Rydapt

FDA Drug Information • Also known as: Rydapt

Brand Names: Rydapt
Drug Class: Kinase Inhibitor [EPC]
Route: ORAL
Dosage Form: CAPSULE, LIQUID FILLED
Product Type: HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION Midostaurin is a kinase inhibitor for oral use. The molecular formula for midostaurin is C 35 H 30 N 4 O 4 . The molecular weight is 570.65 g/mol. The chemical name of midostaurin is Benzamide, N -[(9 S ,10 R ,11 R ,13 R )-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1 H ,9 H -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: 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. Structural Formula

What Is Rydapt Used For?

1 INDICATIONS AND USAGE RYDAPT is a kinase inhibitor indicated for the treatment of adult patients with: Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. ( 1.1 ) Limitations of Use: RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML. Aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL). ( 1.2 ) 1.1 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 an FDA approved test [see Dosage and Administration (2.1), Clinical Studies (14.1)]. Limitations of Use RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML. 1.2 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).

Dosage and Administration

2 DOSAGE AND ADMINISTRATION AML : 50 mg orally twice daily with food. ( 2.1 , 2.2 , 2.4 ) ASM, SM-AHN, and MCL : 100 mg orally twice daily with food. ( 2.3 , 2.4 ) 2.1 Patient Selection Select patients for the treatment of AML with RYDAPT based on the presence of FLT3 mutation positivity [see Clinical Studies (14)] . Information on FDA-approved tests for the detection of FLT3 mutation in AML is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage in Acute Myeloid Leukemia The recommended dose of RYDAPT for patients with AML 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. For a description of the experience with single-agent treatment with RYDAPT beyond induction and consolidation [see Clinical Studies (14.1)] . 2.3 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 10 9 /L attributed to RYDAPT in patients without MCL, or ANC less than 0.5 x 10 9 /L attributed to RYDAPT in patients with baseline ANC value of 0.5-1.5 x 10 9 /L Interrupt RYDAPT until ANC greater than or equal to 1 x 10 9 /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 greater than 21 days and is suspected to be related to RYDAPT. Platelet count less than 50 x 10 9 /L attributed to RYDAPT in patients without MCL, or platelet count less than 25 x 10 9 /L attributed to RYDAPT in patients with baseline platelet count of 25-75 x 10 9 /L Interrupt RYDAPT until platelet count greater than or equal to 50 x 10 9 /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 greater than 21 days and is suspected to be related to RYDAPT. Hemoglobin less than 8 g/dL attributed to RYDAPT in patients without MCL, or life-threatening anemia attributed to RYDAPT in patients with baseline hemoglobin value of 8 to 10 g/dL Interrupt RYDAPT until hemoglobin greater than or equal to 8 g/dL, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue if low hemoglobin persists for greater than 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,...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Pulmonary Toxicity [see Warnings and Precautions (5.2)] AML : The most common adverse reactions (≥ 20%) were febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, electrocardiogram (ECG) QT prolonged, and upper respiratory tract infection. ( 6.1 ) ASM, SM-AHN, or MCL : The most common adverse reactions (≥ 20%) were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://report.novartis.com/ or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Acute Myeloid Leukemia The safety evaluation of RYDAPT (50 mg twice daily with food) in patients with newly diagnosed FLT3 mutated AML is based on a randomized, double-blind, trial of RYDAPT (n = 345) or placebo (n = 335) with chemotherapy [see Clinical Studies (14.1)] . The overall median duration of exposure was 42 days (range, 2 to 576 days) for patients in the RYDAPT plus chemotherapy arm versus 34 days (range, 1 to 465 days) for patients in the placebo plus chemotherapy arm. On the RYDAPT plus chemotherapy arm, 35% of patients completed induction and consolidation therapy, compared to 25% of patients on the placebo plus chemotherapy arm. The most frequent (incidence greater than or equal to 20%) adverse drug reactions (ADRs) in the RYDAPT plus chemotherapy arm were febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, ECG QT prolonged, and upper respiratory tract infections. The most frequent Grade 3/4 adverse reactions (incidence ≥ 10%) were febrile neutropenia, device-related infection, and mucositis. The most frequent serious adverse reaction (≥ 10%) in patients in the RYDAPT plus chemotherapy arm was febrile neutropenia (16%), which occurred at a similar rate in the placebo arm (16%). Discontinuation due to any adverse reaction occurred in 9% of patients in the RYDAPT arm versus 6% in the placebo arm. The most frequent (> 1%) Grade 3/4 adverse reactions leading to discontinuation in the RYDAPT arm was renal insufficiency (1%). Excluding deaths due to disease progression, no fatal adverse reactions occurred in the study. Overall, the most frequent non-treatment related cause of death in the RYDAPT plus chemotherapy arm was sepsis (2%) and occurred at a similar rate in the placebo arm (2%). Table 2 presents the frequency category of adverse reactions reported in the randomized trial in patients with newly diagnosed FLT3 mutated AML. Adverse reactions are listed according to body system. Within each body system, the adverse reactions are ranked by frequency, with the most frequent reactions first. Table 3 presents the key laboratory abnormalities from the same randomized trial in patients with newly diagnosed FLT3 mutated AML. Table 2: Common Adverse Reactions (≥ 10% Incidence and ≥ 2% More Frequent on the Midostaurin Arm) of Patients with Acute Myeloid Leukemia in Study 1 All Grades Grades ≥ 3 Adverse Reaction RYDAPT + chemo n = 229 1 % Placebo + chemo n = 226 1 % RYDAPT + chemo n = 345 1 % Placebo + chemo n = 335 1 % Gastrointestinal disorders Nausea 83 70 6 10 Mucositis a 66 62 11 13 Vomiting 61 53 3 5 Hemorrhoids 15 11 1 0 Blood and lymphatic system disorders Febrile neutropenia 83 81 84 83 Petechiae 36 27 1 1 Nervous system disorders Headache a 46 38 3 3 Musculoskeletal and...

Drug Interactions

7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors : Strong CYP3A4 inhibitors may increase exposure to midostaurin and its active metabolites. Consider alternative therapies that do not strongly inhibit CYP3A4 or monitor for increased risk of adverse reactions. ( 7.1 ) Strong CYP3A4 Inducers : Avoid concomitant use as strong CYP3A4 inducers decrease exposure to midostaurin and its active metabolites. ( 7.1 ) CYP2B6, BCRP, OATP1B1 Substrates : Dose adjustments for coadministered CYP2B6, BCRP, and OATP1B1 substrates may be necessary with RYDAPT. ( 7.2 ) 7.1 Effect of Other Drugs on RYDAPT Table 6 lists the potential effects of the coadministration of strong CYP3A modulators on RYDAPT. Table 6: Drug Interactions with RYDAPT That Affect Midostaurin Strong CYP3A Inhibitors a The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength). b The induction potency of St. John’s wort may vary widely based on preparation. Clinical Impact Coadministration of RYDAPT with strong CYP3A inhibitors may increase midostaurin concentrations. The increase in midostaurin concentrations may be pronounced if strong CYP3A inhibitors are administered during the first week of RYDAPT administration [see Clinical Pharmacology (12.3)]. Increased midostaurin concentrations may increase the risk of toxicity. Prevention or Management Consider alternative therapies that do not strongly inhibit CYP3A activity. Alternatively, with coadministration of RYDAPT and strong CYP3A inhibitors, monitor patients for increased risk of adverse reactions, especially during the first week of consecutive RYDAPT administration in advanced SM population, and during first week of RYDAPT administration in each cycle of chemotherapy in AML population. Examples Boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, grapefruit juice a , idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, troleandomycin, voriconazole Strong CYP3A Inducers Clinical Impact Coadministration of RYDAPT with strong CYP3A inducers may decrease midostaurin concentrations [see Clinical Pharmacology (12.3)]. Decreased midostaurin concentrations may reduce efficacy. Prevention or Management Avoid coadministration of RYDAPT with strong CYP3A4 inducers. Examples Carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort b 7.2 Effect of RYDAPT on Other Drugs CYP2B6 Substrates RYDAPT decreased the systemic exposure of a sensitive CYP2B6 substrate [see Clinical...

Contraindications

4 CONTRAINDICATIONS RYDAPT is contraindicated in patients with hypersensitivity to midostaurin or to any of the excipients [see Description (11)]. 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 (6.1)]. Hypersensitivity to midostaurin or any of the excipients. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to RYDAPT during pregnancy. Females who may have been exposed to RYDAPT during pregnancy directly or through a male partner receiving RYDAPT therapy should contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://report.novartis.com/ . 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 (12.1)] . 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 area under the curve (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...

How Supplied

16 HOW SUPPLIED/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 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Store in the original container to protect from moisture.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.