Drug Interaction Report

MONITOR: Coadministration with oritavancin may decrease the plasma concentrations and therapeutic effects drugs that are substrates of CYP450 3A4 and/or 2D6. The proposed mechanism is increased clearance due to oritavancin-mediated induction of these isoenzymes. In a screening drug interaction study in 16 healthy volunteers, a single 1,200 mg dose of oritavancin decreased midazolam systemic exposure (AUC) by 18% and the urinary dextromethorphan-to-dextrorphan ratio by 31%, indicating weak induction of CYP450 3A4 and 2D6, respectively.

MANAGEMENT: Caution is advised when oritavancin used concomitantly with drugs that are substrates of CYP450 3A4 and/or 2D6, particularly sensitive substrates or those for which minimal concentration changes may lead to therapeutic failure. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever oritavancin is added to or withdrawn from therapy. Individual product labeling for the CYP450 3A4 and/or 2D6 substrate(s) should be consulted for further guidance.

ADJUST DOSING INTERVAL: The presence of food may increase the absorption and toxicity of pexidartinib. Administration of pexidartinib with a high-fat meal increased peak plasma concentration (Cmax) and systemic exposure (AUC) by 100% and prolonged the time to reach peak plasma concentration (Tmax) by 2.5 hours.

GENERALLY AVOID: Grapefruit or grapefruit juice may increase the plasma concentration and risk of adverse effects of pexidartinib, including potentially fatal hepatotoxicity. The mechanism is inhibition of CYP450 3A4-mediated metabolism of pexidartinib by certain compounds present in grapefruits. Concomitant administration of itraconazole, a strong CYP450 3A4 inhibitor, increased pexidartinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 48% and 70%, respectively.

MANAGEMENT: Pexidartinib should be administered on an empty stomach, at least one hour before or two hours after a meal or snack. Consumption of grapefruit or grapefruit juice should generally be avoided during pexidartinib therapy. If concomitant use is unavoidable, the dose of pexidartinib should be reduced according to the manufacturer's recommendations. If concomitant use of grapefruit or grapefruit juice is discontinued, the dose of pexidartinib may be increased (after 3 plasma half-lives of a strong CYP450 3A4 inhibitor) to the dose that was used prior to consumption of grapefruit or grapefruit juice.