drugs for epilepsy

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Drugs for EpilepsyTreatment of epilepsy should begin with a singledrug, increasing the dosage gradually until seizuresare controlled or adverse effects become unaccept-able. If seizures persist, expert clinicians generallyprescribe at least one and sometimes a second alter-native drug as monotherapy before considering use oftwo drugs at the same time. When used for the appro-priate seizure type, antiepileptic drugs are roughlyequivalent in efficacy. The choice of drug is usuallybased on factors such as ease of use, adverse effects,interactions with other drugs, presence of comorbidconditions and cost.1

Controlled trials are difficult to conduct in patientswith epilepsy; use of a placebo would be unethical,and patients whose seizures are controlled by onemedication are understandably reluctant to be random-ized to another. Newer antiepileptic drugs (AEDs) areusually initially approved by the FDA only as adjunc-tive therapy for partial seizures, but many may also beeffective 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 indicationfor use as an anticonvulsant. It is particularly effectivefor treatment of partial and secondarily generalizedtonic-clonic seizures, but may make absence ormyoclonic seizures worse. Carbamazepine induces itsown metabolism; serum concentrations often fall aftera few weeks of treatment. Storing carbamazepinetablets (both brand and generic) in humid conditionscan cause concretion of the tablets, resulting in poorbioavailability and therapeutic failure.

Other Uses – Carbamazepine is also used for bipolardisorder and for treatment of pain due to trigeminalneuralgia.

Adverse Effects – Carbamazepine can cause drowsi-ness, blurred vision, diplopia, headache, dizziness,ataxia, nausea and vomiting. Its cognitive effects caninterfere with learning. Use of an extended-releaseformulation has been associated with fewer CNSadverse effects.

Tables1. Drugs of Choice Page 92. Some Antiepileptic Drugs Pages 10-11


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Volume 11 (Issue 126) February 2013www.medicalletter.orgTake CME exams

Partial, Including Secondarily Generalized Seizures

Drugs of Choice: Some Alternatives:Lamotrigine TopiramateCarbamazepine ValproateLevetiracetam GabapentinOxcarbazepine Zonisamide

PhenytoinPregabalinLacosamideEzogabine

Primary Generalized Tonic-Clonic Seizures

Drugs of Choice: Some Alternatives:Valproate TopiramateLamotrigine ZonisamideLevetiracetam Phenytoin

Absence Seizures

Drugs of Choice: Alternatives:Ethosuximide LamotrigineValproate Clonazepam

ZonisamideLevetiracetam

Atypical Absence, Myoclonic, Atonic Seizures

Drugs of Choice: Alternatives:Valproate TopiramateLamotrigine ZonisamideLevetiracetam Clonazepam

FelbamateClobazamRufinamide

1.Some of the drugs listed here have not been approved for such useby the FDA. Approved indications are included in the text.

Table 1. Drugs of Choice1

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Drugs for Epilepsy

Mild leukopenia and hyponatremia are fairly com-mon. With high doses of the drug, thrombocytopeniacan occur, but it is usually reversible if the drug isdiscontinued. Aplastic anemia, agranulocytosis, car-diac toxicity, aseptic meningitis, intractable diarrheaand hepatitis are rare. Circulating concentrations ofthyroid hormones may be reduced even though TSHremains normal. Abnormal color perception canoccur rarely.

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

Usual AdultDrug Oral Formulations Daily Dosage1 Cost2

Carbamazepine – generic 200 mg tabs; 100 mg chewable 800-1600 mg $ 6.87Tegretol (Novartis) tabs; 100 mg/5 mL susp in 2 or 3 doses3 136.80

extended release – generic 100, 200 mg ER caps and tabs; 800-1600 mg in 93.38300 mg ER caps, 400 mg ER tabs 2 doses3

Tegretol XR 100, 200, 400 mg ER tabs 139.20Carbatrol (Shire) 100, 200, 300 mg ER caps 212.74

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 3.820.5, 1, 2 mg disintegrating tabs

Klonopin (Genentech) 0.5, 1, 2 mg tabs 154.96

Ethosuximide – generic 250 mg caps; 250 mg/5 mL syrup 750-1250 mg in 2 doses 85.96Zarontin (Pfizer) 154.68

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 518.87Felbatol (Meda) 600 mg/5 mL susp 704.38

Gabapentin – generic 100, 300, 400 mg caps; 100, 1800-3600 mg in 3 doses 55.58300, 400, 600, 800 mg tabs;250 mg/5 mL soln

Neurontin (Pfizer) 100, 300, 400 mg caps; 376.99600, 800 mg tabs;250 mg/5 mL soln

Lacosamide – Vimpat (UCB) 50, 100, 150, 200 mg tabs; 200-400 mg in 2 doses 439.6110 mg/mL soln

Lamotrigine – generic 2, 5, 25, 50, 100, 150, 200, 250 mg 100-500 mg in 2 doses 7.29tabs; 2, 5, 25 mg chewable tabs

Lamictal (GSK) 25, 100, 150, 200 mg tabs; 197.522, 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

Lamictal XR 381.18

Levetiracetam – generic 250, 500, 750, 1000 mg tabs; 1000-3000 mg in 2 doses 30.24Keppra (UCB) 100 mg/mL soln 313.13

extended release – generic 500, 750 mg ER tabs 1000-3000 mg 114.28Keppra XR once daily 283.87

Oxcarbazepine – generic 150, 300, 600 mg tabs; 1200-2400 mg in 2 doses 105.37Trileptal (Novartis) 300 mg/5 mL susp 417.56

extended-releaseOxtellar 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 isprescribed as adjunctive therapy or monotherapy, or is used concomitantly with one or more interacting drugs. Dosage may also need to beadjusted 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 retailprices may be higher.

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

Table 2. Some Antiepileptic Drugs

Treatment Guidelines from The Medical Letter • Vol. 11 ( Issue 126) • February 201310

Drugs for Epilepsy


other ethnic groups, be tested for this allele beforestarting the drug.

Drug Interactions – Carbamazepine is a strong induc-er of multiple hepatic enzymes; it can reduce serumconcentrations and possibly the effectiveness of manyother drugs, including other AEDs. Carbamazepine ismetabolized by CYP3A4; inducers or inhibitors of theenzyme can decrease or increase carbamazepine con-centrations.

CLOBAZAM — Clobazam (Onfi) is a benzodi-azepine FDA-approved only for use as adjunctivetreatment for seizures associated with the Lennox-Gastaut syndrome in patients 2 years old.4 It has beenwidely used for years in Canada and other countries forthe treatment of many types of seizures.

Adverse Effects – The most frequent adverse effectsof 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 stoppedabruptly. Clobazam is classified as a schedule IV con-trolled substance; tolerance, dependence and abusehave 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 mildinducer of CYP3A4. Clobazam is metabolized to itsactive metabolite mainly by CYP3A4, which is fur-ther metabolized by CYP2C19. Concomitant use ofdrugs that inhibit CYP2C19, such as fluconazole

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Usual AdultDrug Oral Formulations Daily Dosage1 Cost2

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 doses3 $15.8420 mg/5 mL elixir

Phenytoin – generic 30, 100, 200, 300 mg caps; 300-400 mg 28.75125 mg/5 mL susp; 50 mg in 1-3 doses3,5

chewable tabs

Dilantin (Pfizer) 30, 100 mg caps 46.85Dilantin-125 125 mg/5 mL suspDilantin 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 dosesLyrica (Pfizer) 25, 50, 75, 100, 150, 200, 225, 183.49

300 mg caps; 20 mg/mL soln

Primidone – generic 50, 250 mg tabs 750-1250 mg in 3 34.90Mysoline (Valeant) or 4 doses 663.63

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

Tiagabine – generic 2, 4 mg tabs 32-56 mg in 1285.60Gabitril (Cephalon) 2, 4, 12, 16 mg tabs 2-4 doses 628.00

Topiramate – generic 15, 25 mg caps; 25, 50 100, 200 mg tabs 200-400 mg in 16.28Topamax (Janssen) 25, 50, 100, 200 mg tabs 2 doses 512.75Topamax Sprinkle 15, 25 mg caps 860.36

ValproateValproic acid – generic 250 mg caps; 250 mg/5 mL syrup 1000-3000 mg 44.40Depakene (Abbott) in 2-3 doses3 367.90Stavzor (Noven) 125, 250, 500 mg delayed-release caps 245.88

Divalproex sodium – generic 125, 250, 500 mg delayed-release tabs; 1000-3000 mg in 38.99125 mg caps 2-3 doses3

Depakote (Abbott) 125, 250, 500 mg delayed-release tabs 237.74Depakote Sprinkle 125 mg delayed-release caps 250.27

extended-release – generic 250, 500 mg ER tabs 1250-3500 mg once daily3 62.51Depakote ER 264.84

Vigabatran – Sabril (Lundbeck) 500 mg tabs; 500 mg powder 3 g in 2 doses 8115.98for soln (50 mg/mL)

Zonisamide – generic 25, 50, 100 mg caps 100-400 mg in 1 or 2 doses 24.27Zonegran (Eisai) 133.80

4. Cost not yet available.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.

Table 2. Some Antiepileptic Drugs (continued)

Drugs for Epilepsy


(Diflucan, and generics) or omeprazole (Prilosec, andgenerics), can increase serum concentrations of theactive metabolite.

CLONAZEPAM — Clonazepam (Klonopin, andgenerics) is a benzodiazepine approved to treatLennox-Gastaut syndrome, myoclonic and atonicseizures. It is also used to treat absence seizures resist-ant to treatment with other antiepileptic drugs. It isgenerally less effective for absence seizures than etho-suximide or valproate, and development of tolerance toits effects is common.

Other Uses – Clonazepam is also approved by theFDA for treatment of panic disorder and is used to treatother types of anxiety disorders.

Adverse effects – Clonazepam can cause drowsiness,ataxia and behavior disorders. Withdrawal symptomsincluding seizures can occur after abrupt discontinuation.

Drug Interactions – Clonazepam is partially metabo-lized by CYP3A4; inducers of this enzyme, such ascarbamazepine and phenytoin, may reduce serum con-centrations of clonazepam and strong inhibitors, suchas clarithromycin (Biaxin, and generics), can increasethem.

ETHOSUXIMIDE — Ethosuximide (Zarontin, andgenerics) is approved for treatment of absence seizuresand is usually well tolerated. Its elimination half-life isabout 60 hours in adults, but only about 30 hours inchildren.5 It is not effective in generalized tonic-clonicor partial seizures.

Adverse Effects – Ethosuximide can cause nausea,vomiting, lethargy, hiccups, headache and behavorialchanges. Psychotic behavior can occur. Hematologicabnormalities, erythema multiforme, Stevens-Johnsonsyndrome and systemic lupus erythematosus (SLE)have been reported.

Drug Interactions – Ethosuximide is partially metab-olized by CYP3A4; inducers of CYP3A4 maydecrease serum concentrations of the drug and stronginhibitors can increase them.

EZOGABINE — Ezogabine (Potiga) is FDA-approved for adjunctive treatment of partial onsetseizures in adults.6 It is available in Europe as retiga-bine (Trobalt). Ezogabine acts through potassiumchannel activation.

Adverse Effects – The most frequent adverse effectsof ezogabine are dizziness, somnolence and fatigue.Confusion, tremor, abnormal coordination, memory

12

impairment, blurred vision, asthenia and aphasia canoccur. Weight gain (1.2-2.7 kg), urinary retention,sometimes requiring catheterization, psychotic symp-toms and hallucinations have been reported. Like otherrecently approved AEDs, it is a schedule V controlledsubstance because of reports of euphoria.

Drug Interactions – Carbamazepine and phenytoincan decrease ezogabine serum concentrations; anincrease in the dosage of ezogabine may be needed.Ezogabine decreases renal clearance of digoxin. QTinterval prolongation has been reported with ezo-gabine; monitoring is recommended in patients alsotaking other drugs that can prolong the QT interval.

GABAPENTIN — Gabapentin (Neurontin, andgenerics) is FDA-approved for adjunctive treatment ofpartial seizures with and without secondary general-ization in adults and children age 3 years old and isalso effective, but not FDA-approved, as monotherapyfor these same types of seizures. Like carbamazepine,gabapentin can exacerbate myoclonic seizures.

Other Uses – Gabapentin is also FDA-approved fortreatment of neuropathic pain, and a prodrug,gabapentin encarbil (Horizant), is approved for restlesslegs syndrome.7

Adverse Effects – Gabapentin can cause somnolence,dizziness, ataxia, fatigue, nystagmus, blurred visionand confusion. Edema, weight gain and movement dis-orders have been reported. Behavioral changes haveoccurred in children, especially those with underlyingbehavioral or developmental problems.

Drug Interactions – Unlike some other AEDs,gabapentin does not induce or inhibit hepatic microso-mal enzymes.

LACOSAMIDE — Oral lacosamide (Vimpat) isFDA-approved as add-on therapy for adults with par-tial onset seizures.8 Lacosamide is also available in anIV formulation for short-term use. The drug works byslowly inactivating voltage dependent sodium chan-nels.

Adverse Effects – The most frequent adverse effectsof oral lacosamide are dizziness, headache, nausea,vomiting, fatigue, ataxia, diplopia, somnolence andtremor. 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 andinhibitor of CYP2C19, but no clinically significantdrug 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 isadvised in patients with cardiac conduction problemsand in those taking other drugs that may prolong thePR interval such as beta blockers or calcium channelblockers.

LAMOTRIGINE — Lamotrigine (Lamictal, andgenerics) is FDA-approved for adjunctive therapy inpatients 2 years old with partial seizures, primarygeneralized tonic-clonic seizures or generalizedseizures of Lennox-Gastaut syndrome. It is alsoapproved 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 ascarbamazepine and better tolerated.9 Some reportssuggest lamotrigine can make myoclonus worse, par-ticularly in severe myoclonic epilepsy of infancy.Lamotrigine may be less effective than ethosuximideor valproic acid for absence seizures in children, butsome clinicians use it as first-line treatment because ofits tolerability.10

Other Uses – Lamotrigine can improve depression insome patients with epilepsy and is FDA-approved formaintenance treatment of bipolar disorder.

Adverse Effects – The most common adverse effectsof lamotrigine have been dizziness, ataxia, somno-lence, headache, diplopia, nausea, vomiting, rash,insomnia and incoordination. Acute hepatitis has beenreported. Life-threatening rashes including Stevens-Johnson syndrome have occurred rarely, usually dur-ing the first 2 months of use. The risk may be increasedby high starting doses, rapid increases in dosage or co-administration with valproate. The manufacturer rec-ommends discontinuing lamotrigine at the first sign ofrash. Lamotrigine causes fewer adverse cognitiveeffects than carbamazepine or topiramate. Cases ofaseptic meningitis have been reported in pediatric andadult patients taking lamotrigine.

Drug Interactions – Lamotrigine does not induce orinhibit CYP450 enzymes. Enzyme-inducing drugs,such as carbamazepine, reduce lamotrigine concentra-tions. Valproate increases lamotrigine concentrationsmore than 2-fold.

LEVETIRACETAM — Oral levetiracetam (Keppra,and generics) is FDA-approved as adjunctive therapyfor adults and children 1 month old with partialseizures, adults and children 6 years old with pri-mary generalized tonic-clonic seizures, and adults and

adolescents 12 years old with myoclonic seizures. Itis commonly used as monotherapy for partial onsetand generalized seizures and may also be effective inchildren with seizures of Lennox-Gastaut syndrome,and in absence seizures.11,12 Levetiracetam is alsoavailable in an IV formulation.

Adverse Effects – Dizziness, somnolence and weak-ness occur commonly. Behavioral changes such asagitation, hostility and irritability, hallucinations andpsychosis have also occurred, especially in patientswith 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 inhematocrit and white blood cell count, which do notrequire discontinuation of the drug, occur rarely.Levetiracetam appears to have a low incidence ofadverse cognitive effects.

Drug Interactions – Levetiracetam is not an inhibitoror substrate of CYP450 enzymes. No clinically signif-icant drug-drug interactions have been reported.

OXCARBAZEPINE — Oxcarbazepine (Trileptal,and generics) is chemically similar to carbamazepinebut causes less induction of hepatic enzymes andunlike carbamazepine, oxcarbazepine does not induceits own metabolism. It is approved by the FDA fortreatment of partial seizures as monotherapy oradjunctive therapy in adults and children 4 years old,and as adjunctive therapy in children 2 years old.Like carbamazepine, oxcarbazepine is also effective insecondarily generalized seizures, but may makemyoclonic and absence seizures worse. Oxcarbazepinehas been as effective as phenytoin, carbamazepine orvalproate in treatment of partial seizures, and may bebetter tolerated. Most of its clinical effect is due to the10-monohydroxy metabolite (MHD), which has a half-life of 8-10 hours.

Other Uses – Oxcarbazepine is used off-label fortreatment 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 ofthe drug and the likelihood of adverse effects. Stevens-Johnson syndrome and toxic epidermal necrolysishave occurred, and multi-organ hypersensitivity reac-tions have been reported. Cross-reactivity with carba-mazepine hypersensitivity occurs in 20-30% ofpatients. Hyponatremia is more common with oxcar-bazepine than with carbamazepine.

13

Drugs for Epilepsy


Drug Interactions – Oxcarbazepine inducesCYP3A4/5 and inhibits CYP2C19. It can increasephenytoin levels by up to 40%. Levels of the activemetabolite are reduced in the presence of enzyme-inducing drugs such as phenobarbital or phenytoin.

PERAMPANEL — Perampanel (Fycompa) wasrecently approved by the FDA as adjunctive treatmentfor partial-onset seizures in patients 12 years old,13-15

but has not yet been marketed in the US. It acts as anantagonist at the AMPA glutamate receptor.

Adverse Effects – The most frequent adverse effectsof perampanel are dizziness and drowsiness. Weightgain, mood change, ataxia, dysarthria, diplopia, verti-go, nausea and fatigue have also been reported. Seriouspsychiatric 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 mayincrease serum concentrations of perampanel andinducers 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 choicebecause of its complicated pharmacokinetics, adverseeffect 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 ofphenytoin available for IV and IM use.

Adverse Effects – Nystagmus may occur with thera-peutic serum concentrations of phenytoin and isusually present at higher concentrations. Drowsiness,ataxia and diplopia are more likely to occur at totalserum concentrations >20 mcg/mL, but can also occurat lower levels, particularly in patients with lowserum albumin levels and in the elderly. Phenytoinmay interfere with cognitive function related tolearning. Cerebellar atrophy has been reported withlong-term use and after acute intoxication. Gingivalhyperplasia, 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, sometimeswith hepatitis, fever and lymphadenopathy; rarely itprogresses to exfoliative dermatitis or Stevens-Johnson syndrome. Asian patients who test positive forHLA-B*1502 may have an increased risk of seriousskin reactions with phenytoin or fosphenytoin. Patientswho develop hypersensitivity reactions to phenytoin

14

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

Less common adverse effects include megaloblasticanemia, a lupus-like syndrome, peripheral neuropathy,nephritis, and hepatitis leading rarely to fatal hepaticnecrosis. 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 injurythan older IV formulations, but at rapid infusion rates itcan cause transient paresthesias and pruritus.

Drug Interactions – Phenytoin is metabolized byCYP2C9 and 2C19; inducers and inhibitors of theseenzymes may affect its serum concentrations. Like car-bamazepine, phenytoin is a strong enzyme inducer; itcan reduce serum concentrations and possibly theeffectiveness of many other drugs, including otherAEDs. It may initially cause an increase in warfarinresponse followed by a reduction in its anticoagulanteffect.

PREGABALIN — Pregabalin (Lyrica, and generics)is FDA-approved for adjunctive treatment of partialseizures in adults.16 Its mechanism of action is similarto that of gabapentin, suggesting it will not be useful inthe treatment of myoclonic seizures.

Other Uses – Pregabalin is also FDA-approved fortreatment of neuropathic pain and fibromyalgia;17 it isapproved in Europe for treatment of generalized anxi-ety disorder.

Adverse Effects – Pregabalin causes somnolence,dizziness, ataxia, weight gain, dry mouth, blurredvision, peripheral edema and confusion. Newly devel-oped myoclonus has been reported in patients withepilepsy taking pregabalin. Pregabalin, like many newantiepileptic drugs, is a schedule V controlled sub-stance due to reports of euphoria.

Drug Interactions – Like gabapentin, pregabalin hasno significant drug-drug interactions.

RUFINAMIDE — Rufinamide (Banzel) is FDA-approved for adjunctive treatment of Lennox-Gastautsyndrome in patients 4 years old.18 It appears to beparticularly effective for treatment of atonic seizures.19

There is also evidence that adjunctive treatment withrufinamide reduces the frequency of partial seizures,but it is not FDA-approved for such use.20

Adverse Effects – The most frequent adverse effects ofrufinamide are somnolence and vomiting. Headache,dizziness, fatigue, nausea, diplopia and tremor have

Drugs for Epilepsy


been reported. Rufinamide can shorten the QT intervalin some patients; it should not be prescribed to patientswith short QT syndrome or to those taking other drugsknown to shorten the QT interval (such as digoxin andmagnesium).

Drug Interactions – Rufinamide is a mild inducer ofCYP3A4. It has been shown to reduce ethinyl estradi-ol, norethindrone and triazolam concentrations, andcould have a similar effect on other drugs metabolizedby CYP3A4.

TOPIRAMATE — Topiramate (Topamax, and gener-ics) is approved for partial and primary generalizedtonic-clonic seizures as monotherapy or adjunctivetherapy in adults and children 2 years old. It is alsoapproved as adjunctive therapy for children 2 yearsold with Lennox-Gastaut syndrome and is effective inatonic seizures in children.

Other Uses – Topiramate is also FDA-approved formigraine 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 effectsof topiramate are drowsiness, dizziness, headache andataxia. Nervousness, confusion, paresthesias, weightloss and diplopia can occur. Psychomotor slowing,word-finding difficulty, impaired concentration, andinterference with memory are common, particularlywith rapid dose escalation and higher maintenancedoses, and may require dosage reduction or stoppingthe drug. Acute myopia associated with secondaryangle closure glaucoma, which is infrequent butsevere, typically occurs within one month of startingtreatment. Liver failure, oligohidrosis, hyperthermiaand heat stroke have been reported. Renal stones haveoccurred due to metabolic acidosis caused by inhibi-tion of carbonic anhydrase.

Drug Interactions – Topiramate is a mild inducer ofCYP3A and an inhibitor of CYP2C19. It can increaseserum lithium levels, particularly at high doses.Carbamazepine and phenytoin decrease topiramateconcentrations. Concomitant use of valproic acid andtopiramate has been associated with hyperammonemiaand hypothermia. Use of topiramate with other car-bonic anhydrase inhibitors such as zonisamide oracetazolamide could increase the severity of metabolicacidosis.

VALPROATE — Valproic acid (Depakene, andgenerics) and divalproex sodium (Depakote, andgenerics) dissociate to valproate in the GI tract.Valproate is approved by the FDA as monotherapy or

adjunctive therapy for complex partial seizures andabsence seizures and as adjunctive therapy for multipleseizure types that involve absence. Because it is effec-tive and usually well tolerated, valproate is widelyused 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 effectivein controlling secondarily generalized seizures. Aonce-daily extended-release formulation (DepakoteER) is as effective as Depakote. It is not bioequivalentto older formulations, so when switching from val-proate capsules or delayed-release tablets to DepakoteER, 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 migraineprophylaxis and bipolar disorder.

Adverse Effects – Drowsiness due to valproate is usu-ally mild and transient, and adverse cognitive effectsare generally minimal. Nausea and vomiting can beminimized by using the enteric-coated formulation(Depakote), by taking the drug with food, and by slowtitration to an optimal dose. Weight gain is common.Use of valproate has been associated with polycysticovary syndrome, hyperinsulinemia, lipid abnormali-ties, hirsutism and menstrual disturbances in women,and with increased serum androgen concentrations inmen. Dose-related tremor, transient hair thinning andloss, decreased platelet function, and thrombocyto-penia can also occur.

Serious adverse effects of the drug are uncommon, butfatal liver failure has occurred, particularly in children<2 years old taking valproate in combination withother AEDs and in patients with developmental delayand metabolic disorders; liver failure has also beenreported in older children and adults taking valproatealone. Valproate can interfere with conversion ofammonia to urea. It can cause lethargy associated withincreased blood ammonia concentrations and fatalhyperammonemic encephalopathy has occurred inpatients with genetic defects in urea metabolism; thedrug is contraindicated in these patients. Life-threaten-ing pancreatitis, interstitial nephritis, reversible parkin-sonism and edema requiring diuretics for control haveoccurred rarely.

Drug Interactions – Valproate has fewer drug interac-tions than carbamazepine or phenytoin. Enzyme induc-ing AEDs increase valproate clearance. Carbapenemantibiotics, such as imipenem, also significantly

15

Drugs for Epilepsy


reduce valproate concentrations. Valproate is a weakenzyme inhibitor; it can increase serum concentrationsof some other AEDs, including carbamazepine, pheny-toin, phenobarbital, ethosuximide, lamotrigine andrufinamide, and tricyclic antidepressants.

VIGABATRIN — Vigabatrin (Sabril) is FDA-approved as monotherapy for infantile spasms and asadd-on therapy for complex partial seizures refractoryto several other AEDs.23 In the US, it is available onlythrough a restricted distribution program calledSHARE (Support, Help, and Resources for Epilepsy)due to concerns about retinal toxicity and permanentvisual field loss. This program requires that prescribersand pharmacists register, and that patients undergomonitoring for visual field loss.

Adverse Effects – The most serious adverse effect ofvigabatrin is concentric peripheral visual field deficit(pVFD) which is potentially irreversible. Patients areusually unaware of the visual field loss, particularly in itsinitial mild phase. Evidence suggests that pVFD is rareduring the first 6 months of treatment; patients without agood response to this therapy should be taken off thedrug within this time. Headache, fatigue, pain, balancedisorder, dizziness, somnolence, depression (includingsuicidality), expressive language disorder, pruritus andweight gain have also been reported.

Drug Interactions – Vigabatrin is not significantlymetabolized. It can lower serum concentrations ofphenytoin by inducing CYP2C9, but it does not induceother 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 havea broad spectrum of activity (infantile spasms,myoclonic, generalized and atypical absence seizures),and there is considerable experience worldwide withits use in children, as monotherapy, and for otherseizure types.

Other Uses – Zonisamide also appears to be effectivefor migraine prophylaxis and for weight loss in obesepatients 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. FatalStevens-Johnson syndrome and toxic epidermal necro-lysis have been reported. Oligohidrosis, hyperthermiaand heat stroke have occurred in children. Psychosis,psychomotor slowing, word-finding difficulty andimpaired concentration can occur. Aplastic anemia and

16

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

Drug Interactions – Zonisamide is metabolized byCYP3A4; drugs that induce or inhibit CYP3A4 couldaffect serum concentrations of zonisamide. Zonisamidedoes not inhibit the metabolism of drugs metabolizedby CYP450 enzymes. Use of zonisamde with other car-bonic anhydrase inhibitors such as topiramate couldincrease the risk of renal stone formation.

OTHER DRUGS — Felbamate (Felbatol) isapproved as monotherapy or adjunctive therapy of par-tial and secondarily generalized seizures, and foradjunctive therapy of seizures associated with theLennox-Gastaut syndrome in patients who have failedother drugs. There is an appreciable risk of aplastic ane-mia and hepatic failure, estimated at about 1:3000-5000patients. Phenobarbital and primidone (Mysoline,and others) are effective for partial and secondarilygeneralized tonic-clonic seizures, but they have a high-er incidence of sedation compared to other drugs.Tiagabine (Gabitril) is approved only for adjunctivetreatment of partial seizures, and is associated with gas-trointestinal and CNS adverse effects. Use innonepileptic patients (for bipolar disorder, anxiety andneuropathic pain) has been associated with develop-ment of new-onset seizures and status epilepticus.26

Rectal administration of diazepam gel (DiastatAcuDial) is approved for intermittent use in the treat-ment of increased seizure activity in patients takingother antiepileptic drugs. When given rectally,diazepam is rapidly and completely absorbed. DiastatAcuDial is supplied as a prefilled syringe with either10 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, 17.5or 20 mg) for single-dose administration by the care-giver. At-home use of rectal diazepam in children mayhelp terminate seizure activity and reduce emergencyroom visits.27

OTHER ISSUES — Suicidality – The FDA reportedin 2008 that a meta-analysis of data from placebo-con-trolled studies of 11 AEDs found an increased risk ofsuicidal behavior and ideation in patients taking thesedrugs: 0.43% of patients on AEDs (n=27,863) com-pared to 0.22% of those on placebo (n=16,029). Theoverall incidence was extremely low, however, and itsclinical significance was questionable. The results of alarge cohort study among patients in the US suggestthat gabapentin, lamotrigine, oxcarbazepine andtiagabine, 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 ofAEDs in patients with epilepsy was not associatedwith an increased risk of suicide-related events, butpatients with depression taking AEDs did have anincreased 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, hasalso been associated with decreases in bone mineraldensity.

AEDs and Oral Contraceptives – Enzyme-inducingAEDs such as carbamazepine, phenytoin, primidone,and phenobarbital, and, to a lesser extent, felbamate,topiramate, oxcarbazepine, rufinamide, clobazam andperampanel, may decrease serum concentrations ofestrogens and/or progestins, possibly resulting in con-traceptive failure.30 Use 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 donot 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 inactive tablets.

AEDs and Pregnancy – AEDs should be used asmonotherapy 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 duringpregnancy.31

Most pregnant patients exposed to antiepileptic drugsdeliver normal infants, but fetal exposure to olderAEDs, particularly valproate and phenobarbital, cancause congenital anomalies, including oral cleft andcardiac, urinary tract and neural tube defects.32

Children exposed to valproate in utero have also beenreported to have lower IQs.33 Available data from preg-nancy registries suggest that use of some newer AEDssuch as lamotrigine, levetiracetam, oxcarbazepine andgabapentin is associated with low rates of major mal-formations.34 Topiramate appears to increase the riskof oral cleft35 and has been associated with hypospa-dias in male infants.

Pregnancy itself tends to induce the metabolism ofAEDs, particularly lamotrigine; monitoring lamotrig-ine serum concentrations may improve seizure con-trol.36 Use of an enzyme-inducing AED such asphenytoin, 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 inthe final month of pregnancy, but whether it reducesthe 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 nowavailable. In general, a generic drug offers a lower-costalternative that is roughly bioequivalent (pharmacoki-netic parameters within 80-125%) to the brand-namedrug. A meta-analysis of randomized controlled trialscomparing use of brand-name and generic forms ofphenytoin, carbamazapine and valproate found no dif-ference in seizure control.38 However, switchingbetween generic products could lead to significant dif-ferences in total and peak serum concentrations.39 Ifpossible, prescription refills should be from the samemanufacturer.

1. E Perucca and T Tomson. The pharmacological treatment of epilepsy inadults. Lancet Neurol 2011; 10:446.

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*1502screening in Taiwan. N Engl J Med 2011; 364:1126.

4. Clobazam (Onfi) for Lennox-Gastaut Syndrome. Med Lett Drugs Ther2012; 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-Gastautsyndrome. Pediatric Neurol 2004; 30:254.

12. J Cavitt and M Privitera. Levetiracetam induces a rapid and sustainedreduction of generalized spike-wave and clinical absence. Arch Neurol2004; 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-onsetseizures: randomized phase III study 304. Neurology 2012; 79:589.

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

16. Pregabalin (Lyrica) for neuropathic pain and epilepsy. Med Lett DrugsTher 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 DrugsTher 2005; 47:9.

17


Drugs for Epilepsy

22. Two new drugs for weight loss. Med Lett Drugs Ther 2012; 54:69.23. Vigabatrin (Sabril) for epilepsy. Med Lett Drugs Ther 2010; 52:14.24. SE Mohammadianenejad et al. Zonisamide versus topiramate in

migraine prophylaxis: a double-blind randomized clinical trial. ClinNeuropharmacol 2011; 34:174.

25. KM Gadde et al. Zonisamide for weight reduction in obese adults: a 1-year randomized controlled trial. Arch Intern Med 2012; 172:1557.

26. CM Flowers et al. Seizure activity and off-label use of tiagabine. NEngl J Med 2006; 354:773.

27. C O’Dell et al. Rectal diazepam gel in the home management ofseizures in children. Pediatr Neurol 2005; 33:166.

28. E Patorno et al. Anticonvulsant medications and the risk of suicide,attempted suicide, or violent death. JAMA 2010; 303:1401.

29. AArana et al. Suicide-related events in patients treated with antiepilep-tic drugs. N Engl J Med 2010; 363:542.

30. DS Reddy. Clinical pharmacokinetic interactions between antiepilepticdrugs and hormonal contraceptives. Expert Rev Clin Pharmacol 2010;3:183.

31. CL Harden et al. Practice parameter update: management issues forwomen with epilepsy–focus on pregnancy (an evidence-based review):teratogenesis and perinatal outcomes: report of the Quality StandardsSubcommittee and Therapeutics and Technology AssessmentSubcommittee of the American Academy of Neurology and AmericanEpilepsy Society. Neurology 2009; 73:133.

32. J Jentink et al. Valproic acid monotherapy in pregnancy and major con-genital malformations. N Engl J Med 2010; 362:2185.

33. KJ Meador et al. Effects of fetal antiepileptic drug exposure: outcomesat age 4.5 years. Neurology 2012; 78:1207.

34. D Mølgaard-Nielsen and A Hviid. Newer-generation antiepilepticdrugs and the risk of major birth defects. JAMA 2011; 305:1996.

35. S Hernández-Diaz et al. Comparative safety of antiepileptic drugs dur-ing pregnancy. Neurology 2012; 78:1692.

36. PB Pennell et al. Lamotrigine in pregnancy: clearance, therapeuticdrug monitoring, and seizure frequency. Neurology 2008; 70:2130.

37. CL Harden et al. Practice parameter update: management issues forwomen with epilepsy–focus on pregnancy (an evidence-based review):vitamin K, folic acid, blood levels, and breastfeeding: report of theQuality Standards Subcommittee and Therapeutics and TechnologyAssessment Subcommittee of the American Academy of Neurologyand American Epilepsy Society. Neurology 2009; 73:142.

38. AS Kesselheim et al. Seizure outcomes following the use of genericversus brand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs 2010; 70:605.

39. GL Krauss et al. Assessing bioequivalence of generic antiepilepsydrugs. Ann Neurol 2011; 70:221.

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1. Drawbacks of carbamazepine include:a. multiple interactions with other drugsb. may make myoclonic seizures worsec. cognitive and other CNS effectsd. all of the above

Issue 126

2. An obese 45-year-old woman with frequent migraines needs adrug to treat partial seizures. Which of the following drugs may beeffective for her seizure disorder and also be helpful in treatingher other conditions?

a. clobazamb. gabapentinc. perampaneld. topiramate

Issue 126

3. Which one of the following drugs is not a good choice for an 8-year-old girl with absence seizures?

a. carbamazepineb. ethosuximidec. lamotrigined. valproic acid

Issue 1264. Gabapentin is used for:

a. partial seizures b. neuropathic painc. restless legs syndromed. all of the above

Issue 126

5. Compared to carbamazepine in elderly patients with newly diag-nosed seizures, lamotrigine has been:

a. less effectiveb. better toleratedc. more effectived. less well tolerated

Issue 126

6. Levetiracetam:a. does not have significant interactions with other drugsb. has a low incidence of cognitive effectsc. is effective for generalized and partial seizuresd. all of the above

7. Phenytoin is no longer considered a drug of choice for partialseizures due to:

a. its complicated pharmacokinetics and dosingb. its adverse effect profilec. frequent drug interactionsd. all of the above

Issue 126

8. Pregabalin:a. is effective in treating myoclonic seizuresb. is used to treat fibromyalgiac. interacts with many other drugsd. none of the above

Issue 126

9. Caution is advised if rufinamide is taken with other drugs that:a. increase serum serotonin levelsb. are sympathomimeticc. affect hepatic transaminasesd. shorten the QT interval

Issue 126

10. Valproate is:a. safe in pregnancyb. not available genericallyc. effective and usually well toleratedd. none of the above

Issue 126

11. Many antiepileptic drugs can induce the metabolism of oral hor-monal contraceptives, reducing their efficacy. Which of the follow-ing antiepileptic drugs would be the safest choice in a woman tak-ing an oral contraceptive?

a. carbamazepineb. levetiracetamc. perampaneld. topiramate

Issue 126

12. Most pregnant patients exposed to antiepileptic drugs duringpregnancy deliver normal infants, but major malformations canoccur. The highest risk appears to be with:

a. valproate and phenobarbitalb. carbamazepine and phenytoinc. lamotrigine and carbamazepined. phenytoin and lamotrigine

Issue 126

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