Usage
Midostaurin is prescribed for:
- Acute Myeloid Leukemia (AML): Specifically for newly diagnosed adult patients with FLT3 mutation-positive AML, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy. It is not indicated as a single-agent induction therapy for AML.
- Systemic Mastocytosis: This includes aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).
Pharmacological Classification: Midostaurin is a multi-kinase inhibitor, primarily targeting FLT3, KIT, PDGFR, VEGFR2, and members of the serine/threonine kinase family.
Mechanism of Action: Midostaurin inhibits multiple tyrosine kinases, including FLT3, which plays a crucial role in the proliferation and survival of leukemic cells in AML. It also inhibits KIT, a key driver in the pathogenesis of systemic mastocytosis. This combined kinase inhibition reduces cell proliferation and promotes apoptosis in malignant cells.
Alternate Names
- International Nonproprietary Name (INN): Midostaurin
- Brand Name: Rydapt
How It Works
Pharmacodynamics: Midostaurin exerts its anti-cancer effects by inhibiting multiple tyrosine kinases crucial for cell signaling pathways involved in cell proliferation, survival, and angiogenesis. It blocks the abnormal activation of these kinases that contribute to tumor growth and progression.
Pharmacokinetics:
- Absorption: Midostaurin is administered orally and is well-absorbed, with its bioavailability enhanced when taken with food.
- Metabolism: Midostaurin undergoes hepatic metabolism, primarily through CYP3A4. It also inhibits CYP2B6. This necessitates caution when co-administered with drugs metabolized by these enzymes.
- Elimination: Excretion occurs predominantly via biliary/fecal route.
Mode of Action: Midostaurin binds to the ATP-binding site of target kinases, including FLT3 and KIT, preventing their activation. This inhibits downstream signaling pathways that promote uncontrolled cell growth and survival.
Dosage
Standard Dosage
Adults:
- AML (in combination therapy): 50 mg orally twice daily (approximately 12 hours apart) with food on Days 8-21 of each cycle of induction and consolidation chemotherapy.
- ASM, SM-AHN, and MCL: 100 mg orally twice daily with food.
Children:
The safety and efficacy of midostaurin have not been established in pediatric patients.
Special Cases:
- Elderly Patients: No specific dose adjustments are needed for elderly patients, but caution is advised in those aged ≥60 years old with AML, and consideration should be given to their performance status and comorbidities.
- Patients with Renal Impairment: No dose adjustment is required for mild or moderate renal impairment.
- Patients with Hepatic Dysfunction: No dose adjustment is required for mild, moderate, or severe hepatic impairment.
- Patients with Comorbid Conditions: Careful assessment and potential dose modifications may be necessary for patients with underlying cardiac issues, particularly QTc prolongation.
Clinical Use Cases
Midostaurin’s clinical use is currently limited to the treatment of AML (in combination with chemotherapy) and systemic mastocytosis. It is not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose reductions or interruptions might be necessary due to adverse events such as pulmonary infiltrates or other non-hematological toxicities. QTc prolongation also warrants dosage modification or withholding.
Side Effects
Common Side Effects:
Nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea. Febrile neutropenia, mucositis, petechiae, epistaxis, device-related infection, and hyperglycemia are common in patients with AML receiving concomitant chemotherapy.
Rare but Serious Side Effects:
Severe bone marrow suppression, including neutropenia, thrombocytopenia, and anemia, may occur. QTc prolongation, cardiac dysfunction, hypersensitivity reactions (including anaphylaxis), pulmonary toxicity, and severe hepatic dysfunction are rare but serious adverse reactions.
Long-Term Effects:
The potential long-term effects of midostaurin are still under investigation.
Adverse Drug Reactions (ADR):
Severe hypersensitivity reactions, QTc prolongation, significant left ventricular ejection fraction (LVEF) reduction, severe pulmonary toxicity, and drug-induced liver injury.
Contraindications
- Hypersensitivity to midostaurin or any of its components.
- Concomitant use with strong CYP3A4 inducers (e.g., carbamazepine, rifampicin, phenytoin, St. John’s Wort).
Drug Interactions
- Strong CYP3A4 Inhibitors: Concomitant use can increase midostaurin exposure and toxicity. Consider alternative therapies or close monitoring.
- Strong CYP3A4 Inducers: Contraindicated as they significantly decrease midostaurin exposure and efficacy.
- CYP2B6 Substrates: Midostaurin inhibits CYP2B6; adjust dosages of concomitant CYP2B6 substrates accordingly.
- QT Prolonging Drugs: Caution is advised as concurrent use increases the risk of QTc prolongation.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D. Midostaurin can cause fetal harm. Women of childbearing potential should use effective contraception during treatment and for 4 months after the last dose. Males with female partners of reproductive potential should also use contraception during treatment and for 4 months after the last dose.
- Breastfeeding: It is unknown if midostaurin is excreted in human milk. Breastfeeding is not recommended during treatment and for at least 4 months after the last dose.
Drug Profile Summary
- Mechanism of Action: Multi-kinase inhibitor targeting FLT3, KIT, and other tyrosine kinases.
- Side Effects: Nausea, vomiting, diarrhea, myelosuppression, QTc prolongation, pulmonary toxicity.
- Contraindications: Hypersensitivity, strong CYP3A4 inducers.
- Drug Interactions: Strong CYP3A4 inhibitors/inducers, CYP2B6 substrates, QT prolonging drugs.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy, not recommended while breastfeeding.
- Dosage: AML: 50 mg BID, Systemic Mastocytosis: 100 mg BID. Adjustments required for specific toxicities.
- Monitoring Parameters: Complete blood counts, liver function tests, renal function tests, ECG (for QTc interval), and monitoring for signs of infection and pulmonary toxicity.
Popular Combinations
- AML: Midostaurin is used in combination with cytarabine and daunorubicin for induction, and with high-dose cytarabine for consolidation therapy.
Precautions
- General Precautions: Assess cardiac function, renal and hepatic function, and pregnancy status (in women of childbearing potential) before starting treatment. Monitor for myelosuppression, infections, and other adverse effects.
- Specific Populations: See section on “Dosage - Special Cases.”
- Lifestyle Considerations: Patients should avoid grapefruit and its juice during treatment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Midostaurin?
A: For FLT3-mutated AML (in combination with chemotherapy): 50 mg twice daily on days 8-21 of each cycle. For systemic mastocytosis: 100 mg twice daily.
Q2: What are the most common side effects?
A: Gastrointestinal issues (nausea, vomiting, diarrhea), myelosuppression, fatigue, infections, and QTc prolongation.
Q3: What are the contraindications to using Midostaurin?
A: Known hypersensitivity to midostaurin and concomitant use of strong CYP3A4 inducers.
Q4: How does Midostaurin interact with other medications?
A: It interacts with CYP3A4 inhibitors and inducers, CYP2B6 substrates, and drugs that prolong the QT interval.
Q5: Can Midostaurin be used during pregnancy or breastfeeding?
A: Midostaurin is contraindicated during pregnancy and should be avoided during breastfeeding.
Q6: What is the mechanism of action of Midostaurin?
A: It is a multi-kinase inhibitor primarily targeting FLT3 and KIT, disrupting cell signaling and leading to reduced proliferation and apoptosis of malignant cells.
Q7: How should Midostaurin be administered?
A: Orally, twice daily, with food.
Q8: What monitoring is required during Midostaurin therapy?
A: Regular blood counts, liver and renal function tests, ECGs (to monitor QTc interval), and assessment for signs of infection or pulmonary toxicity.
Q9: What should be done if a dose is missed?
A: Skip the missed dose and resume the normal schedule with the next dose. Do not double the dose.
Q10: How are adverse events managed during Midostaurin treatment?
A: Dosage adjustments, interruptions, or discontinuation might be needed, based on the severity and type of adverse event. Supportive care should be provided as necessary.
