Mechanism of Action: 

The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test systems designed to detect anticonvulsant activity, felbamate has properties in common with other marketed anticonvulsants. Felbamate is effective in mice and rats in the maximal electroshock test, the subcutaneous pentylenetetrazol seizure test, and the subcutaneous picrotoxin seizure test. Felbamate also exhibits anticonvulsant activity against seizures induced by intracerebroventricular administration of glutamate in rats and N-methyl-D,L-aspartic acid in mice. Protection against maximal electroshock-induced seizures suggests that felbamate may reduce seizure spread, an effect possibly predictive of efficacy in generalized tonic-clonic or partial seizures. Protection against pentylenetetrazol-induced seizures suggests that felbamate may increase seizure threshold, an effect considered to be predictive of potential efficacy in absence seizures.

Receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex. Felbamate is not effective in protecting chick embryo retina tissue against the neurotoxic effects of the excitatory amino acid agonists NMDA, kainate, or quisqualate in vitro. 

The monocarbamate, p-hydroxy, and 2-hydroxy metabolites were inactive in the maximal electroshock­-induced seizure test in mice. The monocarbamate and p-hydroxy metabolites had only weak (0.2 to 0.6) activity compared with felbamate in the subcutaneous pentylenetetrazol seizure test. These metabolites did not contribute significantly to the anticonvulsant action of felbamate. 

Pharmacokinetics: 

The numbers in the pharmacokinetic section are mean ± standard deviation. 

Felbamate is well-absorbed after oral administration. Over 90% of the radioactivity after a dose of 1,000 mg 14 C felbamate was found in the urine. Absolute bioavailability (oral vs. parenteral) has not been measured. The tablet was shown to be bioequivalent to the capsule used in clinical trials, and pharmacokinetic parameters of the tablet and suspension are similar. There was no effect of food on absorption of the tablet. 

Following oral administration, felbamate is the predominant plasma species (about 90% of plasma radioactivity). About 40% to 50% of absorbed dose appears unchanged in urine, and an additional 40% is present as unidentified metabolites and conjugates. About 15% is present as parahydroxyfelbamate, 2­-hydroxyfelbamate, and felbamate monocarbamate, none of which have significant anticonvulsant activity. 

Binding of felbamate to human plasma protein was independent of felbamate concentrations between 10 micrograms/mL and 310 micrograms/mL. Binding ranged from 22% to 25%, mostly to albumin, and was dependent on the albumin concentration. 

Felbamate is excreted with a terminal half-life of 20 to 23 hours, which is unaltered after multiple doses. Clearance after a single 1,200 mg dose is 26±3 mL/hr/kg, and after multiple daily doses of 3,600 mg is 30±8 mL/hr/kg. The apparent volume of distribution was 756±82 mL/kg after a 1,200 mg dose. Felbamate Cmax and AUC are proportionate to dose after single and multiple doses over a range of 100 mg to 800 mg single doses and 1,200 mg to 3,600 mg daily doses. Cmin (trough) blood levels are also dose proportional. Multiple daily doses of 1,200 mg, 2,400 mg and 3,600 mg gave Cmin values of 30±5, 55±8 and 83±21 micrograms/mL (N=10 patients). Linear and dose proportional pharmacokinetics were also observed at doses above 3,600 mg/day up to the maximum dose studied of 6,000 mg/day. Felbamate gave dose proportional steady-state peak plasma concentrations in children age 4 to 12 over a range of 15 mg/kg/day, 30 mg/kg/day and 45 mg/kg/day with peak concentrations of 17 micrograms/mL, 32 micrograms /mL and 49 micrograms/mL. 

The effects of race and gender on felbamate pharmacokinetics have not been systematically evaluated, but plasma concentrations in males (N=5) and females (N=4) given felbamate have been similar. The effects of felbamate kinetics on hepatic functional impairment have not been evaluated. 

Renal Impairment:

Felbamate's single dose monotherapy pharmacokinetic parameters were evaluated in 12 otherwise healthy individuals with renal impairment. There was a 40% to 50% reduction in total body clearance and 9 to 15 hours prolongation of half-life in renally impaired subjects compared to that in subjects with normal renal function. Reduced felbamate clearance and a longer half-life were associated with diminishing renal function. 

Pharmacodynamics: 

Typical Physiologic Responses:   


1\. Cardiovascular: In adults, there is no effect of felbamate on blood pressure. Small but statistically significant mean increases in heart rate were seen during adjunctive therapy and monotherapy; however, these mean increases of up to 5 bpm were not clinically significant. In children, no clinically relevant changes in blood pressure or heart rate were seen during adjunctive therapy or monotherapy with felbamate. 

2\. Other Physiologic Effects: The only other change in vital signs was a mean decrease of approximately 1 respiration per minute in respiratory rate during adjunctive therapy in children. In adults, statistically significant mean reductions in body weight were observed during felbamate monotherapy and adjunctive therapy. In children, there were mean decreases in body weight during adjunctive therapy and monotherapy; however, these mean changes were not statistically significant. These mean reductions in adults and children were approximately 5% of the mean weights at baseline.