In July 1993, felbamate (Felbatol) originally was approved by the US Food and Drug Administration (FDA) for use as monotherapy or in combination with other anticonvulsant agents in the management of partial seizures with or without secondary generalization in adults. Felbamate also was approved by FDA at that time for use in combination with other anticonvulsant agents in the management of partial and generalized seizures associated with Lennox-Gastaut syndrome in children and has been designated an orphan drug by FDA for the treatment of this latter syndrome. However, because use of the drug has since been associated with marked increases in the incidences of aplastic anemia and acute hepatic failure, the manufacturer in conjunction with FDA warns that the drug should only be initiated or continued in the management of such seizures when, in the clinician's judgment, the patient's seizure disorder is refractory to alternative safer therapy and is so severe that the benefits of felbamate therapy are believed to outweigh the possible risk of aplastic anemia or acute hepatic failure. For patients already receiving the drug, the likelihood that abrupt withdrawal would pose an even greater risk than that of possible felbamate-associated aplastic anemia or acute hepatic failure also should be considered in the decision to discontinue therapy with the drug. Decisions about the potential benefits and risks of felbamate therapy generally should be made in consultation with appropriate hematologic and hepatic disease experts.
The manufacturer has notified pharmacists that felbamate is not being recalled and may continue to be dispensed in response to a bona fide physician prescription. The manufacturer states that felbamate will continue to be available in the US for those patients with severe, refractory seizure disorders in whom, in the opinion of the clinician, benefits of the drug outweigh the potential risk for aplastic anemia and hepatic failure. However, clinicians should prescribe felbamate only if therapy with the drug is absolutely necessary. Therapy with felbamate should be initiated or continued only after the risks associated with use of the drug have been discussed completely with the patient, parent, or guardian and written informed consent has been obtained; patient information/consent forms for felbamate may be obtained from the manufacturer or by photocopy reproduction of the form included in the manufacturer's labeling.
Clinicians and pharmacists interested in further information on felbamate should contact Meda Pharmaceuticals at 800-526-3840. All cases of aplastic anemia or acute hepatic failure associated with felbamate therapy should be reported promptly to Meda Pharmaceuticals at 800-526-3840 or to the FDA MedWatch program by phone (800-FDA-1088), by fax (800-FDA-0178), by the internet (http://www.fda.gov/Safety/MedWatch/), or by mail (MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787).
Although the comparative efficacy of therapeutically effective dosages remains to be established, the anticonvulsant potential of felbamate in patients with partial seizures with or without secondary generalization has been established in studies comparing therapeutic dosages of felbamate with relatively low dosages of valproic acid. In 2 such studies, adult patients with partial seizures were randomly assigned to receive either felbamate up to 3.6 g daily administered in 4 divided doses or valproic acid 15 mg/kg daily during a 112-day treatment period. Both studies were designed only to demonstrate the anticonvulsant activity of felbamate monotherapy using low-dosage valproate as a control; this study design, described as a low-dose active-control trial, is intended to avoid the interpretational difficulties of no-difference (i.e., equivalent) therapeutic outcomes in studies of investigational anticonvulsant agents and therefore is not intended to determine comparative efficacy. The primary variable used to measure anticonvulsant activity was the number of patients in each group who met at least one of the following escape criteria and consequently exited the study: (1) a twofold increase in average monthly seizure frequency, (2) a twofold increase in the highest 2-day seizure frequency, (3) a single generalized tonic-clonic seizure if none occurred during the baseline period, or (4) a prolongation of generalized seizure duration (serial seizures or status epilepticus) deemed by the investigator to require intervention. In these studies, 14-40% of patients receiving felbamate met escape criteria and exited the study compared with 78-90% of patients receiving low-dosage valproic acid, indicating that felbamate alone has anticonvulsant activity in patients with partial seizures; however, because of study design, no conclusions regarding comparative efficacy with valproic acid can be made.
Felbamate also may potentiate the anticonvulsant activity of other agents in the management of refractory partial seizures. In a double-blind, placebo-controlled crossover trial, patients with refractory partial seizures who received felbamate administered concomitantly with phenytoin and carbamazepine had fewer seizures during each treatment sequence than patients who received placebo with phenytoin and carbamazepine. However, in a 3-period, crossover study of patients with complex partial seizures receiving carbamazepine in combination with either felbamate (usually 3 g daily) or placebo, felbamate-induced reductions in plasma concentrations of carbamazepine were believed to have contributed to the lack of effect of the drug on seizure frequency. Among patients who underwent reduction or discontinuance of a standard regimen of anticonvulsant therapy during evaluation for surgery of an intractable seizure disorder, those who subsequently received concomitant felbamate had greater time to onset of fourth seizure than patients who received placebo.
In children with Lennox-Gastaut syndrome, maximum tolerated dosage of felbamate (up to 45 mg/kg [not exceeding 3.6 g] daily) has reduced the frequency of atonic seizures, generalized tonic-clonic seizures, and total seizures when added to the patient's standard regimen of anticonvulsant therapy. Improvements in quality-of-life parameters (increased alertness and verbal responsiveness) also have been reported by parents or guardians in such children.
The efficacy of monotherapy or combination therapy with felbamate for the management of partial seizures and Lennox-Gastaut syndrome reportedly is not influenced by patient gender.