Drug Interaction Report

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may decrease the plasma concentrations of pimavanserin, which is primarily metabolized by the isoenzyme. In a drug interaction study designed to measure pre- and post-pimavanserin levels following rifampin administration (a potent CYP450 3A4 inducer), Cmax and AUC were decreased by 71% and 91%, respectively, compared to pre-rifampin plasma concentrations. A physiologically based pharmacokinetic simulation with a moderate CYP450 3A4 inducer (efavirenz) predicted Cmax and AUC of pimavanserin will be decreased by approximately 60% and 70%, respectively.

MANAGEMENT: Coadministration of potent or moderate CYP450 3A4 inducers with pimavanserin should be avoided.

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.