Drug Interaction Report

MONITOR: Coadministration with bosentan may decrease the plasma concentrations and therapeutic effects of sirolimus and tacrolimus. The proposed mechanism is increased clearance due to bosentan-mediated induction of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of sirolimus and tacrolimus. In addition, concomitant use with sirolimus or tacrolimus may increase the plasma concentrations of bosentan. The mechanism for this interaction has not been delineated.

MANAGEMENT: Given the risk of therapeutic failure and organ rejection associated with inadequate immunosuppressant drug levels, caution is advised if bosentan is used concomitantly with sirolimus or tacrolimus. Sirolimus and tacrolimus blood levels should be checked frequently, and the dosage adjusted accordingly whenever bosentan is added to or withdrawn from therapy. In addition, patients should be monitored for adverse effects associated with bosentan, such as hepatotoxicity and decreases in hemoglobin and hematocrit.

ADJUST DOSING INTERVAL: Consumption of food can decrease the rate and extent of gastrointestinal absorption of sirolimus. Also, the consumption of grapefruit juice may result in increased sirolimus trough concentrations.

MANAGEMENT: Experts recommend that this drug be taken either at least one hour prior to eating or consistently with or without food to avoid variations in sirolimus blood levels. The manufacturer recommends against using grapefruit juice for dilution of sirolimus doses. Patients should be monitored for clinical and laboratory evidence of altered immunosuppressant effects.