Gabapentin, lamotrigine, felbamate, topiramate and fosphenytoin

Newer antiepileptic drugs: gabapentin, lamotrigine, felbamate, topiramate and fosphenytoin

William J. Curry

Newer antiepileptic drugs may

control seizures more effectively,

but their significant

potential for serious side

effects requires a thorough

knowledge of the drugs and careful

consideration of the risks and benefits.

Gabapentin

Gabapentin (Neurontin) has been approved

as adjunctive therapy in adults with partial

seizures with or without secondary generalization

(Table 1). A gamma-aminobutyric acid

(GABA) analog, gabapentin does not interact

with GABA receptors. Its mechanism of action is

unknown.

TABLE 1

Comparison of Newer anticonvulsant Drugs

Anticonvulsant Indication Age

Gabapentin Adjunctive therapy for [is greater than] 12

(Neurontin) practical seizures with years

or without secondary

generalization

Lamotrigine Adjunctive therapy for [is greater than] 16

(Lamictal) partial seizures with years

or without secondary

generalization

Felbamate Adjunctive therapy or [is greater than] 14

(Felbatol) monotherapy in adults years for adults;

when seizures are so 2 to 14 years for

severe as to warrant use children

despite risk of aplastic

anemia or hepatic

failure; in children

with Lennox-Gastaut

syndrome when seizures

are not controlled

Topiramate Adjunctive therapy for [is greater than] 16

(Topamax) partial onset of seizures years

Fosphenytoin Status epilepticus;

(Cerebyx) parenteral maintenance of

phenytoin levels;

parenteral treatment

and/or prevention of

seizures

Anticonvulsant Dosing range Availability

Gabapentin Begin with 300 mg daily; 100-mg, 300-mg

(Neurontin) increase to 900 to 1,800 and 400-mg

mg daily given every 6 capsules

to 8 hours

Lamotrigine Begin with 50 mg daily; 25-mg, 100-mg,

(Lamictal) increase to 300 to 500 150-mg and

mg daily given every 12 200-mg scored

hours; for concomitant tablets

use with valproic acid

(Depakene): begin with

25 mg every other day;

increase to 150 mg daily

given every 12 hours

Felbamate Adults: begin with 1,200 400-mg and

(Felbatol) mg daily given every 6 600-mg scored

to 8 hours tablets; 600 mg

per 5-mL

suspension

Children: 15 to 45 mg

per kg per day given

every 6 to 8 hours

Topiramate Begin with 50 mg daily; 25-mg, 100-mg

(Topamax) increase to 50 to 400 and 200-mg

mg daily given every caplets

12 hours

Fosphenytoin For status epilepticus: 2-mL vials

(Cerebyx) 22.5 to 30 mg per kg IV (150 mg); 10-mL

vials (750 mg)

For nonemergent therapy:

15 to 30 mg per kg IV or

IM, followed by 6 to

12 mg per kg IV or IM

for maintenance therapy

Anticonvulsant Side effects

Gabapentin Somnolence, fatigue, ataxia,

(Neurontin) dizziness, gastrointestinal

upset, dyspnea

Lamotrigine Rash, including life-threatening

(Lamictal) rashes, dizziness, ataxia,

blurred vision, nausea

Felbamate Anorexia, vomiting,

(Felbatol) insomnia, somnolence,

aplastic anemia,

hepatotoxicity

Topiramate Dizziness, somnolence,

(Topamax) ataxia, confusion, fatigue,

paresthesias, speech

difficulties, diplopia,

impaired concentration

and nausea

Fosphenytoin Pruritus, nystagmus,

(Cerebyx) dizziness, somnolence,

ataxia, nausea,

tinnitus, hypotension,

and groin discomfort

with infusion

and 400-mg capsules[3] (Table 1). The average

cost of 30 days of treatment at the lowest

recommended dosage is approximately $88.[6]

Gabapentin may be used as adjunctive therapy

in adults with poorly controlled partial seizures.

In the future, gabapentin may become first-line

therapy in patients with newly diagnosed

epilepsy. At present, it has not been approved by

the US. Food and Drug Administration for use

in children. Gabapentin is easy to use and has

relatively mild side effects. Lack of drug-drug

interactions make it an attractive therapy.

Lamotrigine

Lamotrigine (Lamictal) is included in the

phenyltriazine class. It is used as adjunctive

therapy or monotherapy in adults with partial

seizures with or without secondary generalization.

The mechanism of action is unknown.

Lamotrigine has been shown to act at

voltage-sensitive sodium channels, stabilizing

neural membranes and inhibiting the release

of excitatory neural transmitters.[2]

Lamotrigine is well absorbed orally, with up

to 98 percent bioavailability. Absorption is not

affected by food. Approximately 55 percent of

the drug is protein bound; therefore, clinical

interaction with other protein-bound drugs is

unlikely. Ninety percent of the drug undergoes

glucuronic acid conjugation in the liver,

with the conjugate and the remaining 10 percent

of unmetabolized drug excreted in the

urine.[7] Clearance is markedly increased by the

co-administration of other antiepileptic drugs

that induce hepatic enzymes. These include

carbamazepine (Tegretol), phenobarbital,

phenytoin (Dilantin) and primidone (Mysoline).

The half-life of lamotrigine may be

reduced by about 50 percent with concomitant

use of one or more of these medications

(Tables 2 and 3). However, when combined

with valproic acid, its elimination is decreased,

and its half-life may be more than doubled.

TABLE 3

Effects of Standard Anticonvulsants on Drug Levels of Newer

Anticonvulsants

Standard anticonvulsants

Newer anticonvulsants Phenytoin (Dilantin) Valproic acid

(Depakene)

Gabapentin (Neurontin) — —

Lamotrigine (Lamictal) Decreased 50% Increased 100%

Felbamate (Felbatol) Decreased 40% —

Topiramate (Topamax) Decreased 48% Decreased 14%

Fosphenytoin (Cerebyx) Slight increase No data

Standard anticonvulsants

Newer anticonvulsants Carbamazepine Phenobarbital

(Tegretol)

Gabapentin (Neurontin) — —

Lamotrigine (Lamictal) Decreased 40% Decreased 40%

Felbamate (Felbatol) Decreased 40% No data

Topiramate (Topamax) Decreased 40% No data

Fosphenytoin (Cerebyx) — Slight increase

patients taking felbamate will have aplastic

anemia. The fatality rate of this complication

approaches 30 percent. Aplastic anemia

may not manifest itself until several months

after initiation of treatment, and patients

may remain at risk for an undetermined

amount of time after treatment is discontinued.

The syndrome may begin without

warning and may not be reliably detected by

routine testing. Patients taking felbamate

should remain alert for signs of infection,

bleeding and easy bruising, or symptoms of

anemia such as fatigue or weakness.[1,8]

Hepatotoxicity leading to hepatic failure is

estimated to occur in one in every 24,000 to

34,000 patients taking felbamate. Felbamate

should not be used in patients with a history

of hepatic dysfunction.[1,8]

The need for monitoring drug levels has not

been established. However, baseline laboratory

testing should include a complete blood

count, platelet count and reticulocyte count,

as well as determination of liver enzyme levels.

Hematologic evaluations should be performed

frequently during treatment and after

discontinuation of treatment. Liver enzyme

levels should be determined every one to two

weeks, and felbamate therapy should be

discontinued if the aspartate aminotransferase,

alanine aminotransferase or bilirubin levels

increase above baseline.

Because of serious side effects, felbamate is

not recommended as first-line therapy in the

treatment of seizures. The manufacturer recommends

its use only in patients who do not

adequately respond to alternative therapy and

whose epilepsy is so severe that the substantial

risks of aplastic anemia and hepatic failure are

deemed acceptable.[8] Its use requires that the

physician be thoroughly familiar with the

drug. The manufacturer recommends that

written consent be obtained before initiation

of therapy.

Monotherapy in adults should begin with

1,200 mg of felbamate daily, given in divided

doses every six to eight hours. Daily dosages

should increase by 600 mg every two weeks to

a total daily dosage of 2,400 to 3,600 mg. As

adjunctive therapy, treatment should begin at

1,200 mg daily, given in divided doses every

six to eight hours. If the patient is taking

phenytoin, valproic acid or carbamazepine, a

20 to 35 percent reduction in the dosage of

these drugs is recommended during felbamate

therapy. Levels of antiepileptic drugs should

be followed as the dosage of felbamate is

increased to 2,400 to 3,600 mg daily.

The beginning dosage of felbamate in children

aged two to 14 years with Lennox-Gastaut

syndrome is 15 mg per kg, given in three

to four divided doses. Dosages of other

antiepileptic drugs should be reduced by 20

percent, with further reductions based on side

effects or drug levels. The daily dosage of

felbamate should increase by 15 mg per kg

weekly, to a maximum of 45 mg per kg.[9]

Felbamate is available in 400-mg and 600-mg

tablets, and as a suspension of 600 mg per

5 mL (Table 1). The cost of one month o

treatment at the lowest recommended maintenance

dosage is approximately $52.[6]

Topiramate

Topiramate (Topamax) has been approved

for adjunctive treatment in adults with partial

seizures. It has a novel chemical structure

derived from D-fructose that blocks voltage-sensitive

sodium channels, enhances the activity

of GABA, an inhibitory neurotransmitter,

and blocks the action of glutamate, an excitatory

neurotransmitter. It is also a weak carbonic

anhydrase inhibitor.[11]

Topiramate is well absorbed orally with a

bioavailability of 80 percent. It is less than 20

percent protein bound. When used alone, 20

percent of the drug is metabolized. With

concurrent use of other antiepileptic drugs, 50

percent of the drug is metabolized. Excretion

is primarily renal, with 50 to 80 percent of

each dose excreted unchanged. The half-life is

20 to 30 hours.

A 30 percent and 48 percent median reduction

in seizure frequency occurs at dosages of

200 mg and 400 mg per day, respectively. No

improvement in seizure reduction occurs at

dosages above 400 Mg.[12] The only known

contraindication is hypersensitivity to the drug.

Side effects include dizziness and somnolence

(which are not dose related), ataxia, impaired

concentration, confusion, fatigue, paresthesias,

speech difficulties, diplopia and nausea.[13]

There is an increased risk of nephrolithiasis,

which may be due to carbonic anhydrase inhibition.[14]

Concomitant use of topiramate with

other carbonic anhydrase inhibitors such as

dichlorphenamide (Daranide) or acetazolamide

(Diamox) should be avoided.

Topiramate increases phenytoin concentration

by 25 percent and decreases valproic acid

concentration by 11 percent (Table 2). Topiramate

does not change the concentration of

carbamazepine, phenobarbital or primidone

when coadministered. Concentrations of topiramate

decrease up to 48 percent when

phenytoin is coadministered, up to 40 percent

with coadministration of carbamazepine and

up to 14 percent with valproic acid.

Topiramate is classified as a category C

medication during pregnancy. It is not known

if it is excreted in human breast milk.

Overdoses have been managed to date with

prompt induction of emesis or lavage. Topiramate

is effectively removed by hemodialysis.

The starting dosage is 50 mg per day given

in the evening, increasing by 50 mg per week

until a dosage of 200 mg given twice daily is

reached. It is not necessary to monitor drug

levels. Dosing beyond 400 mg per day does

not increase efficacy. Topiramate can be taken

with food, if desired. Patients with impaired

renal function should use one half the recommended

dosage.

Topiramate is available in 25-mg, 100-mg

and 200-mg coated tablets. The cost of one

month’s therapy at 400 mg per day is approximately

$181.[6]

Fosphenytoin

Fosphenytoin (Cerebyx) is a phenytoin

precursor that is rapidly converted after

parenteral administration. It is indicated for

short-term parenteral use when the oral form

is unavailable or less advantageous.[15] In

addition to its use as a short-term substitute for

oral phenytoin, fosphenytoin can be used to

control status epilepticus and to prevent and

control seizures during neurosurgery.

The use of parenteral phenytoin is complicated

by poor solubility, high alkalinity,

hypotension, cardiac arrhythmias and the

potential for soft tissue injury with extravasation.

However, fosphenytoin can be administered

intravenously or intramuscularly with a

low risk of tissue irritation. No significant

electrocardiographic changes have been noted

with either intravenous or intramuscular

administration. Mild decrements in mean systolic

blood pressure have been reported with

intravenous administration.

Therapeutic serum levels of phenytoin are

attained within 10 minutes of infusion of

intravenous fosphenytoin.[16] Peak serum

phenytoin levels are attained 90 minutes after

intramuscular administration. Fosphenytoin

administered intravenously or intramuscularly

is 100 percent bioavailable and is 90 to 95

percent protein bound. A 15-mg dose of

fosphenytoin is equivalent to 1 mg of phenytoin.

Fosphenytoin i6 contraindicated in patients

with hypersensitivity to phenytoin or other

hydantoins, and in patients with sinoatrial

block, second- and third-degree atrioventricular

block and Stokes’-Adams syndrome.[13]

Common adverse effects include pruritus,

nystagmus, dizziness, somnolence, ataxia,

nausea, tinnitus and hypotension. Up to 64

percent of patients experience groin discomfort

on intravenous administration, which

usually dissipates within 60 minutes.

Concomitant use with carbamazepine or

diazepam (Valium) has shown no effect on

fosphenytoin binding. Fosphenytoin binding

did decrease in patients with excessive

concentrations of phenobarbital or valproic acid.

For patients with status epilepticus, 22.5 to

30 mg per kg of fosphenytoin should be

administered intravenously at a rate of 100 to

150 mg per minute. For nonemergent therapy

or to prevent seizures, 15 to 30 mg per kg can

be administered intravenously or intramuscularly

in a loading dose, followed by a daily

maintenance dosage of 6 to 12 mg per kg.

Patients who are already at therapeutic levels

of oral phenytoin can be given fosphenytoin at

1.5 times the daily oral phenytoin dose. The

approximate cost of a 10-mL vial of 750 mg of

fosphenytoin is $54.[6]

The authors thank John Y. Oh, M.D., and Robert L.

Jones, D. Ed., for review of the manuscript.

REFERENCES

[1.] Dichter MA, Brodie MJ. New antiepileptic drugs. N

Engl J Med 1996;334:1583-90.

[2.] Ramsay RE. Advances in the pharmacotherapy of

epilepsy. Epilepsia 1993;34(Suppl 5):S9-16.

[3.] Gabapentin. Package insert. Morris Plains, N.J.:

Parke-Davis, December 1994.

[4.] Laxer KD. Guidelines for treating epilepsy in the

age of felbamate, vigabatrin, lamotrigine, and

gabapentin. West J Med 1994; 161:309-14.

[5.] Rosner H, Rubin L, Kestenbaum A. Gabapentin

adjunctive therapy in neuropathic pain states. Clin

J Pain 1996;12:56-8.

[6.] Red book. Montvale, N.J.: Medical Economics

Data, 1997.

[7.] Lamotrigine. Package insert. Research Triangle

Park, N.C.: Glaxo Wellcome Inc., March 1997.

[8.] Palmer KJ, McTavish D. Felbamate. A review of its

pharmacodynamic and phamacokinetic properties,

and therapeutic efficacy in epilepsy. Drugs 1993;

45(6):1041-65.

[9.] Jensen PK. Felbamate in the treatment of refractory

partial-onset seizures. Epilepsia 1993;34(Suppl

7):S25-9.

[10.] Felbamate. Package insert. Cranbury, N.J.: Wallace

Laboratories, November 1995.

[11.] Medical Science Bulletin 1997;20(236):1.

[12.] Faught E, Wilder BJ, Ramsay RE, Reife RA, Kramer

LID, Pledger GW, et al. Topiramate placebo-controlled

dose-ranging trial in refractory partial epilepsy using

200-, 400- and 600-mg daily dosages. Neurology

1996;46:1684-90.

[13.] Olin B, ed. Drug facts and comparisions. St. Louis:

Facts and Comparisons, Inc., 1997:283u-y.

[14.] Shorvon SD. Safety of topiramate: adverse events

and relationships to dosing. Epilepsia 1996;37

(Suppl 2):18-22.

[15.] Fosphenytoin. Package insert. Morris Plains, N.J.:

Parke-Davis, 1996.

[16.] Allen FH Jr, LeGarda S, et al. Safety, tolerance, and

pharmacokinetics of intravenous fosphenytoin

(Cerebyx) in status epilepticus [Abstract]. Epilepsia

1995;36(Suppl 4):90.

WILLIAM J. CURRY, M.D., is co-medical director of Pennsylvania State Family

Health, Middletown, and assistant professor in the Department of Family and

Community Medicine at the Milton S. Hershey Medical Center, Hershey, Pa. He

received his medical degree from Pennsylvania State University College of

Medicine, Hershey, and completed a residency in family practice at the U.S.

Air Force Regional Hospital Eglin, Eglin Air Force Base, Fla.

DAVID L. KULLING, M.D., is assistant professor in the Department of Family

and Community Medicine and the Department of Orthopaedics and Rehabilitation

at the Milton S. Hershey Medical Center. He graduated from the Muntch

University of Technology and completed a residency in family practice at the

Allegheny Family Physicians Residency Program of the Altoona (Pa.) Hospital.

He also completed a primary care sports medicine fellowship at the University

of Michigan Medical School, Ann Arbor. He holds certificates of added

qualification in geriatric medicine and sports medicine.

Address correspondence to David L. Kulling, M.D., Pennsylvania State

University, Milton S. Hershey Medical Center Department of Family and

Community Medicine, PO. Box 850, Hershey PA 17033-0850. Reprints are not

available from the authors.

Richard W. Sloan,

M.D., R.PH.,

coordinator of this

series, is chairman

and residency

program director

of the Department

of Family Medicine at

York (Pa.) Hospital

and clinical associate

professor in family

and community

medicine at the

Milton S. Hershey

Medical Center,

Pennsylvania State

University, Hershey, Pa.

COPYRIGHT 1998 American Academy of Family Physicians

COPYRIGHT 2008 Gale, Cengage Learning