Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of macitentan, which is primarily metabolized by the isoenzyme. In ten healthy male subjects pretreated with macitentan (30 mg initially, followed by 10 mg once daily) for 5 days, coadministration with the potent CYP450 3A4 inducer rifampin (600 mg once daily) on days 6 through 12 reduced macitentan systemic exposure (AUC) by 79% and trough plasma concentration (Cmin) by 93% compared to macitentan administered alone. An initial increase in the Cmin of the active metabolite of macitentan was observed following the addition of rifampin on day 6, but a gradual decrease occurred with continued dosing, resulting in concentrations on day 12 that were similar to those observed with macitentan alone. There was also no significant effect of rifampin on the AUC of the active metabolite, which has been reported to be approximately 5-fold less potent than macitentan in vitro, but whose systemic exposure in human is 2.5-fold higher than that of macitentan.

MANAGEMENT: Concomitant use of macitentan with potent CYP450 3A4 inducers should generally be avoided.