Am Fam Physician. 1998;57(3):513-520
Twenty-five to 40 percent of patients with epilepsy continue to have seizures despite optimal treatment with traditional antiepileptic drugs. Treatment with standard anticonvulsants such as phenytoin, carbamazepine, valproic acid and phenobarbital is often complicated by side effects and by failure to adequately control seizures. Up to 61 percent of patients with seizures report having side effects with antiepileptic drugs. After a 15-year hiatus since the last new antiepileptic drug was marketed, five new drugs have been approved by the U.S. Food and Drug Administration for the control of seizures. Three of these, gabapentin, lamotrigine and topiramate, are approved for use in adults with partial seizures with or without generalization. Felbamate is approved for the above indication and also for use in children with Lennox-Gastaut syndrome, a rare childhood seizure disorder. Felbamate and lamotrigine have the potential of significant side effects and should be prescribed by physicians experienced in managing patients with complicated epilepsy. Fosphenytoin is a parenteral prodrug of phenytoin that is more tolerable than parenteral phenytoin.
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 (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.
|Anticonvulsant||Indication||Age||Dosing range||Availability||Side effects|
|Gabapentin (Neurontin)||Adjunctive therapy for partial seizures with or without secondary generalization||>12 years||Begin with 300 mg daily; increase to 900 to 1,800 mg daily given every 6 to 8 hours||100-mg, 300-mg and 400-mg capsules||Somnolence, fatigue, ataxia, dizziness, gastrointestinal upset, dyspnea|
|Lamotrigine (Lamictal)||Adjunctive therapy for partial seizures with or without secondary generalization||>16 years||Begin with 50 mg daily; increase to 300 to 500 mg daily given every 12 hours; for concomitant use with valproic acid (Depakene): begin with 25 mg every other day; increase to 150 mg daily given every 12 hours||25-mg, 100-mg, 150-mg and 200-mg scored tablets||Rash, including life-threatening rashes, dizziness, ataxia, blurred vision, nausea|
|Felbamate (Felbatol)||Adjunctive therapy or monotherapy in adults when seizures are so severe as to warrant use despite risk of aplastic anemia or hepatic failure; in children with Lennox-Gastaut syndrome when seizures are not controlled||>14 years for adults; 2 to 14 years for children||Adults: begin with 1,200 mg daily given every 6 to 8 hours||400-mg and 600-mg scored tablets; 600 mg per 5-mL suspension||Anorexia, vomiting, insomnia, somnolence, aplastic anemia, hepatotoxicity|
|Children: 15 to 45 mg per kg per day given every 6 to 8 hours|
|Topiramate (Topamax)||Adjunctive therapy for partial onset of seizures||>16 years||Begin with 50 mg daily; increase to 50 to 400 mg daily given every 12 hours||25-mg, 100-mg and 200-mg caplets||Dizziness, somnolence, ataxia, confusion, fatigue, paresthesias, speech difficulities, diplopia, impaired concentration and nausea|
|Fosphenytoin (Cerebyx)||Status epilepticus; parenteral maintenance of phenytoin levels; parenteral treatment and/or prevention of seizures||For status epilepticus: 22.5 to 30 mg per kg IV||2-mL vials (150 mg); 10-mL vials (750 mg)||Pruritus, nystagmus, dizziness, somnolence, ataxia, nausea, tinnitus, hypotension, and groin discomfort with infusion|
|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|
Gabapentin is well absorbed orally, circulates mostly unbound in the plasma and is excreted unchanged in the kidneys without appreciable metabolism in the body. Oral bioavailability is approximately 60 percent and is not affected by food. The half-life is five to seven hours and is related to the creatinine clearance. Therefore, excretion is decreased in patients with renal impairment and decreased cardiac function, and in elderly patients.1 Gabapentin can be removed from the system through hemodialysis.
In clinical studies,2 gabapentin was found to be effective in adults with refractory partial seizures and was also effective in preventing the progression of partial seizures to generalized tonic-clonic seizures.
Because gabapentin has no known pharmacokinetic interactions with any other antiepileptic drugs, it is useful in patients taking other antiepileptic medication.
The only known contraindication to gabapentin is hypersensitivity to the drug. As with any antiepileptic drug, withdrawal should be gradual, performed over a minimum of one week to minimize the risk of withdrawal seizures and status epilepticus. Side effects include somnolence, fatigue, ataxia, dizziness, gastrointestinal upset, dyspnea and a sense of well-being.3 Patients should be counseled that these effects could impair driving and the ability to safely operate complex machinery. Use of alcohol can magnify these effects.
Gabapentin has shown no effect on phenytoin (Dilantin), carbamazepine (Tegretol), valproic acid (Depakene) and phenobarbital levels (Table 2). No clinically important interaction has been demonstrated with oral contraceptives. However, when taken concurrently with antacids, the bioavailability of gabapentin is reduced by 20 percent. We recommend allowing two hours to elapse after using antacids and before taking gabapentin. Gabapentin may also cause a urine dipstick test to show a false-positive result for protein.
|Standard anticonvulsants||Newer anticonvulsants|
|Gabapentin (Neurontin)||Lamotrigine (Lamictal)||Felbamate (Felbatol)||Topiramate (Topamax)||Fosphenytoin (Cerebyx)|
|Phenytoin (Dilantin)||—||—||Increased 25%||— or increased 25%||—|
|Valproic acid (Depakene)||—||Decreased 25%||Increased 40%||Decreased 11%||—|
|Carbamazepine (Tegretol)||—||—||Decreased 30%||—||—|
|Carbamazepine epoxide||—||—||Increased 55%||—||—|
High doses of gabapentin have caused pancreatic acinar cell carcinoma in laboratory rats; however, in humans, pancreatic carcinoma is usually ductal in origin.4 Increased rates of pancreatic tumor occurrence have not been reported in patients using gabapentin, although data to date are limited.
Overdoses of 15 times the usual daily dose have resulted in diplopia, slurred speech, drowsiness, lethargy and diarrhea. In all reports of overdose, the patients recovered with supportive care. If necessary, overdose can be treated with hemodialysis.
Gabapentin has been shown to be toxic to the fetus in laboratory rats and is, thus, considered a category C medication during pregnancy. It should be used during pregnancy only if the potential benefit justifies the potential risks. It is not known whether gabapentin is excreted into breast milk.
Gabapentin has been found to be useful in the treatment of neuropathic pain. It is effective in decreasing intractable pain at antiepileptic dosages with minimal side effects and minimal drug interactions,5 although it currently is not officially indicated for this use.
The usual dosage is 900 to 1,800 mg daily, divided into three doses. Dosing should begin with 300 mg daily and increase by an additional 300 mg every one to three days.1 Dosages up to 3,600 mg have been given. The dosage should be adjusted according to creatinine clearance.
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 U.S. 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 (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.
|Newer anticonvulsants||Standard anticonvulsants|
|Phenytoin (Dilantin)||Valproic acid (Depakene)||Carbamazepine (Tegretol)||Phenobarbital|
|Lamotrigine (Lamictal)||Decreased 50%||Increased 100%||Decreased 40%||Decreased 40%|
|Felbamate (Felbatol)||Decreased 40%||—||Decreased 40%||No data|
|Topiramate (Topamax)||Decreased 48%||Decreased 14%||Decreased 40%||No data|
|Fosphenytoin (Cerebyx)||Slight increase||No data||—||Slight increase|
Lamotrigine does not impair cognition and has a relatively broad spectrum of activity against multiple types of seizures. Three multicenter clinical studies have demonstrated its efficacy as adjunctive therapy in adults with refractory partial seizures.2
The only contraindication to lamotrigine is hypersensitivity to the drug. The need for monitoring drug levels has not been established. The most frequently encountered adverse reactions include dizziness, ataxia, somnolence, headache, blurred vision, nausea, vomiting and rash. Up to 10 percent of patients discontinue lamotrigine therapy because of side effects. One case of acute hepatic failure has been reported. Because lamotrigine depresses the central nervous system, patients who are taking it should be cautioned about driving or operating complex machinery.
A macular, papular or erythematous rash may develop in approximately 10 percent of patients during the first four to six weeks of treatment with lamotrigine. Although the rash often resolves with continued use, it may sometimes be indicative of serious systemic involvement. The occurrence of a rash or systemic symptoms such as fever or lymphadenopathy necessitates prompt discontinuation of the drug and medical evaluation. One in every 1,000 adults treated with lamotrigine develops severe, life-threatening rashes such as Stevens-Johnson syndrome, toxic epidermal necrolysis and angioedema with fever, facial swelling and lymphadenopathy. This risk is increased more than threefold with co-administration of valproic acid.
In children, the risk of developing a life-threatening rash is one in 50. Hence, use of lamotrigine is not indicated in children under 16 years of age.7 The risk of rash may increase if lamotrigine is given at higher than recommended dosages or if initial dosing is accelerated over recommendations provided by the manufacturer.2
Because of the potential for severe life-threatening skin reactions, the FDA has required that the manufacturer of lamotrigine publish a special warning on the label of this product.
There is a risk of withdrawal seizures if therapy is discontinued abruptly; thus, gradual tapering of the medication over a two-week period is recommended. Caution is advised in patients with conditions that could affect elimination such as renal or hepatic impairment or the co-administration of valproic acid. Dosage reduction is mandated in patients with significant renal impairment.
Lamotrigine binds to melanin-containing tissues such as the iris of the eye, but the long-term effects of this binding and accumulation are unknown. Use in pregnant patients is recommended only if the benefit outweighs the potential risks. Lamotrigine is classified as a category C medication during pregnancy. A registry of pregnant patients using lamotrigine is maintained by the manufacturer. The drug is found in breast milk; thus nursing is not recommended during treatment. Lamotrigine is contraindicated for use in patients under the age of 16 because of the increased risk of developing a life-threatening rash.
Overdoses of up to 10 times the usual daily dosage have been reported. Recovery occurred with supportive care. There is no specific antidote.
The starting dosage in patients who are not taking valproic acid should be 50 mg daily for two weeks, increasing to 50 mg twice daily for an additional two weeks, and then increasing by 100 mg per day weekly to a maintenance level of 150 to 250 mg twice daily.2
In patients who are taking valproic acid plus other anticonvulsant drugs that induce hepatic enzymes, the initial starting dosage should be reduced to 25 mg every other day for two weeks, then increased to 25 mg daily for two weeks. The dosage may be increased by 25 to 50 mg daily every one to two weeks up to a maximum of 75 mg twice daily.
Felbamate (Felbatol) is approved for adjunctive or monotherapy in adults with partial seizures with or without secondary generalization. It is also approved for use in children with Lennox-Gastaut syndrome, a childhood disorder with multiple seizure types, slow spike-wave electroencephalograms, mental retardation and resistance to standard therapy with antiepileptic drugs. The mechanism of action is not known, but it has been shown to have weak inhibitory effects on GABA receptor binding sites. Because of serious potential toxicity, felbamate should be reserved for rare, compassionate use by physicians experienced in treating patients with epilepsy that is difficult to control.
Felbamate is absorbed well orally with bioavailability greater than 90 percent. Absorption is not affected by food.8 Metabolism occurs by the hepatic cytochrome P450 system, but 40 to 50 percent of the drug is excreted unchanged in the urine. Felbamate affects the steady-state concentrations of other antiepileptic drugs that depend on hepatic metabolism. The addition of felbamate increases the levels of phenytoin and valproic acid and decreases the levels of carbamazepine while concurrently increasing its epoxide concentration (Table 2). The addition of phenytoin or carbamazepine reduces felbamate levels by 40 percent (Table 3). Because felbamate is only 25 percent protein bound, minimal binding effects occur with protein-bound drugs.9
Felbamate is also considered a category C medication during pregnancy. Because it is found in breast milk, breast feeding is not recommended for patients taking felbamate. Pediatric use is approved only for adjunctive therapy in children with Lennox-Gastaut syndrome.
The most common side effects include anorexia, vomiting, insomnia, nausea, headache, dizziness and somnolence.10 One overdose has been reported. The patient improved with supportive care. Clinical effects of overdose included epigastric distress and tachycardia.
After initial marketing of the drug, two very serious toxic effects appeared: aplastic anemia and hepatic failure. The risk of aplastic anemia in patients taking felbamate is 100 times greater than it is in the general population. One in every 3,600 to 5,000 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
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-Gas-taut 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
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 top-iramate 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 (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 1.5-mg dose of fosphenytoin is equivalent to 1 mg of phenytoin.
Fosphenytoin is 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