Drug Interaction Report

MONITOR: Coadministration of sirolimus or tacrolimus with other drugs that are also metabolized by CYP450 3A4 may result in elevated plasma concentrations of the macrolide immunosuppressant and/or the coadministered drug(s). The mechanism is decreased drug clearance due to competitive inhibition of CYP450 3A4 activity. Although clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of the drugs should be considered.

MANAGEMENT: Pharmacologic responses and/or plasma drug levels should be monitored more closely whenever a macrolide immunosuppressant or another substrate of CYP450 3A4 is added to or withdrawn from therapy, and the dosage(s) adjusted as necessary.

GENERALLY AVOID: Coadministration with grapefruit juice may slightly increase the oral bioavailability and delay the onset of action of sildenafil. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In a randomized, crossover study with 24 healthy male volunteers, ingestion of 250 mL of grapefruit juice one hour before and concurrently with a 50 mg dose of sildenafil increased the mean area under the plasma concentration-time curve (AUC) of sildenafil and its pharmacologically active N-desmethyl metabolite by 23% and 24%, respectively, compared to water. Peak plasma concentrations (Cmax) were unaltered, but the time to reach sildenafil Cmax was prolonged by 0.25 hour. The observed increase in sildenafil bioavailability is unlikely to be of clinical significance in most individuals. However, pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability and may be significant in the occasional susceptible patient. Indeed, one subject in the study had a 2.6-fold increase in sildenafil concentrations.

MANAGEMENT: It may be advisable to avoid administration of sildenafil with grapefruit juice to prevent potential toxicity and delay in onset of action.

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.