Drug Interaction Report

GENERALLY AVOID: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of ticagrelor, which is primarily metabolized by the isoenzyme. In 14 healthy volunteers, administration of a single 180 mg oral dose of ticagrelor on day 12 of treatment with the potent CYP450 3A4 inducer rifampin (600 mg once daily for 14 days) decreased mean ticagrelor peak plasma concentration (Cmax), systemic exposure (AUC) and plasma half-life by 73%, 86% and 67%, respectively, compared to administration of ticagrelor alone. Mean Cmax of the major active metabolite was unchanged in the presence of rifampin, but mean AUC decreased by 46% and plasma half-life by 50%. Inhibition of platelet aggregation (IPA) was also assessed in the study. Mean IPA at 12 hours was 87% with ticagrelor alone versus 63% in combination with rifampin; corresponding values at 24 hours were 70% and 15%, respectively. It is not known to what extent ticagrelor may interact with weak and moderate CYP450 3A4 inducers.

MANAGEMENT: Concomitant use of ticagrelor with CYP450 3A4 inducers should generally be avoided. Otherwise, caution is advised, and patients should be closely monitored for diminished clinical response to ticagrelor therapy. Alternative treatment may be required if an interaction is suspected.

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.