Midostaurin (Monograph)

Brand name: Rydapt
Drug class: Antineoplastic Agents
- Fms-like Tyrosine Kinase-3 Inhibitor
- Flt-3 Inhibitor
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical name: N-[(9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl]-N-methyl-benzamide
Molecular formula: C₃₅H₃₀N₄O₄
CAS number: 120685-11-2

Medically reviewed by Drugs.com on May 11, 2023. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases including fms-like tyrosine kinase-3 (Flt-3).

Uses for Midostaurin

Acute Myeloid Leukemia (AML)

Used in combination with cytarabine and daunorubicin as a component of induction therapy followed by use in combination with high-dose cytarabine as a component of consolidation therapy for newly diagnosed AML harboring Flt-3 mutation (designated an orphan drug by FDA for this use).

FDA-approved companion diagnostic test (e.g., LeukoStrat CDx Flt-3 mutation assay) required to confirm presence of Flt-3 mutation prior to initiation of therapy.

Not indicated for use as single-agent induction therapy in patients with AML.

Systemic Mastocytosis

Single-agent therapy for aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematologic neoplasm (SM-AHN; also known as systemic mastocytosis with an associated hematologic non-mast-cell-lineage disease [SM-AHNMD] ), and mast cell leukemia (designated an orphan drug by FDA for these uses).

Midostaurin Dosage and Administration

General

• Confirm presence of Flt-3 mutation prior to initiation of therapy for AML.

• Premedicate with an antiemetic agent. In principal efficacy studies of midostaurin as single-agent therapy for advanced systemic mastocytosis, antiemetic agents (e.g., serotonin type 3 [5-HT₃] receptor antagonists) were administered 1–2 hours prior to each dose of midostaurin, with additional antiemetic agents administered as required following midostaurin administration.

• Consult respective manufacturers' labelings or published protocols for dosage, method of administration, and administration sequence of other drugs used in combination regimens for AML.

Administration

Oral Administration

Administer twice daily (approximately every 12 hours) with food.

Swallow capsules whole; do not open or crush.

Dosage

Adults

AML

Oral

Induction therapy: 50 mg twice daily on days 8–21 of each cycle; use in combination with cytarabine and daunorubicin. Given for up to 2 cycles in the principal efficacy study.

Consolidation therapy: 50 mg twice daily on days 8–21 of each 28-day cycle; use in combination with high-dose cytarabine. Given for up to 4 cycles in the principal efficacy study.

Post-consolidation therapy^{† [off-label]}: Continuous therapy with midostaurin 50 mg twice daily was given for up to 12 additional 28-day cycles in the principal efficacy study.

Systemic Mastocytosis

Oral

100 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Adjustment of Midostaurin for Systemic Mastocytosis

Adverse effects resulting in dosage adjustments, generally during the initial 5 months of therapy, occurred in 56% of patients receiving midostaurin for systemic mastocytosis in principal efficacy studies. Median time to first dosage modification for toxicity was 1.6 months.

Monitor patients for adverse effects at least weekly for initial 4 weeks of therapy, every other week for the following 8 weeks of therapy, and then monthly thereafter.

Hematologic Toxicity in Patients with Systemic Mastocytosis

Oral

For ANC <1000/mm³ (except in patients with mast cell leukemia) or for ANC <500/mm³ in patients who have a baseline ANC of 500–1500/mm³, interrupt therapy until ANC ≥1000/mm³; upon resumption, reduce dosage to 50 mg twice daily. If a reduced dosage of 50 mg twice daily is tolerated, dosage may be returned to 100 mg twice daily.

For platelet count <50,000/mm³ (except in patients with mast cell leukemia) or for platelet count <25,000/mm³ in patients who have a baseline platelet count of 25,000–75,000/mm³, interrupt therapy until platelet count ≥50,000/mm³; upon resumption, reduce dosage to 50 mg twice daily. If a reduced dosage of 50 mg twice daily is tolerated, dosage may be returned to 100 mg twice daily.

For hemoglobin concentration <8 g/dL (except in patients with mast cell leukemia) or for life-threatening anemia in patients who have a baseline hemoglobin concentration of 8–10 g/dL, interrupt therapy until hemoglobin concentration ≥8 g/dL; upon resumption, reduce dosage to 50 mg twice daily. If a reduced dosage of 50 mg twice daily is tolerated, dosage may be returned to 100 mg twice daily.

If prolonged treatment-related neutropenia, thrombocytopenia, or anemia (i.e., lasting >21 days) occurs, discontinue therapy.

GI Effects in Patients with Systemic Mastocytosis

Oral

If grade 3 or 4 nausea and/or vomiting occurs despite optimal antiemetic therapy, interrupt therapy for 3 days (6 doses); upon resumption of therapy, reduce dosage to 50 mg twice daily. If a reduced dosage of 50 mg twice daily is tolerated, dosage may be returned to 100 mg twice daily.

Other Nonhematologic Effects in Patients with Systemic Mastocytosis

Oral

If other grade 3 or 4 nonhematologic toxicity occurs, interrupt therapy until toxicity improves to grade 2 or less; upon resumption of therapy, reduce dosage to 50 mg twice daily. If a reduced dosage of 50 mg twice daily is tolerated, dosage may be returned to 100 mg twice daily.

Special Populations

No special population dosage recommendations at this time.

Cautions for Midostaurin

Contraindications

• Known hypersensitivity to midostaurin or any ingredient in the formulation.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions (e.g., dyspnea, flushing, chest pain, angioedema), including anaphylactic shock, reported.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings; embryofetal toxicity demonstrated in animals.

Confirm pregnancy status within 7 days prior to initiating midostaurin therapy. Avoid pregnancy during therapy. Women of childbearing potential and men who are partners of such women should use effective contraceptive methods while receiving midostaurin and for ≥4 months after the drug is discontinued. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Interstitial Lung Disease/Pneumonitis

Interstitial lung disease (ILD) and pneumonitis, sometimes fatal, reported.

Monitor for pulmonary symptoms suggestive of ILD or pneumonitis. If manifestations of ILD or pneumonitis occur without an infectious etiology, discontinue therapy.

Prolongation of QT Interval

QT_c-interval prolongation reported in clinical studies; no clinically important effect observed in a short-term study specifically evaluating potential QT-interval effects, but study duration was inadequate to assess effect of CGP-52421 (an active metabolite) at steady-state exposures.

Consider periodic monitoring of ECGs during concomitant use of drugs known to prolong the QT interval.

Impairment of Fertility

May impair male and female fertility.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Midostaurin and its metabolites distribute into milk in rats; not known whether they distribute into human milk. Effects on nursing infants and milk production also unknown. Discontinue nursing during therapy and for ≥4 months after drug discontinuance.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In phase 3 clinical trials in patients with advanced systemic mastocytosis, no overall differences in safety and efficacy relative to younger adults observed, but increased sensitivity cannot be ruled out.

Insufficient experience in patients ≥65 years of age with AML to determine whether they respond differently than younger adults.

Use with caution; consider patient's eligibility for concomitant chemotherapy and greater frequency of concomitant disease and drug therapy in this age group.

Hepatic Impairment

In a population pharmacokinetic analysis, pharmacokinetics of midostaurin and its metabolites not altered by mild or moderate hepatic impairment. (See Special Populations under Pharmacokinetics.)

Data lacking in patients with severe hepatic impairment.

Renal Impairment

In a population pharmacokinetic analysis, pharmacokinetics of midostaurin and its metabolites not altered by mild or moderate renal impairment. (See Special Populations under Pharmacokinetics.)

Data lacking in patients with severe renal impairment.

Common Adverse Effects

In combination with chemotherapy in patients with previously untreated AML (occurring more commonly than with chemotherapy alone): Febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, upper respiratory tract infection, hemorrhoids, arthralgia, hyperhidrosis, prolonged aPTT, insomnia, renal impairment, hypocalcemia, elevated ALT concentrations, hypernatremia.

Monotherapy in patients with advanced systemic mastocytosis: Nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, dyspnea, arthralgia, cough, urinary tract infection, GI hemorrhage, rash, dizziness, pleural effusion, epistaxis, insomnia, prolonged QT interval, renal impairment, herpes simplex virus infection, pneumonia, hyperglycemia, lymphopenia, leukopenia, anemia, thrombocytopenia, neutropenia, elevated alkaline phosphatase concentrations, hypocalcemia, elevated concentrations of pancreatic enzymes (e.g., amylase, lipase), hyperuricemia, elevated aminotransferase (ALT or AST) and γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations, hyponatremia, hyperbilirubinemia, hypoalbuminemia, hypokalemia, elevated S_cr concentrations, hyperkalemia, hypophosphatemia, hypomagnesemia.

Interactions for Midostaurin

Midostaurin and its active metabolites (CGP-52421 and CGP-62221) metabolized principally by CYP3A4. Midostaurin, CGP-52421, and CGP-62221 inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, and 2E1 and induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, and 3A in vitro.

At clinically relevant concentrations, midostaurin, CGP-52421, and CGP-62221 inhibit organic anion transport protein (OATP) 1A1 and induce multidrug resistance protein (MRP) 2. In vitro, midostaurin is not a substrate of P-glycoprotein (P-gp) or MRP2.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible increased systemic exposure to midostaurin and its active metabolites and increased risk of adverse effects. Extent of interaction is dependent on duration of midostaurin dosing; effects may be greatest when potent CYP3A inhibitors are administered during first week of midostaurin therapy. (See Bioavailability under Pharmacokinetics.) Consider alternative agent with less CYP3A inhibition potential. Alternatively, monitor for adverse effects, particularly during the first week of midostaurin therapy (including first week of midostaurin therapy in each cycle when used in combination with chemotherapy). (See Specific Drugs and Foods under Interactions.)

CYP3A inducers: Possible decreased systemic exposure to midostaurin and its active metabolites and reduced efficacy of midostaurin. Avoid concomitant use with potent CYP3A4 inducers. Some clinicians also recommend avoiding concomitant use with moderate CYP3A4 inducers. (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A substrates: No substantial effect on AUC of a probe CYP3A substrate when midostaurin administered for only 4 days; however, results are inconclusive since findings may not reflect midostaurin's enzyme induction potential at steady state. (See Bioavailability under Pharmacokinetics.)

Drugs that Prolong the QT Interval

Possible additive effect on QT-interval prolongation. (See Prolongation of QT Interval under Cautions.)

Consider periodic monitoring of ECGs during concomitant use.

Specific Drugs and Foods

Midostaurin Pharmacokinetics

Absorption

Bioavailability

Following oral administration in fasted state or following a meal, peak plasma midostaurin concentrations attained in 1–3 or 2.5–3 hours, respectively.

Following repeated administration, trough concentrations of midostaurin and its CGP-62221 and CGP-52421 metabolites exhibit time-dependent pharmacokinetics and there is lack of proportionality between dosage and systemic exposure, possibly because of autoinduction of own metabolism.

Maximum trough concentrations of midostaurin and CGP-62221 are achieved in 8 days, then decline (by about 50–60%) to steady-state values by day 28; plasma concentrations of CGP-52421 continue to increase until day 28. CGP-52421 and CGP-62221 account for approximately 38 and 28%, respectively, of total plasma concentrations of the drug.

Maximum trough and steady-state concentrations of midostaurin, CGP-62221, and CGP-52421 at a dosage of 50 mg twice daily are similar to those achieved at a dosage of 100 mg twice daily (both dosages given with food).

Food

Administration with high-fat, high-calorie meal (900–1000 calories, 50% of calories from fat) increased midostaurin AUC by 1.6-fold and decreased peak plasma concentrations by 27%.

Administration with standard meal (450 calories, 25% of calories from fat) increased midostaurin AUC by 1.2-fold and decreased peak plasma concentrations by 20%.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

>99.8% (mainly α₁-acid glycoprotein).

Elimination

Metabolism

Principally metabolized by CYP3A4 to active O-demethylated (CGP-62221) and hydroxyl (CGP-52421) metabolites. Metabolites further metabolized by CYP3A4.

Elimination Route

Eliminated in feces (95% of recovered dose [4% as unchanged drug and 91% as metabolites]) and urine (5%).

Half-life

Midostaurin: 21 hours.

CGP-62221: 32 hours.

CGP-52421: 482 hours.

Special Populations

Mild (total bilirubin concentrations 1–1.5 times the ULN or AST concentration exceeding the ULN) or moderate (total bilirubin concentrations 1.5–3 times the ULN with any AST concentration) hepatic impairment does not substantially affect pharmacokinetics. Data lacking for severe hepatic impairment (total bilirubin concentrations >3 times the ULN with any AST concentration).

Mild or moderate renal impairment (Cl_cr ≥30 mL/minute) does not substantially affect pharmacokinetics. Data lacking for severe renal impairment (Cl_cr 15–29 mL/minute).

Age (20–94 years), gender, and race do not substantially affect pharmacokinetics.

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C). Store in original container to protect from moisture.

Actions

• Inhibits receptor tyrosine kinases including Flt-3.

• Inhibits wild-type Flt-3, mutant Flt-3, vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptors (i.e., PDGFR-α, PDGFR-β), and members of the protein kinase C (PKC) family of tyrosine kinases.

• Induces apoptosis in leukemic cells expressing Flt-3 mutations (i.e., internal tandem duplications [ITD], tyrosine kinase domain [TKD] point mutations) or overexpressing wild-type Flt-3 and PDGFR.

• Inhibits stem cell factor receptor (c-Kit) signaling resulting in apoptosis in mast cells and inhibition of c-Kit-induced cell proliferation and histamine release.

Advice to Patients

• Importance of instructing patients to read the manufacturer's patient information before initiating midostaurin therapy.

• If a dose is missed or vomited, importance of administering the next dose at the regularly scheduled time; do not administer an additional dose to make up for a missed dose.

• Risk of ILD or pneumonitis. Importance of informing clinician immediately if new or worsening cough, chest pain, or shortness of breath occurs.

• Risk of diarrhea, nausea, or vomiting. Importance of informing clinician if any of these symptoms occur or persist despite optimal supportive therapy.

• Risk of impaired fertility in men and women.

• Risk of fetal harm. Necessity of advising women of child-bearing potential and men who are partners of such women that they should use an effective method of contraception while receiving the drug and for ≥4 months after discontinuance of therapy. Importance of women informing clinicians if they are or plan to become pregnant. If pregnancy occurs, advise pregnant women of potential risk to the fetus.

• Importance of advising women to avoid breast-feeding while receiving the drug and for ≥4 months after discontinuance of therapy.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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