Drug Interaction Report

MONITOR: Coadministration with levacetylleucine may increase the plasma concentrations (AUC) and adverse effects of drugs that are substrates of the P-glycoprotein (P-gp) efflux transporter. Levacetylleucine is a P-gp inhibitor in vitro. However, clinical data are not available.

MANAGEMENT: If coadministration is clinically necessary, more frequent clinical monitoring for P-gp substrate related adverse reactions is advised and dose adjustments may be required, particularly when levacetylleucine is initiated or withdrawn from concomitant therapy. Consultation with package labeling of the concomitant medication may be advisable.

GENERALLY AVOID: Coadministration of protein-bound sirolimus intravenous suspension with grapefruit juice may increase the systemic exposure to sirolimus. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of sirolimus by certain compounds present in grapefruit. However, grapefruit juice primarily inhibits CYP450 3A4-mediated first-pass metabolism in the gut wall and may have limited effects on medications that are not administered orally. No formal studies evaluating the drug interaction potential of protein-bound sirolimus have been conducted. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

MANAGEMENT: The manufacturer recommends avoiding grapefruit and grapefruit juice during treatment with protein-bound sirolimus.