Drug Interactions between bosentan and Kisqali Femara Co-Pack

MONITOR: Coadministration with bosentan may decrease the plasma concentrations of drugs that are substrates of the CYP450 2C9 and/or 3A4 isoenzymes. The mechanism is accelerated clearance due to induction of those isoenzymes by bosentan.

MANAGEMENT: When drugs that are known substrates of CYP450 2C9 and/or 3A4 are coadministered with bosentan, the possibility of a diminished therapeutic response to those drugs should be considered. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs, particularly those with a narrow therapeutic range, whenever bosentan is added to or withdrawn from therapy.

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

MONITOR: Coadministration of bosentan with a drug that is both a substrate as well as inhibitor of CYP450 2C9 and/or 3A4 may result in increased plasma concentrations of bosentan and decreased plasma concentrations of the other drug. Bosentan itself is a substrate and inducer of both CYP450 2C9 and 3A4. Theoretically, bosentan may induce metabolism of the coadministered drug while its own metabolism may be inhibited by the coadministered drug. According to the product labeling, administration of bosentan (125 mg orally twice a day) in combination with the potent CYP450 3A4 inhibitor ketoconazole resulted in approximately 2-fold increases in bosentan plasma concentrations. It is conceivable that concomitant administration of both a CYP450 2C9 inhibitor and a CYP450 3A4 inhibitor may lead to even larger increases in bosentan plasma concentrations.

MANAGEMENT: When a drug that is both a substrate as well as inhibitor of CYP450 2C9 and/or 3A4 is coadministered with bosentan, the possibility of diminished therapeutic response to the coadministered drug should be considered. Clinical and/or laboratory monitoring may be appropriate whenever bosentan is added to or withdrawn from therapy, and the dosage of the concomitant drug adjusted as necessary. The possibility of prolonged and/or increased pharmacologic effects of bosentan, including serious adverse effects such as hepatotoxicity, should also be considered. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, 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 combination CYP450 2C9/3A4 inhibitors (e.g., delavirdine, imatinib, miconazole, mifepristone, voriconazole) should probably be avoided also, if possible.