Drug Interaction Report

MONITOR: Coadministration with fostamatinib may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme and/or P-glycoprotein (P-gp) transporter. The proposed mechanism is decreased clearance in the intestine and/or liver due to inhibition of CYP450 3A4-mediated metabolism and P-gp-mediated efflux by fostamatinib. According to the product labeling, administration of a single 40 mg dose of the CYP450 3A4 substrate simvastatin with fostamatinib 100 mg twice daily increased simvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) by 113% and 64%, respectively. In addition, simvastatin acid Cmax increased by 83% and AUC increased by 64%. When the P-gp substrate digoxin (0.25 mg once daily) was administered with fostamatinib (100 mg twice daily), digoxin Cmax and AUC increased by 70% and 37%, respectively.

MANAGEMENT: Caution is advised when fostamatinib is used concurrently with drugs that are known substrates of CYP450 3A4 and/or P-gp, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever fostamatinib is added to or withdrawn from therapy.

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.