Download Antiepilepsy Drugs: pharmacodynamics and

Epilepsy Board Review Manual
Statement of
Editorial Purpose
The Epilepsy Board Review Manual is a study
guide for trainees and practicing physicians
preparing for board examinations in epilepsy.
Each manual reviews a topic essential to the
current management of patients with epilepsy.
PUBLISHING STAFF
PRESIDENT, Group PUBLISHER
Bruce M. White
Antiepilepsy Drugs:
Pharmacodynamics and
Principles of Drug Selection
Contributor and Editor:
Thomas R. Henry, MD
Professor of Neurology, Director, Comprehensive
Epilepsy Center, University of Minnesota Medical School,
Minneapolis, MN
Contributor:
Jeannine M. Conway, PharmD
Assistant Professor of Pharmacy, University of Minnesota
College of Pharmacy, Minneapolis, MN
Senior EDITOR
Robert Litchkofski
executive vice president
Barbara T. White
executive director
of operations
Jean M. Gaul
Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Principles of Drug Selection and Dosing. . . . . . . 1
Summary of Antiepileptic Drugs . . . . . . . . . . . . 12
Other Considerations. . . . . . . . . . . . . . . . . . . . . 17
NOTE FROM THE PUBLISHER:
This publication has been developed with­
out involvement of or review by the Amer­
ican Board of Psychiatry and Neurology.
Board Review Questions. . . . . . . . . . . . . . . . . . . 18
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
Epilepsy Board Review Manual
Antiepilepsy Drugs:
Pharmacodynamics and Principles of Drug Selection
Jeannine M. Conway, PharmD, and Thomas R. Henry, MD
Introduction
Pharmacologic management of seizures in individual patients mainly involves drug selection
based on the individual patient’s epilepsy syndrome and risks for toxicity with particular agents,
followed by ongoing surveillance for antiseizure
efficacy and adverse effects. These aspects of
the interaction between particular drugs and individuals’ brains and other organ systems are
considered the pharmacodynamics of antiepileptic
drugs (AEDs), in distinction to the absorption, distribution, and elimination of drugs and drug-drug
interactions, or pharmacokinetics, of AEDs. Drug
selection by epilepsy syndrome may be informed
by randomized prospective trials with explicit entry
criteria that define a syndrome and report efficacy
of an AED versus placebo with statistically rigorous
analyses, and by expert consensus statements.1,2
In addition to warnings and toxicity information issued by the U.S. Food and Drug Administration
(FDA), expert consensus statements also play a
major role in avoidng and managing adverse effects of AEDs.3
Principles of drug selection and
dosing
Initial monotherapy
A dilemma encountered by prescribers is determining which antiepileptic medication should be
prescribed first. The majority of the data indicate
that, particularly for focal seizures, medications
are essentially equally efficacious, but some statistically significant differences can be found in
tolerability and side effects.4–7 The great majority
of industry-sponsored clinical trials are designed
as placebo-controlled, add-on therapy, prospective trials in subjects whose seizures are not well
controlled by their current medications. The inclusion criteria may vary slightly, but they most often
include adults with a diagnosis of complex partial
seizures. As a result, most AEDs are launched
initially to market to be used as adjunctive therapy with an existing AED regimen (Table 1).
It is therefore difficult to extrapolate the results
of those studies to all patients seen in clinic,
as many may not be refractory and may not be
adults.
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www.turner-white.comEpilepsy Volume 1, Part 6 1
Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
Table 1. Antiepileptic Drug FDA-Approved Indications
Medication
First generation
Carbamazepine
Ethosuximide
Phenobarbital
Phenytoin
Valproic acid†
Second generation
Clobazam
Felbamate
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Pregabalin
Rufinamide
Tiagabine
Topiramate
Vigabatrin
Zonisamide
Third generation
Ezogabine
Lacosamide
Perampanel
FDA-Approved Indications
POS, GTC seizures, mixed seizure patterns*
Absence seizures*
Not an FDA-approved medication
Control of GTC seizures (grand mal) and CPS (psychomotor, temporal lobe) and prevention and treatment of seizures
occurring during or following neurosurgery
Monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to age 10 years with
CPS that occur either in isolation or in association with other types of seizures; also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children aged ≥10 years, and
adjunctively in adults and children aged ≥10 years with multiple seizure types that include absence seizures
Adjunctive treatment of seizures associated with LGS in patients aged ≥2 years
Monotherapy or adjunctive therapy in the treatment of POS, with and without generalization, in adults with epilepsy and
as adjunctive therapy in the treatment of partial and generalized seizures associated with LGS in children
Adjunctive therapy in the treatment of POS with and without secondary generalization in patients over age 12 years with
epilepsy; also indicated as adjunctive therapy in the treatment of POS in pediatric patients aged 3–12 years
Adjunctive therapy for the following seizure types in patients aged ≥2 years: POS, primary GTC seizures, generalized
seizures of LGS; indicated for conversion to monotherapy in adults (age ≥16 years) with POS who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED
Adjunctive therapy in the treatment of POS in adults and children aged ≥1 month with epilepsy and as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents aged ≥12 years with JME; also indicated as adjunctive therapy in the treatment of primary GTC seizures in adults and children aged ≥6 years with idiopathic generalized
epilepsy
Monotherapy or adjunctive therapy in the treatment of POS in adults and as monotherapy in the treatment of POS in
children aged ≥4 years with epilepsy, and as adjunctive therapy in children aged ≥2 years with POS
Adjunctive therapy for adult patients with POS
Adjunctive treatment of seizures associated with LGS in children aged ≥4 years and adults
Adjunctive therapy in adults and children aged ≥12 years in the treatment of POS
Initial monotherapy in patients aged ≥2 years with POS or primary GTC seizures; safety and effectiveness in patients
who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established
in controlled trials; also indicated as adjunctive therapy for adults and pediatric patients ages 2–16 years with POS or
primary GTC seizures, and in patients aged ≥2 years with seizures associated with LGS
Adjunctive therapy for adult patients with refractory CPS who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss and monotherapy for pediatric patients with
infantile spasms for whom the potential benefits outweigh the potential risk of vision loss
Adjunctive therapy in the treatment of POS in adults with epilepsy
Adjunctive treatment of POS in patients aged ≥18 years
Adjunctive therapy in the treatment of POS in patients with epilepsy aged ≥17 years
Adjunctive therapy for the treatment of POS with or without secondarily generalized seizures in patients with epilepsy
aged ≥12 years
AED = antiepileptic drug; CPS = complex partial seizures; GTC = generalized tonic-clonic; JME = juvenile myoclonic epilepsy; LGS = LennoxGastaut syndrome; POS = partial-onset seizures.
*Age of patients not specified by label.
†Age not specified in enteric-coated valproate label; extended-release approved for children aged ≥ 10 years. Avoid use in children under 2 years
due to risk of hepatotoxicity.
2 Hospital Physician Board Review Manual
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Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
Table 2. Drug Selection for New Seizure Diagnosis
Seizure Type
First-line AED
Medications to Avoid
Generalized tonic-clonic
Carbamazepine, lamotrigine, oxcarbazepine,
topiramate, valproate
If juvenile myoclonic epilepsy is suspected, or absence
seizures: carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, vigabatrin
Focal seizures
Absence
Carbamazepine, lamotrigine, oxcarbazepine,
phenobarbital, phenytoin, topiramate, valproate
Ethosuximide, lamotrigine, valproate
Myoclonic
Levetiracetam, valproate, topiramate
Tonic or atonic
Valproate
A recent study by Brodie and colleagues8 has
provided additional insight into how patients respond to medications prescribed initially after a
new diagnosis of epilepsy. They followed 1098
newly diagnosed patients for a median duration
of 7.5 years. Causes of epilepsy were idiopathic
for 23%, symptomatic for 41%, and cryptogenic
for 35%. Their analysis revealed that 4 patterns
emerge: early and sustained seizure freedom
(37%), delayed and sustained seizure freedom
(22%), fluctuation between periods of seizure freedom and relapse (16%), and never seizure-free for
any complete year (25%).8
Selecting an Agent
An initial medication is selected based on the
patient's seizure type or syndrome (Table 2). Joint
statements from American Academy of Neurology and American Epilepsy Society,9,10 and most
recently from the NICE guidelines from the United
Kingdom, also provide guidance on selecting
medications for various seizure syndromes.11 Once
the seizure type or syndrome has been determined, other patient-specific factors should be
taken into consideration. These include age, health
Carbamazepine, gabapentin, oxcarbazepine, phenytoin,
pregabalin, tiagabine, vigabatrin
Carbamazepine, gabapentin, oxcarbazepine, phenytoin,
pregabalin, tiagabine, vigabatrin
Carbamazepine, gabapentin, oxcarbazepine, pregabalin,
tiagabine, vigabatrin
conditions, concurrent medications, medication
insurance coverage and cost considerations, and
the patient’s ability and preference to take the
medication as prescribed. An understanding of the
pharmacokinetic properties of the various AEDs
is useful to differentiate the medications available.
Table 3 summarizes typical dosing for AEDs.
Subsequent Therapy
If the first prescribed AED does not adequately
control seizures, a second medication should be
considered. There is adequate data to support the
newer AEDs as adjunctive treatment.9,10 Ideally,
the first medication should remain at the current
(and/or tolerated) dose, while the second medication is titrated up to a therapeutic dose.12 Once the
new drug is at steady-state, the first medication
can be tapered off, depending on how the patient
is responding to the new regimen. If the first AED
resulted in a treatment emergent side effect, such
as a significant rash or other hypersensitivity reaction, discontinuing it immediately is likely the most
appropriate action. A second AED could be initiated with an oral or intravenous loading dose to
provide adequate seizure protection.
www.turner-white.comEpilepsy Volume 1, Part 6 3
Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
Table 3. Dosing of Antiepileptic Drugs
Drug
Dosage Forms
Available Strengths
Typical Oral Dosing Range and Frequency
Carbamazepine (Carbatrol,
Tegretol,Tegretol XR)
Capsule (ER)
Oral suspension
Tablet (IR)
Chewable tablet
Tablet (ER)
Tablet
100, 200, 300 mg
100 mg/5 mL
200 mg
100 mg
100, 200, 400 mg
5, 10, 20 mg
Child (initial, monotherapy): 5–10 mg/kg/day
Adult (initial, monotherapy): 5 mg/kg/day
Child (typical maintenance): 10–40 mg/day
Adult (typical maintenance): 1000–2000 mg/day
Clonazepam (Klonopin)
Tablet
ODT
0.5, 1, 2 mg
0.125, 0.25, 0.5,
1, 2 mg
Diazepam (Diastat)
Rectal gel
Oral solution
2.5, 5, 7.5, 10, 12.5,
15, 20 mg
5 mg/5 mL
Divalproex (Depakote)
Capsule (sprinkle)
Tablet (ER)
Tablet (DR)
125 mg
250, 500 mg
125, 250, 500 mg
Ethosuximide (Zarontin)
Capsule
Oral solution
250 mg
250 mg/5 mL
Clobazam (Onfi)
4 Hospital Physician Board Review Manual
Adult/Child age ≥2 years >30 kg (adjunct): Initially
10 mg orally daily (in 2 divided doses), titrating to
20 mg daily (in 2 divided doses) on day 7 and to 40 mg
daily (2 divided doses) on day 14
Adult/Child age ≥2 years ≤30 kg (adjunct): Initially 5 mg
orally daily (in 2 divided doses), titrating to 10 mg daily
(2 divided doses) on day 7 and to 20 mg daily (2 divided
doses) on day 14
Adult: 0.5 mg orally TID initially; may increase daily dose
by 0.5–1 mg orally every 3 days to a maximum total
daily dose of 20 mg (in 3 divided doses)
Child (up to age 10 years, or 30 kg): Initially 0.01–0.03
mg/kg/day orally divided into 2 to 3 daily doses; may increase by 0.25–0.5 mg every 3 days to a maximum total
daily dose of 0.1–0.2 mg/kg/day (in 3 divided doses)
Adult (adjunct): 2–10 mg orally BID–QID
Adult (adjunct): 0.2 mg/kg rectally (round up to available
rectal dose); may repeat in 4–12 hours, no more than 1
episode every 5 days, and 5 episodes per month
Child: varies by age and severity; refer to PI
Adult (adjunct): 10–15 mg/kg/day orally; may increase
dosage 5–10 mg/kg/wk to achieve optimal clinical response (maximum 60 mg/kg/day or less with a therapeutic range of 50–100 µg/mL)
Child age 10–18 years (adjunct): 10–15 mg/kg/day orally;
may increase dosage 5–10 mg/kg/wk to achieve optimal
clinical response (maximum 60 mg/kg/day or less with a
therapeutic range of 50–100 µg/mL)
Adult (absence seizure): 500 mg orally adjusted by
250-mg increments every 4–7 days to desired therapeutic effect (doses >1.5 g/day must be supervised
by the patient’s physician)
Child age 3–6 years (absence seizure): 250 mg orally
daily, increase daily dose by 250 mg every 4–7 days
as needed (doses >1.5 g/day must be supervised by
the patient’s physician)
Child age >6 years (absence seizure): 500 mg orally
daily; increase daily dose by 250 mg every 4–7 days
as needed (doses >1.5 g/day must be supervised by
the patient’s physician)
(continued on page 5)
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Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
Table 3. Dosing of Antiepileptic Drugs (continued)
Drug
Dosage Forms
Available Strengths
Typical Oral Dosing Range and Frequency
Ezogabine (Potiga)
Tablet
50, 200, 300, 400 mg
Felbamate (Felbatol)
Tablet
Oral suspension
400, 600 mg
600 mg/5 mL
Gabapentin (Neurontin)
Capsule
Oral solution
Tablet
100, 300, 400 mg
250 mg/5 mL
100, 300, 400, 600,
800 mg
Lacosamide (Vimpat)
Tablet
Oral solution
Injection solution
50, 100, 150, 200 mg
10 mg/mL
10 mg/mL
Lamotrigine (Lamictal)
Tablet (IR)
Tablet (ER)
Chewable tablet
ODT
Tablet
Oral solution
Tablet (ER)
25, 100, 150, 200 mg
25, 50, 100, 200 mg
2, 5, 25 mg
25, 50, 100, 200 mg
250, 500, 750, 1000 mg
100 mg/mL
500, 750 mg
Adult (age ≥18 years, adjunct): Start with 100 mg TID for
1 week; increase to maintenance dose at weekly intervals
by no more than 150 mg/day; optimal effective dose between 200 mg TID to 400 mg TID
Child age 2–14 years (Lennox-Gastaut): 15 mg/kg/day in
3 to 4 divided doses; increase by 15 mg/kg/day increments
at weekly intervals; maximum dose of 45 mg/kg/day or
3600 mg/day (whichever is less)
Adult/Child 14+ years (initial): 1200 mg/day in 3 to 4 divided doses; may increase in 600-mg increments every
2 weeks to 2400–3600 mg/day
Adult (maintenance): 3600 mg/day
Adult (adjunct): 300 mg TID; may increase up to 1800 mg/
day in divided doses
Child age 3–12 years (initial): 10–15 mg/kg/day in 3 divided doses
Child age 3–4 years (maintenance): Titrate upwards over
3 days to 40 mg/kg/day in 3 divided doses
Child age 5–12 years (maintenance): Titrate upwards over
3 days to 25–35 mg/kg/day in 3 divided doses
Adult age 17+ years (adjunct): Oral, IV: start with 50 mg
orally BID, and increase by 50 mg BID every week to an
initial therapeutic dose of 100 mg BID; maximum recommended dose is 200 mg BID; when switching from oral to
IV formulations, the total daily dose and frequency should
be the same; IV therapy should only be used temporarily
Dose depends on presence of valproic acid or enzymeinducing AED and type of seizure; refer to PI
Tablet
Oral suspension
Tablet (ER)
150, 300, 600 mg
300 mg/5 mL
150, 300, 600 mg
Levetiracetam
(Keppra, Keppra XR)
Oxcarbazepine (Trileptal,
Oxtellar)
Adult (adjunct): Start with 500 mg orally BID; increase
daily doses by 1000 mg every 2 weeks; target of
3000 mg/day
Child: Dose varies by type of seizure and age; refer to PI
Adult age 16+ years (adjunct): Initial dose of 1000 mg
once daily; may be adjusted in increments of 1000 mg
every 2 weeks to a maximum recommended daily dose of
3000 mg
Adult (initial): 300 mg BID
Adult (maintenance): 600 mg BID
Child age 2–4 years (adjunct): 8–10 mg/kg/day in 2 divided doses; consider using 16–20 mg/kg/day divided in 2
divided doses if weight <20 kg
Child age 4–16 years (initial conversion): 8–10 mg/kg/day
in 2 divided doses
Child age 4–16 years (target maintenance): range depends
on patient weight
(continued on page 6)
www.turner-white.comEpilepsy Volume 1, Part 6 5
Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
Table 3. Dosing of Antiepileptic Drugs (continued)
Drug
Dosage Forms
Available Strengths
Typical Oral Dosing Range and Frequency
Perampanel (Fycompa)
Tablet
2, 4, 6, 8, 10, 12 mg
Phenobarbital (Luminal)
Oral elixir
Tablet
Initial: 2 mg once daily at betime, if patient is not on enzyme inducer; 4 mg once daily at bedtime, if patient is on
enyzme-inducing AED; may increase by a maximum of 2
mg daily every week (or 2 weeks) to a maximum of
12 mg once daily
Adult (maintenance): 50–100 mg orally BID–TID
Child (maintenance): 15–50 mg orally BID–TID
Phenytoin
(Dilantin, Phenytek)
Pregabalin (Lyrica)
Capsule (ER)
Capsule (IR)
Oral suspension
Chewable tablet
Capsule
Primidone (Mysoline)
Tablet
Rufinamide (Banzel)
Tablet
Oral suspension
Tiagabine (Gabitril)
Tablet
20 mg/5 mL
15, 16.2, 30, 32.4, 60,
64.8, 97.2, 100 mg
30, 100, 200, 300 mg
Due to wide interindividual variability in metabolism and
absorption, regimen must be individualized
100 mg
100 mg/4 mL, 125 mg/5 mL
50 mg
25, 50, 75, 100, 150, 200, Adult (adjunct): Initial dose no greater than 75 mg orally
225, 300 mg
BID or 50 mg orally TID (150 mg/day) and increase to a
maximum dose of 600 mg/day in divided doses (BID or
TID) based on response and tolerability
Children: Safety and efficacy not established
50, 250 mg
Adult age 8+ years (adjunct or monotherapy):
100–125 mg orally every night for 3 days, then increase
dose by 100–125 mg/day (divided doses) every 3 days
to reach a dose of 250 mg TID–QID
Child age <8 years (adjunct or monotherapy): 50 mg
orally every night for 3 days, then increase dose by
50 mg/day (divided doses) every 3 days to reach a
dose of 125–250 mg TID
200, 400 mg
Adult: Initial dose of 400–800 mg/day in 2 equally divided
doses and increase by 400–800 mg/day every 2 days
40 mg/mL
until a maximum of 3200 mg/day in 2 equally divided
doses is reached
Children age 4+ years: Initial dose of 10 mg/kg/day in
2 equally divided doses and increase by 10 mg/kg increments every other day to a target dose of 45 mg/kg/day
or 3200 mg/day, whichever is less, administered in
2 equally divided doses
2, 4, 12, 16 mg
Adult (adjunct): 4 mg orally daily; may increase dosage
by 4–8 mg/day at weekly intervals to a maximum dose
of 56 mg/day (in 2–4 divided doses)
Child age 12–18 years (adjunct, with enzyme-inducing
AEDs): 4 mg orally daily; may increase dosage by 4 mg/
day after 7 days, then total daily dose may be increased
by 4–8 mg/day at weekly intervals to a maximum dose of
32 mg/day (in 2–4 divided doses) (continued on page 7)
6 Hospital Physician Board Review Manual
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Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
Table 3. Dosing of Antiepileptic Drugs (continued)
Drug
Dosage Forms
Available Strengths
Typical Oral Dosing Range and Frequency
Topiramate (Topamax)
Capsule (sprinkle)
Tablet
15, 25 mg
25, 50, 100, 200 mg
Valproic acid
(Depakene)
(Stavzor)
Capsule
Oral syrup
Capsule (DR)
250 mg
250 mg/5 mL
125, 250, 500 mg
Vigabatrin (Sabril)
Powder for oral solution 500 mg/packet
Tablet
500 mg
Zonisamide (Zonegran)
Capsule
Adult and child age >2 years (initial monotherapy): 25 mg
orally BID (am and pm); may increase each dose by 25 mg
weekly; maximum dose of 200 mg orally BID
Adult (adjunct): 25–50 mg/day orally; may increase dosage by 25–50 mg/day at 1-week intervals to the usual
maintenance dose of 200–400 mg/day in 2 divided doses
Child age 2–16 years (adjunct): Start with maximum 25 mg
(range of 1–3 mg/kg/day) orally at bedtime for the first week,
then increase by 1–3 mg/kg/day (in 2 divided doses) at 1–2
week intervals to the usual effective dosage of 5–9 mg/kg/
day
Adult (adjunct): 10–15 mg/kg/day orally (in 2–3 divided
doses if total daily dose >250 mg); may increase dosage
5–10 mg/kg/week to achieve optimal clinical response
(maximum 60 mg/kg/day or less with a therapeutic range
of 50–100 µg/mL)
Child age 10–18 years (adjunct): Dose as an adult
Child age <10 years: Safety and efficacy not established
Adult (adjunct): 500 mg BID; may increase dosage by 500
mg/day at 1-week intervals to the usual maintenance dose
of 1500 mg BID
Child age 1 month–2 years (infantile spasms): Initial dose
of 50 mg/kg/day (in 2 divided doses); can titrate 25–50 mg/
kg/day every 3 days to maximum dose of 150 mg/kg/day
Age 16+ years (adjunct): 100 mg/day orally; may increase
dosage by 100 mg/day every 2 weeks to the usual effective
dosage range of 100–600 mg/day in 1 to 2 divided doses;
no additional benefit seen with doses >400 mg/day
25, 50, 100 mg
AED = antiepileptic drug; BID = twice daily; DR = delayed release; ER = extended release; IR = immediate release; ODT = orally disintegrating
tablet; PI = package insert; QID = 4 times daily; TID = 3 times daily.
Toxicity
Side Effects
In the case of AEDs, side effects are concentrationrelated, idiosyncratic, or due to chronic exposure.
Table 4 provides a summary of side effects for the
various agents. Concentration-related side effects
result from an exaggeration of the pharmacologic
effects of a medication.13 Sedation, ataxia, and
headache are examples. These side effects generally are reversible with a dose reduction. It may be
difficult to achieve the fine balance between con-
trolling seizures and side effects for some patients,
and multiple trials of different medications may be
necessary.
Some patients remain on AEDs for decades,
and chronic exposure side effects must be considered. Some chronic effects impact weight.
Valproic acid is highly associated with weight gain,
as are gabapentin and pregabalin, while topiramate and zonisamide are associated with weight
loss.14–16 Bone health and the impact of AEDs on
bone density have been of great concern over
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Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
Table 4. Adverse Effects of Antiepileptic Drugs
Acute Side Effects
Drug
Carbamazepine
Clobazam
Divalproex
Ethosuximide
Ezogabine
Felbamate
Gabapentin
Lacosamide
Lamotrigine
Levetiracetam
Oxcarbazepine
Perampanel
Phenobarbital
Concentration-Dependent
Idiosyncratic
Diplopia, dizziness, drowsiness,
Blood dyscrasias, rash
nausea, unsteadiness, lethargy
Common side effects: somnolence or sedation, drooling, constipation, cough,
urinary tract infection, aggression, insomnia, dysarthria, fatigue
Tremors, unsteadiness
Hepatic failure, pancreatitis
Ataxia, drowsiness, GI distress,
Blood dyscrasias, rash
unsteadiness, hiccoughs
Common side effects: dizziness, fatigue, confusion, hallucination, vertigo,
tremor, problems with coordination, double vision, problems paying attention,
memory impairment, lack of strength, urinary retention, QT prolongation
Anorexia, nausea, vomiting, insomnia, Aplastic anemia, acute hepatic failure
headache
Dizziness, fatigue, somnolence,
Pedal edema
ataxia
Dizziness, nausea, fatigue, ataxia,
Not established
abnormal vision, diplopia, vertigo, and
nystagmus
Diplopia, dizziness, unsteadiness,
Rash
headache
Sedation, behavioral disturbance
Not established
Sedation, dizziness, ataxia, nausea
Rash
Dizziness, somnolence, fatigue,
Not established
irritability, falls, nausea, weight gain,
veritgo, ataxia, gait distrubance, and
balance disorder, hostility and aggression
Ataxia, hyperactivity, headache, unBlood dyscrasias, rash
steadiness, sedation, nausea
the past decade. Unfortunately, it is not entirely
clear which AEDs decrease bone density and
what the mechanism of bone loss is. In the case
of the enzyme-inducing AEDs (carbamazepine,
phenytoin, phenobarbital), it is thought that induction
8 Hospital Physician Board Review Manual
Chronic Side Effects
Hyponatremia
Not established
CNS depression
Behavior changes, headache
Not established
Not established
Weight gain, breast enlargement
Not established
Not established
Not established
Hyponatremia, hemic and lymphatic
system (bone marrow depression,
agranulocytosis, aplastic anemia,
pancytopenia, neutropenia), pancreatitis, and/or lipase and/or amylase
increase, metabolism and nutrition
disorders (folic acid deficiency)
Not established
Behavior changes, connective tissue
disorders, intellectual blunting, metabolic bone disease, mood change,
sedation
(continued on page 9)
of vitamin D metabolism could be responsible,
but research has not consistently demonstrated
this.17,18 While the data are not entirely conclusive, it
is appropriate to ensure that patients are consuming adequate amounts of calcium and vitamin D.
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Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
Table 4. Adverse Effects of Antiepileptic Drugs (continued)
Acute Side Effects
Drug
Concentration-Dependent
Idiosyncratic
Chronic Side Effects
Phenytoin
Ataxia, nystagmus, behavior changes, dizziness, headache, incoordination, sedation, lethargy, cognitive
impairment, fatigue, visual blurring
Blood dyscrasias, rash, immunologic
reaction
Primidone
Behavior changes, headache, nausea, sedation, unsteadiness
Blood dyscrasias, rash
Pregabalin
Dizziness, somnolence, blurred vision Pedal edema, creatine kinase elevation, decreased platelets
Common side effects: nausea, vomiting, dizziness, headache, somnolence, and
fatigue
Dizziness, fatigue, difficulty concenSpike-wave stupor
trating, nervousness, tremor, blurred
vision, depression, weakness
Difficulty concentrating, psychomotor Metabolic acidosis, acute angle
glaucoma, oligohidrosis
slowing, speech or language problems, somnolence/fatigue, dizziness,
headache
GI upset, sedation, unsteadiness,
tremor, thrombocytopenia
Behavior changes, cerebellar syndrome, connective tissue changes,
skin thickening, folate deficiency, gingival hyperplasia, hirsutism, coarsening of facial features, acne, cognitive
impairment, metabolic bone disease,
sedation
Behavior change, connective tissue
disorders, cognitive impairment, sedation
Weight gain
Rufinamide
Tiagabine
Topiramate
Valproic Acid
Vigabatrin
Zonisamide
Common side effects: somnolence, fatigue, weight increase, blurred vision,
nystagmus, tremor, memory impairment, arthralgia, abnormal coordination,
confusion
Sedation, dizziness, cognitive impair- Rash, oligohydrosis
ment, nausea
The body of evidence showing that the enzymeinducing AEDs have a negative effect on cholesterol levels and cardiac risk factors is growing, and
the patient’s risk for cardiac events should also be
considered when prescribing an AED.19–21
Idiosyncratic reactions are the most worrisome
of the side effects. These reactions are unpredictable and can range from minor (pedal edema)
to life-threatening, including hepatic failure and
angranulocytosis. When these reactions occur,
discontinuation of the offending agents is almost
Not established
Not established
Kidney stones, weight loss, hyperesthesia
Polycystic ovary–like syndrome (possible), weight gain, hyperammonemia, menstrual cycle irregularities
Not established
Kidney stones, weight loss
always required.22 Recently, there has been progress identifying genetic causes of drug reactions.
Patients who carry the HLA-B*1502 allele are at
high risk to develop severe cutaneous drug reactions when exposed to carbamazepine and phenytoin. This allele is significantly more prevalent
in patients of Asian descent.23 The FDA recommends genetic testing in patients of Asian descent
before initiating carbamazepine. Anticonvulsant
hypersensitivity and drug reaction with eosinophilia
and systemic symptoms (DRESS) are different
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Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
terms for essentially the same clinical diagnoses
and are reported with several AEDs. Symptoms
include hematologic abnormalities, other organ
involvement including liver dysfunction, and skin
rash.24 With the exception of the genetic testing for
carbamazepine, there are no laboratory tests that
can predict which patients are likely to develop
hypersensitivity reactions. Once a patient experiences a hypersensitivity reaction, a new medication must be selected cautiously as cross-reactivity
may occur. There is evidence that cross-reactivity
occurs between the aromatic AEDs, phenytoin,
carbamazepine, and oxcarbazepine approximately
30% of the time.25
Teratogenicity
Determining if a medication causes birth defects
is a complex research question. It is critical to collect
data prospectively and with a large enough sample
size to truly capture whether exposure to medications increases the risk of birth defects. The literature
is also challenging to interpret because of variability
in how research groups have tracked and defined
what they reported as birth defects. In the past 12
months, several groups have published data that
are helping better characterize the teratogenicity
of AEDs. The North American Pregnancy Registry
recently analyzed 4899 women on AED monotherapy and 442 women with epilepsy and no AED exposure.26 The AEDs associated with higher risk of birth
defects compared to unexposed patients were topiramate, valproate, and phenobarbital. This analysis
did not detect any correlation of birth defects to
doses of AEDs. An analysis of data from 3909
women on monotherapy carbamazepine, lamotrigine, valproic acid, or phenobarbital from the EURAP
database did demonstrate increased risks of malformations based on dose of AEDs.27 The reference group was women on lamotrigine taking less
10 Hospital Physician Board Review Manual
than 300 mg/day. AED doses that had statistically
higher odds for major congenital malformations
were: carbamazepine >1000 mg/day, phenobarbital
≥150 mg/per day, valproic acid ≥700 to <1500 mg
per day, and valproic acid ≥1500 mg per day.
Data on the newer medications is lacking in this
data set. A recent report from Denmark examined
1532 pregnancies (of 837,795 live births, nationally)
exposed to lamotrigine, oxcarbazepine, topiramate,
gabapentin, or levetiracetam.28 They found no difference between the infants exposed versus the infants not exposed. The numbers of infants exposed
to individual medications was quite low, and that
limited the ability to detect if certain medications are
more problematic. These new studies help clarify
that monotherapy is best at the lowest dose possible.
The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study group is investigating
the effects of monotherapy AED exposure during pregnancy on children. There were enough
women taking carbamazepine, lamotrigine, phenytoin, and valproate monotherapy to further
investigate the impact of those medications on
children at age 3 years.29 This study found that,
while controlling for maternal IQ, the children exposed to valproate had statistically significantly
lower IQs.29 A further analysis of verbal and nonverbal abilities determined that children exposed
to valproate had lower scores as compared to the
other AEDs.30 Additionally, the verbal abilities for
each of the AED-exposed groups were lower than
the normative data. The investigators followed-up
with the children at age 4.5 years and found that
the differences persist: children exposed to valproate have reduced IQs and all 4 AED exposure
groups have reduced verbal abilities.31
Pre-pregnancy planning discussions with women
should include balancing the risks of seizures with
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Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
possible medication effects, and valproate should
be avoided if possible. Folic acid supplementation
should be initiated prior to conception at a dose of
at least 0.4 µg/day.32 Consultation and monitoring
by an obstetrician is recommended.33 For women
who are not planning conception, ensuring they
are using adequate contraception is critical. Many
AEDs interact with hormonal contraceptives, regardless of the route of delivery, including implants, patches, and vaginal rings.34 Patient education is crucial, so that the risks engendered by
unplanned pregnancies are minimized.
First-generation drugs
Generally, the first-generation AEDs all undergo
hepatic metabolism. The majority of them are highly bound to protein, they are all involved in numerous drug interactions, and most exhibit nonlinear
pharmacokinetics.
Acetazolamide
Acetazolamide is a carbonic anhydrase inhibitor
that has acedotally been used to treat catamenial
epilepsy.37
Benzodiazepines
Suicidality
All prescribers should be aware of the FDA
warning issued in 2008 regarding suicidal behavior and ideation and AEDs.35 This warning was
based on a meta-analysis of pooled data from 199
clinical trials of carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine,
pregabalin, tiagabine, topiramate, valproate, and
zonisamide. The FDA has applied the warning to
all AEDs, even those not included in this analysis.
There is debate among the epilepsy community
as to whether this warning is appropriate and warranted.36 Regardless, depression is not uncommon
in patients with epilepsy, and prescribers should
discuss mood and assess for adverse effects of
AEDs.
Summary of Antiepileptic drugs
Information comparing or contrasting the various
AEDs is summarized in Table 3 and Table 4. Here,
notable aspects of the various medications are discussed. For information about the pharmacokinetic
characteristics of AEDs, refer to the previous article
in this series (Epilepsy Board Review Manual, Volume 1, Part 5).
12 Hospital Physician Board Review Manual
Benzodiazepines are freqently used to treat cluster seizures or prolonged seziures. Lorazepam and
diazepam are available as intravenous solutions, oral
solutions (intensols), and tablets. Additionally, diazepam is available as a rectal gel for home treatment
of cluster seizures.38 It is currently under investigation for intramuscular delivery via an autoinjector.39
These medications are usually dosed intermittently
and reserved as rescue therapy aimed at preventing emergency department visits or hospitalization.
There is increasing evidence that midazolam delivery
intramuscularly in the ambulance has comparable
efficacy to intravenous lorazepam at prehosptial
seizure cessation.40 An intranasal delivery formula of
midazolam is also under investigation as an alternative to rectal diazepam.41 Clonazepam is indicated
for daily, regular dosing for myoclonic, akinetic, and
Lennox-Gastaut seizures, but tolerance develops
and loss of efficacy may occurr.42
Carbamazepine
Carbamazepine induces its own hepatic clearance (autoinduction) and has an active metabolite
(carbamazepine-10, 11-epoxide) that also exerts
some antiseizure effects.43,44 Carbamazepine's
primary metabolic pathway is CYP 3A4, which is
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Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
responsible for metabolizing numerous medications. Carbamazepine causes enzyme induction,
resulting in many drug interactions.45 The efficacy
of carbamazepine has been demonstrated in
many studies. A Veterans Affairs Epilepsy Cooperative study demonstrated that it was as efficacious as phenytoin, phenobarbital, and primidone,
but better tolerated than phenobarbital and primidone.46 A subsequent VA study demonstrated
that carbamazepine was better at controlling focal
seizures and better tolerated than valproic acid.47
Most recently, carbamazepine was shown to be
as efficacious as lamotrigine and gabapentin but
not as well tolerated in an elderly veteran population with new-onset seizures.48
Ethosuximide
Ethosuximide is primarily indicated to treat absence seizures, which usually begin in childhood. In
a recent study that compared ethosuximide, valproic acid, and lamotrigine, both ethosuximide and valproic acid demonstrated similar efficacy for absence
seizures, but ethosuximide was better tolerated.49
Phenobarbital
Phenobarbital has been used as an anticonvulsant for a century. It was introduced to market prior to the FDA requiring medications to
be approved based on evidence of efficacy. It
has an extremely long half-life (72–124 hours)
and is extensively metabolized through the liver.
It does, however, have a linear dose/concentration relationship. It also causes induction of
hepatic enzymes, resulting in numerous drug
interactions. Its use is limited by side effects,
including sedation and cognitive impairment.50
It had been used in the past to treat febrile seizures
in children, but concern about lower IQs and lack
of impact on later seizures has reduced its use.51
Phenytoin
Phenytoin is unusual due to its saturable, nonlinear metabolism, resulting in greater than expected blood concentrations when increasing doses.
Depending on the patient, very small increases
in dose (10%–30%) can cause a greater than
doubling of the blood concentration.52 The primary
metabolic pathways are CYP 2C9 and 2C19. The
CYP 2C9 pathway becomes saturated first, and
then the CYP 2C19 pathway becomes involved.
Several polymorphisms of CYP 2C9 and 2C19 have
been identified,53 but there is no current recommendation to routinely test patients prior to initiating
phenytoin treatment. This leads to substantial interpatient variability and unpredictability between dose
and concentration. Prescribers must be cautious
when adjusting doses because small (10%–20%)
changes can potentially result in very large changes in blood levels and side effects. Intravenous
phenytoin has a pH of 11 and is incompatible in
many intravenous solutions. It must be infused
no faster than 50 mg/min, and patients should
have electrocardiographic monitoring for potential
arrhythmias.54 Fosphenytoin is a pro-drug of phenytoin and is rapidly hydrolyzed by phosphatases
into phenytoin. This allows for a better tolerated
intravenous formulation that can be delivered more
quickly and safely. It can also be administered intramuscularly if necessary.55
Primidone
Primidone is metabolized into 2 active metabolites: phenylethylmalonamide and phenobarbital.
As a result, it has a side effect and drug interaction
profile similar to phenobarbital. While primidone
was first clinically used in 1952, the study that
established its efficacy was the VA Cooperative
Study that compared primidone to carbamazepine,
phenytoin, and phenobarbital.50
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Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
Valproic Acid
Valproic acid is available in many formulations,
requiring the prescriber to be vigilant that the product desired is the one prescribed (and dispensed
from the pharmacy). Valproic acid is available as
syrup, a liquid-filled capsule, and a delayed-release
capsule. To overcome the frequent gastrointestinal upset, it is also available as divalproex sodium
(2 valproic acid molecules bound to sodium), which
dissociates into valproic acid. It is available as a
sprinkle, an enteric-coated tablet (delays medication release until after passing through the stomach), and an extended-release tablet (designed to
release the medication over 24 hours). It is also
important to note that the extended-release formulation is not equivalent to the enteric-coated formulation. Only 80% to 90% of the dose in the extendedrelease formulations is released.56 The intravenous
formulation is valproate sodium, the sodium salt
form of valproic acid. While valproic acid is a broadspectrum AED and used for several seizure types,
it is less frequently being recommended for use in
women with child- bearing potential (see Teratogenicity section). As valproic acid doses increase, the
protein binding sites saturate, resulting in a less than
expected increase in blood concentrations as the
doses get higher.57
metabolite can accumulate in patients who have
lower levels of functional CYP 2C19 enzyme, and
they should be started on lower doses.59
Felbamate
In 1993, felbamate was the first new AED to
be approved in 15 years. During the first 12 to 18
months of use, cases of aplastic anemia (33 patients) and hepatic failure (18 patients) were reported. This has resulted in felbamate being reserved
for patients whose seizures remain uncontrolled
despite multiple trials of AEDs in which the benefit
of adding felbamate outweighs the risks.60 Liver
function tests and hematologic evaluations should
be done as clinically appropriate. It was investigated in patients with focal seizures61–63 and seizures
associated with Lennox-Gastaut syndrome.64,65
Gabapentin
The first AED that did not interact with other
medications was gabapentin. Its use as an AED
is limited by a short half-life that requires frequent
dosing (3 to 4 times a day) to maintain consistent
exposure. It is completely eliminated from the body
through the kidneys. As patients age and their kidney function declines, the interval between doses
can be extended.66
Second-generation drugs
Lamotrigine
The second- (and third-) generation AEDs offer
new mechanisms of action, fewer drug interactions, and different adverse effect profiles as compared to the first-generation agents.
Lamotrigine is notable for its significant drug
interaction with valproic acid and for potentially
increasing the risk of developing a severe rash.67
The half-life of lamotrigine with no interacting medications is approximately 25 hours. Valproic acid
inhibits the clearance of lamotrigine, resulting in an
increase in the half-life (~70 hrs), while enzymeinducers (phenytoin, carbamazepine, phenobarbital) increase the clearance, resulting in a decrease
in the half-life (~12 hrs).68 This requires conservative
Clobazam
Clobazam has been used internationally for
30 years, but only recently has received FDA
approval. It is a benzodiazepine indicated for use
in patients with Lennox-Gastaut syndrome.58 The
14 Hospital Physician Board Review Manual
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Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
lamotrigine dosing when adding it to a regimen
that contains valproic acid. If a patient currently
taking lamotrigine requires the addition of valproic
acid, the patient should be closely monitored and
a significant dose reduction of lamotrigine will likely
be required. Relatively low doses of valproic acid
have been shown to significantly inhibit lamotrigine.69 Beyond the use of lamotrigine as adjunctive
treatment for focal seizures, there is evidence that
lamotrigine is efficacious as adjunctive treatment
for primary generalized seizures70 and as monotherapy treatment for focal or primary generalized
seizures.71 It can also be considered for treatment
of juvenile myoclonic epilepsy,72 particularly in
women with child-bearing potential. Lamotrigine
is approved for conversion to monotherapy by the
FDA.
Oxcarbazepine is an analog of carbamazepine
that is approved for montherapy use by the FDA. It
is rapidly metabolized to an active metabolite, the
monohydroxylated derivative (MHD). If monitoring
of blood levels is desired, the MHD level should be
measured. Oxcarbazepine does not induce liver
enzymes to the same extent as carbamazepine,
resulting in less clinically significant drug interactions.76 Hyponatremia can occur and may result in
discontinuation of the medication.77 If a patient had
a hypersensitivity reaction to carbamazepine, there
is a 25% to 30% risk that a hypersensitivity reaction will occur with oxcarbazepine.78 There is evidence to support oxcarbazepine being prescribed
as either monotherapy or adjunctive therapy for
focal seizures for both adults and children.79–81
Levetiracetam
Pregabalin
The second AED that does not interact with
other medications is levetiracetam. It has become
one of the first-line agents because of its convenient dosing (twice a day) and decreasing cost
since becoming available generically several years
ago. Its use is limited by its side effects. A recent
report of patients enrolled in open-label, long-term
follow-up found that the most common side effects resulting in discontinuation were depression,
insomnia, anxiety, and nervousness.73 Levetiracetam is frequently used as monotherapy clinically.
A meta-analysis from 2011 concluded there is
adequate data to support adjunctive use, but there
was not enough data to support monotherapy.74
A recent prospective, open-label, randomized,
multicenter study that compared lamotrigine and
levetiracetam monotherapy in newly diagnosed
patients, with either focal or generalized seizures,
showed no difference in efficacy or tolerability between the medications.75
Pregabalin is the third AED that does not interact with other medications. It is primarily used
for neuropathic pain due to shingles, fibromyalgia, diabetes, and spinal cord injuries. Approximately 90% of a dose is eliminated in the urine
unchanged. A recent meta-analysis of pregabalin monotherapy data determined there was
no available data assessing pregabalin use in
patients with generalized tonic-clonic seizures.82
The limited data assessing monotherapy for focal
seizures show similar tolerability as compared to
lamotrigine and slightly less efficacy, but there
were study design limitations.83
Oxcarbazepine
Rufinamide
The clearance of rufinamide is increased by
the enzyme-inducers (phenytoin, carbamazepine,
phenobarbital) and inhibited by valproic acid. The
mechanism of the interaction with valproic acid is
not entirely clear.84 The molecule is insoluble in
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Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
water and dissolution is slow and erratic, resulting in lower bioavailability for the higher strength
tablets.85 The FDA approval was based on 138
subjects with generalized seizures with LennoxGastaut.86 An additional study of patients with focal
seizures demonstrated efficacy, but to a smaller
magnitude compared to the previous study.87
es and efficacy. Patients must also enroll with
the program for safety monitoring and to obtain
the medication. The new guidelines for infantile
spasms place vigabatrin after adrenocorticotropic
hormone as the only 2 medications with evidence
of efficacy.1
Zonisamide
Tiagabine
Clinical experience with tiagabine has resulted
in a number of reports of tiagabine-induced nonconvulsive status epilpeticus.88–90 In 2005 the FDA
issued a warning about seizures in patients taking
tiagabine for non–seizure-related reasons.91 This
has resulted in very limited prescribing for primary
generalized seizures, and data supports use as
an add-on treatment in refractory partial onset seizures.9,10
Topiramate
Topiramate is notable for its effects on cognition, including word finding difficulty.92 Weight loss,
kidney stones, and paresthesias can also occur
with topiramate treatment. It has multiple mechanisms of action and also is indicated for migraine
prophylaxis and weight loss (in combination with
phentermine). There is evidence to support monotherapy use for both focal and primary generalized
tonic-clonic seizures.93
Vigabatrin
While vigabatrin has been used internationally
for about 35 years, due to visual field defects and
potentially permanent vision changes, vigabatrin is
subject to a risk evaluation and mitigation strategy
through the FDA.94,95 Vigabatrin is only available
through the manufacturer via the Share program,
which requires prescribers to register and work
with the manufacturer to monitor for vision chang16 Hospital Physician Board Review Manual
Zonisamide is a multi-mechanism AED with
weak carbonic anhydrase inhibition that shares
a very similar side effect profile with topiramate.
Additionally, if patients are allergic to sulfa medications, zonisamide should not be prescribed. It
has a very long half-life, which may be preferable
for patients who have difficulty taking medications
more than once a day.96 Initially, the higher than
expected rates of renal calculi in clinical studies
resulted in delaying zonisamide’s development in
the United States;97 however, additional studies
provided evidence that the rates were not excessively high.98,99
Third-generation drugs
Ezogabine
While ezogabine was under investigational studies, its generic name was retigabine; that is still
the generic name approved by the European
Union. Ezogabine brings a new mechanism of action to the AED choices as a potassium channel
agonist.100 Unlike other AEDS, ezogabine exerts
an effect on urinary bladder muscles and causes
urinary retention.101 Current evidence supports adjunctive therapy for focal seizures.102,103
Lacosamide
Lacosamide is also free of significant drug interactions with other AEDs. Its mechanism of action
is attributed to slow inactivation of sodium channels.104 Lacosamide was studied with total daily
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Antiepilepsy Drugs: Pharmacodynamics and Principles of Drug Selection
doses of 200, 400, and 600 mg.105 In this study,
efficacy was seen with the 200-mg and 400-mg
doses, but without additional response at the 600mg dose. Side effects were greater at the 600-mg
dose. An additional study compared 200 mg versus 400 mg and found no difference in efficacy
between the doses.106 A third study compared 400
mg versus 600 mg and demonstrated they were
similarly efficacious.107 Post hoc analysis of the
clinical trials indicates that lacosamide is best tolerated when used in combination with non–sodium
channel blocking AEDs. Patients did not tolerate
higher dosages of lacosamide when also taking
phenytoin, carbamazepine, oxcarbazepine, and
lamotrigine.108
Perampanel
As a recently approved AED, perampanel has
a unique mechanism of action as the first AMPA
inhibitor reducing the action of glutamate.109 It is
also notable for its long half-life, which enables
once-daily dosing.109 Three clinical trials have
been conducted evaluating a variety of doses.110–112
While a new mechanism of action provides options
for patients, perampanel appears to have some
significant psychiatric effects that will require close
monitoring, including aggression, hostility, irritability, and anger.113
Other considerations
Many of the AEDs are now available as generic
products. There is much concern that generic
AEDs are not truly equivalent to the innovator
products. The American Academy of Neurology has issued a statement that opposes AED
substitution without prescriber consent.114 Bioequivalence is determined by the rate and extent
a generic medication is absorbed as compared to
the innovator formulation. Generally, these studies are conducted as single-dose fed and fasting
randomized cross-over (and occasionally multiple-dose) studies in healthy adults. If the rate and
absorption 90% confidence intervals are within
80% to 125% of the innovator product, they are
determined to be bioequivalent (FDA guidance).
Most of the data to date indicating that there may
be problems with switching from branded AEDs to
a generic is observational and lacks the rigor of a
randomized, placebo-controlled clinical study design. A 2010 meta-analysis found only 9 randomized controlled trials that were available for their
analysis, and all were published between 1986
and 1997.115 The Agency for Healthcare Research
Quality conducted a comparative effectiveness
review to examine the data surrounding effectiveness and safety of antiepileptic medications in
patients with epilepsy. As part of the review, they
examined the data available on innovator versus
generic drugs.116 The strength of evidence for the
18 articles that met inclusion criteria was rated
primarily as low or insufficient. They did not detect
a difference between generics and innovators in
terms of seizure occurrence, seizure frequency,
blood concentrations, or adverse events.
There are continuing discussions between the
neurology community and the FDA as to how
equivalence should be best determined. It is
important to recognize that there is no requirement for bioequivalence testing between generic
manufacturers. In lieu of data either supporting
or disproving generic-to-generic equivalency, it is
best if a patient can be maintained on the same
manufacturer, if possible. A generic manufacturer
can be specified by the prescriber by indicating
“dispense as written, medically necessary.” The
laws surrounding if and how a pharmacist can substitute when dispensing medication vary by state.
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