"The U.S. Food and Drug Administration yesterday approved Briviact (brivaracetam) as an add-on treatment to other medications to treat partial onset seizures in patients age 16 years and older with epilepsy.
Epilepsy is a brain disorder "...
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.
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 1000 mg 14C felbamate was found in the urine. Absolute bioavailability (oral vs. parenteral) has not been measured. The tablet and suspension were each 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; the effect of food on absorption of the suspension has not been evaluated.
Following oral administration, felbamate is the predominant plasma species (about 90% of plasma radioactivity). About 40-50% 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 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 20-23 hours, which is unaltered after multiple doses. Clearance after a single 1200 mg dose is 26±3 mL/hr/kg, and after multiple daily doses of 3600 mg is 30±8 mL/hr/kg. The apparent volume of distribution was 756±82 mL/kg after a 1200 mg dose. Felbamate Cmax and AUC are proportionate to dose after single and multiple doses over a range of 100-800 mg single doses and 1200-3600 mg daily doses. Cmin (trough) blood levels are also dose proportional. Multiple daily doses of 1200,2400, and 3600 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 3600 mg/day up to the maximum dose studied of 6000 mg/day. Felbamate gave dose proportional steady-state peak plasma concentrations in children age 4-12 over a range of 15,30, and 45 mg/kg/day with peak concentrations of 17, 32, 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.
Felbamate's single dose monotherapy pharmacokinetic parameters were evaluated in 12 otherwise healthy individuals with renal impairment. There was a 40-50% reduction in total body clearance and 9-15 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.
Typical Physiologic Responses
- 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.
- 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.
The results of controlled clinical trials established the efficacy of Felbatol® (felbamate) as monotherapy and adjunctive therapy in adults with partial-onset seizures with or without secondary generalization and in partial and generalized seizures associated with Lennox-Gastaut syndrome in children.
Felbatol® Monotherapy Trials in Adults
Felbatol® (3600 mg/day given QID) and low-dose valproate (15 mg/kg/day) were compared as monotherapy during a 112-day treatment period in a multicenter and a single-center double-blind efficacy trial. Both trials were conducted according to an identical study design. During a 56-day baseline period, all patients had at least four partial-onset seizures per 28 days and were receiving one antiepileptic drug at a therapeutic level, the most common being carbamazepine. In the multicenter trial, baseline seizure frequencies were 12.4 per 28 days in the Felbatol® group and 21.3 per 28 days in the low-dose valproate group. In the single-center trial, baseline seizure frequencies were 18.1 per 28 days in the Felbatol® group and 15.9 per 28 days in the low-dose valproate group. Patients were converted to monotherapy with Felbatol® or low-dose valproic acid during the first 28 days of the 112-day treatment period. Study endpoints were completion of 112 study days or fulfilling an escape criterion. Criteria for escape relative to baseline were: (1) twofold increase in monthly seizure frequency, (2) twofold increase in highest 2-day seizure frequency, (3) single generalized tonic-clonic seizure (GTC) if none occurred during baseline, or (4) significant prolongation of GTCs. The primary efficacy variable was the number of patients in each treatment group who met escape criteria.
In the multicenter trial, the percentage of patients who met escape criteria was 40% (18/45) in the Felbatol® group and 78% (39/50) in the low-dose valproate group. In the single-center trial, the percentage of patients who met escape criteria was 14% (3/21) in the Felbatol® group and 90% (19/21) in the low-dose valproate group. In both trials, the difference in the percentage of patients meeting escape criteria was statistically significant (P < .001) in favor of Felbatol®. These two studies by design were intended to demonstrate the effectiveness of Felbatol® monotherapy. The studies were not designed or intended to demonstrate comparative efficacy of the two drugs. For example, valproate was not used at the maximally effective dose.
Felbatol® Adjunctive Therapy Trials in Adults
A double-blind, placebo-controlled crossover trial consisted of two 10-week outpatient treatment periods. Patients with refractory partial-onset seizures who were receiving phenytoin and carbamazepine at therapeutic levels were administered Felbatol® (felbamate) as add-on therapy at a starting dosage of 1400 mg/day in three divided doses, which was increased to 2600 mg/day in three divided doses. Among the 56 patients who completed the study, the baseline seizure frequency was 20 per month. Patients treated with Felbatol® had fewer seizures than patients treated with placebo for each treatment sequence. There was a 23% (P=.018) difference in percentage seizure frequency reduction in favor of Felbatol®.
Felbatol® 3600 mg/day given QID and placebo were compared in a 28-day double-blind add-on trial in patients who had their standard antiepileptic drugs reduced while undergoing evaluations for surgery of intractable epilepsy. All patients had confirmed partial-onset seizures with or without generalization, seizure frequency during surgical evaluation not exceeding an average of four partial seizures per day or more than one generalized seizure per day, and a minimum average of one partial or generalized tonic-clonic seizure per day for the last 3 days of the surgical evaluation. The primary efficacy variable was time to fourth seizure after randomization to treatment with Felbatol® or placebo. Thirteen (46%) of 28 patients in the Felbatol® group versus 29 (88%) of 33 patients in the placebo group experienced a fourth seizure. The median times to fourth seizure were greater than 28 days in the Felbatol® group and 5 days in the placebo group. The difference between Felbatol® and placebo in time to fourth seizure was statistically significant (P=.002) in favor of Felbatol®.
Felbatol® Adjunctive Therapy Trial in Children with Lennox-Gastaut Syndrome
In a 70-day double-blind, placebo-controlled add-on trial in the Lennox-Gastaut syndrome, Felbatol® 45 mg/kg/day given QID was superior to placebo in controlling the multiple seizure types associated with this condition. Patients had at least 90 atonic and/or atypical absence seizures per month while receiving therapeutic dosages of one or two other antiepileptic drugs. Patients had a past history of using an average of eight antiepileptic drugs. The most commonly used antiepileptic drug during the baseline period was valproic acid. The frequency of all types of seizures during the baseline period was 1617 per month in the Felbatol® group and 716 per month in the placebo group. Statistically significant differences in the effect on seizure frequency favored Felbatol® over placebo for total seizures (26% reduction vs. 5% increase, P < .001), atonic seizures (44% reduction vs. 7% reduction, P=.002), and generalized tonic-clonic seizures (40% reduction vs. 12% increase, P=.017). Parent/guardian global evaluations based on impressions of quality of life with respect to alertness, verbal responsiveness, general well-being, and seizure control significantly (P < .001) favored Felbatol® over placebo.
When efficacy was analyzed by gender in four well-controlled trials of felbamate as adjunctive and monotherapy for partial-onset seizures and Lennox-Gastaut syndrome, a similar response was seen in 122 males and 142 females.
Last reviewed on RxList: 9/17/2012
This monograph has been modified to include the generic and brand name in many instances.
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