Drug Interactions between brivaracetam and carbamazepine

MONITOR: Coadministration with potent inducers of CYP450 isoenzymes may decrease the plasma concentrations of brivaracetam, which is partially metabolized by CYP450 2C19. In healthy study subjects, administration of brivaracetam with the potent CYP450 inducer rifampin (600 mg/day for 5 days) resulted in a 45% decrease in brivaracetam systemic exposure (AUC). When given with the enzyme-inducing antiepileptic drugs carbamazepine, phenytoin and phenobarbital, the AUC of brivaracetam decreased by 26%, 21%, and 19%, respectively, without significant effects on pharmacologic response based on a population pharmacokinetic/pharmacodynamic analysis of placebo-controlled phase 3 studies. Conversely, concomitant use of phenytoin with a supratherapeutic dose of brivaracetam (400 mg/day) resulted in a 20% increase in phenytoin peak plasma concentration (Cmax) and AUC. Following administration of carbamazepine with brivaracetam dosages of 50 mg/day, 100 mg/day and 200 mg/day, no significant pharmacokinetic changes were observed for carbamazepine, but the plasma concentrations of carbamazepine epoxide (an active metabolite associated with neurotoxicity) increased by a mean of 37%, 62% and 98%, respectively. Coadministration of brivaracetam 200 mg twice daily and carbamazepine 300 mg twice daily for two weeks increased the AUC of carbamazepine epoxide by approximately 160% in 13 healthy male subjects. No safety risks were observed with these increases. Brivaracetam is a moderate reversible inhibitor of epoxide hydrolase, the enzyme that catalyzes the hydrolysis of carbamazepine epoxide to an inactive metabolite.

MANAGEMENT: The potential for diminished pharmacologic effects of brivaracetam should be considered during coadministration with potent CYP450 enzyme inducers. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever a CYP450 inducer is added to or withdrawn from therapy. For patients receiving concomitant carbamazepine or phenytoin therapy, blood levels should be monitored following initiation or discontinuation of brivaracetam. Dosage reductions for carbamazepine and phenytoin may be required if tolerability issues arise.