Drug Interaction Report

MONITOR: In vitro data suggest that coadministration with potent inhibitors of P-glycoprotein (e.g., cyclosporine) and/or organic anion transporting polypeptide (e.g., cyclosporine, ritonavir) may increase the plasma concentrations of ambrisentan, which is a substrate of these transporters. In healthy volunteers, steady-state coadministration of ambrisentan and cyclosporine resulted in a 2-fold increase in ambrisentan exposure. The interaction has not been studied with other P-gp or OATP inhibitors.

MANAGEMENT: Because ambrisentan is associated with dose-related hepatotoxicity, concomitant use with potent inhibitors of P-gp and/or OATP should be approached with caution. Patients should be advised to notify their physician if they experience signs and symptoms of liver injury such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of midostaurin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. 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. Ketoconazole, a potent CYP450 3A4 inhibitor, has been shown to increase midostaurin systemic exposure (AUC) by greater than 10-fold in healthy volunteers. Increased exposure to midostaurin may increase the risk of adverse effects such as nausea, vomiting, diarrhea, edema, hyperglycemia, hyperuricemia, QT prolongation, neutropenia, lymphopenia, thrombocytopenia, and anemia.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of midostaurin. Relative to fasting conditions, midostaurin systemic exposure (AUC) increased by approximately 1.2-fold when administered with a standard meal (457 calories; 50 g fat, 21 g proteins, 18 g carbohydrates) and 1.6-fold when administered with a high-fat meal (1007 calories; 66 g fat, 32 g proteins, 64 g carbohydrates), while midostaurin peak plasma concentration (Cmax ) decreased by 20% and 27%, respectively.

MANAGEMENT: The manufacturer recommends taking midostaurin with food. Midostaurin was administered with food in clinical trials. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with midostaurin.