Felbamateinteractions

The drug interaction data described in this section were obtained from controlled clinical trials and studies involving otherwise healthy adults with epilepsy. Use in Conjunction with Other Antiepileptic Drugs (see DOSAGE AND ADMINISTRATION ): The addition of felbamate to antiepileptic drugs (AEDs) affects the steady-state plasma concentrations of AEDs. The net effect of these interactions is summarized in Table 2: *Not administered but an active metabolite of carbamazepine. **No significant effect. Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs AED Coadministered AED Concentration Felbamate Concentration Phenytoin ↑ ↓ Valproate ↑ ↔** Carbamazepine (CBZ) *CBZ epoxide ↓ ↑ ↓ Phenobarbital ↑ ↓ Specific Effects of Felbamate on Other Antiepileptic Drugs: Phenytoin: Felbamate causes an increase in steady-state phenytoin plasma concentrations. In 10 otherwise healthy subjects with epilepsy ingesting phenytoin, the steady-state trough (C min ) phenytoin plasma concentration was 17±5 micrograms/mL. The steady-state C min increased to 21±5 micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to 1800 mg/day in six of these subjects increased the steady-state phenytoin C min to 25±7 micrograms/mL. In order to maintain phenytoin levels, limit adverse experiences, and achieve the felbamate dose of 3600 mg/day, a phenytoin dose reduction of approximately 40% was necessary for eight of these 10 subjects. In a controlled clinical trial, a 20% reduction of the phenytoin dose at the initiation of felbamate therapy resulted in phenytoin levels comparable to those prior to felbamate administration.

Carbamazepine: Felbamate causes a decrease in the steady-state carbamazepine plasma concentrations and an increase in the steady-state carbamazepine epoxide plasma concentration. In nine otherwise healthy subjects with epilepsy ingesting carbamazepine, the steady-state trough (C min ) carbamazepine concentration was 8±2 micrograms/mL. The carbamazepine steady-state C min decreased 31% to 5±1 micrograms/mL when felbamate (3000 mg/day, divided into three doses) was coadministered. Carbamazepine epoxide steady-state C min concentrations increased 57% from 1.0±0.3 to 1.6±0.4 micrograms/mL with the addition of felbamate. In clinical trials, similar changes in carbamazepine and carbamazepine epoxide were seen.

Valproate: Felbamate causes an increase in steady-state valproate concentrations. In four subjects with epilepsy ingesting valproate, the steady-state trough (C min ) valproate plasma concentration was 63±16 micrograms/mL. The steady-state C min increased to 78±14 micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to 2400 mg/day increased the steady-state valproate C min to 96±25 micrograms/mL. Corresponding values for free valproate C min concentrations were 7±3, 9±4, and 11±6 micrograms/mL for 0, 1200, and 2400 mg/day felbamate, respectively. The ratios of the AUCs of unbound valproate to the AUCs of the total valproate were 11.1%, 13.0%, and 11.5%, with coadministration of 0, 1200, and 2400 mg/day of felbamate, respectively. This indicates that the protein binding of valproate did not change appreciably with increasing doses of felbamate.

Phenobarbital: Coadministration of felbamate with phenobarbital causes an increase in phenobarbital plasma concentrations. In 12 otherwise healthy male volunteers ingesting phenobarbital, the steady-state trough (C min ) phenobarbital concentration was 14.2 micrograms/mL. The steady-state C min concentration increased to 17.8 micrograms/mL when 2400 mg/day of felbamate was coadministered for one week. Effects of Other Antiepileptic Drugs on Felbamate: Phenytoin: Phenytoin causes an approximate doubling of the clearance of felbamate at steady-state and, therefore, the addition of phenytoin causes an approximate 45% decrease in the steady-state trough concentrations of felbamate as compared to the same dose of felbamate given as monotherapy.

Carbamazepine: Carbamazepine causes an approximate 50% increase in the clearance of felbamate at steady-state and, therefore, the addition of carbamazepine results in an approximate 40% decrease in the steady-state trough concentrations of felbamate as compared to the same dose of felbamate given as monotherapy.

Valproate: Available data suggest that there is no significant effect of valproate on the clearance of felbamate at steady-state. Therefore, the addition of valproate is not expected to cause a clinically important effect on felbamate plasma concentrations.

Phenobarbital: It appears that phenobarbital may reduce plasma felbamate concentrations. Steady-state plasma felbamate concentrations were found to be 29% lower than the mean concentrations of a group of newly diagnosed subjects with epilepsy also receiving 2400 mg of felbamate a day. Effects of Antacids on Felbamate: The rate and extent of absorption of a 2400 mg dose of felbamate as monotherapy given as tablets was not affected when coadministered with antacids. Effects of Erythromycin on Felbamate: The coadministration of erythromycin (1000 mg/day) for 10 days did not alter the pharmacokinetic parameters of C max, C min, AUC, Cl/kg or T max at felbamate daily doses of 3000 or 3600 mg/day in 10 otherwise healthy subjects with epilepsy. Effects of Felbamate on Low-Dose Combination Oral Contraceptives: A group of 24 nonsmoking, healthy white female volunteers established on an oral contraceptive regimen containing 30 µg ethinyl estradiol and 75 µg gestodene for at least 3 months received 2400 mg/day of felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles. Felbamate treatment resulted in a 42% decrease in the gestodene AUC 0-24, but no clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. No volunteer showed hormonal evidence of ovulation, but one volunteer reported intermenstrual bleeding during felbamate treatment.