Drug Interaction Report

MONITOR: The risk of peripheral neuropathy may be increased during concurrent use of two or more agents that are associated with this adverse effect. Patient risk factors include diabetes and age older than 60 years. In some cases, the neuropathy may progress or become irreversible despite discontinuation of the medications.

MANAGEMENT: Caution is advised during concomitant use of agents with neurotoxic effects. Patients should be monitored closely for symptoms of neuropathy such as burning, tingling, pain, or numbness in the hands and feet. Since the development of peripheral neuropathy may be dose-related for many drugs, the recommended dosages should generally not be exceeded. Consideration should be given to dosage reduction or immediate discontinuation of these medications in patients who develop peripheral neuropathy to limit further damage. If feasible, therapy should generally be reinstituted only after resolution of neuropathy symptoms or return of symptoms to baseline status. In some cases, permanent dosage reductions may be required.

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.