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  • CLASSES

    Small Molecule Antineoplastic Multikinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral tyrosine kinase inhibitor
    Used for the treatment of adult patients with newly diagnosed acute myeloid leukemia that is FLT3 mutation-positive, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation; also used for advanced systemic mastocytosis
    Interstitial lung disease and pneumonitis have been reported; monitor for pulmonary toxicity

    COMMON BRAND NAMES

    Rydapt

    HOW SUPPLIED

    Rydapt Oral Cap: 25mg

    DOSAGE & INDICATIONS

    For the treatment of acute myelogenous leukemia (AML).
    NOTE: The FDA has designated midostaurin as an orphan drug for the treatment of AML.
    For the treatment of newly diagnosed, FLT3 mutation-positive AML in combination with standard cytarabine and daunorubicin induction and consolidation therapy.
    NOTE: Evaluate patients for the presence of the FLT3 mutation using an FDA-approved detection test (http://www.fda.gov/CompanionDiagnostics).
    Oral dosage
    Adults

    50 mg orally twice daily on days 8 to 21 of each cycle of induction therapy with cytarabine and daunorubicin; additionally, give midostaurin 50 mg orally twice daily on days 8 to 21 of each cycle of consolidation with high-dose cytarabine therapy. Administer prophylactic antiemetic therapy prior to midostaurin. Coadministration of certain drugs may need to be avoided; review drug interactions. Treatment with midostaurin plus standard chemotherapy resulted in significantly improved overall survival compared with placebo plus standard chemotherapy (74.7 months vs. 25.6 months; hazard ratio, 0.78; 95% CI, 0.63 to 0.96; p = 0.009) in adult patients (median age, 47.9 years; range, 18 to 60.9 years) with newly diagnosed FLT3-mutated acute myelogenous leukemia (AML) in a randomized, double-blind, phase III trial (the RATIFY trial; n = 717). Patients received midostaurin 50 mg PO twice daily (n = 360) or placebo (n = 357) on days 8 to 21 in combination with daunorubicin (60 mg/m2 IV daily on days 1, 2, and 3) and cytarabine (200 mg/m2 as a continuous IV infusion daily on days 1 to 7) for up to 2 cycles of induction therapy followed by high-dose cytarabine (3 grams/m2 IV over 3 hours every 12 hours on days 1, 3, and 5) for up to four 28-day cycles of consolidation therapy. After consolidation therapy, patients who remained in remission received either midostaurin (50 mg PO twice daily for 14 days) or placebo, according to the initial randomization assignment, for up to 12 additional 28-day cycles. Patients with acute promyelocytic leukemia or therapy-related AML were excluded from this study.

    For the treatment of systemic mastocytosis.
    NOTE: The FDA has designated midostaurin as an orphan drug for the treatment of mastocytosis.
    For the treatment of aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, or mast cell leukemia.
    Oral dosage
    Adults

    100 mg orally twice daily until disease progression. Administer prophylactic antiemetic therapy prior to midostaurin. Coadministration of certain drugs may need to be avoided; review drug interactions. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop severe toxicity. The overall response rate in the first 6 cycles was 60% in patients with aggressive systemic mastocytosis (n = 16), systemic mastocytosis with an associated hematologic neoplasm (n = 57), or mast-cell leukemia (n = 16) who received six 4-weeks cycles of midostaurin in a nonrandomized phase II trial; 45% of patients had a major response defined as complete resolution of 1 or more C-finding. The median duration of response was 24.1 months. At a median follow-up time of 26 months (range, 12 to 54 months), the median progression-free survival and overall survival times were 14.1 months and 28.7 months, respectively. In this study, the primary efficacy population included patients with at least 1 measurable C-finding (e.g., anemia or thrombocytopenia) that was considered to be related to mastocytosis; 58% of patients had not received prior treatment for advanced systemic mastocytosis.

    MAXIMUM DOSAGE

    Adults

    100 mg PO twice daily.

    Geriatric

    100 mg PO twice daily.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Take midostaurin twice daily with food; separate doses by approximately 12 hours.
    Swallow whole; do not open or crush capsules.
    If a dose is missed or vomited, skip the dose and take the next dose at the usual scheduled time.

    STORAGE

    Rydapt:
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    History of angioedema

    Use of midostaurin is contraindicated in patients who have had a history of angioedema or hypersensitivity reaction to midostaurin or any of the excipients in the product. Severe hypersensitivity reactions (e.g., anaphylactic shock and angioedema) have been reported with midostaurin therapy.

    Pneumonitis, pulmonary toxicity

    Pulmonary toxicity has been reported with midostaurin therapy; some cases were fatal. Monitor patients for pulmonary toxicity (e.g., new cough, chest discomfort, or shortness of breath); discontinue midostaurin in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology.

    Nausea/vomiting

    Gastrointestinal (GI) toxicity (e.g., nausea/vomiting) has been reported with midostaurin therapy. Administer prophylactic antiemetic therapy. Temporary interruption of therapy and a dosage reduction may be necessary in patients with advanced systemic mastocytosis who develop severe GI toxicity.

    Anemia, neutropenia, thrombocytopenia

    Hematologic toxicity (e.g., anemia, neutropenia, and thrombocytopenia) has been reported with midostaurin therapy. In patients with advanced systemic mastocytosis, evaluate complete blood counts including a differential prior to therapy, at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter during midostaurin therapy. Temporary interruption of therapy and a dosage reduction may be necessary in patients with advanced systemic mastocytosis who develop severe hematologic toxicity.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, geriatric, heart failure, hepatic disease, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    QT prolongation has been reported with midostaurin therapy. If midostaurin is taken concurrently with medications that can prolong the QT interval, consider interval assessment with electrocardiograms. Use midostaurin with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.

    Pregnancy

    Midostaurin may cause fetal harm when administered during pregnancy, based on its mechanism of action and animal studies. Advise females of reproductive potential to avoid becoming pregnant while taking midostaurin. Discuss the potential hazard to the fetus if midostaurin is used during pregnancy or if a patient becomes pregnant while taking this drug. Women exposed to midostaurin during pregnancy should enroll in the pregnancy registry that monitors women and their children by contacting Novartis Pharmaceuticals Corporation at 1-888-669-6682 or https://psi.novartis.com/. Embryo-fetal toxicities including reduced fetal birth weight in rabbits and late embryo-fetal death, dilated lateral brain ventricles, extra ribs, and reduced fetal birth weight with effects on fetal growth (e.g., severe renal pelvic cavitation and widened anterior fontanelle) in rats were observed when pregnant animals received midostaurin at doses that resulted in drug exposures that were lower than those observed with the recommended human dose.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during midostaurin treatment. Pregnancy testing within 7 days prior to starting midostaurin therapy is recommended for females of reproductive potential. These patients should avoid pregnancy and use effective contraception during therapy and for 4 months after the last midostaurin dose. Due to male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception during and for 4 months after midostaurin therapy. Women who received midostaurin during pregnancy or who have been exposed through a male partner taking midostaurin should enroll in the pregnancy registry that monitors women and their children by contacting Novartis Pharmaceuticals Corporation at 1-888-669-6682 or https://psi.novartis.com/. Based on information from animal studies, infertility may occur in females or males of reproductive potential. It is not known if infertility is reversible.

    Breast-feeding

    It is not known if midostaurin or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from midostaurin, women should discontinue breast-feeding during midostaurin therapy and for at least 4 months after the last dose.

    ADVERSE REACTIONS

    Severe

    nephrotoxicity / Delayed / 0-25.0
    bronchospasm / Rapid / 0-23.0
    hyperkalemia / Delayed / 0-23.0
    elevated hepatic enzymes / Delayed / 3.0-20.0
    hyperglycemia / Delayed / 7.0-18.0
    GI bleeding / Delayed / 0-14.0
    erythema multiforme / Delayed / 0-14.0
    pleural effusion / Delayed / 6.0-13.0
    renal failure (unspecified) / Delayed / 0-12.0
    stomatitis / Delayed / 0-11.0
    hyperuricemia / Delayed / 0-11.0
    fatigue / Early / 0-9.0
    asthenia / Delayed / 0-9.0
    diarrhea / Early / 0-8.0
    colitis / Delayed / 0-8.0
    prolonged bleeding time / Delayed / 0-8.0
    infection / Delayed / 0-8.0
    dyspnea / Early / 0-7.0
    peripheral edema / Delayed / 0-7.0
    edema / Delayed / 0-7.0
    hyperamylasemia / Delayed / 0-7.0
    hypocalcemia / Delayed / 2.0-7.0
    abdominal pain / Early / 0-6.0
    vomiting / Early / 0-6.0
    nausea / Early / 0-6.0
    heart failure / Delayed / 0-6.0
    hypokalemia / Delayed / 0-6.0
    back pain / Delayed / 4.0-5.0
    bone pain / Delayed / 0-5.0
    musculoskeletal pain / Early / 4.0-5.0
    fever / Early / 0-5.0
    hyponatremia / Delayed / 0-5.0
    thrombosis / Delayed / 0-5.0
    sinusitis / Delayed / 0-4.0
    pharyngitis / Delayed / 1.0-4.0
    myocardial infarction / Delayed / 0-4.0
    pericardial effusion / Delayed / 0-4.0
    hyperbilirubinemia / Delayed / 0-4.0
    pulmonary edema / Early / 0-3.0
    epistaxis / Delayed / 3.0-3.0
    headache / Early / 1.0-3.0
    cystitis / Delayed / 0-3.0
    rash / Early / 0-3.0
    maculopapular rash / Early / 0-3.0
    arthralgia / Delayed / 0-2.0
    constipation / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    petechiae / Delayed / 0-1.0
    QT prolongation / Rapid / 0-1.0
    hypoalbuminemia / Delayed / 0-1.0
    hypophosphatemia / Delayed / 0-1.0
    hypernatremia / Delayed / 0-1.0
    anaphylactic shock / Rapid / 0-0.7
    thrombocytopenia / Delayed / 27.0
    neutropenia / Delayed / 22.0
    anemia / Delayed / 38.0
    leukopenia / Delayed / 19.0
    lymphopenia / Delayed / 42.0
    angioedema / Rapid / Incidence not known

    Moderate

    hypomagnesemia / Delayed / 0-20.0
    hemorrhoids / Delayed / 0-15.0
    hypotension / Rapid / 0-9.0
    hypertension / Early / 0-8.0
    hematoma / Early / 0-6.0
    angina / Early / 0-4.0
    gastritis / Delayed / 0-3.0
    hypercalcemia / Delayed / 0-3.0
    pneumonitis / Delayed / 0-2.0
    chest pain (unspecified) / Early / Incidence not known

    Mild

    hyperhidrosis / Delayed / 0-14.0
    dizziness / Early / 0-13.0
    insomnia / Early / 11.0-12.0
    xerosis / Delayed / 0-7.0
    weight gain / Delayed / 6.0-7.0
    dyspepsia / Early / 0-6.0
    tremor / Early / 4.0-6.0
    chills / Rapid / 0-5.0
    vertigo / Early / 0-5.0
    flushing / Rapid / Incidence not known

    DRUG INTERACTIONS

    Albuterol: (Minor) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Alfuzosin: (Major) The concomitant use of midostaurin and alfuzosin may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Based on electrophysiology studies performed by the manufacturer, alfuzosin may also prolong the QT interval in a dose-dependent manner.
    Amiodarone: (Major) Avoid the concomitant use midostaurin and amiodarone if possible; both drugs have been reported to increase the QT interval. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Major) The concomitant use of midostaurin and tricyclic antidepressants (TCAs) may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Major) The concomitant use of midostaurin and tricyclic antidepressants (TCAs) may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid the concomitant use of midostaurin and clarithromycin as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Coadministration may also increase the risk of QT prolongation. Consider an alternative agent to replace clarithromycin. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Consider interval assessments of QT by electrocardiogram. Midostaurin is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the concomitant use of midostaurin and clarithromycin as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Coadministration may also increase the risk of QT prolongation. Consider an alternative agent to replace clarithromycin. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Consider interval assessments of QT by electrocardiogram. Midostaurin is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Anagrelide: (Major) The concomitant use of midostaurin and anagrelide may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms (ECG) to monitor the QT interval. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
    Apalutamide: (Major) Avoid the concomitant use of midostaurin and apalutamide as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Apomorphine: (Major) The concomitant use of midostaurin and apomorphine may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
    Arformoterol: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aripiprazole: (Major) The concomitant use of midostaurin and aripiprazole may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Avoid the concomitant use of midostaurin and arsenic trioxide; both drugs have been reported to increase the QT interval. Discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If use of these drugs together is unavoidable, frequently monitor electrocardiograms. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Torsade de pointes, QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use.
    Artemether; Lumefantrine: (Major) Avoid the concomitant use of midostaurin and artemether if possible; both drugs have been reported to increase the QT interval. If use of midostaurin and artemether; lumefantrine is required, consider electrocardiogram monitoring. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin and in patients who received artemether; lumefantrine. (Major) Avoid the concomitant use of midostaurin and artemether; lumefantrine if possible; both drugs have been reported to increase the QT interval. If use of midostaurin and artemether; lumefantrine is required, consider electrocardiogram monitoring. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin and in patients who received artemether; lumefantrine.
    Asenapine: (Major) Avoid the concomitant use of midostaurin and asenapine; both drugs have been reported to increase the QT interval. If coadministration cannot be avoided, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Atazanavir: (Major) Avoid the concomitant use of midostaurin and atazanavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace atazanavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; atazanavir boosted with ritonavir or cobicistat is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Atazanavir; Cobicistat: (Major) Avoid the concomitant use of midostaurin and atazanavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace atazanavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; atazanavir boosted with ritonavir or cobicistat is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study. (Major) Avoid the concomitant use of midostaurin and cobicistat as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace cobicistat. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Atomoxetine: (Major) The concomitant use of midostaurin and atomoxetine may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid the concomitant use of midostaurin and phenobarbital as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Azithromycin: (Major) The concomitant use of midostaurin and azithromycin may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Reports of QT prolongation and torsade de pointes have been reported during postmarketing surveillance of azithromycin.
    Bedaquiline: (Major) The concomitant use of midostaurin and bedaquiline may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms (ECG) to monitor the QT interval during therapy. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the concomitant use of midostaurin and phenobarbital as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) The concomitant use of midostaurin and metronidazole may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has been reported in a limited number of case reports with metronidazole use.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) The concomitant use of midostaurin and metronidazole may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has been reported in a limited number of case reports with metronidazole use.
    Brigatinib: (Moderate) Monitor for a decrease in the efficacy of midostaurin if coadministration with brigatinib is necessary. Midostaurin is a sensitive CYP3A4 substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    Budesonide; Formoterol: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Buprenorphine: (Major) The concomitant use of midostaurin and buprenorphine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. Avoid the concomitant use of midostaurin and buprenorphine buccal film. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Buprenorphine; Naloxone: (Major) The concomitant use of midostaurin and buprenorphine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. Avoid the concomitant use of midostaurin and buprenorphine buccal film. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Carbamazepine: (Major) Avoid the concomitant use of midostaurin and carbamazepine as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Ceritinib: (Major) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and midostaurin; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval; QT prolongation was also reported in patients who received midostaurin in clinical trials.
    Chloramphenicol: (Major) Avoid the concomitant use of midostaurin and chloramphenicol as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace chloramphenicol. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Chloroquine: (Major) Avoid the concomitant use midostaurin and chloroquine if possible; both drugs have been reported to increase the QT interval. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Chloroquine administration is associated with an increased risk of QT prolongation and torsade de pointes.
    Chlorpromazine: (Major) The concomitant use of midostaurin and chlorpromazine may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). The risk of QT prolongation and TdP is generally higher at elevated concentrations of phenothiazines. However, case reports have included patients receiving therapeutic doses of chlorpromazine.
    Ciprofloxacin: (Major) The concomitant use of midostaurin and ciprofloxacin may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Rare cases of QT prolongation and torsade de pointes have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Because of the potential for torsade de pointes (TdP), use of midostaurin with cisapride is contraindicated. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Citalopram: (Major) Avoid the concomitant use midostaurin and citalopram if possible; both drugs have been reported to increase the QT interval. If use of these drugs together is necessary, monitor electrocardiograms. Discontinue citalopram in patients who experience persistent QTc measurements above 500 milliseconds. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Citalopram causes dose-dependent QT interval prolongation.
    Clarithromycin: (Major) Avoid the concomitant use of midostaurin and clarithromycin as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Coadministration may also increase the risk of QT prolongation. Consider an alternative agent to replace clarithromycin. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Consider interval assessments of QT by electrocardiogram. Midostaurin is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Clomipramine: (Major) The concomitant use of midostaurin and tricyclic antidepressants (TCAs) may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clozapine: (Major) The concomitant use of midostaurin and clozapine may lead to additive QT interval prolongation. If these drugs are used together, obtain electrocardiograms to monitor the QT interval. Electrolyte imbalances should be corrected prior to initiating treatment with clozapine. Baseline assessments of serum potassium and magnesium levels should be performed, as well as periodic evaluation during treatment, in patients at risk for electrolyte imbalances. The drug should be discontinued if the QT interval exceeds 500 milliseconds. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Treatment with clozapine has been associated with QT prolongation, torsade de pointes, cardiac arrest, and sudden death.
    Cobicistat: (Major) Avoid the concomitant use of midostaurin and cobicistat as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace cobicistat. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid the concomitant use of midostaurin and cobicistat as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace cobicistat. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of midostaurin and cobicistat as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace cobicistat. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Codeine; Phenylephrine; Promethazine: (Moderate) The concomitant use of midostaurin and promethazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Data from a small study evaluating the influence of intravenous promethazine on cardiac repolarization concluded that although promethazine may prolong the QT interval, it has no influence on the transmural dispersion of repolarization; therefore, the risk of torsadogenic action with promethazine is very low.
    Codeine; Promethazine: (Moderate) The concomitant use of midostaurin and promethazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Data from a small study evaluating the influence of intravenous promethazine on cardiac repolarization concluded that although promethazine may prolong the QT interval, it has no influence on the transmural dispersion of repolarization; therefore, the risk of torsadogenic action with promethazine is very low.
    Conivaptan: (Major) Avoid the concomitant use of midostaurin and conivaptan as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace conivaptan. According to the manufacturer of conivaptan (strong CYP3A4 inhibitor), subsequent treatment with CYP3A substrates, such as midostaurin, may be initiated no sooner than 1 week after completion of conivaptan therapy. The manufacturer of midostaurin recommends that if coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Crizotinib: (Major) Avoid coadministration of crizotinib with midostaurin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval was also reported in patients who received midostaurin in clinical trials.
    Darunavir: (Major) Avoid the concomitant use of midostaurin and darunavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace darunavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; darunavir boosted with ritonavir or cobicistat is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Darunavir; Cobicistat: (Major) Avoid the concomitant use of midostaurin and cobicistat as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace cobicistat. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study. (Major) Avoid the concomitant use of midostaurin and darunavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace darunavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; darunavir boosted with ritonavir or cobicistat is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid the concomitant use of midostaurin and cobicistat as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace cobicistat. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study. (Major) Avoid the concomitant use of midostaurin and darunavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace darunavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; darunavir boosted with ritonavir or cobicistat is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of midostaurin and ritonavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace ritonavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Dasatinib: (Major) The concomitant use of midostaurin and dasatinib may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. Correct electrolyte imbalances such as hypokalemia and hypomagnesemia prior to starting dasatinib therapy. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin and in patients who received dasatinib.
    Degarelix: (Major) The concomitant use of midostaurin and degarelix may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QTc prolongation has also been reported with the use of degarelix.
    Delavirdine: (Major) Avoid the concomitant use of midostaurin and delavirdine as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace delavirdine. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Desflurane: (Major) The concomitant use of midostaurin and halogenated anesthetics may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Desipramine: (Major) The concomitant use of midostaurin and tricyclic antidepressants (TCAs) may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Major) Consider obtaining electrocardiograms to monitor the QT interval if midostaurin is used with other drugs that prolong the QT interval. For patients taking a deutetrabenazine dosage more than 24 mg/day with midostaurin, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. QT prolongation has been reported in patients who received midostaurin during clinical trials.
    Dextromethorphan; Promethazine: (Moderate) The concomitant use of midostaurin and promethazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Data from a small study evaluating the influence of intravenous promethazine on cardiac repolarization concluded that although promethazine may prolong the QT interval, it has no influence on the transmural dispersion of repolarization; therefore, the risk of torsadogenic action with promethazine is very low.
    Dextromethorphan; Quinidine: (Major) The concomitant use of midostaurin and quinidine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Quinidine is a Class IA antiarrhythmic agent; it is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Quinidine should be discontinued if significant QT prolongation or TdP occur during therapy.
    Diltiazem: (Major) Avoid the concomitant use of midostaurin and diltiazem as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace diltiazem. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; diltiazem is a CYP3A4 inhibitor.
    Disopyramide: (Major) The concomitant use of midostaurin and disopyramide may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. Closely monitor patients who experience QT prolongation greater than 25% compared with baseline; consider discontinuing disopyramide if the ectopy persists. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Disopyramide is considered to have a well-established risk for QT prolongation and torsades de pointes (TdP) (or polymorphic ventricular tachycardia) and is capable of inducing QT prolongation or TdP even at low therapeutic doses.
    Dofetilide: (Severe) Because of the potential for torsade de pointes (TdP), use of midostaurin with dofetilide is contraindicated. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    Dolasetron: (Major) The concomitant use of midostaurin and dolasetron may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms (ECG) to monitor the QT interval. Monitor electrolytes prior to and during dolasetron therapy and correct electrolyte abnormalities before starting therapy. ECG monitoring is recommended in elderly patients and patients with congestive heart failure, bradycardia, or renal impairment. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Dolasetron may cause dose-dependent ECG interval changes including PR and QTc prolongation and QRS widening. Ventricular tachycardia, ventricular fibrillation, and torsade de pointes have been reported following IV administration of dolasetron in post-marketing surveillance.
    Dolutegravir; Rilpivirine: (Major) The concomitant use of midostaurin and rilpivirine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Major) The concomitant use of midostaurin and donepezil may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms (ECG) to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. There have been case reports of QT prolongation and torsade de pointes with donepezil therapy.
    Donepezil; Memantine: (Major) The concomitant use of midostaurin and donepezil may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms (ECG) to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. There have been case reports of QT prolongation and torsade de pointes with donepezil therapy.
    Doxepin: (Major) The concomitant use of midostaurin and tricyclic antidepressants (TCAs) may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Dronedarone: (Severe) Because of the potential for torsade de pointes (TdP), use of midostaurin with dronedarone is contraindicated. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds (msec) at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 msec at doses of 1,600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Avoid coadministration of midostaurin with droperidol; both drugs have been reported to increase the QT interval. If coadministration cannot be avoided, use extreme caution and monitor electrocardiograms; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
    Efavirenz: (Major) The concomitant use of midostaurin and efavirenz may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Efavirenz; Emtricitabine; Tenofovir: (Major) The concomitant use of midostaurin and efavirenz may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) The concomitant use of midostaurin and efavirenz may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Eliglustat: (Major) The concomitant use of midostaurin and eliglustat may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) The concomitant use of midostaurin and rilpivirine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) The concomitant use of midostaurin and rilpivirine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Encorafenib: (Major) Avoid coadministration of encorafenib and midostaurin due to the potential for additive QT prolongation. Concurrent use may also result in increased toxicity or decreased efficacy of midostaurin. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. QT prolongation was reported in patients who received midostaurin, a sensitive CYP3A4 substrate, in clinical trials.
    Enflurane: (Major) The concomitant use of midostaurin and halogenated anesthetics may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Enzalutamide: (Major) Avoid the concomitant use of midostaurin and enzalutamide as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Eribulin: (Major) The concomitant use of midostaurin and eribulin may lead to additive QT interval prolongation. If these drugs are used together, monitor electrocardiograms and observe patients closely for QT interval prolongation. Additionally, correct hypokalemia and hypomagnesemia prior to starting eribulin; monitor electrolytes periodically during therapy. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Erythromycin: (Major) The concomitant use of midostaurin and erythromycin may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. Electrolyte abnormalities should be corrected prior to erythromycin therapy. Patients predisposed to torsade de pointes (TdP) who require IV erythromycin should not receive more than 15 mg/min. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Systemic erythromycin has been reported to cause QT prolongation resulting in ventricular arrhythmias of the TdP type; fatalities have been reported. Elderly patients may also be more susceptible to the development of torsades de pointes than younger patients.
    Erythromycin; Sulfisoxazole: (Major) The concomitant use of midostaurin and erythromycin may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. Electrolyte abnormalities should be corrected prior to erythromycin therapy. Patients predisposed to torsade de pointes (TdP) who require IV erythromycin should not receive more than 15 mg/min. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Systemic erythromycin has been reported to cause QT prolongation resulting in ventricular arrhythmias of the TdP type; fatalities have been reported. Elderly patients may also be more susceptible to the development of torsades de pointes than younger patients.
    Escitalopram: (Major) The concomitant use of midostaurin and escitalopram may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. In rare instances, QT prolongation and torsade de pointes have been reported during therapeutic use of escitalopram and following overdose.
    Ezogabine: (Major) The concomitant use of midostaurin and ezogabine may lead to additive QT interval prolongation. If these drugs are used together, monitor the QT interval with electrocardiograms. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has occurred in healthy volunteers during ezogabine administration.
    Fingolimod: (Major) The concomitant use of midostaurin and fingolimod may lead to additive QT interval prolongation. If these drugs are used together, monitor the QT interval with electrocardiograms. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of torsade de pointes in patients with bradycardia.
    Flecainide: (Major) The concomitant use of midostaurin and flecainide may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation with ventricular tachycardia and torsade de pointes have been reported with flecainide.
    Fluconazole: (Severe) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as midostaurin, is contraindicated. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. During post-marketing surveillance, rare cases of QT prolongation and torsade de pointes have been reported with fluconazole use.
    Fluoxetine: (Major) The concomitant use of midostaurin and fluoxetine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. Electrolyte imbalances should be corrected prior to initiating treatment with fluoxetine. Discontinue fluoxetine and obtain prompt cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation and ventricular arrhythmias, including torsade de pointes, have been reported in patients treated with fluoxetine.
    Fluoxetine; Olanzapine: (Major) The concomitant use of midostaurin and fluoxetine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. Electrolyte imbalances should be corrected prior to initiating treatment with fluoxetine. Discontinue fluoxetine and obtain prompt cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation and ventricular arrhythmias, including torsade de pointes, have been reported in patients treated with fluoxetine. (Major) The concomitant use of midostaurin and olanzapine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. There have been case reports of significant QT prolongation occurring with olanzapine therapy.
    Fluphenazine: (Minor) The concomitant use of midostaurin and fluphenazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Additionally, fluphenazine is associated with a possible risk for QT prolongation.
    Fluticasone; Salmeterol: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and midostaurin. QT prolongation was reported in patients who received midostaurin in clinical trials. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Consider obtaining electrocardiograms to monitor the QT interval midostaurin is used with other drugs that prolong the QT interval.
    Formoterol: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fosamprenavir: (Major) Avoid the concomitant use of midostaurin and fosamprenavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace fosamprenavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Foscarnet: (Major) Avoid the concomitant use of midostaurin and foscarnet; both drugs have been reported to increase the QT interval. Obtain electrocardiograms (ECG) and electrolyte concentrations before and periodically during treatment with foscarnet. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation and ventricular arrhythmia, including torsade de pointes, have been reported in postmarketing surveillance of foscarnet.
    Fosphenytoin: (Major) Avoid the concomitant use of midostaurin and fosphenytoin as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Gemifloxacin: (Major) The concomitant use of midostaurin and gemifloxacin may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and midostaurin together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. QT prolongation has been reported in patients who received midostaurin in clinical trials.
    Glasdegib: (Major) Avoid coadministration of glasdegib with midostaurin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation was reported in patients who received midostaurin in clinical trials.
    Glycopyrrolate; Formoterol: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Goserelin: (Major) The concomitant use of midostaurin and goserelin may lead to additive QT interval prolongation. If these drugs are used together, consider periodic monitoring of electrocardiograms and electrolytes. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval.
    Granisetron: (Major) The concomitant use of midostaurin and granisetron may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has been reported with IV and oral granisetron in post-marketing surveillance. In a randomized, single-blind, parallel study of healthy patients treated with the granisetron patch (Sancuso, n = 60) or IV granisetron (10 mcg/kg, n = 60), the baseline corrected QTcF for Sancuso was below 10 milliseconds suggesting no effects on QT prolongation.
    Grapefruit juice: (Major) Avoid the concomitant use of midostaurin and grapefruit juice as significantly increased exposure of midostaurin and its active metabolite may occur resulting in increased toxicity. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; grapefruit juice is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Halogenated Anesthetics: (Major) The concomitant use of midostaurin and halogenated anesthetics may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Haloperidol: (Major) The concomitant use of midostaurin and haloperidol may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation and torsade de pointes have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) The concomitant use of midostaurin and halogenated anesthetics may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Histrelin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and midostaurin is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Prolongation of the QT interval was also reported in patients who received midostaurin in clinical trials.
    Hydroxychloroquine: (Major) The concomitant use of midostaurin and hydroxychloroquine may lead to additive QT interval prolongation. If these drugs are used together, perform electrocardiogram monitoring during hydroxychloroquine therapy. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Ventricular arrhythmias (i.e., ventricular fibrillation and ventricular tachycardia) and torsade de pointes have been reported in patients taking hydroxychloroquine.
    Hydroxyzine: (Major) The concomitant use of midostaurin and hydroxyzine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation and torsade de pointes have been reported in postmarketing surveillance of hydroxyzine.
    Ibutilide: (Major) The concomitant use of midostaurin and ibutilide may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin and in patients who received ibutilide.
    Idelalisib: (Major) Avoid the concomitant use of midostaurin and idelalisib as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace idelalisib. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Iloperidone: (Major) Avoid the concomitant use of midostaurin and iloperidone; both drugs have been reported to increase the QT interval. If coadministration cannot be avoided, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Imipramine: (Major) The concomitant use of midostaurin and tricyclic antidepressants (TCAs) may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indacaterol: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indinavir: (Major) Avoid the concomitant use of midostaurin and indinavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace indinavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with midostaurin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and midostaurin have been associated with QT prolongation.
    Isoflurane: (Major) The concomitant use of midostaurin and halogenated anesthetics may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of midostaurin and rifampin as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin (50 mg on day 9) was administered in combination with rifampin (600 mg/day on days 1 to 14) in a drug interaction study.
    Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of midostaurin and rifampin as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin (50 mg on day 9) was administered in combination with rifampin (600 mg/day on days 1 to 14) in a drug interaction study.
    Itraconazole: (Major) Avoid the concomitant use of midostaurin and itraconazole as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Coadministration may also increase the risk of QT prolongation. Consider an alternative agent to replace itraconazole. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Consider interval assessments of QT by EKG. Midostaurin is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin (100 mg twice daily on days 1 to 2 and 50 mg twice daily on days 3 to 28) was administered in combination with itraconazole (100 mg twice daily on days 22 to 28 for 13 doses) compared with day 21 Cmin levels with midostaurin alone in a drug interaction study.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with midostaurin due to an increased risk of QT prolongation; midostaurin exposure may also be decreased. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of midostaurin. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation was reported in patients who received midostaurin in clinical trials.
    Ketoconazole: (Major) Avoid the concomitant use of midostaurin and ketoconazole as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Coadministration may also increase the risk of QT prolongation. Consider an alternative agent to replace ketoconazole. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Consider interval assessments of QT by EKG. Midostaurin is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin (50 mg on day 6) was administered in combination with ketoconazole (400 mg/day on days 1 to 10) in a placebo-controlled, drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Lapatinib: (Major) The concomitant use of midostaurin and lapatinib may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram and electrolyte monitoring. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes have been reported in postmarketing experience.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with midostaurin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QT interval was also reported in patients who received midostaurin in clinical trials.
    Letermovir: (Moderate) An increase in the plasma concentration of midostaurin may occur if given with letermovir; this increase in drug concentration may be pronounced if letermovir is administered during the first week of midostaurin therapy. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be further amplified. If possible, consider alternative therapies. If all 3 drugs must be administered together, monitor for adverse reactions, especially during the first week of consecutive midostaurin administration in advanced systemic mastocytosis population, and during first week of midostaurin administration in each cycle of chemotherapy in AML population. Midostaurin is a sensitive CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given together the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration with another strong CYP3A4 inhibitor increased midostaurin exposure by 10.4-fold.
    Leuprolide: (Major) The concomitant use of midostaurin and leuprolide may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval.
    Leuprolide; Norethindrone: (Major) The concomitant use of midostaurin and leuprolide may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval.
    Levalbuterol: (Minor) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levofloxacin: (Major) The concomitant use of midostaurin and levofloxacin may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Levofloxacin has been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Lithium: (Major) The concomitant use of midostaurin and lithium may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation also has been reported with serum concentrations of lithium in the therapeutic range.
    Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with midostaurin due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. QT prolongation was reported in patients who received midostaurin in clinical trials.
    Long-acting beta-agonists: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Loperamide: (Major) The concomitant use of midostaurin and loperamide may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes, and cardiac arrest.
    Loperamide; Simethicone: (Major) The concomitant use of midostaurin and loperamide may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes, and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Avoid the concomitant use of midostaurin and lopinavir; ritonavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Coadministration may also increase the risk of QT prolongation. Consider an alternative agent to replace lopinavir; ritonavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Consider interval assessments of QT by EKG. Midostaurin is a CYP3A4 substrate; lopinavir; ritonavir is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study. (Major) Avoid the concomitant use of midostaurin and ritonavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace ritonavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of midostaurin and lumacaftor; ivacaftor as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of midostaurin and lumacaftor; ivacaftor as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as midostaurin. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. QT prolongation was also reported in patients who received midostaurin in clinical trials.
    Maprotiline: (Major) The concomitant use of midostaurin and maprotiline may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Mefloquine: (Major) The concomitant use of midostaurin and mefloquine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
    Meperidine; Promethazine: (Moderate) The concomitant use of midostaurin and promethazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Data from a small study evaluating the influence of intravenous promethazine on cardiac repolarization concluded that although promethazine may prolong the QT interval, it has no influence on the transmural dispersion of repolarization; therefore, the risk of torsadogenic action with promethazine is very low.
    Metaproterenol: (Minor) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Methadone: (Major) The concomitant use of midostaurin and methodone may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes, especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Metronidazole: (Major) The concomitant use of midostaurin and metronidazole may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has been reported in a limited number of case reports with metronidazole use.
    Mifepristone: (Major) The concomitant use of midostaurin and mifepristone may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. Use the lowest effective dose of mifepristone to minimize the risk of QT prolongation. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Mifepristone has been associated with dose-dependent prolongation of the QT interval.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and midostaurin. QT prolongation was reported in patients who received midostaurin in clinical trials. Consider obtaining electrocardiograms to monitor the QT interval if it is used with other drugs that prolong the QT interval. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mitotane: (Major) Avoid the concomitant use of midostaurin and mitotane as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Moxifloxacin: (Major) The concomitant use of midostaurin and moxifloxacin may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin.
    Nefazodone: (Major) Avoid the concomitant use of midostaurin and nefazodone as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace nefazodone. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Nelfinavir: (Major) Avoid the concomitant use of midostaurin and nelfinavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace nelfinavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and midostaurin; significant prolongation of the QT interval may occur. If concomitant use is required, consider ECG monitoring. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Nortriptyline: (Major) The concomitant use of midostaurin and tricyclic antidepressants (TCAs) may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Major) The concomitant use of midostaurin and octreotide may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy.
    Ofloxacin: (Major) The concomitant use of midostaurin and ofloxacin may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin.
    Olanzapine: (Major) The concomitant use of midostaurin and olanzapine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. There have been case reports of significant QT prolongation occurring with olanzapine therapy.
    Olodaterol: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of midostaurin and ritonavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace ritonavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Ondansetron: (Major) The concomitant use of midostaurin and ondansetron may lead to additive QT interval prolongation. If these drugs are used together, perform electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Ondansetron has been associated with QT prolongation and torsade de pointes.
    Osimertinib: (Major) Avoid coadministration of midostaurin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation was also reported in patients who received midostaurin in clinical trials.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of midostaurin with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. QT prolongation was reported in patients who received midostaurin in clinical trials. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Paliperidone: (Major) Avoid the concomitant use of midostaurin and paliperidone if possible; both drugs have been reported to increase the QT interval. If concomitant use is necessary, closely monitor for evidence of QT prolongation (e.g., electrocardiograms) during concurrent use. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to cause QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Panobinostat: (Major) Avoid the concomitant use of midostaurin and panobinostat; both drugs have been reported to increase the QT interval. Obtain an electrocardiogram at baseline and periodically during panobinostat treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or greater during therapy; permanently discontinue if QT prolongation does not resolve. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial.
    Pasireotide: (Major) The concomitant use of midostaurin and pasireotide may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram (ECG) monitoring. Obtain a baseline ECG prior to starting pasireotide and perform serum electrolyte monitoring; patients receiving long-acting pasireotide who are at risk for QT prolongation should also be monitored for an effect on the QT interval at the time of maximum drug concentration (21 days after injection). In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin and in patients who received pasireotide.
    Pazopanib: (Major) The concomitant use of pazopanib other drugs that prolong the QT interval like midostaurin is not advised. If these drugs are used together, consider electrocardiogram (ECG) monitoring. Obtain a baseline ECG prior to starting pazopanib and periodically during therapy and perform serum electrolyte monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Prolonged QT interval and torsades de pointes have been observed with pazopanib therapy.
    Pentamidine: (Major) The concomitant use of midostaurin and pentamidine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Systemically adminstered pentamidine is considered to be associated with a well-established risk for QT prolongation and torsade de pointes (TdP). Extremely limited evidence in case reports suggest inhaled pentamidine may be associated with possible TdP; however, systemic absorption of inhaled pentamidine is limited.
    Perphenazine: (Minor) The concomitant use of midostaurin and perphenazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Additionally, perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Major) The concomitant use of midostaurin and tricyclic antidepressants (TCAs) may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) The concomitant use of midostaurin and perphenazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Additionally, perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Phenobarbital: (Major) Avoid the concomitant use of midostaurin and phenobarbital as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Phenylephrine; Promethazine: (Moderate) The concomitant use of midostaurin and promethazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Data from a small study evaluating the influence of intravenous promethazine on cardiac repolarization concluded that although promethazine may prolong the QT interval, it has no influence on the transmural dispersion of repolarization; therefore, the risk of torsadogenic action with promethazine is very low.
    Phenytoin: (Major) Avoid the concomitant use of midostaurin and phenytoin as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is primarily metabolized by CYP3A4; phenytoin is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Pimavanserin: (Major) Avoid the concomitant use of midostaurin and pimavanserin; both drugs have been reported to increase the QT interval. If coadministration cannot be avoided, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Pimavanserin may cause QT prolongation; one pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation in the therapeutic range.
    Pimozide: (Severe) Because of the potential for TdP, use of midostaurin with pimozide is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Pirbuterol: (Minor) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Posaconazole: (Severe) The concurrent use of posaconazole with drugs that are associated with QT prolongation and are CYP3A4 substrates, such as midostaurin, is contraindicated. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes (TdP). Additionally, posaconazole is a strong CYP3A4 inhibitor. Significantly increased exposure of midostaurin and its active metabolites may occur, further increasing the risk of cardiac toxicities and other serious adverse effects.
    Primaquine: (Major) The concomitant use of midostaurin and primaquine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Primidone: (Major) Avoid the concomitant use of midostaurin and primidone as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; phenobarbital, the active metabolite of primidone, is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Procainamide: (Major) The concomitant use of midostaurin and procainamide may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram (ECG) monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes.
    Prochlorperazine: (Minor) The concomitant use of midostaurin and prochlorperazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Additionally, prochlorperazine is associated with a possible risk for QT prolongation. Prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Promethazine: (Moderate) The concomitant use of midostaurin and promethazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Data from a small study evaluating the influence of intravenous promethazine on cardiac repolarization concluded that although promethazine may prolong the QT interval, it has no influence on the transmural dispersion of repolarization; therefore, the risk of torsadogenic action with promethazine is very low.
    Propafenone: (Major) The concomitant use of midostaurin and propafenone may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. QT prolongation and torsade de pointes have occurred during propafenone therapy.
    Protriptyline: (Major) The concomitant use of midostaurin and tricyclic antidepressants (TCAs) may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quetiapine: (Major) Avoid the concomitant use of midostaurin and quetiapine; both drugs have been reported to increase the QT interval. If coadministration cannot be avoided, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) The concomitant use of midostaurin and quinidine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Quinidine is a Class IA antiarrhythmic agent; it is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Quinidine should be discontinued if significant QT prolongation or TdP occur during therapy.
    Quinine: (Major) Avoid the concomitant use of midostaurin and quinine; both drugs have been reported to increase the QT interval. If coadministration cannot be avoided, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has been reported with quinine therapy; rarely, potentially fatal cardiac arrhythmias (e.g., torsades de pointes and ventricular fibrillation) have occurred.
    Ranolazine: (Major) The concomitant use of midostaurin and ranolazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Additionally, ranolazine increased the QTc interval compared with placebo in a clinical trial.
    Ribociclib: (Major) Avoid coadministration of midostaurin with ribociclib due to the risk of QT prolongation; exposure to midostaurin may also increase. Midostaurin is a sensitive CYP3A4 substrate that has been associated with QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Additive QT prolongation may occur. Coadministration with another strong CYP3A4 inhibitor increased midostaurin exposure by 10.4-fold, and increased concentrations of CGP62221 by 3.5-fold.
    Ribociclib; Letrozole: (Major) Avoid coadministration of midostaurin with ribociclib due to the risk of QT prolongation; exposure to midostaurin may also increase. Midostaurin is a sensitive CYP3A4 substrate that has been associated with QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Additive QT prolongation may occur. Coadministration with another strong CYP3A4 inhibitor increased midostaurin exposure by 10.4-fold, and increased concentrations of CGP62221 by 3.5-fold.
    Rifampin: (Major) Avoid the concomitant use of midostaurin and rifampin as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin (50 mg on day 9) was administered in combination with rifampin (600 mg/day on days 1 to 14) in a drug interaction study.
    Rilpivirine: (Major) The concomitant use of midostaurin and rilpivirine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Risperidone: (Major) The concomitant use of midostaurin and risperidone may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram (ECG) monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Pooled data from controlled trials indicate there are no statistically significant differences in mean changes from baseline in ECG parameters including QT, QTc, and PR intervals when risperidone is compared to placebo. However, post-marketing reports of overdose indicate that QT prolongation and torsade de pointes have occurred.
    Ritonavir: (Major) Avoid the concomitant use of midostaurin and ritonavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace ritonavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Romidepsin: (Major) The concomitant use of midostaurin and romidepsin may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring at baseline and periodically during treatment. Correct electrolyte abnormalities, particularly potassium and magnesium levels, prior to starting romidepsin. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin and in patients who received romidepsin.
    Salmeterol: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Saquinavir: (Severe) Concomitant use of midostaurin and saquinavir boosted with ritonavir is contraindicated, as significantly increased exposure of midostaurin and its active metabolites may occur resulting in serious adverse effects, including QT prolongation. Both midostaurin and saquinavir boosted with ritonavir have been associated with QT prolongation. Additionally, midostaurin is a CYP3A4 substrate; saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Sertraline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QT prolongation was reported in patients who received midostaurin in clinical trials. Consider obtaining electrocardiograms to monitor the QT interval if coadministration is required.
    Sevoflurane: (Major) The concomitant use of midostaurin and halogenated anesthetics may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Short-acting beta-agonists: (Minor) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Solifenacin: (Major) The concomitant use of midostaurin and solifenacin may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation and torsade de pointes have been reported during postmarketing surveillance of solifenacin.
    Sorafenib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of sorafenib with midostaurin is necessary; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib has been associated with QT prolongation. Prolongation of the QT interval was also reported in patients who received midostaurin in clinical trials.
    Sotalol: (Major) The concomitant use of midostaurin and sotalol may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. Consider sotalol dose reduction or discontinuation if the QTc interval is greater than 500 milliseconds (msec); serious consideration to dose reduction or drug discontinuation should occur in patients with a QTc interval greater than 550 msec. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation and torsade de pointes have been reported with sotalol in clinical trials.
    St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of midostaurin and St. John's Wort as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Sunitinib: (Major) Consider obtaining electrocardiograms to monitor the QT interval if midostaurin is used with other drugs that prolong the QT interval, such as sunitinib. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). Prolongation of the QT interval was also reported in patients who received midostaurin in clinical trials.
    Tacrolimus: (Major) The concomitant use of midostaurin and tacrolimus may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. There are post-marketing reports of QT prolongation and torsade de pointes with systemic tacrolimus administration.
    Tamoxifen: (Major) Caution is advised with the concomitant use of tamoxifen and midostaurin due to an increased risk of QT prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telavancin: (Major) The concomitant use of midostaurin and telavancin may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin and in patients who received telavancin.
    Telithromycin: (Major) Avoid the concomitant use of midostaurin and telithromycin as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Coadministration may also increase the risk of QT prolongation. Consider an alternative agent to replace telithromycin. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Consider interval assessments of QT by EKG. Midostaurin is a CYP3A4 substrate; telithromycin is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Terbutaline: (Minor) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tetrabenazine: (Major) Avoid the concomitant use of midostaurin and tetrabenazine; both drugs have been reported to increase the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Thioridazine: (Severe) Because of the potential for torsade de pointes (TdP), use of midostaurin with thioridazine is contraindicated. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Thioridazine is associated with a well-established risk of QT prolongation and TdP.
    Tiotropium; Olodaterol: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tipranavir: (Major) Avoid the concomitant use of midostaurin and tipranavir boosted with ritonavir as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace tipranavir/ritonavir. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; tipranavir boosted with ritonavir is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Tolterodine: (Major) The concomitant use of midostaurin and tolterodine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Toremifene: (Major) Avoid coadministration of midostaurin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval was reported in patients who received midostaurin in clinical trials.
    Trazodone: (Major) Avoid the concomitant use of midostaurin and trazodone; both drugs have been reported to increase the QT interval. If coadministration cannot be avoided, consider electrocardiogram monitoring. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes.
    Tricyclic antidepressants: (Major) The concomitant use of midostaurin and tricyclic antidepressants (TCAs) may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) The concomitant use of midostaurin and trifluoperazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Additionally, trifluoperazine is associated with a possible risk for QT prolongation. Trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Trimipramine: (Major) The concomitant use of midostaurin and tricyclic antidepressants (TCAs) may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Triptorelin: (Major) The concomitant use of midostaurin and triptorelin may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval.
    Umeclidinium; Vilanterol: (Moderate) Concomitant use may result in additive effects on the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Vandetanib: (Major) Avoid coadministration of vandetanib with midostaurin due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Prolongation of the QT interval was also reported in patients who received midostaurin in clinical trials.
    Vardenafil: (Major) The concomitant use of midostaurin and vardenafil may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Both therapeutic and supratherapeutic doses of vardenafil produced an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
    Vemurafenib: (Major) The concomitant use of midostaurin and vemurafenib may lead to additive QT interval prolongation. Monitor ECG and serum electrolytes prior to and during vemurafenib therapy. If the QTc interval exceeds 500 milliseconds (msec) during therapy, hold vemurafenib; resume at a lower dose once the QTc is below 500 msec. Permanently discontinue vemurafenib if the QTc increases to greater than 500 msec and to greater than 60 msec from baseline after the correction of associated risk factors. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QTc prolongation was reported in patients who received vemurafenib in a multicenter, open-label, single-arm trial.
    Venlafaxine: (Major) The concomitant use of midostaurin and venlafaxine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation occurred in patients who received venlafaxine in clinical trials; additionally, QT prolongation and torsade de pointes have been reported in postmarketing surveillance of venlafaxine.
    Voriconazole: (Major) Avoid the concomitant use of midostaurin and voriconazole as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Coadministration may also increase the risk of QT prolongation. Consider an alternative agent to replace voriconazole. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Consider interval assessments of QT by EKG. Midostaurin is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Vorinostat: (Major) The concomitant use of midostaurin and vorinostat may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. Correct any electrolyte imbalance prior to starting vorinostat; monitor serum electrolytes during therapy. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has been reported in patients who received vorinostat in a clinical study and in a retrospective analysis; however, the QTc interval was not prolonged following a single 800-mg vorinostat dose in a randomized, 2-period, crossover study designed to assess the impact of vorinostat on ventricular repolarization in patients with advanced cancer.
    Ziprasidone: (Major) Concomitant use of ziprasidone and midostaurin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QT prolongation was reported in patients who received midostaurin in clinical trials. Consider obtaining electrocardiograms to monitor the QT interval if ziprasidone and midostaurin are used together.

    PREGNANCY AND LACTATION

    Pregnancy

    Midostaurin may cause fetal harm when administered during pregnancy, based on its mechanism of action and animal studies. Advise females of reproductive potential to avoid becoming pregnant while taking midostaurin. Discuss the potential hazard to the fetus if midostaurin is used during pregnancy or if a patient becomes pregnant while taking this drug. Women exposed to midostaurin during pregnancy should enroll in the pregnancy registry that monitors women and their children by contacting Novartis Pharmaceuticals Corporation at 1-888-669-6682 or https://psi.novartis.com/. Embryo-fetal toxicities including reduced fetal birth weight in rabbits and late embryo-fetal death, dilated lateral brain ventricles, extra ribs, and reduced fetal birth weight with effects on fetal growth (e.g., severe renal pelvic cavitation and widened anterior fontanelle) in rats were observed when pregnant animals received midostaurin at doses that resulted in drug exposures that were lower than those observed with the recommended human dose.

    Counsel patients about the reproductive risk and contraception requirements during midostaurin treatment. Pregnancy testing within 7 days prior to starting midostaurin therapy is recommended for females of reproductive potential. These patients should avoid pregnancy and use effective contraception during therapy and for 4 months after the last midostaurin dose. Due to male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception during and for 4 months after midostaurin therapy. Women who received midostaurin during pregnancy or who have been exposed through a male partner taking midostaurin should enroll in the pregnancy registry that monitors women and their children by contacting Novartis Pharmaceuticals Corporation at 1-888-669-6682 or https://psi.novartis.com/. Based on information from animal studies, infertility may occur in females or males of reproductive potential. It is not known if infertility is reversible.

    MECHANISM OF ACTION

    Midostaurin is a multiple receptor tyrosine kinase inhibitor. In vitro, midostaurin and its metabolites, CGP62221 and CGP52421, inhibit the activity of wild-type FLT3, FLT3-mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), platelet-derived growth-factor (PDGF) receptor, vascular endothelial growth-factor receptor-2 (VEGFR2), and members of the serine/threonine kinase protein kinase C family. FLT3 ligand binds to its receptor leading to activation of downstream signaling cascades which mediates differentiation and growth of leukemia cells. FLT3 mutations are present in about one-third of patients with acute myelogenous leukemia. Midostaurin induces apoptosis in leukemic cells expressing ITD- and TKD-mutant FLT3 receptors or overexpressing wild-type FLT3 and PDGF receptors. Systemic mastocytosis is a myeloid malignancy that is caused by the accumulation of abnormal mast cells. The KIT D816V mutation is present in approximately 90% of patients. Midostaurin also inhibits KIT signaling, cell proliferation, and histamine release and induces apoptosis in mast cells.

    PHARMACOKINETICS

    Midostaurin is administered orally. In vitro, midostaurin and its metabolites are highly bound to plasma proteins (99.8%), primarily alpha 1-acid glycoprotein. It has an estimated geometric mean volume of distribution of 95.2 L (coefficient of variation (CV), 31%). Midostaurin if metabolized in the liver, primarily by CYP3A4; metabolites CGP62221, and CGP52421 accounted for 28% (+/- 2.7%) and 38 % (+/- 6.6%) of the total circulating radioactively following radiolabeled midostaurin administration. The geometric mean terminal half-life values were 19 hours (CV, 39%), 32 hours (CV, 31%), and 482 hours (CV, 25%) for midostaurin, CGP62221, and CGP52421, respectively. Fecal excretion accounts for 95% of the recovered dose, with 91% of the dose excreted as metabolites and 4% of the dose as unchanged parent drug; 5% of the recovered dose was excreted in the urine.
     
    Affected cytochrome P450 isoenzymes: CYP3A4
    Midostaurin is primarily metabolized by CYP3A4. Use should be avoided with strong CYP3A4 inhibitors and inducers. Coadministration with midazolam (a sensitive CYP3A4 substrate) did not affect the exposure of midazolam in a drug interaction study. In vitro, midostaurin and and/or its metabolites inhibit CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP2E1, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and OATP1B1 and induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A.

    Oral Route

    Steady-state Cmin (trough) values are achieved at approximately 28 days. Steady-state midostaurin, CGP62221, and CGP52421 Cmin values were similar following midostaurin 50 mg PO twice daily or 100 mg PO twice daily with food. In the fasted state, the midostaurin Tmax occurs at 1 to 3 hours post-dose.
    Effects of Food: The midostaurin AUC values increased by 1.2-fold and 1.6-fold and the Cmax values decreased by 20% and 27% when midostaurin was administered with a standard meal (457 calories; 50 g fat; 21 g protein; and 18 g carbohydrates) and a high-fat meal (1,007 calories; 66 g fat; 32 g protein; and 64 g carbohydrates), respectively, compared with midostaurin administered in a fasted state. Additionally, the midostaurin median Tmax was delayed from 2.5 to 3 hours when midostaurin was administered with a standard or high-fat meal. Midostaurin should be administered with food.