I. Basic Drug Information

Generic Name: Midostaurin

Brand Names: Rydapt, Leidepa, Midostar

Dosage Form and Strength: Soft Capsules; 25 mg/capsule; 28 capsules/box

Manufacturer: Zydus Healthcare Ltd

Pharmacological Class: Multi-targeted Tyrosine Kinase Inhibitor (FLT3, KIT, PDGFR, VEGFR, etc.)

Mechanism of Action: Inhibits kinases such as FLT3 mutations (ITD/TKD) and KIT D816V, thereby blocking signaling pathways critical for tumor cell proliferation and survival; exerts specific inhibitory effects on mast cell-associated diseases.

Molecular Formula: C₃₅H₃₀N₄O₄

Molecular Weight: 570.65 g/mol

Storage Conditions: Protect from moisture; store at 20–25°C (excursions between 15–30°C are permitted for short periods); keep container tightly closed.

Shelf Life: 24 months

II. Indications

1. Acute Myeloid Leukemia (AML)

Used in combination with daunorubicin and cytarabine for induction therapy, followed by high-dose cytarabine for consolidation therapy, in newly diagnosed adult patients with FLT3-mutated AML. Following the achievement of complete remission, the drug may be continued as monotherapy for maintenance. It is not indicated for use as monotherapy for the induction treatment of AML. 2. Systemic Mastocytosis-Related Diseases (Adults)

Aggressive Systemic Mastocytosis (ASM)

Systemic Mastocytosis with Associated Hematological Neoplasm (SM-AHN)

Mast Cell Leukemia (MCL)

III. Dosage and Administration

1. AML (FLT3-mutated)

Recommended Dosage: 50 mg orally, twice daily (approximately 12 hours apart), taken with food.

Treatment Schedule:

Induction Chemotherapy (Daunorubicin + Cytarabine): Administer on Days 8–21 of each cycle.

Consolidation Chemotherapy (High-dose Cytarabine): Administer on Days 8–21 of each cycle.

Maintenance Therapy: Continue as monotherapy following consolidation until disease progression or intolerable toxicity.

2. ASM/SM-AHN/MCL

Recommended Dosage: 100 mg orally, twice daily, taken with food; continue until disease progression or intolerable toxicity.

3. Management of Missed Doses

If more than 6 hours remain before the next scheduled dose, take the missed dose immediately; if 6 hours or less remain, skip the missed dose and do not take a double dose. 4. Dosage Adjustment (Adverse Reactions)

Hematologic Toxicity: If ANC < 1 × 10⁹/L or platelets < 50 × 10⁹/L, suspend treatment until recovery; then resume at the original dose or a reduced dose.

Non-hematologic Toxicity: For Grade ≥ 3 toxicity, suspend treatment. Once toxicity resolves to Grade ≤ 1: for AML, reduce dose to 50 mg BID; for ASM/SM-AHN/MCL, reduce dose to 50 mg BID—if intolerance persists, discontinue the drug.

Hepatic and Renal Impairment: No adjustment required for mild to moderate impairment; use is not recommended for severe impairment (Child-Pugh Class C, CrCl < 30 mL/min).

IV. Adverse Reactions

1. Common Adverse Reactions (≥ 20%)

AML: Nausea, vomiting, diarrhea, stomatitis, headache, musculoskeletal pain, febrile neutropenia, rash, elevated transaminases, hemorrhage.

ASM/SM-AHN/MCL: Nausea, vomiting, diarrhea, abdominal pain, fatigue, edema, rash, elevated transaminases, thrombocytopenia, anemia.

2. Serious Adverse Reactions (Requiring Urgent Management)

Pulmonary Toxicity: Interstitial lung disease/pneumonitis (dyspnea, cough, fever); discontinue the drug immediately and seek medical attention.

Embryo-Fetal Toxicity: Teratogenic; contraindicated in pregnant women. Men and women of reproductive potential must use effective contraception during treatment and for 4 months after discontinuing the drug.

Hematologic Toxicity: Severe neutropenia, thrombocytopenia, anemia.

Hepatotoxicity: Elevated transaminases, elevated bilirubin; monitor liver function periodically.

Hypersensitivity Reactions: Rash, angioedema, dyspnea.

V. Precautions

1. Monitoring for Pulmonary Toxicity

Monitor for respiratory symptoms during treatment; if pneumonitis is suspected, discontinue the drug immediately and initiate corticosteroid therapy.

2. Monitoring for Hepatotoxicity

Assess ALT/AST/bilirubin levels prior to treatment, at the start of each treatment cycle, and as clinically indicated; for elevations of Grade ≥ 3, suspend/reduce the dose or discontinue the drug. 3. Embryo-Fetal Toxicity

Contraindicated in pregnant women; discontinue the drug or discontinue breastfeeding during lactation.

Women of Childbearing Potential: Must have a negative pregnancy test within 7 days prior to treatment; must use highly effective contraception during treatment and for 4 months after discontinuing the drug.

Men of Childbearing Potential: Must use contraception during treatment and for 4 months after discontinuing the drug.

4. Drug Interactions

Strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin): Avoid co-administration; significantly increases plasma drug concentrations and increases toxicity risk.

Strong CYP3A4 Inducers (e.g., rifampin, carbamazepine): Avoid co-administration; decreases plasma drug concentrations and may compromise efficacy.

Moderate CYP3A4 Inhibitors: Closely monitor for toxicity; reduce dosage if necessary.

P-gp Substrates (e.g., digoxin): Monitor plasma drug concentrations and adjust dosage when co-administered.

5. Other Considerations

Avoid administration of live vaccines.

Exercise caution when driving or operating machinery, as fatigue and dizziness may occur.

VI. Contraindications

Patients with hypersensitivity to midostaurin or to any of the excipients.

Pregnant and breastfeeding women.

Patients with severe hepatic impairment (Child-Pugh Class C).

VII. Use in Specific Populations

Children/Adolescents: Safety and efficacy have not been established; use is not recommended.

Geriatric Patients (≥65 years): No dosage adjustment required; closely monitor for adverse reactions.

Renal Impairment: No dosage adjustment required for mild to moderate impairment; use is not recommended in severe impairment.

Hepatic Impairment: No dosage adjustment required for mild impairment; use with caution and reduce dosage in moderate impairment; contraindicated in severe impairment.

VIII. Overdosage

No specific antidote is available. In the event of an overdose, provide symptomatic and supportive care, and monitor vital signs and organ function. IX. Pharmacology and Toxicology

1. Pharmacokinetics

Well absorbed following oral administration; bioavailability is higher when taken with food.

Time to Peak Concentration (Tmax): 1–3 hours; Half-life: Approximately 27 hours.

Primarily metabolized via CYP3A4; elimination occurs predominantly via feces.

2. Toxicology Studies

Genotoxicity: Negative.

Reproductive Toxicity: Teratogenic and embryotoxic; studies in rats and rabbits demonstrated fetal developmental abnormalities.

Carcinogenicity: Long-term studies have not been conducted.

Product Specifications

Product Name: Midostaurin Capsules 25 mg × 28 Capsules/Box (Midostar Midostaurin Soft Gelatin Capsule 25 mg)

Common Name: Midostaurin Capsules

Active Ingredient: Midostaurin

Dosage Form: Capsule

Specification: 25 mg/capsule; 28 capsules/box

Manufacturer: Zydus Healthcare Ltd

Indications: 1. Acute Myeloid Leukemia (AML)

Used in combination with daunorubicin and cytarabine for induction therapy, followed by high-dose cytarabine for consolidation therapy, in newly diagnosed adult patients with FLT3-mutated AML. Following achievement of complete remission, it may be used as monotherapy for maintenance. It must not be used as monotherapy for the induction treatment of AML. 2. Systemic Mastocytosis-Related Diseases (Adults)

Aggressive Systemic Mastocytosis (ASM)

Systemic Mastocytosis with Associated Hematological Neoplasm (SM-AHN)

Mast Cell Leukemia (MCL)

Dosage and Administration: 1. AML (FLT3-mutated)

Recommended Dose: 50 mg orally, twice daily (approximately 12 hours apart), taken with food.

Treatment Schedule

Induction Chemotherapy (Daunorubicin + Cytarabine): Administer on Days 8–21 of each cycle.

Consolidation Chemotherapy (High-dose Cytarabine): Administer on Days 8–21 of each cycle.

Maintenance Therapy: Continue as monotherapy following consolidation until disease progression or intolerable toxicity.

2. ASM/SM-AHN/MCL

Recommended Dose: 100 mg orally, twice daily, taken with food; continue until disease progression or intolerable toxicity.

3. Missed Dose

If more than 6 hours remain before the next scheduled dose, take the missed dose immediately; if 6 hours or less remain, skip the missed dose and do not take a double dose.