Rydapt Drug Interactions

Midostaurin undergoes extensive hepatic metabolism mainly through CYP3A4 enzymes which are either induced or inhibited by a number of concomitant medicinal products.
Effect of other medicinal products on Rydapt: Medicinal products or substances known to affect the activity of CYP3A4 may affect the plasma concentrations of midostaurin and therefore the safety and/or efficacy of Rydapt.
Strong CYP3A4 inducers: Concomitant use of Rydapt with strong inducers of CYP3A4 (e.g. carbamazepine, rifampicin, enzalutamide, phenytoin, St. John's Wort [Hypericum perforatum]) is contraindicated (see Contraindications). Strong CYP3A4 inducers decrease exposure of midostaurin and its active metabolites (CGP52421 and CGP62221). In a study in healthy subjects, co-administration of the strong CYP3A4 inducer rifampicin (600 mg daily) to steady state with a 50 mg single dose of midostaurin decreased midostaurin C_max by 73% and AUC_inf by 96% on average, respectively. CGP62221 exhibited a similar pattern. The mean AUC_last of CGP52421 decreased by 60%.
Strong CYP3A4 inhibitors: Strong CYP3A4 inhibitors may increase midostaurin blood concentrations. In a study with 36 healthy subjects, co-administration of the strong CYP3A4 inhibitor ketoconazole to steady state with a single dose of 50 mg midostaurin led to a significant increase in midostaurin exposure (1.8-fold C_max increase and 10-fold AUC_inf increase) and 3.5-fold increase in AUC_inf of CGP62221, while the C_max of the active metabolites (CGP62221 and CGP52421) decreased by half (see Pharmacology: Pharmacokinetics under Actions). At steady state of midostaurin (50 mg twice daily for 21 days), with the strong CYP3A4 inhibitor itraconazole at steady state in a subset of patients (N=7), midostaurin steady-state exposure (C_min) was increased by 2.09-fold. C_min of CGP52421 was increased by 1.3-fold, whereas no significant effect in exposure of CGP62221 was observed (see Precautions).
Effect of Rydapt on other medicinal products: Midostaurin is not an inhibitor of CYP3A4 in vivo. The pharmacokinetics of midazolam (sensitive CYP3A4 probe) were not affected following three days' dosing of midostaurin in healthy subjects.
Based on in vitro data, midostaurin and/or its metabolites have the potential to inhibit CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2E1 and CYP3A4/5 enzymes.
Based on in vitro data, midostaurin and/or its metabolites have the potential to induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4 enzymes. Midostaurin inhibited OATP1B1, BCRP and P-glycoprotein (P-gp) in vitro (see Pharmacology: Pharmacokinetics under Actions). The combination of data on in vivo midostaurin auto-induction upon repeated dosing and increase in plasma 4β-OH cholesterol levels suggest that midostaurin may be at least a moderate CYP3A4 inducer in vivo.
In vivo studies have not been conducted for the investigation of induction and inhibition of enzymes and transporters by midostaurin and the active metabolites. Medicinal products with a narrow therapeutic range that are substrates of CYP1A2 (e.g. tizanidine), CYP2D6 (e.g. codeine), CYP2C8 (e.g. paclitaxel), CYP2C9 (e.g. warfarin), CYP2C19 (e.g. omeprazole), CYP2E1 (e.g. chlorzoxazone), CYP3A4/5 (e.g. tacrolimus), CYP2B6 (e.g. efavirenz), P-gp (e.g. paclitaxel), BCRP (e.g. atorvastatin) or OATP1B1 (e.g. digoxin) should be used with caution when administered concomitantly with midostaurin and may need dose adjustment to maintain optimal exposure (see Pharmacology: Pharmacokinetics under Actions).
It is currently unknown whether midostaurin may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method of contraception (see Use in Pregnancy & Lactation).
Food interactions: In healthy subjects, midostaurin absorption (AUC) was increased by an average of 22% when Rydapt was co-administered with a standard meal and by an average of 59% when co-administered with a high-fat meal. Peak midostaurin concentration (C_max) was reduced by 20% with a standard meal and by 27% with a high-fat meal versus on an empty stomach (see Pharmacology: Pharmacokinetics under Actions).
Rydapt is recommended to be administered with food.