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Rydapt

Last reviewed on RxList: 3/13/2020
Drug Description

RYDAPT®
(midostaurin) Capsules

DESCRIPTION

RYDAPT (midostaurin) is a multikinase inhibitor for oral use. The molecular formula for midostaurin is C35H30N4O4. The molecular weight is 570.65 g/mole. The chemical name of midostaurin is N-[(2S,3R,4R,6R)-3-Methoxy-2-methyl-16- oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27- nonaen-4-yl]-N-methylbenzamide. The chemical structure of midostaurin is shown below:

RYDAPT® (midostaurin) Structural Formula Illustration

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

Indications

INDICATIONS

Acute Myeloid Leukemia

RYDAPT is indicated, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by a FDA approved test [see DOSAGE AND ADMINISTRATION, Clinical Studies].

Limitations Of Use

RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML.

Systemic Mastocytosis

RYDAPT is indicated for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

QUESTION

What is leukemia? See Answer
Dosage

DOSAGE AND ADMINISTRATION

Patient Selection

Select patients for the treatment of AML with RYDAPT based on the presence of FLT3 mutation positivity [see Clinical Studies]. Information on FDA-approved tests for the detection of FLT3 mutation in AML is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage In Acute Myeloid Leukemia

The recommended dose of RYDAPT for patients with acute myeloid leukemia is 50 mg orally twice daily with food on Days 8 to 21 of each cycle of induction with cytarabine and daunorubicin and on Days 8 to 21 of each cycle of consolidation with high-dose cytarabine [see Clinical Studies]. For a description of the experience with single-agent treatment with RYDAPT beyond induction and consolidation, see Clinical Studies.

Recommended Dosage In ASM, SM-AHN, And MCL

The recommended dose of RYDAPT for patients with ASM, SM-AHN, and MCL is 100 mg orally twice daily with food. Continue treatment until disease progression or unacceptable toxicity occurs. Table 1 provides recommendations for dose modifications of RYDAPT in patients with ASM, SM-AHN, and MCL. Monitor patients for toxicity at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter while on treatment.

Table 1: RYDAPT Dose Modifications for Patients with Systemic Mastocytosis

Criteria RYDAPT Dosing
ANC less than 1 x 109/L attributed to RYDAPT in patients without MCL, or ANC less than 0.5 x 109/L attributed to RYDAPT in patients with baseline ANC value of 0.5-1.5 x 109/L Interrupt RYDAPT until ANC greater than or equal to 1 x 109/L, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue RYDAPT if low ANC persists for > 21 days and is suspected to be related to RYDAPT.
Platelet count less than 50 x 109/L attributed to RYDAPT in patients without MCL, or platelet count less than 25 x 109/L attributed to RYDAPT in patients with baseline platelet count of 25-75 x 109/L Interrupt RYDAPT until platelet count greater than or equal to 50 x 109/L, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue if low platelet count persists for > 21 days and is suspected to be related to RYDAPT.
Hemoglobin less than 8 g/L attributed to RYDAPT in patients without MCL, or life-threatening anemia attributed to RYDAPT in patients with baseline hemoglobin value of 8 -10 g/L Interrupt RYDAPT until hemoglobin greater than or equal to 8 g/L, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue if low hemoglobin persists for > 21 days and is suspected to be related to RYDAPT.
Grade 3/4 nausea and/or vomiting despite optimal anti-emetic therapy Interrupt RYDAPT for 3 days (6 doses), then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily.
Other Grade 3/4 non-hematological toxicities Interrupt RYDAPT until event has resolved to ≤ Grade 2, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily.
ANC: Absolute Neutrophil Count
CTCAE severity: Grade 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms.

Recommended Administration

  • Administer prophylactic anti-emetics before treatment with RYDAPT to reduce the risk of nausea and vomiting.
  • Administer RYDAPT orally with food, twice daily at approximately 12 hour intervals [see CLINICAL PHARMACOLOGY]. Do not open or crush RYDAPT capsules.
  • If a dose of RYDAPT is missed or vomited, do not make up the dose; take the next dose at the usual scheduled time.
  • Consider interval assessments of QT by EKG if RYDAPT is taken concurrently with medications that can prolong the QT interval.

HOW SUPPLIED

Dosage Forms And Strengths

25 mg capsules: pale orange oblong soft capsule with red ink imprint ‘PKC NVR'.

Storage And Handling

RYDAPT 25 mg capsules

Pale orange oblong soft capsule with red ink imprint "PKC NVR"; available in:

56 soft capsules..............NDC 0078-0698-99

Contents: Each carton contains two inner packs, each with 28 capsules (7 blister cards with 4 capsules each)

112 soft capsules..............NDC 0078-0698-19

Contents: Each carton contains four inner packs, each with 28 capsules (7 blister cards with 4 capsules each)

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature. Store in the original package to protect from moisture.

Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936. Revised: April 2017

Warnings & Precautions

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal reproduction studies, RYDAPT may cause fetal harm when administered to pregnant women. In animal studies, midostaurin caused embryo-fetal toxicities, including late embryofetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose. Advise pregnant women of the potential risk to the fetus. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating RYDAPT therapy. Advise females of reproductive potential to use effective contraception during treatment with RYDAPT and for at least 4 months after the last dose. Advise males with female partners to use effective contraception during treatment with RYDAPT and for 4 months after the last dose [see Use In Specific Populations, CLINICAL PHARMACOLOGY].

Pulmonary Toxicity

Cases of interstitial lung disease and pneumonitis, some fatal, have occurred in patients treated with RYDAPT as monotherapy or with chemotherapy. Monitor patients for pulmonary symptoms. Discontinue RYDAPT in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

  • Pulmonary Adverse Reactions: Inform patients to seek medical attention for new cough, chest discomfort, or shortness of breath [see WARNINGS AND PRECAUTIONS].
  • Gastrointestinal Adverse Reactions: Inform patients that RYDAPT can cause nausea, vomiting, and diarrhea. Advise patients to contact their healthcare provider if these symptoms occur or are persisting despite supportive medications [see ADVERSE REACTIONS].
  • Embryo-Fetal Toxicity
    • Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RYDAPT and for at least 4 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
    • Advise male patients with female partners of reproductive potential to use effective contraception during treatment with RYDAPT and for 4 months after the last dose [see Use In Specific Populations].
  • Lactation
    • Advise women not to breastfeed during treatment with RYDAPT and for at least 4 months after the final dose [see Use In Specific Populations].
  • Infertility
    • Advise females and males of reproductive potential that RYDAPT may impair fertility [see Use In Specific Populations, Nonclinical Toxicology].

Nonclinical Toxicology

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).

Use In Specific Populations

Pregnancy

Risk Summary

Based on mechanism of action and findings in animal reproduction studies, RYDAPT may cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. There are no available data on RYDAPT use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, oral administration of midostaurin to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose [see Data]. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

When midostaurin was administered to female rats prior to mating and through the first week of pregnancy at a dose of 60 mg/kg/day (approximately 0.1 times the human exposure at the recommended dose based on AUC), there were increases in pre- and post-implantation loss, including total litter loss, resulting in a reduction in the number of live embryos.

During organogenesis, midostaurin administered at oral doses greater than or equal to 3 mg/kg/day (approximately 0.004 times the human exposure at the recommended dose by AUC) to pregnant female rats caused late embryo-fetal death. Dilated lateral brain ventricles were observed in offspring of rats given doses greater than or equal to 3 mg/kg/day. Extra rib and reduced fetal birth weight with effects on fetal growth (severe renal pelvic cavitation and widened anterior fontanelle) were observed in the absence of maternal toxicity at the highest dose of 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). Midostaurin administered orally to pregnant rabbits during organogenesis led to maternal toxicity with spontaneous abortions and some delay in fetal growth (reduced fetal birth weight) at doses greater than or equal to 10 mg/kg/day (approximately 0.01 times the human exposure at the recommended dose by AUC).

In an oral pre- and postnatal development study in the rat, adverse effects upon maternal performance included dams with signs of dystocia and a lower live litter size at 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). For the F1 offspring, lower body weights, accelerated complete eye opening and delayed auricular startle ontogeny were noted at 30 mg/kg/day.

Lactation

Risk Summary

There are no data on the presence of midostaurin or its active metabolites in human milk, the effect on the breastfed infant, or the effect on milk production. Orally administered midostaurin and its active metabolites pass into the milk of lactating rats within 1 hour of a 30 mg/kg/day dose, with approximately 5 times more in the milk of lactating rats compared to plasma. Because of the potential for serious adverse reactions in breastfed infants from RYDAPT advise women not to breastfeed during treatment with RYDAPT and for at least 4 months after the last dose.

Females And Males Of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating RYDAPT.

Contraception

Females

RYDAPT may cause fetal harm when administered to a pregnant woman [see Pregnancy]. Advise females of reproductive potential to use effective contraception during treatment with RYDAPT and for 4 months after the last dose.

Males

Males with female sexual partners of reproductive potential should use effective contraception during RYDAPT treatment and for at least 4 months after stopping treatment with RYDAPT [see Nonclinical Toxicology].

Infertility

Based on findings in animals, RYDAPT may impair fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology].

Pediatric Use

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

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.

Overdosage & Contraindications

OVERDOSE

No Information Provided

CONTRAINDICATIONS

RYDAPT is contraindicated in patients with hypersensitivity to midostaurin or to any of the excipients [see DESCRIPTION]. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see ADVERSE REACTIONS].

Clinical Pharmacology

CLINICAL PHARMACOLOGY

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, VEGFR2, 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.

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: 18.4% vs 10.7%).

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 area under the curve 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].

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 a1-acid glycoprotein in vitro.

Elimination

The geometric mean terminal half-life (% coefficient of variation) is 21 hours (19%) 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 (20-94 years), sex, race, and mild (total bilirubin greater than 1.0 to 1.5 times the upper limit of normal (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 or 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

Effect Of Strong CYP3A4 Inhibitors On Midostaurin

Coadministration of ketoconazole (400 mg daily for 10 days) with a single dose of RYDAPT (50 mg) on Day 6 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].

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].

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].

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.

Clinical Studies

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) to receive RYDAPT 50 mg twice daily (n=360) or placebo (n=357) with food on Days 8- 21 in combination with daunorubicin (60 mg/m2 daily on Days 1 to 3) /cytarabine (200 mg/m2 daily on Days 1 to 7) for up to two cycles of induction and high dose cytarabine (3 g/m2 every 12 hours on Days 1, 3 and 5) for up to four cycles of consolidation, followed by continuous RYDAPT or placebo treatment according to initial assignment for up to 12 additional 28-day cycles. There was no re-randomization at the start of post consolidation therapy. Patients who proceeded to hematopoietic stem cell transplantation (SCT) stopped receiving study treatment.

The randomized patients had a median age of 47 years (range, 18-60 years), 44% were male, and 88% had a performance status of 0-1. AML was de novo onset in 95%. The percentage of patients with FLT3-ITD allelic ratio < 0.7, FLT3-ITD allelic ratio ≥ 0.7, and FLT3-TKD mutations were identical (per randomized FLT3 stratum) on both arms (48%, 30%, and 23%, respectively). Of the 563 patients with NPM1 testing, 58% had an NPM1 mutation. The two treatment groups were generally balanced with respect to the baseline demographics and disease characteristics, except that the placebo arm had a higher percentage of females (59%) than in the midostaurin arm (52%). NPM1 mutations were identified in 55% of patients tested on the midostaurin arm and 60% of patients tested on the placebo arm.

A second course of induction was administered to 25% of the patients, 62% initiated at least one cycle of consolidation, 29% initiated maintenance, and 17% completed all 12 planned cycles of maintenance; 21% of the patients underwent SCT in first CR. The overall rate of SCT (induction failure, first CR or salvage after relapse) was 59% (214/360) of patients in the RYDAPT plus standard chemotherapy arm vs. 55% (197/357) in the placebo plus standard chemotherapy arm. All patients were followed for survival.

Efficacy was established on the basis of overall survival (OS), measured from the date of randomization until death by any cause. The primary analysis was conducted after a minimum follow-up of approximately 3.5 years after the randomization of the last patient. RYDAPT plus standard chemotherapy was superior to placebo plus standard chemotherapy in OS (HR 0.77; 95% CI 0.63, 0.95; 2 sided p=0.016) (Figure 1). Because survival curves plateaued before reaching the median, median survival could not be reliably estimated.

Figure 1: Kaplan-Meier Curve for Overall Survival in Study 1

Kaplan-Meier Curve for Overall Survival in Study 1 - Illustration

The analysis of event-free survival (EFS), defined as a failure to obtain a complete remission (CR) within 60 days of initiation of protocol therapy, or relapse, or death from any cause, showed a statistically significant improvement with a median of 8.2 months for RYDAPT plus standard chemotherapy versus 3.0 months for placebo plus standard chemotherapy with HR 0.78 (95% CI 0.66, 0.93) and 2 sided p=0.005. In an exploratory analysis of EFS defined as a failure to obtain a CR any time during induction, or relapse, or death from any cause with failures assigned as an event on study day 1, the median EFS was 10.6 months for RYDAPT plus standard chemotherapy versus 5.6 months for placebo plus standard chemotherapy with HR 0.72 (95% CI 0.61, 0.86).

Systemic Mastocytosis

Study 2

A single-arm, open-label, multicenter trial evaluated the efficacy of RYDAPT as a single agent in ASM, SM-AHN, and MCL, collectively referred to as advanced SM. The study enrolled 116 adult patients with relapse or progression to 0, 1, or 2 prior regimens for SM. The study excluded patients with serum creatinine > 2.0 mg/dL, hepatic transaminases > 2.5 x upper limit of normal (ULN) or > 5 x ULN if disease-related, total bilirubin > 1.5 x ULN or > 3 x ULN if disease-related, QTc > 450 msec, cardiovascular disease including left-ventricular ejection fraction < 50%, or any pulmonary infiltrates. In addition, the study excluded patients with acute-stage or life-threatening AHN. Patients received RYDAPT 100 mg orally twice daily in 28-day cycles until disease progression or intolerable toxicity.

Of the 116 patients treated, a study steering committee identified 89 patients who had measurable C-findings and were evaluable for response. The median age in this group was 64 years (range: 25 to 82), 64% of patients were male, and nearly all patients (97%) were Caucasian. Among these patients, 36% had prior therapy for SM, and 82% had the KIT D816V mutation detected at baseline. Their median duration of treatment was 11 months (range: < 1 to 68 months), with treatment ongoing in 17%.

Efficacy was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by 6 cycles of RYDAPT by modified Valent criteria for ASM and SM-AHN (Table 7). Table 7 shows responses to RYDAPT according to modified Valent criteria. Confirmed major or partial responses occurred in 46 of 73 patients with a documented KIT D816V mutation, 7 of 16 with wild-type or unknown status with respect to KIT D816V mutation, and 21 of 32 having prior therapy for SM.

Table 7: Efficacy of RYDAPT in Systemic Mastocytosis per Modified Valent Criteria (Study 2)

Modified Valent Criteria: All patients evaluated e
(N = 89)
ASM
(N = 16)
SM-AHN
(N = 57)
MCL
(N = 16)
CR+ICR by 6 cycles, n a,b 19 (21%) 6 (38%) 9 (16%) 4 (25%)
  (95% CI, %) (13, 31) (15, 65) (7, 28) (7, 52)
Median Duration of CR+ICR (months) c NR NR NR NR
  (95% CI) (24.1, NE) (24.1, NE) (7.4, NE) (NE, NE)
  Range d 6.6+, 65.8+ 12.1+, 36.8+ 6.6+, 52.1+ 19.1+, 65.8+
Median Time to CR+ICR (months) 0.5 0.7 0.5 0.3
  Range 0.1, 3.0 0.3, 1.9 0.1, 3.0 0.1, 0.5
NE Not Estimated; NR Not Reached
a Per Study Steering Committee. Response confirmation after ≥ 8 weeks was required. No CRs were reported.
b Patients who received concomitant high-dose corticosteroids were considered unevaluable and were excluded from response assessment.
c Among patients with a response of CR or ICR. The estimated median follow-up for duration of response was 35.4 months overall.
d A + sign indicates a censored value.
e 25 patients were not assessable for the presence of MCL on central histopathology review, and 11 patients with unconfirmed presence of AHN were regarded as not having AHN.

As a post-hoc exploratory analysis, efficacy was also assessed per the 2013 International Working Group- Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRTECNM) consensus criteria. Response after 6 cycles of RYDAPT was determined using a computational algorithm. The efficacy of RYDAPT for MCL was based on the CR results by IWG-MRT-ECNM. There were 115 patients evaluable for response assessment, of whom 47 (41%) had prior therapy for SM, and 93 (81%) had a documented D816V mutation at baseline. Table 8 provides the results of this analysis. Overall response by IWG-MRT-ECNM criteria was reported for 16 (17%) of 93 patients with a documented D816V mutation, and in 8 (17%) of 47 patients having prior therapy for SM.

Table 8: Efficacy of RYDAPT in Systemic Mastocytosis per IWG-MRT-ECNM Consensus Criteria Using an Algorithmic Approach (Study 2)

  All patients evaluated
(N = 115) b, c
ASM
(N = 16)
SM-AHN
(N = 72)
MCL
(N = 21)
Subtype not established
(N = 6)
Overall Response in 6 cycles, n a 19 (17%) 5 (31%) 8 (11%) 4 (19%) 2 (33%)
  (95% CI) (10, 25) (11, 59) (5, 21) (5, 42) (4, 78)
Best Overall Response, n
  Complete Remission 2 (2%) 1 (6%) 0 (0%) 1 (5%) 0 (0%)
  Partial Remission 17 (15%) 4 (25%) 8 (11%) 3 (14%) 2 (33%)
Duration of Response (months) d
  Range 6.8+, 60.5+ 10.2+, 36.4+ 6.8+, 51.8+ 8.6+, 55.9+ 27.3+, 60.5+
a Determined with 12-week confirmation. Patients who received high-dose corticosteroids were considered evaluable for response.
b Median exposure to midostaurin was 11.5 (range: 0.3, 68.3) months.
c 31 patients were not assessable for MCL on central review, and 15 patients with unconfirmed AHN were classified as not having AHN.
d Median DOR was not reached in any subtype. Median follow up for DOR, among all responders, was 35.0 months.

Study 3

Study 3 was a single-arm, multicenter, open-label trial of 26 patients with advanced SM. RYDAPT was administered orally at 100 mg twice daily with food. The median age in this group was 64 years, 58% of patients were male and most were Caucasian (81%). Eligibility criteria were similar to Study 2. By Valent criteria per investigator assessment, of 17 patients with SM-AHN, 10 achieved a response (1 partial, 9 major) by 2 cycles that was sustained for at least 8 weeks. Patients who received concomitant corticosteroids were included. Of the 6 patients with MCL, 1 achieved partial response and 1 achieved major response. Median DOR for either group had not been reached, with DOR ranging from 3.4+ to 79.2+ months in patients with SM-AHN and 28.6+ to 32.1+ months in patients with MCL. The subtype of SM in the remaining 3 patients was unconfirmed.

Medication Guide

PATIENT INFORMATION

RYDAPT®
(rye-dapt)
(midostaurin) capsules

What is RYDAPT?

RYDAPT is an oral prescription medicine used to treat adults:

  • with newly diagnosed with a certain type of acute myeloid leukemia (AML), in combination with certain chemotherapy medicines
    • Your healthcare provider will perform a test to make sure RYDAPT is right for you.
  • with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL)

It is not known if RYDAPT is safe and effective in children.

Do not take RYDAPT if you are allergic to midostaurin or any of the ingredients in RYDAPT. See the end of this leaflet for a complete list of ingredients in RYDAPT.

  • Signs and symptoms of an allergic reaction to RYDAPT have included trouble breathing, flushing, chest pain, throat tightness, and swelling of your lips, mouth, or throat. Get medical help right away if you have any of these signs or symptoms.

Before you take RYDAPT, tell your healthcare provider about all of your medical conditions, including if you:

  • have any lung or breathing problems
  • are pregnant or plan to become pregnant. RYDAPT may cause harm to your unborn baby. Tell your healthcare provider right away if you become pregnant during treatment with RYDAPT or think you may be pregnant.
    • If you are able to become pregnant, your healthcare provider may perform a pregnancy test within 7 days before you start RYDAPT.
    • Females who are able to become pregnant should use effective birth control (contraception) during treatment with RYDAPT and for at least 4 months after the last dose of RYDAPT.
    • Males who have female partners that are able to become pregnant should use effective birth control during treatment with RYDAPT and for at least 4 months after the last dose of RYDAPT.
  • are breastfeeding or plan to breastfeed. It is not known if RYDAPT passes into your breast milk. You should not breastfeed during treatment with RYDAPT and for at least 4 months after the last dose of RYDAPT.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I take RYDAPT?

  • Take RYDAPT exactly as your healthcare provider tells you.
  • Your healthcare provider will tell you how many capsules of RYDAPT you need to take. Do not change your dose unless your healthcare provider tells you to.
  • Your healthcare provider will prescribe medicines to help prevent the nausea and vomiting during treatment with RYDAPT.
  • Take RYDAPT 2 times a day (about every 12 hours apart)
  • Take RYDAPT with food.
  • Do not open or crush RYDAPT capsules.
  • If you miss a dose of RYDAPT, take your next dose at your scheduled time. Do not take an extra dose to make up for a missed dose.
  • If you vomit after taking a dose of RYDAPT, do not take an extra dose. Take your next dose at your scheduled time.

What are the possible side effects of RYDAPT?

RYDAPT may cause serious side effects, including:

  • Lung problems. RYDAPT may cause lung problems that may lead to death when used alone or in combination with other chemotherapy medicines. Get medical help right away if you have any new or worsening lung symptoms, including cough, chest discomfort, or shortness of breath.

The most common side effects of RYDAPT in people with AML include:

  • low white blood cell counts with fever (febrile neutropenia)
  • nausea
  • redness, pain or ulcers on the inside your mouth (mucositis)
  • vomiting
  • headache
  • bruising
  • muscle or bone pain
  • nose bleeds
  • device-related infection
  • high blood sugar levels (hyperglycemia)
  • upper respiratory tract infection

The most common side effects of RYDAPT in people with ASM, SM-AHN, or MCL include:

  • nausea
  • vomiting
  • diarrhea
  • swelling in your hands, feet, or ankles
  • muscle or bone pain
  • stomach-area pain
  • tiredness
  • upper respiratory tract infection
  • constipation
  • fever
  • headache
  • trouble breathing

Call or inform your healthcare provider if nausea, vomiting or diarrhea occurs, gets worse or does not go away.

RYDAPT may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.

Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking RYDAPT if you develop certain side effects during treatment with RYDAPT.

Your healthcare provider will do blood tests to check you for side effects during treatment with RYDAPT.

These are not all of the possible side effects of RYDAPT. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store RYDAPT?

  • Store RYDAPT at room temperature between 68°F to 77°F (20°C to 25°C).
  • Keep RYDAPT in the original package to protect from moisture.

Keep RYDAPT and all medicines out of the reach of children.

General information about the safe and effective use of RYDAPT.

Medicines are sometimes prescribed for conditions not listed in the Patient Information leaflet. Do not take RYDAPT for a condition for which it was not prescribed. Do not give RYDAPT to other people, even if they have the same condition or symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about RYDAPT that is written for healthcare professionals.

What are the ingredients in RYDAPT?

Active ingredient: midostaurin

Inactive ingredients: polyoxyl 40 hydrogenated castor oil, gelatin, polyethylene glycol 400, glycerin 85%, dehydrated alcohol, corn oil mono-di-triglycerides, titanium dioxide, vitamin E, ferric oxide yellow, ferric oxide red, carmine, hypromellose 2910, propylene glycol, and purified water

This Patient Informa ion has been approved by the U.S. Food and Drug Administration

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Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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