midostaurin

Small Molecule Antineoplastic FMS-like Tyrosine Kinase-3 (FLT-3) Inhibitors
Small Molecule Antineoplastic Receptor Tyrosine Kinase c-KIT Inhibitors

Emetic Risk
Moderate/High
Administer routine antiemetic prophylaxis prior to treatment.

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.

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
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
QT prolongation / Rapid / 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
pleural effusion / Delayed / 0-4.0
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
maculopapular rash / Early / 0-3.0
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
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
acute febrile neutrophilic dermatosis / Delayed / Incidence not known
angioedema / Rapid / Incidence not known

Moderate

hypomagnesemia / Delayed / 0-20.0
hemorrhoids / Delayed / 0-15.0
pneumonitis / Delayed / 0-11.0
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
interstitial lung disease / Delayed / 0-1.0
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

Rydapt

Rx

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

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 (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.

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.

Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with midostaurin. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and midostaurin is a BCRP inhibitor.
Adagrasib: (Major) Avoid the concomitant use of midostaurin and adagrasib due to the potential for increased midostaurin exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary, 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. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Midostaurin is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT prolongation. 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 CYP3A inhibitor.
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.
Alpelisib: (Major) Avoid concomitant use of alpelisib with midostaurin due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and midostaurin is a BCRP inhibitor.
Amiodarone: (Major) Concomitant use of midostaurin and amiodarone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with midostaurin. Amisulpride causes dose- and concentration- dependent QT prolongation. QT prolongation was reported in patients who received midostaurin in clinical trials.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP and OATP1B1/3 substrate; midostaurin is a dual BCRP/OATP1B1 inhibitor.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the concomitant use of midostaurin and clarithromycin due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
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 midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
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. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aripiprazole: (Major) Concomitant use of midostaurin and aripiprazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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 due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Atazanavir; Cobicistat: (Major) Avoid the concomitant use of midostaurin and atazanavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone. (Major) Avoid the concomitant use of midostaurin and cobicistat due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily for episodic migraine or 30 mg PO once daily for chronic migraine if coadministered with midostaurin. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of OATP1B1 and OATP1B3 and midostaurin is an OATP inhibitor. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Atomoxetine: (Major) Concomitant use of midostaurin and atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP and OATP1B1/3 substrate; midostaurin is a dual BCRP/OATP1B1 inhibitor.
Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP and OATP1B1/3 substrate; midostaurin is a dual BCRP/OATP1B1 inhibitor.
Azithromycin: (Major) Concomitant use of midostaurin and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking midostaurin. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a BCRP substrate and midostaurin is a BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with midostaurin may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and midostaurin is a BCRP inhibitor.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Brincidofovir: (Moderate) Postpone the administration of midostaurin for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and midostaurin is necessary. Brincidofovir is an OATP1B1 substrate and midostaurin is an OATP1B1 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1 inhibitor.
Buprenorphine: (Major) Concomitant use of midostaurin and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Buprenorphine; Naloxone: (Major) Concomitant use of midostaurin and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bupropion: (Moderate) Monitor for loss of efficacy of bupropion during coadministration of midostaurin as concurrent use may decrease bupropion exposure. A bupropion dose adjustment may be necessary; do not exceed maximum dose. Bupropion is a sensitive substrate of CYP2B6; midostaurin is a moderate CYP2B6 inducer.
Bupropion; Naltrexone: (Moderate) Monitor for loss of efficacy of bupropion during coadministration of midostaurin as concurrent use may decrease bupropion exposure. A bupropion dose adjustment may be necessary; do not exceed maximum dose. Bupropion is a sensitive substrate of CYP2B6; midostaurin is a moderate CYP2B6 inducer.
Cabotegravir; 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.
Carbamazepine: (Major) Avoid the concomitant use of midostaurin and carbamazepine as midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
Ceritinib: (Major) Avoid the concomitant use of midostaurin and ceritinib due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Chloramphenicol: (Major) Avoid the concomitant use of midostaurin and chloramphenicol due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Chloroquine: (Major) Avoid coadministration of chloroquine with midostaurin due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. QT prolongation was reported in patients who received midostaurin in clinical trials.
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.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciprofloxacin: (Major) Concomitant use of ciprofloxacin and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) 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) Concomitant use of citalopram and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clarithromycin: (Major) Avoid the concomitant use of midostaurin and clarithromycin due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Clofazimine: (Major) Concomitant use of clofazimine and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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 due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of promethazine and midostaurin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Codeine; Promethazine: (Moderate) Concomitant use of promethazine and midostaurin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
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 due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Darunavir; Cobicistat: (Major) Avoid the concomitant use of midostaurin and cobicistat due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone. (Major) Avoid the concomitant use of midostaurin and darunavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid the concomitant use of midostaurin and cobicistat due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone. (Major) Avoid the concomitant use of midostaurin and darunavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone. (Moderate) Coadministration of tenofovir alafenamide with midostaurin may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and midostaurin is a BCRP inhibitor.
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) Consider interval assessments of the QT interval by EKG if midostaurin is taken concurrently with degarelix. QT prolongation was reported in patients who received midostaurin in clinical trials. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Delavirdine: (Major) Avoid the concomitant use of midostaurin and delavirdine due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
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.
Deutetrabenazine: (Major) Consider interval assessments of QT by ECG if midostaurin is taken concurrently with deutetrabenazine. QT prolongation was reported in patients who received midostaurin in clinical trials. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Bupropion: (Moderate) Monitor for loss of efficacy of bupropion during coadministration of midostaurin as concurrent use may decrease bupropion exposure. A bupropion dose adjustment may be necessary; do not exceed maximum dose. Bupropion is a sensitive substrate of CYP2B6; midostaurin is a moderate CYP2B6 inducer.
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 due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and diltiazem is a CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
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: (Major) Coadministration of dofetilide and midostaurin is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, consider interval assessments of QT by EKG. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QT prolongation was reported in patients who received midostaurin in clinical trials.
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: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with midostaurin. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and midostaurin is a BCRP inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with midostaurin. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and midostaurin is a BCRP inhibitor.
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. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with midostaurin. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and midostaurin is a BCRP inhibitor.
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.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with midostaurin may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and midostaurin is a BCRP inhibitor.
Dronedarone: (Contraindicated) 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) Avoid the concomitant use of midostaurin and efavirenz as midostaurin exposure may be decreased, which may reduce its efficacy; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Midostaurin is a CYP3A4 substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of midostaurin and efavirenz as midostaurin exposure may be decreased, which may reduce its efficacy; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Midostaurin is a CYP3A4 substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively. (Moderate) Coadministration of tenofovir disoproxil fumarate with midostaurin may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and midostaurin is a BCRP inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of midostaurin and efavirenz as midostaurin exposure may be decreased, which may reduce its efficacy; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Midostaurin is a CYP3A4 substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively. (Moderate) Coadministration of tenofovir disoproxil fumarate with midostaurin may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and midostaurin is a BCRP inhibitor.
Elagolix: (Contraindicated) Coadministration of elagolix with midostaurin is contraindicated as concurrent use may increase elagolix exposure. Elagolix is a substrate of OATP1B1 and midostaurin is an OATP1B1 inhibitor.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Coadministration of elagolix with midostaurin is contraindicated as concurrent use may increase elagolix exposure. Elagolix is a substrate of OATP1B1 and midostaurin is an OATP1B1 inhibitor.
Elbasvir; Grazoprevir: (Contraindicated) Concomitant use of grazoprevir and midostaurin is contraindicated due to the potential for increased grazoprevir exposure. Grazoprevir is a substrate of OATP1B1/3; midostaurin is an inhibitor of OATP1B1.
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.
Eluxadoline: (Major) Reduce the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with midostaurin. Coadministration may increase exposure of eluxadoline. Eluxadoline is an OATP1B1 substrate and midostaurin is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid the concomitant use of midostaurin and cobicistat due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone. (Moderate) Coadministration of tenofovir alafenamide with midostaurin may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and midostaurin is a BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of midostaurin and cobicistat due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone. (Moderate) Coadministration of tenofovir disoproxil fumarate with midostaurin may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and midostaurin is a BCRP inhibitor.
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. (Moderate) Coadministration of tenofovir alafenamide with midostaurin may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and midostaurin is a BCRP inhibitor.
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. (Moderate) Coadministration of tenofovir disoproxil fumarate with midostaurin may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and midostaurin is a BCRP inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with midostaurin may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and midostaurin is a BCRP inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with midostaurin may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and midostaurin is a BCRP inhibitor.
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.
Entrectinib: (Major) Avoid coadministration of entrectinib with midostaurin due to the risk of QT prolongation. If coadministration cannot be avoided, consider interval assessments of QT by EKG. Entrectinib has been associated with QT prolongation. QT prolongation was reported in patients who received midostaurin in clinical trials.
Enzalutamide: (Major) Avoid the concomitant use of midostaurin and enzalutamide as midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
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) Concomitant use of erythromycin and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Escitalopram: (Major) Concomitant use of midostaurin and escitalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; midostaurin is an OATP1B1 inhibitor.
Fenfluramine: (Major) Avoid concurrent use of fenfluramine and midostaurin due to the risk of decreased fenfluramine plasma concentrations, which may reduce its efficacy. If concomitant use is necessary, monitor for decreased efficacy and consider increasing fenfluramine dose as needed. Fenfluramine is a CYP2B6 substrate and midostaurin is a CYP2B6 inducer.
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) Concomitant use of midostaurin and flecainide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluconazole: (Contraindicated) 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) Concomitant use of midostaurin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
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.
Fosamprenavir: (Major) Avoid the concomitant use of midostaurin and fosamprenavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentration

s of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
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 midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
Fostemsavir: (Major) Consider electrocardiogram (ECG) monitoring of the QT interval if midostaurin is taken concurrently with fostemsavir. QT prolongation was reported in patients who received midostaurin in clinical trials. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
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.
Gilteritinib: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and midostaurin is necessary. Consider obtaining periodic electrocardiograms. Both drugs have been associated with QT prolongation.
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.
Glecaprevir; Pibrentasvir: (Moderate) Monitor for an increase in glecaprevir-related adverse reactions if coadministration with midostaurin is necessary. Concomitant use may increase glecaprevir exposure. Glecaprevir is an OATP1B1/3 and BCRP substrate; midostaurin is an OATP1B1 and BCRP inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of midostaurin is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of BCRP and midostaurin is a BCRP inhibitor.
Glyburide: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with midostaurin is necessary. Concomitant use may increase glyburide exposure. Glyburide is a substrate of OATP1B1/3; midostaurin is an OATP1B1 inhibitor.
Glyburide; Metformin: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with midostaurin is necessary. Concomitant use may increase glyburide exposure. Glyburide is a substrate of OATP1B1/3; midostaurin is an OATP1B1 inhibitor.
Goserelin: (Major) Consider periodic monitoring of EGCs for QT prolongation if coadministration of goserelin and midostaurin is necessary. Prolongation of the QT interval was reported in patients who received midostaurin in clinical trials. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc 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) Instruct patients to avoid grapefruit or grapefruit juice during midostaurin treatment due to the potential for increased midostaurin exposure and subsequent toxicity. Midostaurin is a CYP3A4 substrate and grapefruit is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
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.
Histrelin: (Major) Consider periodic monitoring of EGCs for QT prolongation if coadministration of histrelin and midostaurin is necessary. Prolongation of the QT interval was reported in patients who received midostaurin in clinical trials. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
Hydroxychloroquine: (Major) Concomitant use of midostaurin and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of hydroxyzine and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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 due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
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.
Indinavir: (Major) Avoid the concomitant use of midostaurin and indinavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
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 midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of midostaurin and rifampin as midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
Itraconazole: (Major) Avoid the concomitant use of midostaurin and itraconazole due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration of itraconazole with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
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: (Contraindicated) Avoid concomitant use of ketoconazole and midostaurin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of midostaurin, further increasing the risk for adverse effects. 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 and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the AUC values of midostaurin and its metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with midostaurin may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and midostaurin is a BCRP inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid the concomitant use of midostaurin and clarithromycin due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Lapatinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with midostaurin is necessary; correct electrolyte abnormalities prior to treatment. Prolongation of the QT interval was reported in patients who received midostaurin in clinical trials. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
Lefamulin: (Major) Coadministration of lefamulin tablets is contraindicated with midostaurin due to increased midostaurin exposure which may result in QT prolongation and torsade de pointes (TdP). Avoid use of lefamulin injection with midostaurin. If coadministration of lefamulin injection cannot be avoided, ECG monitoring is recommended during treatment. Midostaurin is a sensitive CYP3A4 substrate that has been associated with QT prolongation in clinical trials. Lefamulin is a CYP3A4 inhibitor that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
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) Monitor for an increase in letermovir-related adverse reactions in patients who are NOT also receiving cyclosporine if concomitant use with midostaurin is necessary due to increased letermovir concentrations which may increase the incidence and severity of adverse reactions. Avoid the concomitant use of midostaurin and letermovir WITH cyclosporine due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If unavoidable, monitor for signs and symptoms of midostaurin toxicity, particularly during the first week of therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and an OATP1B1 inhibitor. Letermovir is a OATP1B1/3 substrate and a moderate CYP3A4 inhibitor; however, when given together with cyclosporine, the combined effect may be similar to a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Leuprolide: (Major) Concomitant use of midostaurin and androgen deprivation therapy (i.e., leuprolide) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Leuprolide; Norethindrone: (Major) Concomitant use of midostaurin and androgen deprivation therapy (i.e., leuprolide) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levofloxacin: (Major) Concomitant use of levofloxacin and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and midostaurin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of midostaurin, further increasing the risk for adverse effects. 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 and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the AUC values of midostaurin and its metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively.
Lithium: (Major) Concomitant use of lithium and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Lonafarnib: (Major) Avoid the concomitant use of midostaurin and lonafarnib due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
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 coadministration of lopinavir with midostaurin due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Both drugs have been associated with QT prolongation. (Major) Avoid the concomitant use of midostaurin and ritonavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of midostaurin and lumacaftor; ivacaftor as midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of midostaurin and lumacaftor; ivacaftor as midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
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.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with midostaurin is necessary. Concurrent use may increase the plasma concentrations of maraviroc. Maraviroc is an OATP1B1 substrate; midostaurin is an OATP1B1 inhibitor.
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: (Moderate) Monitor for reduced efficacy of meperidine and signs of opioid withdrawal if coadministration with midostaurin is necessary. Consider increasing the dose of meperidine as needed. If midostaurin is discontinued, consider a dose reduction of meperidine and frequently monitor for signs of respiratory depression and sedation. Meperidine is a substrate of CYP2B6; midostaurin is a weak CYP2B6 inducer. Concomitant use can decrease meperidine exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Methadone: (Major) Concomitant use of midostaurin and methadone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Also monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with midostaurin is necessary. Consider increasing the dose of methadone as needed. If midostaurin is discontinued, consider a dose reduction of methadone and frequently monitor for signs of respiratory depression and sedation. Methadone is a substrate of CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; midostaurin is a weak CYP2B6 inducer. Concomitant use can decrease methadone exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Metronidazole: (Major) Concomitant use of metronidazole and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mifepristone: (Major) Avoid the concomitant use of midostaurin and mifepristone due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Mirtazapine: (Major) Concomitant use of mirtazapine and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mitotane: (Major) Avoid the concomitant use of midostaurin and mitotane as midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
Mobocertinib: (Major) Concomitant use of mobocertinib and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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 due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Nelfinavir: (Major) Avoid the concomitant use of midostaurin and nelfinavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Niacin; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; midostaurin is an OATP1B1 inhibitor.
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.
Nirmatrelvir; Ritonavir: (Major) Avoid the concomitant use of midostaurin and ritonavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Ofloxacin: (Major) Concomitant use of ofloxacin and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Olanzapine; Fluoxetine: (Major) Concomitant use of midostaurin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (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.
Olanzapine; Samidorphan: (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.
Ondansetron: (Major) Concomitant use of ondansetron and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Osilodrostat: (Major) Monitor cortisol concentration and patient's signs and symptoms during coadministration of osilodrostat and midostaurin. Concurrent use may decrease osilodrostat exposure and reduce its efficacy; an increase in osilodrostat dose may be necessary. After discontinuation of midostaurin, monitor cortisol concentration and patient's signs and symptoms; a reduction in osilodrostat dose may be needed. Osilodrostat is a CYP2B6 substrate and midostaurin is a strong CYP2B6 inducer. Additionally, monitor ECGs in patients receiving osilodrostat with midostaurin; both drugs are associated with QT prolongation.
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.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking midostaurin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If concomitant use is necessary, consider ECG monitoring. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. QT prolongation was reported in patients who received midostaurin in clinical trials.
Pacritinib: (Major) Concomitant use of pacritinib and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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) Avoid coadministration of pazopanib and midostaurin due to the potential for increased pazopanib exposure. Pazopanib is a BCRP substrate; midostaurin is a BCRP inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit BCRP. Concomitant use of midostaurin and pazopanib also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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: (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 midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of midostaurin and phenobarbital as midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
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: (Contraindicated) 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.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is an OATP1B1 substrate; midostaurin is an OATP1B1 inhibitor.
Pitolisant: (Major) Avoid coadministration of pitolisant with midostaurin as concurrent use may increase the risk of QT prolongation. If coadministration is necessary, consider interval assessments of QT by EKG. Pitolisant prolongs the QT interval. QT prolongation was reported in patients who received midostaurin in clinical trials.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking midostaurin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, monitor ECGs and for signs and symptoms of infection. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. QT prolongation was reported in patients who received midostaurin in clinical trials.
Posaconazole: (Contraindicated) Avoid concomitant use of midostaurin and posaconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase midostaurin exposure and the risk for other midostaurin-related adverse effects; midostaurin is a CYP3A substrate and posaconazole is a strong CYP3A inhibitor.
Pravastatin: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; midostaurin is an OATP1B1 inhibitor.
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 midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
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) Concomitant use of promethazine and midostaurin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Promethazine; Dextromethorphan: (Moderate) Concomitant use of promethazine and midostaurin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Promethazine; Phenylephrine: (Moderate) Concomitant use of promethazine and midostaurin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Propafenone: (Major) Concomitant use of propafenone and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quetiapine: (Major) Concomitant use of quetiapine and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Quizartinib: (Major) Concomitant use of quizartinib and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Relugolix: (Major) Consider interval assessments of QT by EKG if midostaurin is taken concurrently with relugolix. QT prolongation was reported in patients who received midostaurin in clinical trials. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Consider interval assessments of QT by EKG if midostaurin is taken concurrently with relugolix. QT prolongation was reported in patients who received midostaurin in clinical trials. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Revefenacin: (Major) Avoid concomitant use of revefenacin and midostaurin. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; midostaurin is an inhibitor of OATP1B1.
Ribociclib: (Major) Avoid the concomitant use of midostaurin and ribociclib due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Ribociclib; Letrozole: (Major) Avoid the concomit ant use of midostaurin and ribociclib due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Rifampin: (Major) Avoid the concomitant use of midostaurin and rifampin as midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
Rifapentine: (Major) Avoid the concomitant use of midostaurin and rifapentine as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate and rifapentine 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.
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.
Rimegepant: (Major) Avoid coadministration of rimegepant with midostaurin; concurrent use may increase rimegepant exposure. Rimegepant is a substrate of BCRP and midostaurin is a BCRP inhibitor.
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 due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
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.
Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with midostaurin. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP and OATP1B1/3 substrate and midostaurin is a BCRP and OATP1B1 inhibitor.
Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with midostaurin. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP and OATP1B1/3 substrate and midostaurin is a BCRP and OATP1B1 inhibitor.
Saquinavir: (Contraindicated) Avoid concomitant use of midostaurin and saquinavir due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase midostaurin exposure and the risk for other midostaurin-related adverse effects; midostaurin is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with midostaurin is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. QT prolongation was reported in patients who received midostaurin in clinical trials.
Sertraline: (Major) Concomitant use of sertraline and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
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.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; midostaurin is an OATP1B1 inhibitor.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving midostaurin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. QT prolongation was reported in patients who received midostaurin in clinical trials.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sofosbuvir; Velpatasvir: (Major) Concomitant use of velpatasvir with midostaurin is not recommended due to the risk of decreased plasma concentrations of velpatasvir, which may result in loss of antiviral efficacy. Velpatasvir is a CYP2B6 substrate and midostaurin is a CYP2B6 inducer.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concomitant use of voxilaprevir and midostaurin. Concomitant use may increase voxilaprevir exposure and the risk of voxilaprevir-related adverse reactions. Voxilaprevir is a substrate of OATP1B1/3; midostaurin is an OATP1B1 inhibitor. (Major) Concomitant use of velpatasvir with midostaurin is not recommended due to the risk of decreased plasma concentrations of velpatasvir, which may result in loss of antiviral efficacy. Velpatasvir is a CYP2B6 substrate and midostaurin is a CYP2B6 inducer.
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) Avoid coadministration of sorafenib with midostaurin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. QT prolongation was also reported in patients who received midostaurin in clinical trials.
Sotalol: (Major) Concomitant use of sotalol and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of midostaurin and St. Johns Wort as midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
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.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of midostaurin is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a BCRP substrate and midostaurin is a BCRP inhibitor.
Tamoxifen: (Major) Concomitant use of tamoxifen and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with midostaurin may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and midostaurin is a BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with midostaurin may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and midostaurin is a BCRP inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with midostaurin may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and midostaurin is a BCRP inhibitor.
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: (Contraindicated) 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.
Tipranavir: (Major) Avoid the concomitant use of midostaurin and tipranavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
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.
Topotecan: (Major) Avoid coadministration of midostaurin with oral topotecan due to increased topotecan exposure; midostaurin may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and midostaurin is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
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) Concomitant use of trazodone and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Triclabendazole: (Major) Concomitant use of triclabendazole and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Triptorelin: (Major) Consider periodic monitoring of EGCs for QT prolongation if coadministration of triptorelin and midostaurin is necessary. Prolongation of the QT interval was reported in patients who received midostaurin in clinical trials. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Tucatinib: (Major) Avoid the concomitant use of midostaurin and tucatinib due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with midostaurin. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP drug transporter; midostaurin is a BCRP inhibitor.
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) Concomitant use of vardenafil and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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) Concomitant use of venlafaxine and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Voclosporin: (Major) Consider interval assessments of QT by EKG if midostaurin is taken concurrently with voclosporin. QT prolongation was reported in patients who received midostaurin in clinical trials. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid the concomitant use of midostaurin and clarithromycin due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Voriconazole: (Major) Avoid the concomitant use of midostaurin and voriconazole due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
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.

Rydapt Oral Cap: 25mg

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.

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.

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, CYP2B6, BCRP, OATP1B1
Midostaurin is a CYP3A4 substrate, a weak CYP2B6 inducer, a breast cancer resistance protein (BCRP) inhibitor, and an organic anion transporter polypeptide (OATP)-1BA inhibitor based on a drug interaction studies. Coadministration of midostaurin with midazolam (a sensitive CYP3A4 substrate), pioglitazone (a moderately sensitive CYP2C8 substrate), dextromethorphan (a sensitive CYP2D6 substrate), or digoxin (a sensitive P-glycoprotein substrate) did not affect the substrate AUC values in drug interaction studies. In vitro, midostaurin and/or its metabolites inhibit CYP1A2 and CYP2E1 and induce CYP1A2.

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.

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://report.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.

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 4 months after the last dose.