Drug Interactions between ivacaftor / lumacaftor and macitentan

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.

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GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4 or moderate dual or combined inhibitors of CYP450 3A4 and CYP450 2C9 may increase the plasma concentrations of macitentan. Macitentan is primarily metabolized by CYP450 3A4 and to a minor extent by CYP450 2C8, CYP450 2C9 and CYP450 2C19. In ten healthy subjects, administration of a single 10 mg oral dose of macitentan on day 5 of treatment with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 24 days) resulted in an approximately 2-fold increase in macitentan systemic exposure (AUC) compared to administration alone. Additionally, there was a 26% reduction in 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. The clinical significance of these changes has not been established. Macitentan was well tolerated with or without ketoconazole in the study, and there were no relevant differences in safety parameters between the treatments. In addition, physiologically based pharmacokinetic modeling in poor metabolizers of CYP450 2C9 showed that a 400 mg daily dose of fluconazole, a moderate dual CYP450 3A4 and CYP450 2C9 inhibitor, may increase macitentan exposure by approximately 3.8-fold. However, there was no clinically relevant change in exposure to the active metabolite of macitentan. The clinical significance of these findings is not known.

MANAGEMENT: Caution is advisable if macitentan is used with inhibitors of CYP450 3A4. The product labeling recommends avoiding concomitant use with potent inhibitors (e.g., protease inhibitors, clarithromycin, cobicistat, conivaptan, delavirdine, itraconazole, ketoconazole, nefazodone, posaconazole, voriconazole). The manufacturer of macitentan also recommends avoiding concomitant use with moderate dual inhibitors of CYP450 3A4 and 2C9 (e.g., fluconazole, amiodarone) or in combination with both a moderate CYP450 3A4 inhibitor and a moderate CYP450 2C9 inhibitor.

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