Drug Interaction Report

MONITOR: Sirolimus may be systemically absorbed following topical administration. Theoretically, coadministration with inhibitors of CYP450 3A4 may increase the systemic exposure of sirolimus, which is a substrate of the isoenzyme. Significant increases in systemic exposure have been reported when oral sirolimus was coadministered with potent and moderate CYP450 3A4 inhibitors such as azole antifungal agents, macrolide antibiotics, protease inhibitors, and some calcium channel blockers. No formal studies to evaluate drug interactions with topical sirolimus have been conducted.

MANAGEMENT: Caution is advised if topical sirolimus is prescribed with potent or moderate CYP450 3A4 inhibitors. Patients should be monitored for systemic sirolimus adverse effects including immunosuppression, infection, hyperlipidemia, malignancy, and interstitial lung disease.

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.