Midostaurin

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. 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).

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.

AML: 50 mg orally twice daily with food. ASM, SM-AHN, and MCL: 100 mg orally twice daily with food. Patient Selection Select patients for the treatment of AML with RYDAPT based on the presence of FLT3 mutation positivity. 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 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.

RYDAPT is contraindicated in patients with hypersensitivity to midostaurin or to any of the excipients. 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). Hypersensitivity to midostaurin or any of the excipients.

Embryo-Fetal Toxicity: RYDAPT may cause fetal harm when administered to a pregnant woman. Advise of the potential risk to a fetus. Pulmonary Toxicity: Monitor for symptoms of interstitial lung disease or pneumonitis. Discontinue RYDAPT in patients with signs or symptoms of pulmonary toxicity. Fatal cases have occurred.

The following serious adverse reactions are described elsewhere in the labeling: Pulmonary Toxicity 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. 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.

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. Strong CYP3A4 Inducers: Avoid concomitant use as strong CYP3A4 inducers decrease exposure to midostaurin and its active metabolites. CYP2B6, BCRP, OATP1B1 Substrates: Dose adjustments for coadministered CYP2B6, BCRP, and OATP1B1 substrates may be necessary with RYDAPT.

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). Store in the original container to protect from moisture.