binding is children, with coadministration of val- is decreased by
not clinically significant. It is exten- proic acid, and with faster titration and valproate and increased
sively metabolized in the liver, pre- higher doses. Stevens-Johnson syndrome, by estrogen and
dominantly by glucuronidation, and toxic epidermal necrolysis, or hyper- pregnancy as well as by
then eliminated in the urine. The sensitivity syndrome (1 in 4000) are enzyme inducers.
half-life is about 24 hours in mono- rare serious idiosyncratic adverse effects. h Lamotrigine combined
therapy, at least twice as long when with valproate has
used with valproate and about half as Place in Therapy evidence for synergism.
long when used with an enzyme in-
Lamotrigine is an important first-line
ducer. Estrogen and pregnancy in-
AED for focal seizures and generalized
crease lamotrigine clearance.
tonic-clonic seizures, although it is not
Lamotrigine is a broad-spectrum
FDA approved for initial monotherapy.
AED, although its FDA indications are
Several comparative trials have favored
limited to focal seizures, generalized
lamotrigine over other AEDs for focal
tonic-clonic seizures, and Lennox-
seizures in the balance of tolerability and
Gastaut syndrome. It is less effective
efficacy.5,30 However, it was inferior to
against generalized absence seizures
valproic acid for idiopathic generalized
than valproate and ethosuximide. It
epilepsy23 and inferior to ethosuximide
may be effective against myoclonic
for generalized absence seizures.24
seizures in some patients, but may
Lamotrigine is less sedating and has
exacerbate these seizures in others.
fewer cognitive adverse effects than
Lamotrigine also has an FDA indication
traditional AEDs. Its monotherapy use
for maintenance treatment in bipolar I
is associated with one of the lowest
disorder. Lamotrigine requires a very
rates of teratogenicity, favoring its use
slow titration to avoid the development
in women of childbearing age.
of rash. In monotherapy, it should be
Lamotrigine may have pharmacody-
initiated with 25 mg/d for 2 weeks,
namic interactions with other classic
followed by 50 mg/d for 2 weeks, then
sodium channel blockers, resulting in
100 mg/d. The dose can then be
toxic adverse effects at lower than
increased as needed by 100 mg every
expected serum concentrations. How-
2 weeks. The titration rate is half as fast
ever, its combination with valproate
with adjunctive valproic acid, but can be
can be synergistic, with greater efficacy
twice as fast in the presence of an
than predicted.35,36
enzyme inducer and absence of valproic
acid. A serum concentration is helpful to
guide further titration if seizures are still TOPIRAMATE
not controlled at a dose of 600 mg/d. Topiramate has multiple mechanisms
The suggested therapeutic range is of action, including antagonism of "-
2 mg/L to 20 mg/L.33 The extended- amino-3-hydroxy-5-methylisoxazole-4-
release preparation allows once-daily proprionic acid (AMPA)/kainate recep-
dosing and reduces toxicity from peak tors, augmentation of GABA activity,
levels (Case 7-3). It may even improve and blocking of voltage-gated sodium
efficacy when used 2 times a day in channels. It is available as an oral
patients who are drug resistant.34 preparation.
Dose-related adverse effects include Topiramate has an excellent oral
dizziness, blurred vision, diplopia, un- bioavailability. Its protein binding is not
steadiness, nausea and vomiting, head- clinically significant. It is partially metab-
ache, and tremor. Rash is seen in about olized in the liver, with about 70%

Antiepileptic Drugs
KEY POINT
h Patients may not be
aware of their cognitive
Case 7-3
A 78-year-old woman with a 23-year history of seizures presented reporting
adverse effects while
blurred vision and impaired balance. Her first seizure was a generalized
taking topiramate. It may
tonic-clonic seizure without any warning, after which she was found to have
be necessary to interview
a brain tumor. After biopsy, she received radiation therapy, and follow-up
spouses or other close
MRIs showed no tumor progression. She was treated with phenytoin, and
relatives to elicit evidence
after 3 years with no seizures, she came off phenytoin and remained seizure
of topiramate-induced
free on no seizure medications until 2 years before her visit. She then had a
cognitive dysfunction.
seizure with tingling in the right hand progressing to the elbow over 10 to
20 minutes, followed by drawing up of the right hand for about 10 minutes,
then loss of consciousness followed by generalized jerking activity. She was
started on levetiracetam, but seizures recurred, including an episode of status
epilepticus. She was switched to lamotrigine up to 200 mg 2 times a day, and
after a breakthrough seizure, she was given IV sodium valproate in an
emergency department, and then maintained on divalproex sodium 250 mg
2 times a day. She developed blurred vision, nausea, a feeling of being
drunk, and tremor. Neurologic examination was notable for prominent ataxia.
She could not even stand with her feet together without support. Antiepileptic
drug levels were requested, and she was switched to extended-release
lamotrigine pending the levels. Her lamotrigine level returned at 17.1 mg/L,
and her valproate level was 27 mg/L. When she was called 2 days after the visit
and a reduction in the dose of lamotrigine was suggested, she reported that
she was feeling so much better that she did not need to reduce the dose and
was worried about taking the risk of seizure recurrence.
Comment. This patient should have had a reduction in the dose of
lamotrigine when divalproex sodium was added. Her symptoms of blurred
vision and unsteadiness were related to elevation of lamotrigine serum
concentration, but they improved considerably with switching to an
extended-release preparation, suggesting that most of the symptoms were
related to peak toxicity. The switch to extended-release lamotrigine
eliminated lamotrigine level peaks and associated toxic manifestations.
eliminated unchanged in the urine. Its 25 mg/d and increase the dose by
half-life is approximately 21 hours. It is a 25 mg every week up to 100 mg/d.
mild inducer of CYP 3A4 and a mild Further titration by 25 mg to 50 mg
inhibitor of CYP 2C19. every week can be considered, up to
Topiramate is a broad-spectrum AED 400 mg/d in two divided doses. Extended-
effective against focal and generalized release preparations with once-daily
tonic-clonic seizures. A pilot trial dosing may improve tolerability.
suggested it is not effective for general- Topiramate is less well tolerated than
ized absence seizures.37 It is FDA lamotrigine, the main tolerability issue
approved for migraine prophylaxis and being cognitive adverse effects includ-
as a weight loss preparation in combi- ing cognitive slowing, decreased atten-
nation with phentermine. It is also tion and memory, impaired executive
frequently used off-label for bipolar function, word-finding difficulty, and
disorder. Topiramate has to be titrated reduced verbal fluency. Patients may
gradually to manage cognitive adverse not be aware of these cognitive difficul-
effects. It is suggested to start with ties. Other adverse effects include

KEY POINTS
sedation, fatigue, dizziness, ataxia, and proportion. It should be started at 4 mg h Tiagabine may be
depression. Kidney stones occur in at bedtime and increased by 4 mg every associated with
about 1.5% of individuals. Paresthesia week to an initial target dose of 8 mg dose-related episodes
in the hands and feet is related to 3 times a day. The dose can be of nonconvulsive status
carbonic anhydrase inhibition. Weight increased further by 4 mg every week epilepticus or
loss may occur. Oligohidrosis, hyper- up to 12 mg to 16 mg 3 times a day. A encephalopathy, even in
thermia, and metabolic acidosis may higher dose may be used in the subjects who do not
occur in children. Acute myopia presence of an enzyme inducer. have epilepsy.
and secondary angle-closure glaucoma The most common adverse effects h Levetiracetam is
are reported rarely. Hyperammonemia are dizziness, asthenia, nervousness, the only antiepileptic
may occur when topiramate is used tremor, depression, and emotional drug with
in conjunction with valproate. Topi- lability, which are more common dur- Class I evidence
ramate is associated with increased ing titration. Tiagabine may be asso- of efficacy
birth defects, particularly oral clefts.38 ciated with dose-related episodes of against generalized
myoclonic seizures.
nonconvulsive status epilepticus or
Place in Therapy encephalopathy, which may occur
Although topiramate is FDA approved even in the absence of epilepsy.39,40
for initial monotherapy for focal sei-
zures and generalized tonic-clonic sei- Place in Therapy
zures, it is not a drug of first choice Tiagabine should be reserved for use as
because of its cognitive adverse effects, adjunctive therapy for focal seizures.
unless its use is justified by comorbidity
such as headache or obesity. It is LEVETIRACETAM
effective as adjunctive therapy for focal Levetiracetams main mechanism of
and generalized seizures and Lennox- action is binding to the synaptic vesicle
Gastaut syndrome. protein SV2A. This seems to result in
nonspecific decrease in neurotransmit-
TIAGABINE ter release in a state of neuronal
Tiagabine inhibits GABA reuptake at hyperactivation.41 Levetiracetam is avail-
the synapse. It is available as an oral able in oral and IV formulations.
preparation only. Levetiracetam has an excellent oral
Tiagabine has an excellent oral bio- bioavailability and very low protein bind-
availability. It is 96% protein bound, but ing. It has no hepatic metabolism; 66% is
this is of limited importance since excreted unchanged in the urine and the
dosing decisions are not dependent on rest is hydrolyzed to inactive compounds.
the level, and its serum concentration is The half-life is 6 to 8 hours. It has no known
so low that it does not significantly significant pharmacokinetic interactions.
compete for protein binding. It is Levetiracetam is a broad-spectrum
extensively metabolized in the liver. Its drug, effective against focal seizures,
half-life is 7 to 9 hours in monotherapy, generalized tonic-clonic seizures, and
shortened to 2 to 5 hours in the generalized myoclonic seizures.
presence of an enzyme inducer. Levetiracetam is the only AED with
Tiagabine has a narrow spectrum of Class I evidence for efficacy against
efficacy against focal seizures only. It myoclonic seizures. It is best to start
may exacerbate generalized absence with 500 mg/d in two divided doses or
and myoclonic seizures. It is used off- once at bedtime with the extended-
label in the management of spasticity in release preparation. The dose can then
multiple sclerosis, in the treatment of be increased as needed and as tolerated
addiction, and to increase deep sleep up to 3000 mg/d to 4000 mg/d.

Antiepileptic Drugs
KEY POINT
h Zonisamides long The most common adverse effects are less pronounced than with
half-life of about include somnolence, dizziness, and as- topiramate. Rarely, depression and psy-
60 hours may be an thenia. Irritability and hostility may chosis may occur. Serious rash, such as
advantage in reducing occur, more often in children. Depres- Stevens-Johnson syndrome and toxic
the impact of a sion may also occur. epidermal necrolysis, occur rarely. Kid-
missed dose. ney stones occur in up to 4% of
Place in Therapy patients, but may be prevented with
Although levetiracetam is not FDA adequate hydration. Oligohidrosis, hy-
approved for monotherapy in the perthermia, and metabolic acidosis oc-
United States, it is used widely as a cur rarely, more often in children.
first-line treatment for focal and gen-
eralized tonic-clonic seizures and is Place in Therapy
approved for initial monotherapy in Zonisamide is indicated as initial
Europe. It is also an excellent adjunc- monotherapy for focal seizures in
tive treatment in view of its safety and Europe. In Japan, it is also indicated as
absence of interactions. monotherapy for generalized seizures.
The official FDA indication is for ad-
ZONISAMIDE junctive therapy for focal seizures.
Zonisamide is structurally related to Zonisamide is rarely the first-choice
sulfonamides. It has multiple me- agent for initial monotherapy because
chanisms of action, including blocking of its cognitive adverse effects. However,
T-type calcium channels (predictive of its long half-life could be an advantage,
efficacy against absence seizures), reducing the impact of a missed dose.
blocking sodium channels, and weak
inhibition of carbonic anhydrase activity. LACOSAMIDE
It is available only as an oral preparation. Lacosamide blocks sodium channels,
Zonisamide has excellent oral bio- enhancing slow inactivation, unlike
availability. Protein binding is not clini- most classic sodium channel blockers,
cally significant. It is metabolized in the which enhance fast sodium channel
liver to inactive metabolites. It has a inactivation. It is available in oral as well
long half-life of about 60 hours. It is not as parenteral formulations.
a hepatic enzyme inducer or inhibitor. Oral bioavailability is excellent. Pro-
Zonisamide is considered a broad- tein binding is not clinically significant.
spectrum AED, although Class I trials Lacosamide is converted in the liver to
have only been conducted in patients inactive metabolites, but approximately
with focal seizures. The starting dose is 40% is eliminated unchanged in the urine.
100 mg at bedtime for 2 weeks, then The half-life is approximately 13 hours.
200 mg at bedtime. The dose can be Lacosamide appears to be a narrow-
increased by 100 mg every 2 weeks as spectrum AED against focal seizures.
needed, up to 600 mg/d once at However, preliminary data suggest that
bedtime or in two divided doses. The it does not exacerbate absence or
suggested therapeutic range for plasma myoclonic seizures. The starting dose
concentration is 10 mg/L to 40 mg/L. is 100 mg/d (once at bedtime or in two
Adverse effects include sedation, divided doses) for 1 week, then 100 mg
ataxia, dizziness, nausea, fatigue, agita- 2 times a day. The dose can then be
tion/irritability, and anorexia. Weight titrated as needed by 100 mg every 1 to
loss may occur. Cognitive slowing and 2 weeks until seizures are controlled,
difficulty with concentration may be side effects appear, or a dose of
seen, particularly at higher doses, but 600 mg/d is reached.

KEY POINTS
The most common adverse effects in- Common vigabatrin adverse effects h Although lacosamide
clude dizziness, headache, nausea, vom- include sedation, fatigue, dizziness, and can be effectively
iting, diplopia, fatigue, and sedation, all ataxia. Irritability, behavior changes, psy- combined with another
of which are more common at higher chosis, and depression may also be classic sodium channel
doses. These adverse effects are also more observed. Weight gain may occur. The blocker, it may have
likely when lacosamide is used in conjunc- most concerning adverse effect is a pro- greater efficacy and
tion with other sodium channel blockers.42 gressive and permanent bilateral concen- tolerability in combination
tric visual field constriction, which may with a nonYsodium
Place in Therapy occur in up to 30% to 40% of individuals.44 channel blocker.
Lacosamide is indicated as monotherapy The risk increases with increased daily h Long-term vigabatrin
and as adjunctive therapy for focal dose and increased duration of therapy.45 use may be associated
seizures. The parenteral formulation is with irreversible visual
indicated as short-term replacement Place in Therapy field constriction; hence,
when oral administration is not feasible Vigabatrin use is reserved for adjunctive it should only be
continued if it produces a
in patients taking oral lacosamide; sev- therapy in subjects who have failed
remarkable improvement
eral anecdotal reports also exist of ef- several alternative treatments. Because
in seizure control.
ficacy in status epilepticus. When of the visual toxicity, periodic visual
lacosamide is used asadjunctive therapy, assessment is required at baseline and h Valproate reduces
rufinamide clearance;
it may have greater efficacy and better every 3 months, and treatment should
as a result, a lower
tolerability if it is combined with a be continued only if considerable ben-
starting dose and slower
nonYsodium channel drug.42 efit is observed in the first 3 months. titration rate are
necessary in the
VIGABATRIN RUFINAMIDE presence of valproate.
Vigabatrin is an irreversible inhibitor of Rufinamide is a sodium channel blocker,
GABA transaminase, resulting in accu- although additional mechanisms of ac-
mulation of GABA. It is available as an tion are likely. It is available only as an
oral formulation. Vigabatrin has excel- oral preparation. Oral bioavailability is
lent oral bioavailability and no protein very good with food, but is decreased in
binding. It is not significantly metabo- the absence of food. Protein binding is
lized and is eliminated unchanged in not clinically significant. It is metabolized
the urine. The half-life is 10.5 hours in by enzymatic hydrolysis to an inactive
young adults and 5 to 6 hours in infants. metabolite eliminated in the urine. The
However, its duration of action outlasts half-life is approximately 6 to 10 hours. It
its presence in serum.43 Vigabatrin is a is a weak inhibitor of CYP 2E1 and a
weak inducer of CYP 2C9. weak inducer of CYP 3A4 and uridine
Vigabatrin is a narrow-spectrum drug diphosphate glucuronyltransferase
effective against focal seizures. It may (UDP-GT). The addition of valproate
worsen absence and myoclonic seizures decreases rufinamide clearance and in-
in idiopathic generalized epilepsy.29 creases rufinamide levels by up to 70%.
However, it is effective against infantile Rufinamide is a broad-spectrum AED,
spasms, particularly in the presence of but its efficacy against focal seizures was
tuberous sclerosis. The starting adult not sufficient for an FDA indication. The
dose is 500 mg 2 times a day, then it is starting dose is 400 mg/d, after which it
titrated by 500 mg per week up to 1.5 g is increased by 400 mg every other day
2 times a day. The dose can be until seizure control or until a daily dose of
increased further, as needed, up to 3 g 3200 mg is reached (in two divided doses).
2 times a day, but this increases the risk Rufinamide adverse effects include
of adverse effects with a low chance of dizziness, fatigue, somnolence, and
additional therapeutic benefit. headache. Vomiting may occur in

Antiepileptic Drugs
KEY POINTS
h Long-term ezogabine children. Rufinamide may cause a available as an oral preparation. It has
use has been associated shortening of the QT interval. excellent oral bioavailability and is 95%
with bluish protein-bound. It is extensively metab-
pigmentation of the Place in Therapy olized in the liver. It has a long half-life
skin, nails, and retina. Rufinamide is FDA indicated as adjunc- of about 105 hours. At a dose of 12 mg
h Perampanel has a very tive treatment for seizures associated (not 8 mg), it accelerates the metabo-
long half-life, justifying with Lennox-Gastaut syndrome. lism of levonorgestrel, a progesterone
once-daily dosing. component of the oral contraceptive
EZOGABINE (RETIGABINE) pill.46 Perampanel is effective for focal
Ezogabine (known as retigabine outside seizures, but preliminary data suggest
the United States) is a potassium chan- efficacy against generalized tonic-clonic
nel opener. It is available as an oral seizures.47
preparation. Ezogabines oral bioavail- Perampanel adverse effects include
ability is about 60%. It is about 80% dizziness, somnolence, headache, fa-
protein bound. It is extensively metabo- tigue, ataxia, and blurred vision. Aggres-
lized to the active N-acetyl metabolite sion and hostility may occur, with an
(NAMR), which is also subsequently estimated incidence of about 20% at a
glucuronidated. The half-life is 7 to dose of 12 mg/d.
11 hours for both ezogabine and NAMR.
Ezogabine does not significantly affect Place in Therapy
other AEDs except for a 22% increase in Perampanel is indicated as adjunctive
lamotrigine clearance. treatment for focal seizures and primary
Ezogabine is a narrow-spectrum AED generalized tonic-clonic seizures.
effective only against focal seizures. The
starting dose should be 100 mg 3 times USE OF ANTIEPILEPTIC DRUGS
a day, followed by weekly increments of IN COMBINATION
50 mg 3 times a day up to the target If the first AED fails because of lack of
dose of 600 mg/d to 1200 mg/d. tolerability, it should be replaced with
The most common ezogabine adverse an alternative monotherapy. If the first
effects include dizziness, somnolence, AED fails because of lack of efficacy,
fatigue, confusion, blurred vision, tremor, options of replacement monotherapy
and nausea. Adverse effects are most or adjunctive therapy seem to be
noted during titration and peak after each equal.48 Substitution monotherapy is
dose. Weight gain may occur. Urinary favored when the first AED was not
retention has been reported in 2%. Long- well tolerated or was totally ineffective.
term use has been associated with bluish Substitution monotherapy would also
pigmentation in the skin, nails, and retina. be preferable in elderly patients who
This pigmentation was slowly reversible in already take other medications, in
one patient I have treated. women of childbearing potential con-
templating pregnancy, in patients with
Place in Therapy compliance challenges, and when finan-
Ezogabine is indicated for adjunctive cial restrictions exist. Add-on therapy
treatment of focal seizures. Because of would be preferred if the first AED was
potential long-term toxicity, it should be well tolerated and partially effective, or if
used only when other options have failed. the projected add-on agent has not been
tested in monotherapy. The add-on
PERAMPANEL therapy should not have negative phar-
Perampanel is a noncompetitive AMPA macokinetic interactions with the first
glutamate receptor antagonist. It is AED or other concomitant medications.49

KEY POINTS
For example, the use of an enzyme the treatment of comorbidities such as h Antiepileptic drug
inducer with an AED whose metabolism migraine or bipolar disorder. Consider- combinations with
can be induced will reduce its efficacy. ations in AED choice include the AEDs different mechanisms
Enzyme inhibition is less of a problem as efficacy profile as well as patient-specific of action may have a
long as dosing accommodations are factors. AED combinations should avoid greater probability
made. Evidence exists that combining unfavorable pharmacokinetic and phar- of success.
two AEDs with different mechanisms of macodynamic interactions. h Combinations of two
action is associated with greater balance classic sodium channel
of tolerability and efficacy.50 In particular, REFERENCES blockers, such as
combining two sodium channel blockers 1. Vajda FJ, Eadie MJ. The clinical pharmacology carbamazepine,
of traditional antiepileptic drugs. Epileptic
tends to be associated with pharmacody- oxcarbazepine,
Disord 2014;16(4):395Y408. doi:10.1684/epd.
namic interactions such that adverse ef- lamotrigine, phenytoin,
2014.0704.
fects may be seen even though serum and lacosamide, are
2. Ding D, Zhang Q, Zhou D, et al. Cognitive and associated with higher
concentrations are in the therapeutic mood effects of phenobarbital treatment in
rates of toxicity with
range. Several combinations seem to have people with epilepsy in rural China: a prospective
therapeutic serum
synergistic efficacy in animal models,51 study. J Neurol Neurosurg Psychiatry 2012;
83(12):1139Y1144. doi:10.1136/jnnp-2012-303042. concentrations.
but only one combination has been dem-
onstrated to be synergistic in humans, the 3. Mattson RH, Cramer JA, Collins JF, et al.
Comparison of carbamazepine, phenobarbital,
combination of lamotrigine and valproate.36 phenytoin, and primidone in partial and
secondarily generalized tonic-clonic seizures.
SUICIDALITY AND N Engl J Med 1985;313(3):145Y151.
ANTIEPILEPTIC DRUGS doi:10.1056/NEJM198507183130303.
In 2008, the FDA issued a warning about a 4. Arif H, Buchsbaum R, Weintraub D, et al.
Comparison and predictors of rash associated
possible increase in the risk of suicidality with 15 antiepileptic drugs. Neurology 2007;
linked to the use of AEDs.52 This was 68(20):1701Y1709.
based on a meta-analysis of 199 random- 5. Rowan AJ, Ramsay RE, Collins JF, et al. New
ized clinical trials evaluating a total of 11 onset geriatric epilepsy: a randomized study of
AEDs (used for either an epilepsy, a gabapentin, lamotrigine, and carbamazepine.
Neurology 2005;64(11):1868Y1873.
psychiatric, or other indication) as com-
doi:10.1212/01.WNL.0000167384.68207.3E.
pared to placebo. This meta-analysis
6. Dam M, Ekberg R, Loyning Y, et al. A double-
found an increased occurrence of sui-
blind study comparing oxcarbazepine and
cidal ideation and behavior in the AED carbamazepine in patients with newly
group. The FDA issued a black box diagnosed, previously untreated epilepsy.
warning against the class of AEDs Epilepsy Res 1989;3(1):70Y76.
highlighting the need for increased vigi- 7. Reinikainen KJ, Keranen T, Halonen T, et al.
lance and screening for psychiatric Comparison of oxcarbazepine and
carbamazepine: a double-blind study.
comorbidities and worsening depression Epilepsy Res 1987;1(5):284Y289.
in relation to epilepsy and its treatment.
8. Marson AG, Al-Kharusi AM, Alwaidh M,
For more information on suicidality and et al. The SANAD study of effectiveness of
AED use, refer to the article Manage- carbamazepine, gabapentin, lamotrigine,
ment of Epilepsy Comorbidities by oxcarbazepine, or topiramate for treatment
Joseph I. Sirven, MD, FAAN,53 in this of partial epilepsy: an unblinded
randomised controlled trial. Lancet 2007;369
issue of Continuum. (9566):1000Y1015.
9. Brodie MJ, Overstall PW, Giorgi L.
CONCLUSION Multicentre, double-blind, randomised
In conclusion, many AEDs are available comparison between lamotrigine and
carbamazepine in elderly patients with
for the treatment of epilepsy, with
newly diagnosed epilepsy. The UK
specific advantages and disadvantages. Lamotrigine Elderly Study Group. Epilepsy
Some AEDs have additional efficacy in Res 1999;37(1):81Y87.

Antiepileptic Drugs
10. Reunanen M, Dam M, Yuen AW. A Epilepsia 2015;56(4):546Y555. doi:10.1111/

randomised open multicentre comparative epi.12934.
trial of lamotrigine and carbamazepine as 20. Vajda FJ, O'brien TJ, Hitchcock A, et al.
monotherapy in patients with newly Critical relationship between sodium valproate
diagnosed or recurrent epilepsy. Epilepsy
dose and human teratogenicity: results of the
Res 1996;23(2):149Y155. Australian register of anti-epileptic drugs in
11. Brodie MJ, Richens A, Yuen AW. Double- pregnancy. J Clin Neurosci 2004;11(8):854Y858.
blind comparison of lamotrigine and doi:10.1016/j.jocn.2004.05.003.
carbamazepine in newly diagnosed epilepsy. 21. Christensen J, Grnborg TK, Srensen MJ,
UK Lamotrigine/Carbamazepine Monotherapy et al. Prenatal valproate exposure and risk
Trial Group. Lancet 1995;345(8948):476Y479. of autism spectrum disorders and childhood
12. Saetre E, Perucca E, Isojarvi J, Gjerstad L. An autism. JAMA 2013;309(16):1696Y1703.
international multicenter randomized doi:10.1001/jama.2013.2270.
double-blind controlled trial of lamotrigine 22. Meador KJ, Baker GA, Browning N, et al.
and sustained-release carbamazepine in the Fetal antiepileptic drug exposure and
treatment of newly diagnosed epilepsy in cognitive outcomes at age 6 years
the elderly. Epilepsia 2007;48(7):1292Y1302. (NEAD study): a prospective observational
13. Brodie MJ, Perucca E, Ryvlin P, et al. study. Lancet Neurol 2013;12(3):244Y252.
Comparison of levetiracetam and doi:10.1016/S1474-4422(12)70323-X.
controlled-release carbamazepine in newly 23. Marson AG, Al-Kharusi AM, Alwaidh M,
diagnosed epilepsy. Neurology 2007;68(6): et al. The SANAD study of effectiveness of
402Y408. valproate, lamotrigine, or topiramate for
14. Baulac M, Brodie MJ, Patten A, et al. Efficacy generalised and unclassifiable epilepsy: an
and tolerability of zonisamide versus unblinded randomised controlled trial.
controlled-release carbamazepine for newly Lancet 2007;369(9566):1016Y1026.
diagnosed partial epilepsy: a phase 3, doi:10.1016/S0140-6736(07)60461-9.
randomised, double-blind, non-inferiority 24. Glauser TA, Cnaan A, Shinnar S, et al.
trial. Lancet Neurol 2012;11(7):579Y588. Ethosuximide, valproic acid, and lamotrigine
doi:10.1016/S1474-4422(12)70105-9. in childhood absence epilepsy: initial
15. Azar NJ, Wright AT, Wang L, et al. monotherapy outcomes at 12 months.
Generalized tonic-clonic seizures after acute Epilepsia 2013;54(1):141Y155. doi:10.1111/
oxcarbazepine withdrawal. Neurology 2008; epi.12028.
70(22 pt 2):2187Y2188. doi:10.1212/01.wnl. 25. Mattson RH, Cramer JA, Collins JF. A
0000313152.89906.5a. comparison of valproate with carbamazepine
16. Nolan SJ, Muller M, Tudur Smith C, Marson for the treatment of complex partial seizures
AG. Oxcarbazepine versus phenytoin and secondarily generalized tonic-clonic
monotherapy for epilepsy. Cochrane Data- seizures in adults. The Department of Veterans
base Syst Rev 2013;5:CD003615. doi:10.1002/ Affairs Epilepsy Cooperative Study No. 264
14651858.CD003615.pub3. Group. N Engl J Med 1992;327(11):765Y771.
26. Glauser TA, Cnaan A, Shinnar S, et al.
17. Hebeisen S, Pires N, Loureiro AI, et al.
Ethosuximide, valproic acid, and lamotrigine
Eslicarbazepine and the enhancement of
in childhood absence epilepsy. N Engl J
slow inactivation of voltage-gated sodium
Med 2010;362(9):790Y799. doi:10.1056/
channels: a comparison with carbamazepine,
NEJMoa0902014.
oxcarbazepine and lacosamide.
Neuropharmacology 2015;89:122Y135. 27. Riss J, Cloyd J, Gates J, Collins S.
doi:10.1016/j.neuropharm.2014.09.008. Benzodiazepines in epilepsy: pharmacology
and pharmacokinetics. Acta Neurol Scand
18. Nunes T, Rocha JF, Falco A, et al.
2008;118(2):69Y86. doi:10.1111/j.1600-0404.
Steady-state plasma and cerebrospinal
2008.01004.x.
fluid pharmacokinetics and tolerability
of eslicarbazepine acetate and 28. Gidal BE, DeCerce J, Bockbrader HN, et al.
oxcarbazepine in healthy volunteers. Gabapentin bioavailability: effect of dose
Epilepsia 2013;54(1):108Y116. doi:10.1111/ and frequency of administration in adult
j.1528-1167.2012.03595.x. patients with epilepsy. Epilepsy Res
1998;31(2):91Y99. doi:10.1016/
19. Sperling MR, Harvey J, Grinnell T, et al.
S0920-1211(98)00020-5.
Efficacy and safety of conversion to
monotherapy with eslicarbazepine acetate 29. Perucca E, Gram L, Avanzini G, Dulac O.
in adults with uncontrolled partial-onset Antiepileptic drugs as a cause of worsening
seizures: a randomized historical-control seizures. Epilepsia 1998;39(1):5Y17.
phase III study based in North America. doi:10.1111/j.1528-1157.1998.tb01268.x.

30. Marson AG, Al-Kharusi AM, Alwaidh M, 40. Koepp MJ, Edwards M, Collins J, et al. Status
et al. The SANAD study of effectiveness of epilepticus and tiagabine therapy revisited.
carbamazepine, gabapentin, lamotrigine, Epilepsia 2005;46(10):1625Y1632.
oxcarbazepine, or topiramate for treatment doi:10.1111/j.1528-1167.2005.00263.x.
of partial epilepsy: an unblinded randomised
controlled trial. Lancet 2007;369(9566): 41. Fukuyama K, Tanahashi S, Nakagawa M,
1000Y1015. doi:10.1016/S0140-6736(07)60460-7. et al. Levetiracetam inhibits neurotransmitter
release associated with CICR. Neurosci Lett
31. Kwan P, Brodie MJ, Klviinen R, et al. 2012;518(2):69Y74. doi:10.1016/j.neulet.2012.
Efficacy and safety of pregabalin versus 03.056.
lamotrigine in patients with newly
diagnosed partial seizures: a phase 3, 42. Sake JK, Hebert D, Isojrvi J, et al. A pooled
double-blind, randomised, parallel-group analysis of lacosamide clinical trial data
trial. Lancet Neurol 2011;10(10):881Y890. grouped by mechanism of action of
doi:10.1016/S1474-4422(11)70154-5. concomitant antiepileptic drugs. CNS Drugs
2010;24(12):1055Y1068. doi:10.2165/
32. French J, Kwan P, Fakhoury T, et al. 11587550-000000000-00000.
Pregabalin monotherapy in patients with
partial-onset seizures: a historical-controlled 43. Ben-Menachem E. Medical management of
trial. Neurology 2014;82(7):590Y597. refractory epilepsyVpractical treatment
doi:10.1212/WNL.0000000000000119. with novel antiepileptic drugs. Epilepsia
2014;55(suppl 1):3Y8. doi:10.1111/epi.12494.
33. Hirsch LJ, Weintraub D, Du Y, et al.
Correlating lamotrigine serum concentrations 44. Klviinen R, Nousiainen I, Mantyjarvi M,
with tolerability in patients with epilepsy. et al. Vigabatrin, a gabaergic antiepileptic
Neurology 2004;63(6):1022Y1026. doi:10.1212/ drug, causes concentric visual field defects.
01.WNL.0000138424.33979.0C. Neurology 1999;53(5):922Y926. doi:10.1212/
WNL.53.5.922.
34. Ramey P, Osborn M, Abou-Khalil B.
Conversion from immediate-release to 45. Toggweiler S, Wieser HG. Concentric visual
extended-release lamotrigine improves seizure field restriction under vigabatrin therapy:
control. Epilepsy Res 2014;108(9):1637Y1641. extent depends on the duration of drug
doi:10.1016/j.eplepsyres.2014.08.004. intake. Seizure 2001;10(6):420Y423.
doi:10.1053/seiz.2000.0527.
35. Brigo F, Ausserer H, Tezzon F, Nardone R.
When one plus one makes three: the quest 46. Patsalos PN. The clinical pharmacology profile
for rational antiepileptic polytherapy with of the new antiepileptic drug perampanel: a
supraadditive anticonvulsant efficacy. novel noncompetitive AMPA receptor
Epilepsy Behav 2013;27(3):439Y442. antagonist. Epilepsia 2015;56(1):12Y27. doi:10.
doi:10.1016/j.yebeh.2013.03.010. 1111/epi.12865.
36. Poolos NP, Warner LN, Humphreys SZ, 47. French JA, Krauss GL, Wechsler RT, et al.
Williams S. Comparative efficacy of Perampanel for tonic-clonic seizures in
combination drug therapy in refractory idiopathic generalized epilepsy: a randomized
epilepsy. Neurology 2012;78(1):62Y68. trial [published online ahead of print
doi:10.1212/WNL.0b013e31823ed0dd. August 21, 2015]. Neurology doi:10.1212/WNL.
0000000000001930.
37. Pia-Garza JE, Schwarzman L, Wiegand F,
Hulihan J. A pilot study of topiramate in 48. Semah F, Thomas P, Coulbaut S, Derambure P.
childhood absence epilepsy. Acta Neurol Early add-on treatment vs alternative
Scand 2011;123(1):54Y59. doi:10.1111/ monotherapy in patients with partial epilepsy.
j.1600-0404.2010.01347.x. Epileptic Disord 2014;16(2):165Y174. doi:10.
1684/epd.2014.0650.
38. Hunt S, Russell A, Smithson WH, et al.
Topiramate in pregnancy: preliminary 49. Zaccara G, Perucca E. Interactions between
experience from the UK Epilepsy and antiepileptic drugs, and between
Pregnancy Register. Neurology 2008;71(4): antiepileptic drugs and other drugs. Epileptic
272Y276. doi:10.1212/01.wnl.0000318293. Disord 2014;16(4):409Y431. doi:10.1684/epd.
28278.33. 2014.0714.
39. Azar NJ, Bangalore-Vittal N, Arain A, 50. Margolis JM, Chu BC, Wang ZJ, et al.
Abou-Khalil BW. Tiagabine-induced stupor in Effectiveness of antiepileptic drug
patients with psychogenic nonepileptic combination therapy for partial-onset
seizures: nonconvulsive status epilepticus or seizures based on mechanisms of action.
encephalopathy? Epilepsy Behav 2013;27(2): JAMA Neurol 2014;71(8):985Y993.
330Y332. doi:10.1016/j.yebeh.2013.02.016. doi:10.1001/jamaneurol.2014.808.

Antiepileptic Drugs
51. Stafstrom CE. Mechanisms of action of antiepileptic drugs. www.fda.gov/Drugs/

antiepileptic drugs: the search for DrugSafety/PostmarketDrugSafety
synergy. Curr Opin Neurol 2010;23(2): InformationforPatientsandProviders/
157Y163. doi:10.1097/WCO. ucm100192.htm. Updated August 15, 2013.
0b013e32833735b5. Accessed December 13, 2015.
52. US Food and Drug Administration. 53. Sirven JI. Management of epilepsy
Information for healthcare professionals: comorbidities. Continuum (Minneap Minn)
suicidal behavior and ideation and 2016;22(1 Epilepsy):191Y203.

Antiepileptic Drugs Continuum 2016

Загружено:

Сведения о документе

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Antiepileptic Drugs Continuum 2016

Загружено:

Авторское право:

Доступные форматы

Review Article

Continuum (Minneap Minn) 2016;22(1):132156.

INTRODUCTION dren are highlighted throughout the

132 www.ContinuumJournal.com February 2016

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum (Minneap Minn) 2016;22(1):132156 www.ContinuumJournal.com 133

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

FDA = US Food and Drug Administration.

KEY POINTS 80 to 100 hours. Phenobarbital is a Phenobarbitals main adverse effects

134 www.ContinuumJournal.com February 2016

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Antiepileptic Oral Protein

Continuum (Minneap Minn) 2016;22(1):132156 www.ContinuumJournal.com 135

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Antiepileptic Target Dose; Usual

136 www.ContinuumJournal.com February 2016

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Antiepileptic Target Dose; Usual

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

FIGURE 7-1 Example of the nonlinear kinetics of

138 www.ContinuumJournal.com February 2016

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Case 7-1 h Unlike phenytoin, the

Continuum (Minneap Minn) 2016;22(1):132156 www.ContinuumJournal.com 139

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Multiple comparative monotherapy tri- rivative of oxcarbazepine (after admin-

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum (Minneap Minn) 2016;22(1):132156 www.ContinuumJournal.com 147

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum (Minneap Minn) 2016;22(1):132156 www.ContinuumJournal.com 153

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

10. Reunanen M, Dam M, Yuen AW. A Epilepsia 2015;56(4):546Y555. doi:10.1111/

154 www.ContinuumJournal.com February 2016

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum (Minneap Minn) 2016;22(1):132156 www.ContinuumJournal.com 155

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

51. Stafstrom CE. Mechanisms of action of antiepileptic drugs. www.fda.gov/Drugs/

156 www.ContinuumJournal.com February 2016

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Вам также может понравиться