Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 and/or P-glycoprotein may significantly decrease the plasma concentrations and pharmacologic effects of sirolimus. The mechanism probably involves reduced absorption as well as accelerated clearance of sirolimus due to induction of both intestinal P-glycoprotein drug efflux transporter and hepatic/intestinal CYP450 3A4 isoenzymes. In a study of 14 healthy volunteers, a potent inducer of CYP450 3A4 and P-gp, rifampin (600 mg daily for 14 days) increased the oral clearance of sirolimus (20 mg single dose) by 5.5-fold, representing mean decreases in peak blood concentration (Cmax) and area under the concentration-time curve (AUC) of 71% and 82%, respectively.

MANAGEMENT: Given the risk of organ rejection associated with inadequate immunosuppressant levels, the use of sirolimus with potent inducers of CYP450 3A4 and/or P-gp is not recommended. Alternative therapeutic agents with less enzyme induction potential should be considered.

ADJUST DOSING INTERVAL: Administration with food may increase the oral bioavailability of rifapentine and reduce the incidence of gastrointestinal adverse events. Administration with a high fat meal typically increases rifapentine's maximum concentration (Cmax) and systemic exposure (AUC) by approximately 40% to 50% over that observed when rifapentine is administered under fasting conditions. Rifapentine is often prescribed in combination with isoniazid. When single doses of rifapentine (900 mg) and isoniazid (900 mg) were administered with a low fat, high carbohydrate breakfast, the Cmax and AUC of rifapentine increased by 47% and 51%, respectively. On the other hand, isoniazid's Cmax and AUC decreased by 46% and 23%, respectively.

MANAGEMENT: Products containing oral rifapentine as the sole ingredient recommend administration with a meal to increase bioavailability and reduce the occurrence of gastrointestinal upset, nausea, and/or vomiting. Consultation of product labeling for combination products and/or relevant guidelines may be helpful if rifapentine is combined with a medication that is typically taken on an empty stomach.

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.