• Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation positive (in combination with cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy).
• Aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

Contraindicated in:

• Hypersensitivity
• OB: Pregnancy (may cause fetal harm)
• Lactation: Lactation.

Use Cautiously in:

• Rep: Women of reproductive potential and men with female partners of reproductive potential
• Pedi: Safety and effectiveness not established in children.

CV: QT interval prolongation, edema, hypertension, hypotension, pericardial effusion.

Derm: ↑ sweating, petechiae, rash, dry skin.

EENT: epistaxis, eyelid edema, vertigo.

Endo: hyperglycemia.

F and E: hyperkalemia, hypernatremia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypercalcemia, hyperphosphatemia.

GI: ↑ amylase, ↑ lipase, ↑ liver enzymes, abdominal pain, constipation, diarrhea, gi hemorrhage, hemorrhoids, hyperbilirubinemia, hypoalbuminemia, mucositis, nausea, vomiting, dyspepsia.

GU: renal impairment, ↓ fertility.

Hemat: anemia, neutropenia, thrombocytopenia, lymphopenia.

Metab: ↑ weight, hyperuricemia.

MS: arthralgia.

Neuro: dizziness, fatigue, headache, insomnia, attention disturbance, mental status changes, tremor.

Resp: cough, dyspnea, INTERSTITIAL LUNG DISEASE/PNEUMONITIS, pleural effusion.

Misc: fever, infection, HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS AND ANGIOEDEMA).

Drug-Drug:

• Strong CYP3A inhibitors, including clarithromycin, cobicistat, conivaptan, diltiazem, idelalisib, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, paritaprevir, posaconazole, ritonavir, tipranavir, or voriconazole may ↑ midostaurin levels and risk of toxicity; avoid concurrent use.
• Strong CYP3A inducers, including carbamazepine, enzalutamide, mitotane, phenytoin, or rifampin may ↓ midostaurin levels and its effectiveness; avoid concurrent use.

Drug-Natural Products:

• St. John's wort may ↓ midostaurin levels and its effectiveness; avoid concurrent use.

Drug-Food:

• Grapefruit juice may ↑ midostaurin levels and risk of toxicity; avoid concurrent use.

• Capsules: 25 mg;

Acute Myeloid Leukemia

• PO (Adults): 50 mg twice daily on Days 8–21 of each cycle of induction with cytarabine and daunorubicin and on Days 8–21 of each cycle of consolidation with high-dose cytarabine.

Aggressive Systemic Mastocytosis, Systemic Mastocytosis with Associated Hematological Neoplasm, or Mast Cell Leukemia

• PO (Adults): 100 mg twice daily. Continue until disease progression or unacceptable toxicity.

Rydapt

• Inhibits FLT3 receptor signaling and cell proliferation, and induces apoptosis in ITD- and TKD-mutant expressing leukemic cells, as well as in cells overexpressing wild type FLT3 and PDGFR. It also may inhibit KIT signaling, cell proliferation, and histamine release (and induces apoptosis) in mast cells.

• Improved survival in AML.
• Improved complete or incomplete remission rates in systemic mastocytosis.

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

Absorption: Absorption increased with food (especially a high-fat meal).

Distribution: Extensively distributed to tissues.

Protein Binding: >99%.

Metabolism/Excretion: Primarily metabolized via the liver by the CYP3A4 isoenzyme into 2 active metabolites (CGP62221 and CGP52421). Primarily excreted in the feces (4% as unchanged drug).

Half-life: Midostaurin: 21 hr; CGP62221: 32 hr; CHP52421: 482 hr.

(blood levels)

• Instruct patient to take midostaurin as directed. If a dose is missed or vomited, omit and take next dose at scheduled time; do not double doses. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
• Advise patient to avoid taking grapefruit or grapefruit juice during therapy.
• Advise patient to notify health care professional if signs and symptoms of pulmonary toxicity, hypersensitivity reactions, or nausea and vomiting occur.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort.
• Rep: May cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for 4 mo after last dose of therapy. Advise women to avoid breast feeding during and for at least 4 mo after last dose of midostaurin. Inform patients midostaurin may impair fertility in males and females. Encourage females who may have been exposed to midostaurin during pregnancy directly or through a male partner receiving midostaurin to contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at psi.novartis.com/. This pregnancy exposure registry monitors pregnancy outcomes in women exposed to midostaurin during pregnancy.

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