Drug Interaction Report

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 Clinical and/or laboratory monitoring may be appropriate whenever bosentan is added to or withdrawn from therapy, and the dosage of the concomitant drug adjusted as necessary.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.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.