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.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.

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.