RYDAPT (Page 3 of 6)

8.4 Pediatric Use

Safety and effectiveness of RYDAPT have not been established in pediatric patients.

The safety and effectiveness of an unapproved midostaurin formulation was investigated, but not established in two open-label studies: a study in 22 pediatric patients aged 6 months to 17 years who received midostaurin as a single agent for relapsed or refractory leukemia [NCT00866281] and a study in 4 patients aged 8 to 14 years who received midostaurin in combination with chemotherapy for newly diagnosed FLT3-mutated AML [NCT03591510]. Prolonged Grade 4 neutropenia and thrombocytopenia occurred in 2 of the 4 pediatric patients with AML who received midostaurin in combination with chemotherapy, including anthracyclines, fludarabine, and cytarabine [see Warnings and Precautions (5.3)]. Grade 4 thrombocytopenia lasted for 44 days in one patient and Grade 4 thrombocytopenia and Grade 4 neutropenia lasted for 51 days and 46 days, respectively, in the other patient. These two patients were coadministered an azole antifungal (a strong CYP3A4 inhibitor), which may increase midostaurin concentrations and subsequently, the risk of toxicity [see Drug Interactions (7.1)].

8.5 Geriatric Use

Of the 142 patients with advanced SM in clinical studies of RYDAPT, 64 (45%) were aged 65 and over, and 16 (11%) were aged 75 years and over. No overall differences in safety or response rate were observed between the subjects aged 65 and over compared with younger subjects. Greater sensitivity of older individuals cannot be ruled out.

Clinical studies in AML with RYDAPT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

In general, administration for elderly patients should be cautious, based on patient’s eligibility for concomitant chemotherapy and reflecting the greater frequency of concomitant disease or other drug therapy.

11 DESCRIPTION

Midostaurin is a kinase inhibitor for oral use. The molecular formula for midostaurin is C35 H30 N4 O4 . The molecular weight is 570.65 g/mol. The chemical name of midostaurin is Benzamide, N -[(9S ,10R ,11R ,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H ,9H -diindolo[1,2,3-gh:3′,2′,1′-lm ]pyrrolo[3,4-j ][1,7]benzodiazonin-11-yl ]-N -methyl-. The chemical structure of midostaurin is shown below:

Structural Formula
(click image for full-size original)

RYDAPT is supplied as a soft capsule containing 25 mg of midostaurin. The capsule contains carmine, corn oil mono-di-triglycerides, dehydrated alcohol, ferric oxide red, ferric oxide yellow, gelatin, glycerin 85%, hypromellose 2910, polyethylene glycol 400, polyoxyl 40 hydrogenated castor oil, propylene glycol, purified water, titanium dioxide, and vitamin E.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases. In vitro biochemical or cellular assays have shown that midostaurin or its major human active metabolites CGP62221 and CGP52421 inhibit the activity of wild type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFRα/β, as well as members of the serine/threonine kinase PKC (protein kinase C) family.

Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation and histamine release and induce apoptosis in mast cells.

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of RYDAPT (75 mg twice daily for 3 days) on the QTc interval was evaluated in a randomized, placebo and moxifloxacin controlled, multiple-dose, blinded, parallel study. There was no clinically significant prolongation of QTc interval or relationship between changes in QTc and concentrations for midostaurin and its active metabolites (CGP62221 and CGP52421). The study duration was not long enough to estimate the effects of the metabolite CGP52421 on the QT/QTc interval.

In pooled clinical studies in patients with advanced SM, 4.7% patients had a post-baseline QTcF > 480 ms, no patients had a QTcF > 500 ms, and 6.3% patients had a QTcF > 60 ms compared to baseline.

In a randomized placebo-controlled study in patients with AML, the proportion of patients with QTc prolongation was higher in patients randomized to midostaurin as compared to placebo (QTcF > 480 ms: 10.1% vs 5.7%; QTcF > 500 ms: 6.2% vs 2.6%; QTcF > 60 ms change from baseline: 18.4% vs 10.7%).

12.3 Pharmacokinetics

Midostaurin exhibits time-dependent pharmacokinetics with an initial increase in minimum concentrations (Cmin ) that reach the highest Cmin concentrations during the first week followed by a decline to a steady-state after approximately 28 days. The pharmacokinetics of the CGP62221 showed a similar trend. The plasma concentrations of CGP52421 continued to increase after one month of treatment.

The highest Cmin and steady-state of midostaurin, CGP62221, and CGP52421 were similar when RYDAPT was administered with food at a dose of 50 mg twice daily or 100 mg twice daily.

Absorption

The time to maximal concentrations (Tmax ) occurred between 1 to 3 hours post dose in the fasted state.

Effect of Food

Midostaurin exposure, represented by AUC over time to infinity (AUCinf ), increased 1.2-fold when RYDAPT was coadministered with a standard meal (457 calories, 50 g fat, 21 g proteins, and 18 g carbohydrates) and 1.6-fold when coadministered with a high-fat meal (1007 calories, 66 g fat, 32 g proteins, and 64 g carbohydrates) compared to when RYDAPT was administered in a fasted state. Midostaurin maximum concentrations (Cmax ) were reduced by 20% with a standard meal and by 27% with a high-fat meal compared to a fasted state. Tmax was delayed when RYDAPT was administered with a standard meal or a high-fat meal (median Tmax = 2.5 hrs to 3 hrs) [see Dosage and Administration (2.5)].

Distribution

Midostaurin has an estimated geometric mean volume of distribution (% coefficient of variation) of 95.2 L (31%). Midostaurin and its metabolites are distributed mainly in plasma in vitro. Midostaurin, CGP62221, and CGP52421 are greater than 99.8% bound to plasma protein in vitro. Midostaurin is mainly bound to α1-acid glycoprotein in vitro.

Elimination

The geometric mean terminal half-life (% coefficient of variation) is 19 hours (39%) for midostaurin, 32 hours (31%) for CGP62221 and 482 hours (25%) for CGP52421.

Metabolism

Midostaurin is primarily metabolized by CYP3A4. CGP62221 and CGP52421 (mean ± standard deviation) account for 28 ± 2.7% and 38 ± 6.6% respectively of the total circulating radioactivity.

Excretion

Fecal excretion accounted for 95% of the recovered dose with 91% of the recovered dose excreted as metabolites and 4% of the recovered dose as unchanged midostaurin. Only 5% of the recovered dose was found in urine.

Specific Populations

Age (20 to 94 years), sex, race, mild (total bilirubin greater than 1.0 to 1.5 times the ULN or aspartate aminotransferase (AST) greater than the ULN) or moderate (total bilirubin 1.5 to 3.0 times the ULN and any value for AST) hepatic impairment, and renal impairment (creatinine clearance (CLCr) ≥ 30 mL/min) did not have clinically meaningful effects on the pharmacokinetics of midostaurin, CGP62221, or CGP52421. The pharmacokinetics of midostaurin in patients with baseline severe hepatic impairment (total bilirubin greater than 3.0 times the ULN and any value for AST) or severe renal impairment (CLCr 15 to 29 mL/min) is unknown.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Effect of Strong CYP3A4 Inhibitors on Midostaurin

Coadministration of ketoconazole (a strong CYP3A4 inhibitor) with a single dose of RYDAPT (50 mg) increased AUCinf of midostaurin by 10.4-fold and CGP62221 by 3.5-fold and area under the curve over time to last measurable concentrations (AUC0-t ) of CGP52421 by 1.2-fold compared to a single RYDAPT dose coadministered with placebo [see Drug Interactions (7.1)].

Coadministration of itraconazole (a strong CYP3A4 inhibitor) 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 (a strong CYP3A4 inducer) with a single dose of RYDAPT (50 mg) 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 CYP2B6 Substrates

Coadministration of multiple doses of RYDAPT (50 mg twice daily) at steady-state with a single dose of bupropion (a sensitive CYP2B6 substrate) decreased the AUCinf of bupropion by 48% and hydroxybupropion by 65% [see Drug Interactions (7.2)].

Effect of Midostaurin on CYP3A, CYP2C8, CYP2D6 Substrates

Coadministration of multiple doses of RYDAPT (50 mg twice daily) at steady-state with single doses of midazolam (a sensitive CYP3A substrate) or pioglitazone (a moderate sensitive CYP2C8 substrate) did not affect AUCinf of midazolam or pioglitazone. However, the effect of multiple doses of RYDAPT on sensitive substrates of CYP3A and CYP2C8 during the first week, when midostaurin trough concentrations are highest, is unknown.

Coadministration of a single dose of RYDAPT (100 mg) with a single dose of dextromethorphan (a sensitive CYP2D6 substrate) did not affect the AUCinf of dextromethorphan. The effect of multiple doses of RYDAPT on dextromethorphan is unknown.

Coadministration of multiple doses of RYDAPT (50 mg twice daily) at steady-state with a single dose of a hormonal contraceptive containing ethinyl estradiol and levonorgestrel (CYP3A4 substrates) increased the area under the curve over time to the last measurable concentration (AUClast ) of ethinyl estradiol by 10% and levonorgestrel by 42%. However, the effect of multiple doses of RYDAPT on ethinyl estradiol and levonorgestrel during the first week, when midostaurin trough concentrations are highest, is unknown.

Effect of Midostaurin on P-gp, BCRP, and OATP1B1 Substrates

Coadministration of a single dose of RYDAPT (100 mg) with a single dose of rosuvastatin (BCRP and OATP1B1 substrate) increased the AUClast of rosuvastatin by 48%. RYDAPT 50 mg twice daily at steady state is predicted to increase the AUC of an OATP1B1 substrate up to 2-fold, with unknown effect on a BCRP substrate [see Drug Interactions (7.2)].

Coadministration of a single dose of RYDAPT (100 mg) with a single dose of digoxin (sensitive P-gp substrate) did not affect the AUCinf of digoxin. The effect of multiple doses of RYDAPT on digoxin is unknown.

In Vitro Studies

Effect of Midostaurin on CYP Enzymes

Midostaurin inhibits CYP1A2 and CYP2E1; CGP62221 inhibits CYP1A2 in vitro. Midostaurin, CGP52421, and CGP62221 induce CYP1A2 in vitro.

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