Midostaurin undergoes extensive hepatic metabolism through CYP3A4 enzymes which are either induced or inhibited by a number of concomitant drugs. Based on in vitro data, midostaurin and/or its metabolites have the potential to inhibit and to induce CYP enzymes. Therefore, RYDAPT may be a victim or a perpetrator of drug-drug interactions in vivo.
Effect of other drugs on RYDAPT: Drugs 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 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 RYDAPT led to a significant increase in midostaurin exposure (1.8-fold Cmax increase and 10-fold AUCinf increase) while the peak concentrations of the active metabolites, CGP62221 and CGP52421, decreased by half (see Pharmacology under Actions). Another study evaluated the concomitant administration of multiple dose midostaurin 50 mg twice daily with the strong CYP3A4 inhibitor itraconazole at steady-state in a subset of patients (N=7), and showed that itraconazole increased midostaurin steady-state exposure (Cmin) by only 2.09-fold. During the induction phase of the AML study, up to 62% of patients received midostaurin concomitantly with strong inhibitors of CYP3A4. Upon co-administration with CYP3A4 inhibitors, a 1.44-fold increase in midostaurin exposure (Cmin) was observed. No impact was observed for CGP62221 and CGP52421. Considering the time-dependent pharmacokinetics of midostaurin (see Pharmacology under Actions), the clinical relevance of the interaction of strong CYP3A4 inhibitors on midostaurin exposure seems limited. Caution should be advised when concomitantly administering with midostaurin, medicinal products that are strong inhibitors of CYP3A4, such as, but not limited to antifungals (e.g., ketoconazole), certain antivirals (e.g., ritonavir), macrolide antibiotics (e.g., clarithromycin), and nefazodone. Alternative therapeutics that do not strongly inhibit CYP3A4 activity should be considered. In situations where satisfactory therapeutic alternatives do not exist, patients should be closely monitored for toxicity.
Strong CYP3A4 inducers: Strong CYP3A4 inducers may decrease midostaurin blood concentrations. In a study in healthy subjects, co-administration of the strong CYP3A4 inducer rifampicin (600 mg daily) to steady state with a single dose of midostaurin decreased midostaurin Cmax by 73% and AUCinf by 96%, respectively. Both metabolites, CGP62221 and CGP52421, exhibited a similar pattern. Avoid the concomitant use of RYDAPT with strong CYP3A4 inducers (e.g., carbamazepine, rifampin, St. John's Wort).
Effect of RYDAPT on other drugs: The PK of midazolam (sensitive CYP34A probe) was not affected following four dosing days of midostaurin in healthy subjects. While the dosing period only covered peak exposure to midostaurin, the data suggests that midostaurin is not a strong inducer of CYP3A4 (see Pharmacology under Actions).
Based on in vitro inhibition results, medicinal products with a narrow therapeutic range that are substrates of CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or OATP1B1 should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure (see Pharmacology under Actions).
Drug-food interactions: See Pharmacology under Actions.