midostaurin

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

High Alert

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, systemic mastocytosis with associated hematological neoplasm, or mast cell leukemia.

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.

Therapeutic effects:

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

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.

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	1–3 hr	unknown

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.

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

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.

(Generic available)

Capsules: 25 mg

Assess for signs and symptoms of pulmonary toxicity (new cough, chest discomfort, shortness of breath) periodically during therapy. Discontinue therapy if symptoms occur.
Monitor for nausea and vomiting during therapy. If Grade 3 or 4 vomiting occurs despite antiemetic therapy, hold therapy for 3 days (6 doses); then resume at 50 mg twice daily; if tolerated, ↑ to 100 mg twice daily.
Monitor for signs and symptoms of hypersensitivity reaction (trouble breathing; flushing; chest pain; throat tightness; swelling of lips, mouth, or throat) during therapy. Discontinue therapy and provide supportive care.

Lab Test Considerations:

Verify negative pregnancy test within 7 days before starting therapy.Determine presence of FLT3 mutation positivity with FDA approved test before starting therapy.
- Monitor patients with aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, or mast cell leukemia for toxicity at least weekly for the first 4 wk, every other wk for next 8 wk, and monthly thereafter during therapy. May cause leukopenia, anemia, thrombocytopenia, or neutropenia.If ANC <1 × 10⁹/L attributed to midostaurin in patients without mast cell leukemia, or ANC <0.5 × 10⁹/L attributed to midostaurin in patients with baseline ANC value of 0.5–1.5 × 10⁹/L, hold therapy until ANC ≥1 × 10⁹/L; then resume at 50 mg twice daily; if tolerated, ↑ to 100 mg twice daily. Discontinue therapy if low ANC persists for >21 days and is suspected to be related to midostaruin. If platelet count <50 ×10⁹/L attributed to midostaurin in patients without mast cell leukemia, or platelet count <25 × 10⁹/L attributed to midostaurin in patients with baseline platelet count of 25–75 × 10⁹ /L, interrupt therapy until platelet count ≥50 × 10⁹/L; then resume at 50 mg twice daily; if tolerated, ↑ to 100 mg twice daily. Discontinue if low platelet count persists for >21 days and is suspected to be related to midostaurin. If hemoglobin <8 g/dL attributed to midostaurin in patients without mast cell leukemia, or life-threatening anemia attributed to midostaurin in patients with baseline hemoglobin value of 8–10 g/dL,hold therapy until hemoglobin ≥8 g/dL; then resume at 50 mg twice daily; if tolerated, ↑ to 100 mg twice daily. Discontinue if low hemoglobin persists for >21 days and is suspected to be related to midostaurin.
- May cause hyperglycemia, hypocalcemia, hyperuricemia, hyponatremia, hypokalemia, hyperkalemia, hypophosphatemia, hypomagnesemia, hyperbilirubinemia, and hypoalbuminemia.
- May cause ↑ alkaline phosphatase, AST, ALT, lipase, and serum creatinine.

Administer antiemetics prior to therapy to manage nausea and vomiting.
PO: Administer twice daily, at 12 hr intervals, with food. DNC: Swallow capsules whole; do not open, crush, or chew.

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Take as directed. If a dose is missed or vomited, omit and take next dose at scheduled time; do not double doses.
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.
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.
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 breastfeeding during and for 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 https://psi.novartis.com/. This pregnancy exposure registry monitors pregnancy outcomes in women exposed to midostaurin during pregnancy.

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

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Adv. Reactions/Side Effects ⬆ ⬇

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Assessment ⬆ ⬇

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US Brand Names ⬆