Potential pharmacokinetic interaction between felbamate and phenobarbital

OBJECTIVE: To report a case of a potential pharmacokinetic interaction between felbamate and phenobarbital in a patient with epilepsy. CASE SUMMARY: A patient with a history of a mixed seizure disorder and static encephalopathy who was receiving sodium valproate 750 mg/d and phenobarbital 230 mg/d was initiated on felbamate (as part of a compassionate use program). Upon instituting felbamate, valproate dosage was reduced to 500 mg/d and phenobarbital to 200 mg/d. Felbamate dosage was titrated to approximately 50 mg/kg/d over three weeks. In this patient, plasma phenobarbital concentrations increased from 48 micrograms/mL to 68 micrograms/mL, at which point the patient was hospitalized because of clinically significant neurotoxicity. Phenobarbital dosage was subsequently reduced to 150 mg/d; this resulted in phenobarbital trough concentrations of 60 micrograms/mL. CONCLUSIONS: Felbamate has been shown previously to interact with multiple other anticonvulsant medications, including valproate, phenytoin, and carbamazepine. Felbamate appears to decrease the clearance of valproate, phenytoin, and carbamazepine epoxide to a significant extent, an effect that may be the result of inhibition of the metabolism of these compounds. Carbamazepine plasma concentrations have been demonstrated to decrease following administration of felbamate, suggesting metabolic induction. It is reasonable to suggest that based on these findings and the observations in our patient, felbamate comedication may result in clinically significant increases in plasma phenobarbital concentrations. It would seem prudent, therefore, when initiating or adjusting felbamate therapy in patients receiving this drug combination, to monitor phenobarbital plasma concentrations.