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.