Drug Interaction Report

MONITOR: Coadministration with glofitamab may increase the plasma concentrations of drugs that are substrates of CYP450 isoenzymes. Initiation of glofitamab treatment causes transient release of cytokines that may suppress CYP450 isoenzymes, although the potential for an interaction has not been studied. According to the manufacturer, the highest drug-drug interaction risk would be from the first dose on day 8 of cycle 1, up to 14 days after the first 30 mg dose on day 1 of cycle 2, as well as during and after cytokine release syndrome.

MANAGEMENT: Caution is advised when glofitamab is administered with drugs that are metabolized by CYP450 isoenzymes, particularly sensitive CYP450 substrates and/or those with a narrow therapeutic range, where minimal changes to concentration may lead to significant adverse reactions, such as carbamazepine, colchicine, cyclosporine, disopyramide, phenytoin, quinidine, theophylline, warfarin, macrolide immunosuppressants, vinca alkaloids, and some narcotic analgesics. Clinical and/or laboratory monitoring are recommended, particularly at the initial phase of treatment with glofitamab as well as during and after cytokine release syndrome, and individual product labeling for the CYP450 substrate(s) should be consulted for specific dosage adjustment recommendations.

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.