midostaurin (Rx)

Brand and Other Names:Rydapt
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 25mg

Acute Myeloid Leukemia (AML)

Indicated, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test

50 mg PO BID (~q12hr) 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

Take dose with food

Also see Administration

Systemic Mastocytosis (SM)

Indicated for adults with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL)

100 mg PO BID (~q12hr) with food

Continue treatment until disease progression or unacceptable toxicity

Also see Administration

Dosage Modifications (ASM, SM-AHN, MCL)

ANC <1 x 10^9/L (without MCL) or ANC < 0.5 x 10^9/L with baseline ANC of 0.5-1.5 x 10^9/L

  • Interrupt dosing until ANC ≥1 x 10^9/L, then resume at 50 mg BID; if tolerated, increase to 100 mg BID
  • Discontinue if low ANC persists for >21 days and is suspected to be related to midostaurin

Platelet count <50 x 10^9/L (without MCL) or <25 x 10^9/L with baseline of 25-75 x 10^9/L

  • Interrupt dosing until platelet count ≥50 x 10^9/L, then resume at 50 mg BID; if tolerated, increase to 100 mg BID
  • Discontinue if low platelet count persists for >21 days and is suspected to be related to midostaurin

Hemoglobin <8 g/L (without MCL) or life-threatening anemia with baseline of 8-10 g/L

  • Interrupt dosing until hemoglobin ≥8 g/L, then resume at 50 mg BID; if tolerated, increase to 100 mg BID
  • Discontinue if low platelet count persists for >21 days and is suspected to be related to midostaurin

Grade 3 to 4 nausea and/or vomiting despite optimal antiemetic therapy

  • Interrupt dosing for 3 days (6 doses), then resume at 50 mg BID; if tolerated, increase to 100 mg BID

Other grade 3 to 4 nonhematological toxicities

  • Interrupt dosing until event has resolved to ≤grade 2, then resume at 50 mg BID; if tolerated, increase to 100 mg BID

Dosing Considerations

Administer prophylactic antiemetics before treatment to decrease risk of nausea and vomiting

AML

  • Limitations of use: Not indicated as a single-agent induction therapy for AML
  • Select patients for the treatment of AML based on the presence of FLT3 mutation positivity
  • Information on FDA-approved tests for the detection of FLT3 mutation in AML is available at: http://www.fda.gov/CompanionDiagnostics

ASM, SM-AHN, and MCL

  • Monitor patients for toxicity at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter while on treatment

Safety and efficacy not established

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Interactions

Interaction Checker

and midostaurin

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            Adverse Effects

            >10% (AML)

            Nausea (83%)

            Febrile neutropenia (83%)

            Hypocalcemia (74%)

            Increased ALT, all grades (71%)

            Mucositis (66%)

            Vomiting (61%)

            Headache (46%)

            Petechiae (36%)

            Musculoskeletal pain (33%)

            Epistaxis (28%)

            Device-related infection (24%)

            Hypernatremia (21%)

            Upper respiratory tract infection (20%)

            Hyperglycemia (20%)

            Increased ALT, grades 3 and 4 (20%)

            Hemorrhoids (15%)

            Arthralgia (14%)

            Hyperhidrosis (14%)

            Prolonged aPTT (13%)

            Renal insufficiency (12%)

            Insomnia (12%)

            >10% (SM)

            Nausea (82%)

            Hyperglycemia (80%)

            Vomiting (68%)

            Lymphopenia (66%)

            Leukopenia (61%)

            Anemia (60%)

            Diarrhea (54%)

            Thrombocytopenia (50%)

            Neutropenia (49%)

            Edema (40%)

            Increased alkaline phosphatase (39%)

            Hypocalcemia (39%)

            Lipase increased (37%)

            Hyperuricemia (37%)

            Increased GGT (35%)

            Musculoskeletal pain (35%)

            Hyponatremia (34%)

            Increased AST (32%)

            Increased ALT (31%)

            Fatigue (34%)

            Abdominal pain (34%)

            Upper respiratory tract infection (30%)

            Hyperbilirubinemia (29%)

            Hypoalbuminemia (27%)

            Pyrexia (27%)

            Constipation (29%)

            Headache (26%)

            Hypokalemia (25%)

            Increased creatinine (25%)

            Hyperkalemia (23%)

            Dyspnea (23%)

            Hypophosphatemia (22%)

            Increased amylase (20%)

            Hypomagnesemia (20%)

            Arthralgia (19%)

            Cough (18%)

            Urinary tract infection (16%)

            GI hemorrhage (14%)

            Rash (14%)

            Dizziness (13%)

            Pleural effusion (13%)

            Epistaxis (12%)

            QT prolonged (11%)

            Insomnia (11%)

            Renal insufficiency (11%)

            1-10% (AML)

            Hyperuricemia (8%)

            Hypertension (8%)

            Cellulitis (7%)

            Fungal infection (7%)

            Dry skin (7%)

            Weight increased (7%)

            Pleural effusion (6%)

            Thrombosis (5%)

            Tremor (4%)

            Pericardial effusion (4%)

            Hypercalcemia (3%)

            Eyelid edema (3%)

            1-10% (SM)

            Pneumonia (10%)

            Herpes virus infection (10%)

            Sepsis (9%)

            Hypotension (9%)

            Febrile neutropenia (8%)

            Disturbance in attention (7%)

            Tremor (6%)

            Hematoma (6%)

            Cardiac failure (6%)

            Bronchitis (6%)

            Dyspepsia (6%)

            Weight increased (6%)

            Contusion (6%)

            Cellulitis or erysipelas (5%)

            Vertigo (5%)

            Chills (5%)

            Oropharyngeal pain (4%)

            Myocardial infarction or ischemia (4%)

            Hypersensitivity (4%)

            Mental status changes (4%)

            Pulmonary edema (3%)

            Gastritis (3%)

            Interstitial lung disease or pneumonitis (2%)

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            Warnings

            Contraindications

            Hypersensitivity; reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment)

            Cautions

            Cases of interstitial lung disease and pneumonitis, some fatal, reported with monotherapy or in combination with chemotherapy; monitor for pulmonary symptoms; discontinue if signs or symptoms of interstitial lung disease or pneumonitis occur without an infectious etiology

            Based on its mechanism of action and findings from animal reproduction studies, midostaurin may cause fetal harm when administered to pregnant women (see Pregnancy)

            Drug interaction overview

            • Primarily metabolized by CYP3A4
            • Strong CYP3A4 inhibitors
              • Coadministration with strong CYP3A inhibitors may increase midostaurin concentrations and risk of toxicity Consider alternative therapies that do not strongly inhibit CYP3A activity
              • Alternatively, if coadministered, monitor for increased risk of adverse reactions, especially during the first week of treatment
            • Strong CYP3A inducers
              • Coadministration with strong CYP3A inducers may decrease midostaurin concentrations and reduce efficacy
              • Avoid coadministration with strong CYP3A inducers
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            Pregnancy

            Pregnancy

            A pregnancy exposure registry monitors pregnancy outcomes in women exposed to therapy during pregnancy; Females who may have been exposed to RYDAPT during pregnancy directly or through a male partner receiving RYDAPT therapy should contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://psi.novartis.com/

            Based on mechanism of action and findings in animal reproduction studies, may cause fetal harm when administered to pregnant women

            Administration to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose

            Pregnancy testing: Recommended for females of reproductive potential within 7 days before initiating midostaurin

            Infertility: Based on findings in animals, midostaurin may impair fertility in females and males of reproductive potential

            Contraception

            • Females: Drug may cause fetal harm when administered to a pregnant woman; advise females of reproductive potential to use effective contraception during treatment and for 4 months after the last dose
            • Males: Males with female sexual partners of reproductive potential should use effective contraception during treatment and for at least 4 months after the last dose

            Lactation

            Unknown if distributed in human breast milk

            Orally administered midostaurin and its active metabolites pass into the milk of lactating rats within 1 hr of a 30-mg/kg/day dose, with approximately 5 times more in the milk of lactating rats compared with plasma

            Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for at least 4 months after the last dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Inhibits multiple receptor tyrosine kinases

            In vitro biochemical or cellular assays have shown that midostaurin or its major human active metabolites CGP62221 and CGP52421 inhibit the activity of wild type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFR-alpha/beta, VEGFR2, and members of the serine/threonine kinase PKC (protein kinase C) family

            Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors

            Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation, and histamine release and induce apoptosis in mast cells

            Absorption

            Peak plasma time: 1-3 hr (fasting); 2.5-3 hr (with food)

            Distribution

            Protein bound: >99.8% (including metabolites

            Vd: 95.2 L

            Metabolism

            Primarily metabolized by CYP3A4

            Metabolites: CGP62221 and CGP52421 account for ~28% and 38%, respectively, of the total circulating radioactivity of midostaurin and its metabolites

            Elimination

            Half-life: 21 hr (midostaurin); 32 hr (CGP62221); 482 hr (CGP52421)

            Excretion: 95% feces (91% as metabolites and 4% as unchanged drug); 5% urine

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            Administration

            Oral Administration

            Take with food twice daily at ~12-hr intervals

            Administer prophylactic antiemetics before treatment to reduce the risk of nausea and vomiting

            Swallow capsules whole; do not open or crush capsules

            Consider interval assessments of QT by ECG if coadministered with medications that can prolong the QT interval

            Missed or vomited dose

            • Do not make up the dose by taking another capsule
            • Take the next dose at the usual scheduled time

            Storage

            Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

            Store in the original package to protect from moisture

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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