Drugs for epilepsy

Newer antiepileptic drugs AEDs are usually initially approved by the FDA only as adjunc-tive therapy for partial seizures, but many may also be effective for other types of seizures and

Treatment Guidelines

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Drugs for Epilepsy p 9

Drugs for Epilepsy

Treatment of epilepsy should begin with a single

drug, increasing the dosage gradually until seizures

are controlled or adverse effects become

unaccept-able If seizures persist, expert clinicians generally

prescribe at least one and sometimes a second

alter-native drug as monotherapy before considering use of

two drugs at the same time When used for the

appro-priate seizure type, antiepileptic drugs are roughly

equivalent in efficacy The choice of drug is usually

based on factors such as ease of use, adverse effects,

interactions with other drugs, presence of comorbid

conditions and cost.1

Controlled trials are difficult to conduct in patients

with epilepsy; use of a placebo would be unethical,

and patients whose seizures are controlled by one

medication are understandably reluctant to be

random-ized to another Newer antiepileptic drugs (AEDs) are

usually initially approved by the FDA only as

adjunc-tive therapy for partial seizures, but many may also be

effective for other types of seizures and as

monothera-py, and are commonly used for these additional

indi-cations without FDA approval

CARBAMAZEPINE — Carbamazepine (Tegretol,

and generics) is an older AED with a broad indication

for use as an anticonvulsant It is particularly effective

for treatment of partial and secondarily generalized

tonic-clonic seizures, but may make absence or

myoclonic seizures worse Carbamazepine induces its

own metabolism; serum concentrations often fall after

a few weeks of treatment Storing carbamazepine

tablets (both brand and generic) in humid conditions

can cause concretion of the tablets, resulting in poor

bioavailability and therapeutic failure

Other Uses – Carbamazepine is also used for bipolar

disorder and for treatment of pain due to trigeminal

neuralgia

Adverse Effects – Carbamazepine can cause

drowsi-ness, blurred vision, diplopia, headache, dizzidrowsi-ness, ataxia, nausea and vomiting Its cognitive effects can interfere with learning Use of an extended-release formulation has been associated with fewer CNS adverse effects

Tables

2 Some Antiepileptic Drugs Pages 10-11

Treatment Guidelines

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Volume 11 (Issue 126) February 2013

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Partial, Including Secondarily Generalized Seizures Drugs of Choice: Some Alternatives:

Carbamazepine Valproate Levetiracetam Gabapentin Oxcarbazepine Zonisamide

Phenytoin Pregabalin Lacosamide Ezogabine

Primary Generalized Tonic-Clonic Seizures Drugs of Choice: Some Alternatives:

Levetiracetam Phenytoin

Absence Seizures Drugs of Choice: Alternatives:

Ethosuximide Lamotrigine

Zonisamide Levetiracetam

Atypical Absence, Myoclonic, Atonic Seizures Drugs of Choice : Alternatives:

Levetiracetam Clonazepam

Felbamate Clobazam Rufinamide 1.Some of the drugs listed here have not been approved for such use

by the FDA Approved indications are included in the text.

Table 1 Drugs of Choice 1

Related articles since publication: In Brief: Topiramate Extended-Release Capsules (Qudexy XR) (Dec 8, 2014)

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Revised 10/22/13: See p 11

Mild leukopenia and hyponatremia are fairly

com-mon With high doses of the drug, thrombocytopenia

can occur, but it is usually reversible if the drug is

discontinued Aplastic anemia, agranulocytosis,

car-diac toxicity, aseptic meningitis, intractable diarrhea

and hepatitis are rare Circulating concentrations of

thyroid hormones may be reduced even though TSH

remains normal Abnormal color perception can

occur rarely

Carbamazepine can cause rash, particularly with high starting doses or rapid dose escalation Severe reac-tions, such as Stevens-Johnson syndrome (SJS), are rare The risk of carbamazepine induced SJS is signif-icantly higher in patients with the human leukocyte antigen (HLA)-B*1502 allele, which occurs almost exclusively in Asians.2,3The FDA has recommended that Asian patients, who have a ten-fold higher inci-dence of carbamazepine-induced SJS compared to

Usual Adult

Carbamazepine – generic 200 mg tabs; 100 mg chewable 800-1600 mg $ 6.87 Tegretol (Novartis) tabs; 100 mg/5 mL susp in 2 or 3 doses 3 136.80 extended release – generic 100, 200 mg ER caps and tabs; 800-1600 mg in 93.38

300 mg ER caps, 400 mg ER tabs 2 doses 3

Clobazam – Onfi (Lundbeck) 5, 10, 20 mg tabs 20-40 mg in 1 or 2 doses 375.00 Clonazepam – generic 0.5, 1, 2 mg tabs; 0.125, 0.25, 1.5-8 mg in 2 or 3 doses 3.82

0.5, 1, 2 mg disintegrating tabs

Ethosuximide – generic 250 mg caps; 250 mg/5 mL syrup 750-1250 mg in 2 doses 85.96

Ezogabine – Potiga (GSK/Valeant) 50, 200, 300, 400 mg tabs 600-1200 mg in 3 doses 594.00 Felbamate – generic 400, 600 mg tabs; 2400-3600 mg in 3 or 4 doses 518.87

Gabapentin – generic 100, 300, 400 mg caps; 100, 1800-3600 mg in 3 doses 55.58

300, 400, 600, 800 mg tabs;

250 mg/5 mL soln

600, 800 mg tabs;

250 mg/5 mL soln Lacosamide – Vimpat (UCB) 50, 100, 150, 200 mg tabs; 200-400 mg in 2 doses 439.61

10 mg/mL soln Lamotrigine – generic 2, 5, 25, 50, 100, 150, 200, 250 mg 100-500 mg in 2 doses 7.29

tabs; 2, 5, 25 mg chewable tabs

2, 5, 25 mg chewable tabs; 25, 50,

100, 200 mg disintegrating tabs extended-release – generic 25, 50, 100, 200, 250, 300 mg ER tabs 200-600 mg once daily N.A 4

Levetiracetam – generic 250, 500, 750, 1000 mg tabs; 1000-3000 mg in 2 doses 30.24

extended release – generic 500, 750 mg ER tabs 1000-3000 mg 114.28

Oxcarbazepine – generic 150, 300, 600 mg tabs; 1200-2400 mg in 2 doses 105.37

extended-release

Oxtellar XR (Supernus) 150, 300, 600 mg ER tabs 1200-2400 mg once daily 454.80

1 Most AEDs are started at a low dose and slowly titrated over a period of weeks The usual dosage may vary depending on whether the drug is prescribed as adjunctive therapy or monotherapy, or is used concomitantly with one or more interacting drugs Dosage may also need to be adjusted for renal or hepatic impairment.

2 Wholesale acquisition cost (WAC) for 30 days’ treatment at the lowest usual dosage $ource® Monthly (Selected from FDB MedKnowledge™) January 5, 2013 Reprinted with permission by FDB, Inc All rights reserved ©2012 www.fdbhealth.com/policies/drug-pricing-policy/ Actual retail prices may be higher.

3 Measurement of serum concentrations may be useful to guide therapy Some usual therapeutic serum concentrations are: carbamazepine 4-12 mcg/mL, phenobarbital 10-40 mcg/mL, phenytoin 10-20 mcg/mL, valproate 50-100 mcg/mL Some patients achieve complete seizure control at lower concentrations, and occasional patients need higher concentrations.

4 Cost not yet available.

Table 2 Some Antiepileptic Drugs

Drugs for Epilepsy

other ethnic groups, be tested for this allele before

starting the drug

Drug Interactions – Carbamazepine is a strong

induc-er of multiple hepatic enzymes; it can reduce sinduc-erum

concentrations and possibly the effectiveness of many

other drugs, including other AEDs Carbamazepine is

metabolized by CYP3A4; inducers or inhibitors of the

enzyme can decrease or increase carbamazepine

con-centrations

CLOBAZAM — Clobazam (Onfi) is a

benzodi-azepine FDA-approved only for use as adjunctive

treatment for seizures associated with the

Lennox-Gastaut syndrome in patients 2 years old.4It has been

widely used for years in Canada and other countries for

the treatment of many types of seizures

Adverse Effects – The most frequent adverse effects

of clobazam are somnolence, pyrexia, lethargy, drool-ing, and constipation As with other benzodiazepines, anterograde amnesia, ataxia, and withdrawal symp-toms and seizures can occur if the drug is stopped abruptly Clobazam is classified as a schedule IV con-trolled substance; tolerance, dependence and abuse have been reported

Drug Interactions – Clobazam inhibits CYP2D6;

drugs that are metabolized by CYP2D6, such as

flu-oxetine (Prozac, and generics), may require a

reduc-tion in dosage if taken concurrently It is also a mild inducer of CYP3A4 Clobazam is metabolized to its active metabolite mainly by CYP3A4, which is fur-ther metabolized by CYP2C19 Concomitant use of drugs that inhibit CYP2C19, such as fluconazole

Usual Adult

Perampanel – Fycompa (Eisai) 2, 4, 6, 8, 10, 12 mg tabs 4-12 mg in 1 dose N.A 4 Phenobarbital – generic 15, 30, 60, 100 mg tabs; 90-150 mg in 2 or 3 doses 3 $15.84

20 mg/5 mL elixir Phenytoin – generic 30, 100, 200, 300 mg caps; 300-400 mg 28.75

125 mg/5 mL susp; 50 mg in 1-3 doses 3,5 chewable tabs

Dilantin-125 125 mg/5 mL susp

Dilantin Infatabs 50 mg chewable tabs

Pregabalin – generic 25, 50, 75, 100, 150, 200, 225, 150-600 mg N.A 4

300 mg caps in 2 or 3 doses

300 mg caps; 20 mg/mL soln

Rufinamide – Banzel (Eisai) 200, 400 mg tabs; 40 mg/mL susp 3200 mg in 2 doses 2040.20

Topiramate – generic 15, 25 mg caps; 25, 50 100, 200 mg tabs 100-400 mg in 10.80 6

extended release –

Valproate

Valproic acid – generic 250 mg caps; 250 mg/5 mL syrup 1000-3000 mg 44.40

Stavzor (Noven) 125, 250, 500 mg delayed-release caps 245.88 Divalproex sodium – generic 125, 250, 500 mg delayed-release tabs; 1000-3000 mg in 38.99

Depakote (Abbott) 125, 250, 500 mg delayed-release tabs 237.74

extended-release – generic 250, 500 mg ER tabs 1250-3500 mg once daily 3 62.51

Vigabatran – Sabril (Lundbeck) 500 mg tabs; 500 mg powder 3 g in 2 doses 8115.98

for soln (50 mg/mL) Zonisamide – generic 25, 50, 100 mg caps 100-400 mg in 1 or 2 doses 24.27

5 Adjustments in maintenance dosage above 300 mg/day for adults should usually be made in 25- or 30-mg increments because metabolism becomes saturated.

6 Based on wholesale acquisition cost as of October 5, 2013.

Table 2 Some Antiepileptic Drugs (continued)

(Diflucan, and generics) or omeprazole (Prilosec, and

generics), can increase serum concentrations of the

active metabolite

CLONAZEPAM — Clonazepam (Klonopin, and

generics) is a benzodiazepine approved to treat

Lennox-Gastaut syndrome, myoclonic and atonic

seizures It is also used to treat absence seizures

resist-ant to treatment with other resist-antiepileptic drugs It is

generally less effective for absence seizures than

etho-suximide or valproate, and development of tolerance to

its effects is common

Other Uses – Clonazepam is also approved by the

FDA for treatment of panic disorder and is used to treat

other types of anxiety disorders

Adverse Effects – Clonazepam can cause drowsiness,

ataxia and behavior disorders Withdrawal symptoms

including seizures can occur after abrupt discontinuation

Drug Interactions – Clonazepam is partially

metabo-lized by CYP3A4; inducers of this enzyme, such as

carbamazepine and phenytoin, may reduce serum

con-centrations of clonazepam and strong inhibitors, such

as clarithromycin (Biaxin, and generics), can increase

them

ETHOSUXIMIDE — Ethosuximide (Zarontin, and

generics) is approved for treatment of absence seizures

and is usually well tolerated Its elimination half-life is

about 60 hours in adults, but only about 30 hours in

children.5 It is not effective in generalized tonic-clonic

or partial seizures

Adverse Effects – Ethosuximide can cause nausea,

vomiting, lethargy, hiccups, headache and behavorial

changes Psychotic behavior can occur Hematologic

abnormalities, erythema multiforme, Stevens-Johnson

syndrome and systemic lupus erythematosus (SLE)

have been reported

Drug Interactions – Ethosuximide is partially

metab-olized by CYP3A4; inducers of CYP3A4 may

decrease serum concentrations of the drug and strong

inhibitors can increase them

EZOGABINE — Ezogabine (Potiga) is

FDA-approved for adjunctive treatment of partial onset

seizures in adults.6It is available in Europe as

retiga-bine (Trobalt) Ezogaretiga-bine acts through potassium

channel activation

Adverse Effects – The most frequent adverse effects

of ezogabine are dizziness, somnolence and fatigue

Confusion, tremor, abnormal coordination, memory

impairment, blurred vision, asthenia and aphasia can occur Weight gain (1.2-2.7 kg), urinary retention, sometimes requiring catheterization, psychotic symp-toms and hallucinations have been reported Like other recently approved AEDs, it is a schedule V controlled substance because of reports of euphoria

Drug Interactions – Carbamazepine and phenytoin

can decrease ezogabine serum concentrations; an increase in the dosage of ezogabine may be needed Ezogabine decreases renal clearance of digoxin QT interval prolongation has been reported with ezo-gabine; monitoring is recommended in patients also taking other drugs that can prolong the QT interval

GABAPENTIN — Gabapentin (Neurontin, and

generics) is FDA-approved for adjunctive treatment of partial seizures with and without secondary general-ization in adults and children age 3 years old and is also effective, but not FDA-approved, as monotherapy for these same types of seizures Like carbamazepine, gabapentin can exacerbate myoclonic seizures

Other Uses – Gabapentin is also FDA-approved for

treatment of neuropathic pain, and a prodrug,

gabapentin encarbil (Horizant), is approved for restless

legs syndrome.7

Adverse Effects – Gabapentin can cause somnolence,

dizziness, ataxia, fatigue, nystagmus, blurred vision and confusion Edema, weight gain and movement dis-orders have been reported Behavioral changes have occurred in children, especially those with underlying behavioral or developmental problems

Drug Interactions – Unlike some other AEDs,

gabapentin does not induce or inhibit hepatic microso-mal enzymes

LACOSAMIDE — Oral lacosamide (Vimpat) is

FDA-approved as add-on therapy for adults with par-tial onset seizures.8Lacosamide is also available in an

IV formulation for short-term use The drug works by slowly inactivating voltage dependent sodium chan-nels

Adverse Effects – The most frequent adverse effects

of oral lacosamide are dizziness, headache, nausea, vomiting, fatigue, ataxia, diplopia, somnolence and tremor Like other recently approved AEDs, lacosamide has been designated as a schedule V con-trolled substance because of reports of euphoria

Drug Interactions – Lacosamide is a substrate and

inhibitor of CYP2C19, but no clinically significant drug interactions have been reported A small,

dose-Drugs for Epilepsy

dependent increase in the PR interval has been

report-ed during treatment with lacosamide; caution is

advised in patients with cardiac conduction problems

and in those taking other drugs that may prolong the

PR interval such as beta blockers or calcium channel

blockers

LAMOTRIGINE — Lamotrigine (Lamictal, and

generics) is FDA-approved for adjunctive therapy in

patients 2 years old with partial seizures, primary

generalized tonic-clonic seizures or generalized

seizures of Lennox-Gastaut syndrome It is also

approved as monotherapy as a substitute for

carba-mazepine, phenytoin, phenobarbital, primidone or

val-proate in patients 16 years old with partial seizures

In elderly patients with newly diagnosed partial or

gen-eralized seizures, lamotrigine has been as effective as

carbamazepine and better tolerated.9 Some reports

suggest lamotrigine can make myoclonus worse,

par-ticularly in severe myoclonic epilepsy of infancy

Lamotrigine may be less effective than ethosuximide

or valproic acid for absence seizures in children, but

some clinicians use it as first-line treatment because of

its tolerability.10

Other Uses – Lamotrigine can improve depression in

some patients with epilepsy and is FDA-approved for

maintenance treatment of bipolar disorder

Adverse Effects – The most common adverse effects

of lamotrigine have been dizziness, ataxia,

somno-lence, headache, diplopia, nausea, vomiting, rash,

insomnia and incoordination Acute hepatitis has been

reported Life-threatening rashes including

Stevens-Johnson syndrome have occurred rarely, usually

dur-ing the first 2 months of use The risk may be increased

by high starting doses, rapid increases in dosage or

co-administration with valproate The manufacturer

rec-ommends discontinuing lamotrigine at the first sign of

rash Lamotrigine causes fewer adverse cognitive

effects than carbamazepine or topiramate Cases of

aseptic meningitis have been reported in pediatric and

adult patients taking lamotrigine

Drug Interactions – Lamotrigine does not induce or

inhibit CYP450 enzymes Enzyme-inducing drugs,

such as carbamazepine, reduce lamotrigine

concentra-tions Valproate increases lamotrigine concentrations

more than 2-fold

LEVETIRACETAM — Oral levetiracetam (Keppra,

and generics) is FDA-approved as adjunctive therapy

for adults and children 1 month old with partial

seizures, adults and children 6 years old with

pri-mary generalized tonic-clonic seizures, and adults and

adolescents 12 years old with myoclonic seizures It

is commonly used as monotherapy for partial onset and generalized seizures and may also be effective in children with seizures of Lennox-Gastaut syndrome, and in absence seizures.11,12 Levetiracetam is also available in an IV formulation

Adverse Effects – Dizziness, somnolence and

weak-ness occur commonly Behavioral changes such as agitation, hostility and irritability, hallucinations and psychosis have also occurred, especially in patients with underlying psychiatric diagnoses Serious derma-tological reactions, including Stevens-Johnson syn-drome and toxic epidermal necrolysis, and coordina-tion difficulties have been reported Mild decreases in hematocrit and white blood cell count, which do not require discontinuation of the drug, occur rarely Levetiracetam appears to have a low incidence of adverse cognitive effects

Drug Interactions – Levetiracetam is not an inhibitor

or substrate of CYP450 enzymes No clinically signif-icant drug-drug interactions have been reported

OXCARBAZEPINE — Oxcarbazepine (Trileptal,

and generics) is chemically similar to carbamazepine but causes less induction of hepatic enzymes and unlike carbamazepine, oxcarbazepine does not induce its own metabolism It is approved by the FDA for treatment of partial seizures as monotherapy or adjunctive therapy in adults and children 4 years old, and as adjunctive therapy in children 2 years old Like carbamazepine, oxcarbazepine is also effective in secondarily generalized seizures, but may make myoclonic and absence seizures worse Oxcarbazepine has been as effective as phenytoin, carbamazepine or valproate in treatment of partial seizures, and may be better tolerated Most of its clinical effect is due to the 10-monohydroxy metabolite (MHD), which has a half-life of 8-10 hours

Other Uses – Oxcarbazepine is used off-label for

treatment of bipolar disorder

Adverse Effects – Common adverse effects of

oxcar-bazepine are somnolence, dizziness, diplopia, ataxia, nausea and vomiting Taking the extended-release for-mulation with food increases peak concentrations of the drug and the likelihood of adverse effects Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred, and multi-organ hypersensitivity reac-tions have been reported Cross-reactivity with carba-mazepine hypersensitivity occurs in 20-30% of patients Hyponatremia is more common with oxcar-bazepine than with carbamazepine

Drug Interactions – Oxcarbazepine induces

CYP3A4/5 and inhibits CYP2C19 It can increase

phenytoin levels by up to 40% Levels of the active

metabolite are reduced in the presence of

enzyme-inducing drugs such as phenobarbital or phenytoin

PERAMPANEL — Perampanel (Fycompa) was

recently approved by the FDA as adjunctive treatment

for partial-onset seizures in patients 12 years old,13-15

but has not yet been marketed in the US It acts as an

antagonist at the AMPA glutamate receptor

Adverse Effects – The most frequent adverse effects

of perampanel are dizziness and drowsiness Weight

gain, mood change, ataxia, dysarthria, diplopia,

verti-go, nausea and fatigue have also been reported Serious

psychiatric and behavioral reactions, including

irri-tability, aggression, anger and anxiety, can occur

Drug Interactions – Perampanel is partially

metabo-lized by CYP3A Inhibitors of the enzyme may

increase serum concentrations of perampanel and

inducers may decrease them

PHENYTOIN — Phenytoin (Dilantin, and generics)

is as effective as carbamazepine for treatment of

par-tial and secondarily generalized tonic-clonic seizures,

but is no longer considered a drug of first choice

because of its complicated pharmacokinetics, adverse

effect profile and frequent drug-drug interactions

Different formulations of phenytoin may not be

bio-equivalent, especially at higher doses Fosphenytoin

(Cerebyx, and generics) is a water-soluble prodrug of

phenytoin available for IV and IM use

Adverse Effects – Nystagmus may occur with

thera-peutic serum concentrations of phenytoin and is

usually present at higher concentrations Drowsiness,

ataxia and diplopia are more likely to occur at total

serum concentrations >20 mcg/mL, but can also occur

at lower levels, particularly in patients with low

serum albumin levels and in the elderly Phenytoin

may interfere with cognitive function related to

learning Cerebellar atrophy has been reported with

long-term use and after acute intoxication Gingival

hyperplasia, coarsening of facial features and

hir-sutism can also occur

A morbilliform or scarlatiniform rash may occur,

usu-ally in the first four weeks of treatment, sometimes

with hepatitis, fever and lymphadenopathy; rarely it

progresses to exfoliative dermatitis or

Stevens-Johnson syndrome Asian patients who test positive for

HLA-B*1502 may have an increased risk of serious

skin reactions with phenytoin or fosphenytoin Patients

who develop hypersensitivity reactions to phenytoin

are often susceptible to similar reactions with carba-mazepine and phenobarbital

Less common adverse effects include megaloblastic anemia, a lupus-like syndrome, peripheral neuropathy, nephritis, and hepatitis leading rarely to fatal hepatic necrosis Osteopenia can occur with long-term use Serum folic acid, thyroxine and vitamin K concentra-tions may decrease with long-term therapy Fosphenytoin is less likely to cause soft tissue injury than older IV formulations, but at rapid infusion rates it can cause transient paresthesias and pruritus

Drug Interactions – Phenytoin is metabolized by

CYP2C9 and 2C19; inducers and inhibitors of these enzymes may affect its serum concentrations Like car-bamazepine, phenytoin is a strong enzyme inducer; it can reduce serum concentrations and possibly the effectiveness of many other drugs, including other AEDs It may initially cause an increase in warfarin response followed by a reduction in its anticoagulant effect

PREGABALIN — Pregabalin (Lyrica, and generics)

is FDA-approved for adjunctive treatment of partial seizures in adults.16Its mechanism of action is similar

to that of gabapentin, suggesting it will not be useful in the treatment of myoclonic seizures

Other Uses – Pregabalin is also FDA-approved for

treatment of neuropathic pain and fibromyalgia;17it is approved in Europe for treatment of generalized anxi-ety disorder

Adverse Effects – Pregabalin causes somnolence,

dizziness, ataxia, weight gain, dry mouth, blurred vision, peripheral edema and confusion Newly devel-oped myoclonus has been reported in patients with epilepsy taking pregabalin Pregabalin, like many new antiepileptic drugs, is a schedule V controlled sub-stance due to reports of euphoria

Drug Interactions – Like gabapentin, pregabalin has

no significant drug-drug interactions

RUFINAMIDE — Rufinamide (Banzel) is

FDA-approved for adjunctive treatment of Lennox-Gastaut syndrome in patients 4 years old.18 It appears to be particularly effective for treatment of atonic seizures.19 There is also evidence that adjunctive treatment with rufinamide reduces the frequency of partial seizures, but it is not FDA-approved for such use.20

Adverse Effects – The most frequent adverse effects of

rufinamide are somnolence and vomiting Headache, dizziness, fatigue, nausea, diplopia and tremor have

Drugs for Epilepsy

been reported Rufinamide can shorten the QT interval

in some patients; it should not be prescribed to patients

with short QT syndrome or to those taking other drugs

known to shorten the QT interval (such as digoxin and

magnesium)

Drug Interactions – Rufinamide is a mild inducer of

CYP3A4 It has been shown to reduce ethinyl

estradi-ol, norethindrone and triazolam concentrations, and

could have a similar effect on other drugs metabolized

by CYP3A4

TOPIRAMATE — Topiramate (Topamax, and

gener-ics) is approved for partial and primary generalized

tonic-clonic seizures as monotherapy or adjunctive

therapy in adults and children 2 years old It is also

approved as adjunctive therapy for children 2 years

old with Lennox-Gastaut syndrome and is effective in

atonic seizures in children

Other Uses – Topiramate is also FDA-approved for

migraine prophylaxis and for chronic weight

manage-ment as part of a fixed-dose combination with

phenter-mine (Qsymia).21,22

Adverse Effects – The most frequent adverse effects

of topiramate are drowsiness, dizziness, headache and

ataxia Nervousness, confusion, paresthesias, weight

loss and diplopia can occur Psychomotor slowing,

word-finding difficulty, impaired concentration, and

interference with memory are common, particularly

with rapid dose escalation and higher maintenance

doses, and may require dosage reduction or stopping

the drug Acute myopia associated with secondary

angle closure glaucoma, which is infrequent but

severe, typically occurs within one month of starting

treatment Liver failure, oligohidrosis, hyperthermia

and heat stroke have been reported Renal stones have

occurred due to metabolic acidosis caused by

inhibi-tion of carbonic anhydrase

Drug Interactions – Topiramate is a mild inducer of

CYP3A and an inhibitor of CYP2C19 It can increase

serum lithium levels, particularly at high doses

Carbamazepine and phenytoin decrease topiramate

concentrations Concomitant use of valproic acid and

topiramate has been associated with hyperammonemia

and hypothermia Use of topiramate with other

car-bonic anhydrase inhibitors such as zonisamide or

acetazolamide could increase the severity of metabolic

acidosis

VALPROATE — Valproic acid (Depakene, and

generics) and divalproex sodium (Depakote, and

generics) dissociate to valproate in the GI tract

Valproate is approved by the FDA as monotherapy or

adjunctive therapy for complex partial seizures and absence seizures and as adjunctive therapy for multiple seizure types that involve absence Because it is effec-tive and usually well tolerated, valproate is widely used for myoclonic and atonic seizures and is consid-ered the drug of choice for primary generalized tonic-clonic seizures It is highly effective in treating photo-sensitive epilepsy and juvenile myoclonic epilepsy Valproate is less effective than carbamazepine in con-trolling complex partial seizures, but equally effective

in controlling secondarily generalized seizures A

once-daily extended-release formulation (Depakote ER) is as effective as Depakote It is not bioequivalent

to older formulations, so when switching from

val-proate capsules or delayed-release tablets to Depakote

ER, the daily dosage should be increased by 8-20%.

Valproate is also available in an IV formulation

(Depacon).

Other Uses – Valproate is FDA-approved for migraine

prophylaxis and bipolar disorder

Adverse Effects – Drowsiness due to valproate is

usu-ally mild and transient, and adverse cognitive effects are generally minimal Nausea and vomiting can be minimized by using the enteric-coated formulation

(Depakote), by taking the drug with food, and by slow

titration to an optimal dose Weight gain is common Use of valproate has been associated with polycystic ovary syndrome, hyperinsulinemia, lipid abnormali-ties, hirsutism and menstrual disturbances in women, and with increased serum androgen concentrations in men Dose-related tremor, transient hair thinning and loss, decreased platelet function, and thrombocyto-penia can also occur

Serious adverse effects of the drug are uncommon, but fatal liver failure has occurred, particularly in children

<2 years old taking valproate in combination with other AEDs and in patients with developmental delay and metabolic disorders; liver failure has also been reported in older children and adults taking valproate alone Valproate can interfere with conversion of ammonia to urea It can cause lethargy associated with increased blood ammonia concentrations and fatal hyperammonemic encephalopathy has occurred in patients with genetic defects in urea metabolism; the drug is contraindicated in these patients Life-threaten-ing pancreatitis, interstitial nephritis, reversible parkin-sonism and edema requiring diuretics for control have occurred rarely

Drug Interactions – Valproate has fewer drug

interac-tions than carbamazepine or phenytoin Enzyme induc-ing AEDs increase valproate clearance Carbapenem antibiotics, such as imipenem, also significantly

reduce valproate concentrations Valproate is a weak

enzyme inhibitor; it can increase serum concentrations

of some other AEDs, including carbamazepine,

pheny-toin, phenobarbital, ethosuximide, lamotrigine and

rufinamide, and tricyclic antidepressants

VIGABATRIN — Vigabatrin (Sabril) is

FDA-approved as monotherapy for infantile spasms and as

add-on therapy for complex partial seizures refractory

to several other AEDs.23In the US, it is available only

through a restricted distribution program called

SHARE (Support, Help, and Resources for Epilepsy)

due to concerns about retinal toxicity and permanent

visual field loss This program requires that prescribers

and pharmacists register, and that patients undergo

monitoring for visual field loss

Adverse Effects – The most serious adverse effect of

vigabatrin is concentric peripheral visual field deficit

(pVFD) which is potentially irreversible Patients are

usually unaware of the visual field loss, particularly in its

initial mild phase Evidence suggests that pVFD is rare

during the first 6 months of treatment; patients without a

good response to this therapy should be taken off the

drug within this time Headache, fatigue, pain, balance

disorder, dizziness, somnolence, depression (including

suicidality), expressive language disorder, pruritus and

weight gain have also been reported

Drug Interactions – Vigabatrin is not significantly

metabolized It can lower serum concentrations of

phenytoin by inducing CYP2C9, but it does not induce

other CYP450 enzymes

ZONISAMIDE — Zonisamide (Zonegran, and

oth-ers) is FDA-approved for adjunctive treatment of

par-tial seizures in adults with epilepsy It appears to have

a broad spectrum of activity (infantile spasms,

myoclonic, generalized and atypical absence seizures),

and there is considerable experience worldwide with

its use in children, as monotherapy, and for other

seizure types

Other Uses – Zonisamide also appears to be effective

for migraine prophylaxis and for weight loss in obese

patients but is not approved by the FDA for these

indi-cations.24,25

Adverse Effects – Adverse effects include

somno-lence, dizziness, confusion, anorexia, nausea, diarrhea,

weight loss, agitation, irritability and rash Fatal

Stevens-Johnson syndrome and toxic epidermal

necro-lysis have been reported Oligohidrosis, hyperthermia

and heat stroke have occurred in children Psychosis,

psychomotor slowing, word-finding difficulty and

impaired concentration can occur Aplastic anemia and

agranulocytosis have also been reported Slow titration and dosing with meals may decrease the incidence of adverse effects Zonisamide is a mild carbonic anhy-drase inhibitor and can cause metabolic acidosis, which increases the risk of symptomatic renal stones

Drug Interactions – Zonisamide is metabolized by

CYP3A4; drugs that induce or inhibit CYP3A4 could affect serum concentrations of zonisamide Zonisamide does not inhibit the metabolism of drugs metabolized

by CYP450 enzymes Use of zonisamde with other car-bonic anhydrase inhibitors such as topiramate could increase the risk of renal stone formation

OTHER DRUGS — Felbamate (Felbatol) is

approved as monotherapy or adjunctive therapy of par-tial and secondarily generalized seizures, and for adjunctive therapy of seizures associated with the Lennox-Gastaut syndrome in patients who have failed other drugs There is an appreciable risk of aplastic ane-mia and hepatic failure, estimated at about 1:3000-5000

patients Phenobarbital and primidone (Mysoline,

and others) are effective for partial and secondarily generalized tonic-clonic seizures, but they have a

high-er incidence of sedation compared to othhigh-er drugs

Tiagabine (Gabitril) is approved only for adjunctive

treatment of partial seizures, and is associated with gas-trointestinal and CNS adverse effects Use in nonepileptic patients (for bipolar disorder, anxiety and neuropathic pain) has been associated with develop-ment of new-onset seizures and status epilepticus.26

Rectal administration of diazepam gel (Diastat

AcuDial) is approved for intermittent use in the

treat-ment of increased seizure activity in patients taking other antiepileptic drugs When given rectally,

diazepam is rapidly and completely absorbed Diastat AcuDial is supplied as a prefilled syringe with either

10 mg (which can be used to deliver 5, 7.5 or 10 mg)

or 20 mg (which can be used to deliver 12.5, 15, 17.5

or 20 mg) for single-dose administration by the care-giver At-home use of rectal diazepam in children may help terminate seizure activity and reduce emergency room visits.27

OTHER ISSUES — Suicidality – The FDA reported

in 2008 that a meta-analysis of data from placebo-con-trolled studies of 11 AEDs found an increased risk of suicidal behavior and ideation in patients taking these drugs: 0.43% of patients on AEDs (n=27,863) com-pared to 0.22% of those on placebo (n=16,029) The overall incidence was extremely low, however, and its clinical significance was questionable The results of a large cohort study among patients in the US suggest that gabapentin, lamotrigine, oxcarbazepine and tiagabine, compared with topiramate or

carba-Drugs for Epilepsy

mazepine, may increase the risk of suicidal acts.28

Another cohort study in the UK found that use of

AEDs in patients with epilepsy was not associated

with an increased risk of suicide-related events, but

patients with depression taking AEDs did have an

increased risk.29

Bone Density – Prolonged use of antiepileptic drugs,

particularly those that result in enzyme induction

(phenytoin, carbamazepine, phenobarbital,

primi-done), may increase the risk of osteoporosis

Valproate, which does not induce hepatic enzymes, has

also been associated with decreases in bone mineral

density

AEDs and Oral Contraceptives – Enzyme-inducing

AEDs such as carbamazepine, phenytoin, primidone,

and phenobarbital, and, to a lesser extent, felbamate,

topiramate, oxcarbazepine, rufinamide, clobazam and

perampanel, may decrease serum concentrations of

estrogens and/or progestins, possibly resulting in

con-traceptive failure.30Use of vigabatrin has been

associ-ated with reduced ethinyl estradiol serum

concentra-tions Perampanel and lamotrigine have decreased

lev-els of levonorgestrel Levetiracetam and valproate do

not affect serum concentrations of oral contraceptives

Oral contraceptives can reduce lamotrigine

concentra-tions, which then transiently increase if the

contracep-tive includes a week of inaccontracep-tive tablets

AEDs and Pregnancy – AEDs should be used as

monotherapy at the lowest possible dose in

preg-nant women; the risk to offspring is generally

con-sidered to be less than the risk of seizures during

pregnancy.31

Most pregnant patients exposed to antiepileptic drugs

deliver normal infants, but fetal exposure to older

AEDs, particularly valproate and phenobarbital, can

cause congenital anomalies, including oral cleft and

cardiac, urinary tract and neural tube defects.32

Children exposed to valproate in utero have also been

reported to have lower IQs.33Available data from

preg-nancy registries suggest that use of some newer AEDs

such as lamotrigine, levetiracetam, oxcarbazepine and

gabapentin is associated with low rates of major

mal-formations.34 Topiramate appears to increase the risk

of oral cleft35and has been associated with

hypospa-dias in male infants

Pregnancy itself tends to induce the metabolism of

AEDs, particularly lamotrigine; monitoring

lamotrig-ine serum concentrations may improve seizure

con-trol.36 Use of an enzyme-inducing AED such as

phenytoin, phenobarbital, primidone or

carba-mazepine may cause hemorrhage in the newborn

infant due to vitamin K deficiency; vitamin K supple-mentation has been recommended for the mother in the final month of pregnancy, but whether it reduces the risk of hemorrhagic complications is unclear Newborns should receive vitamin K at delivery.37

Generic Substitution of Brand-Name Drugs –

Generic versions of many antiepileptic drugs are now available In general, a generic drug offers a lower-cost alternative that is roughly bioequivalent (pharmacoki-netic parameters within 80-125%) to the brand-name drug A meta-analysis of randomized controlled trials comparing use of brand-name and generic forms of phenytoin, carbamazapine and valproate found no dif-ference in seizure control.38 However, switching between generic products could lead to significant dif-ferences in total and peak serum concentrations.39 If possible, prescription refills should be from the same manufacturer

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2 WH Chung et al Medical genetics: a marker for Stevens-Johnson syn-drome Nature 2004; 428:486.

3 P Chen et al Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan N Engl J Med 2011; 364:1126.

4 Clobazam (Onfi) for Lennox-Gastaut Syndrome Med Lett Drugs Ther 2012; 54:18.

5 EP Vining Ethosuximide in childhood absence epilepsy - older and bet-ter N Engl J Med 2010; 362:843.

6 Ezogabine (Potiga) for epilepsy Med Lett Drugs Ther 2012; 54:65.

7 Gabapentin encarbil (Horizant) for restless legs syndrome Med Lett Drugs Ther 2011; 53:70.

8 Lacosamide for epilepsy Med Lett Drugs Ther 2009; 51:50.

9 AJ Rowan et al New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine Neurology 2005; 64:1868.

10 TA Glauser et al Ethosuximide, valproic acid, and lamotrigine in child-hood absence epilepsy N Engl J Med 2010; 362:790.

11 EC De Los Reyes Levetiracetam in the treatment of Lennox-Gastaut syndrome Pediatric Neurol 2004; 30:254.

12 J Cavitt and M Privitera Levetiracetam induces a rapid and sustained reduction of generalized spike-wave and clinical absence Arch Neurol 2004; 61:1604.

13 GL Krauss et al Randomized phase III study 306: adjunctive peram-panel for refractory partial-onset seizures Neurology 2012; 78:1408.

14 JA French et al Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304 Neurology 2012; 79:589.

15 JA French et al Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305 Epilepsia 2012 Aug 20 (epub).

16 Pregabalin (Lyrica) for neuropathic pain and epilepsy Med Lett Drugs Ther 2005; 47:75.

17 Pregabalin (Lyrica) for fibromyalgia Med Lett Drugs Ther 2007; 49:77.

18 Rufinamide (Banzel) for epilepsy Med Lett Drugs Ther 2009; 51:18.

19 G Kluger et al Adjunctive rufinamide in Lennox-Gastaut syndrome: a long-term, open-label extension study Acta Neurol Scand 2010; 122:202.

20 V Biton et al A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures Epilepsia 2011; 52:234.

21 Topiramate (Topamax) for prevention of migraine Med Lett Drugs Ther 2005; 47:9.