Coadministration of itraconazole (100 mg twice daily on Days 22-28 for 13 doses) with multiple doses of RYDAPT (100 mg twice daily on Days 1 to 2 and 50 mg twice daily on Days 3 to 28) increased Day 28 Cmin concentrations of midostaurin by 2.1-fold, CGP62221 by 1.2-fold, and CGP52421 by 1.3-fold compared to the respective Day 21 Cmin concentrations with RYDAPT alone [see Drug Interactions (7.1)].

Effect of Strong CYP3A4 Inducers on Midostaurin

Coadministration of rifampicin (600 mg daily on Days 1 to 14) with a single dose of RYDAPT (50 mg) on Day 9 decreased AUCinf of midostaurin by 96% and CGP62221 by 92% and AUC0-t of CGP52421 by 59% [see Drug Interactions (7.1)].

Effect of Midostaurin on Sensitive CYP3A substrates

Midazolam (sensitive CYP3A substrate) AUCinf was not affected following 4 days of RYDAPT administration. The clinical relevance of this interaction is unknown as the RYDAPT was administered for only 4 days.
Effects of Midostaurin

Midostaurin, CGP52421 and CGP62221 inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, and induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A in vitro.
Midostaurin inhibits organic anion transporter polypeptide (OATP) 1A1 and induces multidrug resistance protein (MRP) 2 in vitro.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been performed with midostaurin.
Midostaurin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or in Chinese hamster V97 cells. Midostaurin increased the frequency of polyploidy cells in an in vitro chromosomal aberrations assay in Chinese hamster ovary cells, but was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 200 mg/kg (1200 mg/m2). This dose was approximately 20-fold the recommended human dose, based on body surface area.
Reproductive toxicity was observed in a fertility study, in male and females rats given oral doses of midostaurin at 10, 30 and 60 mg/kg/day (approximately 0.01, 0.05, and 0.1 times, respectively, the AUC at the recommended human dose). In males, testicular degeneration and atrophy was observed at doses greater than or equal to 10 mg/kg/day and reduced sperm count and motility, and a decrease in reproductive organ weights were observed at 60 mg/kg/day. In females, increased resorptions, decreased pregnancy rate, and decreased number of implants and live embryos were observed at 60 mg/kg/day. In a 3-month toxicology study in dogs, there was inhibition of spermatogenesis at doses greater than or equal to 3 mg/kg/day (approximately 0.01 times the exposure at the recommended human dose).
14 CLINICAL STUDIES
14.1 Acute Myeloid Leukemia
Study 1
RYDAPT in combination with chemotherapy was investigated in a randomized, double-blind placebo-controlled trial of 717 patients with newly-diagnosed FLT3-mutated AML. In this study, FLT3 mutation status was determined prospectively with a clinical trial assay and verified retrospectively using the companion diagnostic LeukoStrat® CDx FLT3 Mutation Assay, which is an FDA-approved test for selection of patients with AML for RYDAPT treatment. Patients were stratified by FLT3 mutation status: TKD, ITD with allelic ratio less than 0.7, and ITD with allelic ratio greater than or equal to 0.7. Patients with acute promyelocytic leukemia or therapy-related AML were not eligible. Patients were randomized (1:1