Drug Interaction Report

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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ruxolitinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients treated with ruxolitinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ruxolitinib may be administered with or without food.

The recommended maximum number of medicines in the 'multikinase inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'multikinase inhibitors' category:

• Jakafi (ruxolitinib)
• Rydapt (midostaurin)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.