Midostaurin

Midostaurin
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand

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Black Box Warning

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Overview

Midostaurin is a Acetylcholine release inhibitor, Adrenergic receptor agonist that is FDA approved for the (type of indication of drug) of a list of indications, separated by commas.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include a list of adverse reactions, separated by commas..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Condition 1

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Condition 2

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Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition 1

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• Strength of Evidence: (Category A/B/C) (Link)

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Condition 2

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Non–Guideline-Supported Use

Condition 1

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Condition 2

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Condition 3

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Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition 1

• Dosing Information

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Condition 2

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Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition 1

• Developed by: (Organisation)

• Class of Recommendation: (Class) (Link)

• Strength of Evidence: (Category A/B/C) (Link)

• Dosing Information/Recommendation

• (Dosage)

Condition 2

• Developed by: (Organisation)

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• Strength of Evidence: (Category A/B/C) (Link)

• Dosing Information/Recommendation

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Non–Guideline-Supported Use

Condition 1

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Condition 2

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Condition 3

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Contraindications

CONTRAINDICATIONS

Warnings

Warning Title See full prescribing information for complete Boxed Warning. Condition Name: (Content)

Conidition 1

(Description)

Conidition 2

(Description)

Conidition 3

(Description)

Adverse Reactions

Clinical Trials Experience

Central Nervous System

(list/description of adverse reactions)

Cardiovascular

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Respiratory

(list/description of adverse reactions)

Gastrointestinal

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Hypersensitive Reactions

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Miscellaneous

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Condition 2

Central Nervous System

(list/description of adverse reactions)

Cardiovascular

(list/description of adverse reactions)

Respiratory

(list/description of adverse reactions)

Gastrointestinal

(list/description of adverse reactions)

Hypersensitive Reactions

(list/description of adverse reactions)

Miscellaneous

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Postmarketing Experience

(Description)

Drug Interactions

• Drug 1
• Drug 2
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Drug 1

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Drug 2

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Drug 3

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Drug 4

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Drug 5

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Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): (Description)
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Midostaurin in women who are pregnant.

Labor and Delivery

(Description)

Nursing Mothers

(Description)g

Pediatric Use

(Description)

Geriatic Use

(Description)

Gender

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Race

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Renal Impairment

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Hepatic Impairment

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Females of Reproductive Potential and Males

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Immunocompromised Patients

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Others

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Administration and Monitoring

Administration

(Oral/Intravenous/etc)

Monitoring

Condition 1

(Description regarding monitoring, from Warnings section)

Condition 2

(Description regarding monitoring, from Warnings section)

Condition 3

(Description regarding monitoring, from Warnings section)

IV Compatibility

There is limited information regarding the compatibility of Midostaurin and IV administrations.

Overdosage

Acute Overdose

Signs and Symptoms

(Description)

Management

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Chronic Overdose

Signs and Symptoms

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Management

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Pharmacology

Midostaurin
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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.

Structure

This image is provided by the National Library of Medicine.

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 (C_min) that reach the highest C_min 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 C_min 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 (T_max) 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 (AUC_inf), 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 (C_max) 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 T_max = 2.5 hrs to 3 hrs).

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 (20-94 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

Clinical 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 AUC_inf of midostaurin by 10.4-fold and CGP62221 by 3.5-fold and area under the curve over time to last measurable concentrations (AUC_0-t) of CGP52421 by 1.2-fold compared to a single RYDAPT dose coadministered with placebo.
• 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 C_min concentrations of midostaurin by 2.1-fold, CGP62221 by 1.2-fold, and CGP52421 by 1.3-fold compared to the respective Day 21 C_min concentrations with RYDAPT alone.

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 AUC_inf of midostaurin by 96% and CGP62221 by 92% and AUC_0-t of CGP52421 by 59%.

Effect of Midostaurin on Sensitive CYP3A substrates

• Midazolam (sensitive CYP3A substrate) AUC_inf 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.

In Vitro Studies

Effects of Midostaurin on CYP Enzymes

• Midostaurin inhibits CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A; CGP62221 inhibits CYP1A2, CYP2C8, CYP2C9, and CYP3A; and CGP52421 inhibits CYP2D6 and CYP3A in vitro. Midostaurin, CGP52421, and CGP62221 induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A in vitro.

Effects of Midostaurin on Transporters

• Midostaurin inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); CGP52421 and CGP62221 inhibit organic anion transporter polypeptide (OATP) 1B1 in vitro.

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).

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.

This image is provided by the National Library of Medicine.

• 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.

This image is provided by the National Library of Medicine.

• As a post-hoc exploratory analysis, efficacy was also assessed using modified 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) 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 these criteria. 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 modified 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.

This image is provided by the National Library of Medicine.

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.

How Supplied

• 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)

Storage

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

Images

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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.
• 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.
• 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.
• 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 (8.3)].
• Advise females who may have been exposed to RYDAPT during pregnancy directly or through male partner receiving RYDAPT therapy to contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and /or at https://psi.novartis.com/.

• Lactation

• Advise women not to breastfeed during treatment with RYDAPT and for at least 4 months after the final dose.

• Infertility

• Advise females and males of reproductive potential that RYDAPT may impair fertility.

This image is provided by the National Library of Medicine.

Precautions with Alcohol

Alcohol-Midostaurin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

• Rydapt

Look-Alike Drug Names

There is limited information regarding Midostaurin Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.