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Optimal Use of the Newest
Antiepileptic Drugs and Generics
Peter Pressman, MD
University of California, San Francisco, School of Medicine,
San Francisco, California
A REPORT FROM THE 66th ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY
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1
Indications and Mechanisms
of Action of the Newer AEDs
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2
Indications and Mechanisms of Action of the Newer AEDs:
Stiripentol

Approved in Europe for adjunctive treatment with
clobazam and valproic acid of refractory generalized
tonic-clonic seizures in infants with myoclonic
epilepsy (Dravet syndrome)1

Structurally unrelated to other antiepileptic drugs
(AEDs)

Mechanism of action unknown but is likely diverse

Appears to increase the duration of opening of
-aminobutyric acid type A (GABAA) receptors
(similar to the the action of barbiturates)
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3
Indications and Mechanisms of Action of the Newer AEDs:
Stiripentol

May interact with benzodiazepines

May increase central GABA activity by interfering
with uptake and metabolism2

Inhibits various cytochrome P (CYP) 450 enzymes,
decreasing metabolism of such AEDs as phenytoin,
carbamazepine, and diazepam2–4
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4
Indications and Mechanisms of Action of the Newer AEDs:
Lacosamide

FDA approved for adjunctive treatment of partialonset seizures in patients > 17 years of age

First AED to enhance the slow inactivation state of
voltage-gated sodium channels5,6

May regulate sodium-channel availability over the
long term7

Binds with collapsin response mediator protein,
although effect on the antiepileptic activity of this
drug is unclear5
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5
Indications and Mechanisms of Action of the Newer AEDs:
Rufinamide

FDA approved for adjunctive treatment of seizures
associated with Lennox-Gastaut syndrome in
children  4 years of age and adults

First drug approved in the US with a pediatric
indication before adult use approved

Possesses a novel triazole structure somewhat
similar to that of lamotrigine

Prolongs inactivated state of voltage-gated sodium
channels8

Activity against atonic seizures may involve
additional mechanisms6
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6
Indications and Mechanisms of Action of the Newer AEDs:
Eslicarbazepine Acetate

Approved in Europe for adjunctive treatment of
partial seizures in adults9

Being tested in the US in phase III trials in adults
with partial-onset seizures and in phase II trials for
possible use in bipolar disorder10

Competitive antagonist of fast voltage-gated
potassium channels, stabilizes the inactivated
neuronal state,9 and potentiates GABA currents

May be given once daily11

May enhance slow inactivation of voltage-dependent
sodium channels (similar to lacosamide)
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7
Indications and Mechanisms of Action of the Newer AEDs:
Vigabatrin

FDA approved for adjunctive treatment of adults
with refractory complex partial seizures and
monotherapy for infantile spasm in patients 1 month
to 2 years of age

Benefits must outweigh the risks of potential vision
loss (occurs in up to one third of treated patients)

Irreversibly inhibits GABA transaminase12

Inhibits vesicular GABA transporter and increases
extracellular GABA concentrations in the CNS and
tonic inhibition in extrasynaptic GABA receptors
with prolonged activation6
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8
Indications and Mechanisms of Action of the Newer AEDs:
Ezogabine (Retigabine)

FDA approved as adjunctive therapy for partial
seizures and refractory partial epilepsy in patients
 18 years of age

First AED to target and open voltage-gated
potassium channels

Has a hyperpolarizing effect on neurons and reduces
neuronal hyperexcitability13

At supratherapeutic concentrations, enhances
GABAA-activated currents14

Use may cause urinary retention15,16
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9
Indications and Mechanisms of Action of the Newer AEDs:
Clobazam

FDA approved for adjunctive therapy of LennoxGastaut syndrome in children  2 years of age and
adults.

Can lead up to a 70% reduction in drop seizures17

First approved in Australia in 1970 and used for
years in Europe

Potentiates GABAergic neurotransmission

Less lipophilic and acidic, better tolerated, and less
sedating than 1,4-benzodiazepines

Tolerance to clobazam develops more slowly than
with other AEDs18
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10
Indications and Mechanisms of Action of the Newer AEDs:
Perampanel

FDA approved for adjunctive therapy of partial-onset
seizures, with or without secondarily generalized
seizures, in patients  12 years of age

First inotropic -amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) glutamate receptor
antagonist

Reduces fast excitatory signaling in the brain6,19
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11
Indications and Mechanisms of Action of the Newer AEDs:
Summary
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12
Drug Interactions of the Newer AEDs
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13
Drug Interactions of the Newer AEDs:
Interactions with Other Drug Classes

Use of oral contraceptives may lead to CYP3A4mediated induction by carbamazepine, felbamate,
oxcarbazepine, topiramate, rufinamide,
eslicarbazepine acetate, and perampanel20 and UDPglucuronosyltransferase (UGT)-mediated induction
of lamotrigine and valproic acid

In older patients, CYP2C9-mediated induction of
warfarin by carbamazepine and eslicarbazepine
acetate may occur, as well as inhibition by felbamate
and stiripentol21
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14
Drug Interactions of the Newer AEDs:
Interactions with Other Drug Classes
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15
Pharmacokinetics of the Newer AEDs
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16
Pharmacokinetics of the Newer AEDs:
Lacosamide

Well absorbed; maximum concentration in the blood
(Tmax) reached within 0.5–4 hours

Serum concentrations increase greatly during the
first 3 hours after dosing22

Dosing three times daily may reduce fluctuations and
improve tolerability

Available in both oral and intravenous forms

Predominantly excreted renally23
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17
Pharmacokinetics of the Newer AEDs:
Rufinamide

Dose-dependent absorption; less absorbed in
absence of food

Not highly protein-bound (26%–35%)

Metabolized via non–CYP-dependent hydrolysis

Short half-life

Valproic acid increases serum levels up to 50%24

Serum levels ~19% lower in children compared with
adults25

Therapeutic drug monitoring recommended
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18
Pharmacokinetics of the Newer AEDs:
Eslicarbazepine Acetate

Prodrug: 100% of dose converted into active
metabolite (eslicarbazepine)

Tmax is 2–3 hours

Protein binding is about 40%; volume of distribution
(Vd) is 2.7 L/kg

Induces other CYP isoenzymes, leading to a 12%–
16% increase in clearance of carbamazepine,
lamotrigine, and topiramate

Reduced excretion in patients with renal or hepatic
impairment6,7,26,27
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19
Pharmacokinetics of the Newer AEDs:
Vigabatrin

Low potential for pharmacokinetic interactions

100% bioavailable, with no protein binding and a
Tmax of 1 hour

Has caused irreversible peripheral vision loss in
many patients28

Half-life of biological activity exceeds serum halflife29

Half-life of biologic activity likely depends most on
the regeneration of GABA transaminase, which may
take up to 6 days after administration30
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20
Pharmacokinetics of the Newer AEDs:
Ezogabine

Higher Vd (6.2 L/kg) than that of other AEDs

Metabolized by UGT and N-acetylation

With lamotrigine, can cause a 20% increase in
clearance31,32
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21
Pharmacokinetics of the Newer AEDs:
Clobazam

Close to 100% bioavailability

Protein binding is 85%; Vd is 1 L/kg.

Metabolized by CYP3A4 and CYP2C19

Adverse effects akin to benzodiazepine toxicity may
occur with slow CYP metabolism

Lower doses needed for patients with renal or
hepatic impairment28,33
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22
Pharmacokinetics of the Newer AEDs:
Perampanel

Food may delay absorption by 2 hours

96% protein-bound

Possible displacement interactions with other highly
bound AEDs

High Vd at 77 L/kg

Long half-life, reaching steady-state serum levels
after 14 days

Clearance doubled or tripled with carbamazepine,
oxcarbazepine, or phenytoin

Limited experience so far in clinical practice14,34
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23
Efficacy and Safety of the Newer AEDs
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24
Efficacy and Safety of the Newer AEDs

At least 27% of patients respond favorably to
treatment with a newer AED35,36

Meaningful benefit may be achieved in the majority
of patients with refractory epilepsy

However, < 20% of patients attain freedom from
seizures after trying a third or fourth drug
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25
Efficacy and Safety of the Newer AEDs:
Lacosamide

Dose-response plateaus at 400 mg/d37

Linear relationship between dose and side effects

Dizziness seen in almost 25% of patients and
worsened with concomitant use of another sodiumchannel blocker

Vertigo, ataxia, balance disorders, coordination
abnormalities, and diplopia are also common

Relatively low frequency of somnolence, rash, and
cognitive side effects
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26
Efficacy and Safety of the Newer AEDs:
Lacosamide

Recommended dose is 50 mg twice daily for the first
week.

Increased in weekly intervals by 100 mg/d in two
divided doses, as tolerated, until a goal of 200–400
mg/d in two divided doses is reached

Doses may be halved

Upward titration may be prolonged

May be better tolerated if taken three times daily

No proven benefit of using lacosamide as a single
agent
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27
Efficacy and Safety of the Newer AEDs:
Ezogabine

Modest efficacy

Recommended starting dose is 100 mg three times a
day; then titrate upward to 600–1,200 mg/d in three
divided doses.

Dose-related side effects include somnolence,
dizziness, confusion

Causes potentially severe urinary retention, an
unusual side effect for an AED

Use caution in patients with an enlarged prostate
gland or other problems with urinary voiding

Low rate of rash and cognitive complaints
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28
Efficacy and Safety of the Newer AEDs:
Rufinamide

Particularly successful for atonic seizures or “drop
attacks”

Dosing for children starts at 10 mg/kg/d given in two
divided doses (target dose, 45 mg/kg/d).

In adults, the starting dose is 200 mg twice daily
(maximum dose, 3,200 mg/d).

Prone to interact with other AEDs
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29
Efficacy and Safety of the Newer AEDs:
Clobazam

In patients weighing > 30 kg, dosing ranges from 10
to 40 mg/d given in two divided doses

A conservative starting dose would be 5 mg/d given
for 1 week, followed by 5-mg/d increases at weekly
intervals to reach a goal of 20 mg/d

Often added to valproic acid, felbamate, lamotrigine,
or topiramate
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30
Emerging Uses of the Newer AEDs
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31
Emerging Uses of the Newer AEDs:
Lacosamide

Evidence of a > 50% decrease in the frequency of
epileptic episodes in 18 of 24 patients with
generalized tonic-clonic seizure38

In children, lacosamide is capable of reducing
seizure frequency by 30%–50%, although patients
frequently stopped taking the medication because of
side effects.39–42

Results of using lacosamide for status epilepticus are
conflicting.
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32
Emerging Uses of the Newer AEDs:
Rufinamide

Drug has been evaluated for adjunctive treatment of
focal seizures in children and adults, malignant
migrating partial epilepsy, epilepsy with myoclonic
absence seizures, Dravet syndrome, myoclonic
astatic epilepsy, West syndrome, multifocal
encephalopathy with bifrontal spike-wave
discharges, and other unspecified symptomatic or
cryptogenic generalized seizures.43–50

In almost all cases, responses varied, and no clear
picture emerged from the data.
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33
Emerging Uses of the Newer AEDs:
Clobazam

Additional indications being investigated include:
» Treatment of other electroclinical syndromes
» Monotherapy for focal or generalized seizure in adults
» Adjunctive therapy for focal or generalized seizure in adults
and children

Possible future indications include status epilepticus
and febrile seizures
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34
Generic AEDs: Fact and Fiction
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35
Definitions of Equivalence

Bioequivalence—pharmacokinetic parameters of the
area under the curve (AUC) and maximum serum
concentration (Cmax) fall within a certain range

Therapeutic equivalence—two products have an
equal clinical benefit for a patient

Switchability—no change in therapeutic effect noted
when one drug is exchanged for another
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36
The Crux of the Problem

Neurologists argue that the FDA standards of
bioequivalence do not reliably predict actual
therapeutic equivalence or switchability.

Use of generic AEDs may increase the need for
emergency services.51

A model using data from five generic carbamazepine
products demonstrated AUC variations of up to 21%
and variations in Cmax reaching 40%.52

No rigorous assessment of seizure frequency or
blood levels of AEDs has been done.

Studies of adherence to medication, stress, and sleep
deprivation have been uncontrolled.
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37
Improving Equivalence Research

Results of the Equivalence Among Antiepileptic Drug
Generic and Brand Products in People with Epilepsy
(EQUIGEN) and BEEP studies are expected early in
2013.

Research focuses on bioequivalence rather than
therapeutic equivalence
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38
Improving Equivalence Research

Physicians should:
» Investigate cost differences
» Recognize that patients who are pregnant, have a history of
status epilepticus, or are seizure-free and driving a vehicle
are at higher risk than others

Patients should be counseled about:
» Unauthorized formulation substitution
» Calling a physician if pills in a newly refilled prescription
look different from those used previously
» Medication adherence
» Avoiding triggers like alcohol and sleep deprivation
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39
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