Drug Interaction Report

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 and/or moderate dual or combined inhibitors of CYP450 3A4 and CYP450 2C9. 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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of dronedarone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. According to the product labeling, administration with grapefruit juice resulted in a 2.5-fold increase in dronedarone peak plasma concentration and a 3-fold increase in systemic exposure. Because dronedarone is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of dronedarone. The mechanism of interaction is unknown. According to the product labeling, the absolute bioavailability of dronedarone increases from about 4% when administered in the fasted state to approximately 15% when administered with a high-fat meal.

MANAGEMENT: Patients treated with dronedarone should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Dronedarone should be taken twice daily with the morning and evening meals.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of macitentan, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. The interaction has not been studied with grapefruit juice but has been reported for ketoconazole, a potent CYP450 3A4 inhibitor. In ten healthy subjects, coadministration of a single 10 mg oral dose of macitentan on day 5 of treatment with ketoconazole (400 mg daily for 24 days) resulted in an approximately 2-fold increase in macitentan systemic exposure compared to administration alone. However, the clinical significance of the interaction is unclear. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Until further information is available, patients receiving macitentan therapy should avoid the consumption of grapefruit or grapefruit juice.