Drug Interaction Report

MONITOR: Coadministration with weak inducers of CYP450 3A4 may decrease the plasma concentrations and pharmacologic effects of repotrectinib. According to prescribing information, repotrectinib is primarily metabolized by CYP450 3A4 and is also a substrate of P-gp in vitro. Concomitant use with rifampin, a potent CYP450 3A4 and P-gp inducer, decreased the peak plasma concentration (Cmax) and systemic exposure (AUC) of repotrectinib by 79% and 92%, respectively. Data are not available for repotrectinib in combination with other, less potent CYP450 3A4 inducers. Reduced effectiveness of repotrectinib may occur.

MANAGEMENT: The potential for diminished pharmacologic effects of repotrectinib should be considered during coadministration with weak CYP450 3A4 inducers.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations and adverse effects of repotrectinib. According to prescribing information, repotrectinib is primarily metabolized by CYP450 3A4, and is also a substrate of P-gp in vitro. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with repotrectinib and grapefruit juice but has been reported for other CYP450 3A4 inhibitors. Drug interaction studies have shown that the administration of repotrectinib with itraconazole, a potent CYP450 3A4 and P-gp inhibitor, increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of repotrectinib by 1.7-fold and 5.9-fold, respectively. 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. Increased exposure to repotrectinib may increase the risk of adverse reactions such as dizziness, fatigue, cognitive disorders, ataxia, dysgeusia, peripheral neuropathy, muscular weakness, and dyspnea as well as more serious adverse effects such as interstitial lung disease/pneumonitis, liver transaminase elevations, myalgia with creatinine phosphokinase (CPK) elevation, hyperuricemia, and skeletal fractures.

MANAGEMENT: The manufacturer advises that concomitant use of repotrectinib with grapefruit, grapefruit juice, or supplements that contain grapefruit should be avoided.