Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 2C9 and/or 3A4 may increase the plasma concentrations of bosentan, which is metabolized by these isoenzymes. When bosentan 125 mg orally twice a day was administered with the potent CYP450 3A4 inhibitor ketoconazole, bosentan plasma concentrations increased by approximately 2-fold. Concomitant administration of both a CYP450 2C9 inhibitor and a CYP450 3A4 inhibitor may lead to even larger increases in plasma concentrations of bosentan.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of bosentan, including serious adverse effects such as hepatotoxicity, should be considered during coadministration with CYP450 2C9 or 3A4 inhibitors. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Concomitant administration of bosentan with both a potent CYP450 2C9 inhibitor (e.g., fluconazole, amiodarone) and a potent CYP450 3A4 inhibitor (e.g., ketoconazole, itraconazole, ritonavir) is not recommended. Concomitant administration with dual inhibitors of CYP450 2C9 and 3A4 (e.g., asciminib, delavirdine, imatinib, miconazole, voriconazole) should probably be avoided also, if possible.

ADJUST DOSING INTERVAL: Food may reduce the oral bioavailability of asciminib. When a single 40 mg dose of asciminib was administered with a low-fat meal (400 calories; 25% fat) in healthy volunteers, asciminib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 35% and 30%, respectively, compared to asciminib administered in the fasted state. Administration with a high-fat meal (1000 calories; 50% fat) decreased the Cmax and AUC of asciminib by 68% and 62%, respectively.

MANAGEMENT: To ensure adequate asciminib exposures, food consumption should be avoided for at least 2 hours before and 1 hour after taking asciminib.