Interactions : אינטראקציות

4.5    Interaction with other medicinal products and other forms of interaction

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 section 4.3). 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 Cmax by 73% and AUCinf by 96% on average, respectively. CGP62221 exhibited a similar pattern. The mean AUClast 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 Cmax increase and 10-fold AUCinf increase) and 3.5-fold increase in AUCinf of CGP62221, while the Cmax of the active metabolites (CGP62221 and CGP52421) decreased by half (see section 5.2). 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 (Cmin) was increased by 2.09-fold. Cmin of CGP52421 was increased by 1.3-fold, whereas no significant effect in exposure of
CGP62221 was observed (see section 4.4).

Effect of Rydapt on other medicinal products

Substrates of CYP enzymes
In healthy subjects, co-administration of a single dose of bupropion (CYP2B6 substrate) with multiple doses of midostaurin (50 mg twice daily) at steady state decreased bupropion AUCinf and AUClast by 48% and 49% respectively and Cmax by 55% compared to administration of bupropion alone. This indicates that midostaurin is a mild inducer of CYP2B6. Medicinal products with a narrow therapeutic range that are substrates of CYP2B6 (e.g. bupropion or efavirenz) should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure.

Based on in-vitro data, midostaurin and its active metabolites, CGP52421 and CGP62221, are inhibitors of CYP1A2 and CYP2E1 and inducers of CYP1A2. Therefore, medicinal products with a narrow therapeutic range that are substrates of CYP1A2 (e.g. tizanidine) and CYP2E1 (e.g.
chlorzoxazone) should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure.

Substrates of transporters
In healthy subjects, co-administration of a single dose of rosuvastatin (BCRP substrate) with a single dose of midostaurin (100 mg) increased rosuvastatin AUCinf and AUClast by 37% and 48% respectively; Cmax was approximately doubled (2.01 times) compared to administration of rosuvastatin alone. This indicates that midostaurin has a mild inhibitory effect on BCRP substrates. Medicinal products with a narrow therapeutic range that are substrates of the transporter BCRP (e.g. rosuvastatin or atorvastatin) should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure.

Hormonal contraceptives
There was no clinically significant pharmacokinetic drug-drug interaction between multiple doses of midostaurin (50 mg twice daily) at steady state and oral contraceptives containing ethinyl estradiol and levonorgestrel in healthy women. Therefore it is not anticipated that the contraceptive reliability of this combination will be compromised by co-administration of midostaurin.



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 (Cmax) was reduced by 20% with a standard meal and by 27% with a high-fat meal versus on an empty stomach (see section 5.2).

Rydapt is recommended to be administered with food.