MIDOSTAURIN

Clinical safety rating: caution

Comprehensive clinical and safety monograph for MIDOSTAURIN (MIDOSTAURIN).

How it works

Midostaurin is a multikinase inhibitor that targets FLT3 (FMS-like tyrosine kinase 3), KIT, PDGFRα/β, VEGFR2, and PKC. It inhibits FLT3 receptor signaling and downstream MAPK/ERK and PI3K/AKT pathways, inducing apoptosis in FLT3-mutated cells.

What the body does with it

Metabolism	Primarily metabolized by CYP3A4, producing active metabolites CGP52421 (also CYP3A4) and CGP62221. Midostaurin is a substrate of CYP3A4 and also inhibits CYP3A4 and CYP2C9.
Excretion	Midostaurin is primarily eliminated via feces (approximately 95% of total radioactivity after a single 50 mg oral dose), with <5% excreted in urine. Biliary excretion is the major route for fecal elimination; unchanged midostaurin accounts for <10% of the dose, with the remainder as metabolites.
Half-life	The terminal elimination half-life (t½) of midostaurin is approximately 20 hours (range 17–22 h) for the parent drug and slightly longer for its active metabolite CGP52421 (~30 h). This supports twice-daily dosing while maintaining steady-state concentrations.
Protein binding	Midostaurin is approximately 99.8% bound to plasma proteins, primarily albumin and α-1-acid glycoprotein. This high binding influences volume of distribution and may be affected by hypoalbuminemia.
Volume of Distribution	The apparent volume of distribution (Vd/F) is approximately 1300 L (95 L/kg for a 70 kg patient), indicating extensive tissue distribution. This large Vd reflects penetration into tissues including bone marrow (target site for AML/mastocytosis).
Bioavailability	Absolute oral bioavailability of midostaurin is approximately 30% (range 20–40%). Food does not significantly alter bioavailability and the drug can be taken without regard to meals.
Onset of Action	For FLT3-mutated AML, clinical response (complete remission) is typically assessed within 1–2 months of continuous dosing. For systemic mastocytosis, symptomatic improvement may be observed within 2–4 weeks. Time to peak plasma concentration (Tmax) is 1.5–3 hours after oral administration, but therapeutic effect requires sustained exposure.
Duration of Action	Given the half-life, therapeutic plasma concentrations are maintained over the dosing interval (12 hours). Duration of action is continuous with twice-daily dosing; treatment is continued until disease progression or unacceptable toxicity. In AML, midostaurin is given in combination with chemotherapy for 14 days per cycle; response duration varies but median remission duration is approximately 4–5 months.

Classification & Brands

Dosing & administration

50 mg orally twice daily with food for acute myeloid leukemia (AML) with FLT3 mutation; for advanced systemic mastocytosis, 100 mg orally twice daily.

Dosage form	CAPSULE
Renal impairment	No dose adjustment required for mild-to-moderate renal impairment (CrCl ≥30 mL/min). For severe renal impairment (CrCl <30 mL/min), reduce dose to 50 mg twice daily and monitor for toxicity.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: reduce dose to 50 mg twice daily. Child-Pugh C: avoid use.
Pediatric use	For pediatric AML with FLT3 mutation: 50 mg/m² orally twice daily (based on body surface area). Maximum dose 100 mg twice daily.
Geriatric use	No specific dose adjustment required; monitor renal function and consider reducing to 50 mg twice daily if eGFR <30 mL/min. Increased risk of QT prolongation.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for MIDOSTAURIN (MIDOSTAURIN).

Breastfeeding	No human data; animal studies show excretion in milk. Breastfeeding not recommended during therapy and for at least 7 days after last dose. M/P ratio unknown.
Teratogenic Risk	Midostaurin is embryotoxic and fetotoxic in animal studies. In first trimester, there is potential for major congenital malformations. In second and third trimesters, risk of growth restriction, fetal distress, and premature labor. Cases of spontaneous abortion documented.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to midostaurin or any component of the formulation"]

Clinical Precautions

Precautions

["Pulmonary toxicity: Interstitial lung disease/pneumonitis, including fatalities. Monitor for pulmonary symptoms.","Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for at least 4 months after the last dose.","Risk of hemorrhage: Severe bleeding events reported. Monitor platelet counts and manage bleeding promptly."]

Clinical Tips & Counseling

Drug interactions

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MIDOSTAURIN

Clinical safety rating: caution

Comprehensive clinical and safety monograph for MIDOSTAURIN (MIDOSTAURIN).

How it works

What the body does with it

Metabolism	Primarily metabolized by CYP3A4, producing active metabolites CGP52421 (also CYP3A4) and CGP62221. Midostaurin is a substrate of CYP3A4 and also inhibits CYP3A4 and CYP2C9.
Excretion	Midostaurin is primarily eliminated via feces (approximately 95% of total radioactivity after a single 50 mg oral dose), with <5% excreted in urine. Biliary excretion is the major route for fecal elimination; unchanged midostaurin accounts for <10% of the dose, with the remainder as metabolites.
Half-life	The terminal elimination half-life (t½) of midostaurin is approximately 20 hours (range 17–22 h) for the parent drug and slightly longer for its active metabolite CGP52421 (~30 h). This supports twice-daily dosing while maintaining steady-state concentrations.
Protein binding	Midostaurin is approximately 99.8% bound to plasma proteins, primarily albumin and α-1-acid glycoprotein. This high binding influences volume of distribution and may be affected by hypoalbuminemia.
Volume of Distribution	The apparent volume of distribution (Vd/F) is approximately 1300 L (95 L/kg for a 70 kg patient), indicating extensive tissue distribution. This large Vd reflects penetration into tissues including bone marrow (target site for AML/mastocytosis).
Bioavailability	Absolute oral bioavailability of midostaurin is approximately 30% (range 20–40%). Food does not significantly alter bioavailability and the drug can be taken without regard to meals.
Onset of Action	For FLT3-mutated AML, clinical response (complete remission) is typically assessed within 1–2 months of continuous dosing. For systemic mastocytosis, symptomatic improvement may be observed within 2–4 weeks. Time to peak plasma concentration (Tmax) is 1.5–3 hours after oral administration, but therapeutic effect requires sustained exposure.
Duration of Action	Given the half-life, therapeutic plasma concentrations are maintained over the dosing interval (12 hours). Duration of action is continuous with twice-daily dosing; treatment is continued until disease progression or unacceptable toxicity. In AML, midostaurin is given in combination with chemotherapy for 14 days per cycle; response duration varies but median remission duration is approximately 4–5 months.

Classification & Brands

Dosing & administration

50 mg orally twice daily with food for acute myeloid leukemia (AML) with FLT3 mutation; for advanced systemic mastocytosis, 100 mg orally twice daily.

Dosage form	CAPSULE
Renal impairment	No dose adjustment required for mild-to-moderate renal impairment (CrCl ≥30 mL/min). For severe renal impairment (CrCl <30 mL/min), reduce dose to 50 mg twice daily and monitor for toxicity.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: reduce dose to 50 mg twice daily. Child-Pugh C: avoid use.
Pediatric use	For pediatric AML with FLT3 mutation: 50 mg/m² orally twice daily (based on body surface area). Maximum dose 100 mg twice daily.
Geriatric use	No specific dose adjustment required; monitor renal function and consider reducing to 50 mg twice daily if eGFR <30 mL/min. Increased risk of QT prolongation.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for MIDOSTAURIN (MIDOSTAURIN).

Breastfeeding	No human data; animal studies show excretion in milk. Breastfeeding not recommended during therapy and for at least 7 days after last dose. M/P ratio unknown.
Teratogenic Risk	Midostaurin is embryotoxic and fetotoxic in animal studies. In first trimester, there is potential for major congenital malformations. In second and third trimesters, risk of growth restriction, fetal distress, and premature labor. Cases of spontaneous abortion documented.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to midostaurin or any component of the formulation"]

Clinical Precautions

Precautions

Clinical Tips & Counseling

Drug interactions

Loading safety data…