Midostaurin, an inhibitor of multiple receptor tyrosine kinases including fms-like tyrosine kinase-3 (Flt-3), is an antineoplastic agent.1
Midostaurin is used in combination with cytarabine and daunorubicin as a component of induction therapy followed by use in combination with high-dose cytarabine as a component of consolidation therapy for newly diagnosed acute myeloid leukemia (AML) harboring fms-like tyrosine kinase-3 (Flt-3) mutation.1, 2 Midostaurin has been designated an orphan drug by FDA for the treatment of this cancer.3 An FDA-approved companion diagnostic test (e.g., LeukoStrat® CDx Flt-3 mutation assay) is required to confirm the presence of the Flt-3 mutation prior to initiation of therapy.1 In patients with newly diagnosed AML harboring Flt-3 mutation, the addition of midostaurin to cytarabine-based induction and consolidation therapy substantially prolonged survival.1, 2 Flt-3 mutation is detectable in approximately 30% of patients with newly diagnosed AML.2 Midostaurin is a treatment option as added therapy in certain patients with newly diagnosed AML and as an option for maintenance treatment for patients in remission.3015 Midostaurin is not indicated for use as single-agent induction therapy in patients with AML.1
The indication for midostaurin in the treatment of AML is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (RATIFY) in adults with newly diagnosed AML harboring an internal tandem duplication (ITD) mutation or a point mutation in the tyrosine kinase domain (TKD) of the Flt-3 kinase.1, 2
In this study, 717 adults were randomized in a 1:1 ratio to receive either midostaurin or placebo in combination with standard cytarabine-based induction and consolidation therapy.1, 2 Midostaurin (50 mg twice daily) or placebo was administered on days 8-21 of each cycle of induction therapy and each 28-day cycle of consolidation therapy.1, 2, 10 Induction therapy consisted of daunorubicin 60 mg/m2 daily by short IV infusion on days 1-3 and cytarabine 200 mg/m2 daily by continuous IV infusion on days 1-7 of each cycle for up to 2 cycles;1, 2, 10 a second cycle of induction therapy with the same drug combination was administered if definitive evidence of clinically important residual leukemia was present in the bone marrow on day 21.2 Patients who achieved complete remission (defined as less than 5% leukemic blast cells in the bone marrow, absence of leukemic blast cells in peripheral blood, absolute neutrophil count [ANC] exceeding 1000/mm3, platelet count exceeding 100,000/mm3, and absence of extramedullary disease) following induction therapy received consolidation therapy.2, 10 Consolidation therapy consisted of high-dose cytarabine (3 g/m2 by IV infusion over 3 hours every 12 hours) on days 1, 3, and 5 of each 28-day cycle for up to 4 cycles.1, 2 Patients who remained in complete remission received post-consolidation therapy with midostaurin (50 mg twice daily continuously) or placebo, according to the original treatment assignment, in 28-day cycles for up to 12 cycles (maintenance phase).1, 2, 10
Patients in this study were stratified according to subtype of Flt-3 mutation (TKD or ITD); patients with ITD mutations were further stratified based on mutant-to-wild-type Flt-3 allelic ratio (high ITD was defined as an allelic ratio of 0.7 or greater, and low ITD was defined as an allelic ratio of less than 0.7).1, 2 Patients who proceeded to stem cell transplantation were included in the efficacy analysis, but study treatment was discontinued.1, 10 The primary measure of efficacy was overall survival.1, 2 In this study, 25% of patients received a second cycle of induction therapy, 62% received at least one cycle of consolidation therapy, and 29% received maintenance therapy.1, 2 Among the patients who received maintenance therapy with midostaurin, 58% of these patients completed 12 cycles of therapy.2 Following initial complete remission, induction failure, or salvage therapy after relapse, 59% of midostaurin-treated patients and 55% of placebo recipients underwent stem cell transplantation.1, 2
The median age of patients enrolled in the RATIFY study was 47 years (range: 18-60 years); 44% were male, 88% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and 95% had de novo AML.1, 10 Approximately one-half of patients had a low Flt-3-ITD allelic ratio, 30% had a high Flt-3-ITD allelic ratio, and 23% had Flt-3-TKD mutations.1, 2 In addition, nucleophosmin 1 (NPM1) mutation was present in 58% of 563 patients evaluated for this mutation.1, 10 Baseline characteristics were generally balanced between treatment groups; however, a larger proportion of patients receiving placebo were female (59 versus 52%) or had NPM1 mutation (60 versus 55%) compared with those receiving midostaurin.1, 2
After a minimum follow-up of approximately 3.5 years, midostaurin in combination with cytarabine-based induction and consolidation therapy reduced the risk of death by 23% compared with placebo in combination with cytarabine-based induction and consolidation therapy.1, 2 Because overall survival curves (based on Kaplan-Meier estimates) for both treatment groups reached a plateau after approximately 36 months, median overall survival could not be reliably estimated;1, 2, 10 however, at a follow-up of 6 years, the mean survival time in midostaurin-treated patients was 44 months compared with 38.6 months in placebo recipients.10 Median event-free survival (events defined as failure to obtain a complete remission within 60 days of initiation of therapy, relapse, or death from any cause) was prolonged in midostaurin-treated patients compared with placebo recipients (8.2 versus 3 months; hazard ratio: 0.78); however, many patients were classified as having an early event because of failure to achieve protocol-specified complete remission, and event dates for these patients were assigned as the date of last adequate response assessment prior to day 60.1, 2, 10 Therefore, because of the potential for bias in the estimated effect size, an exploratory analysis of event-free survival in which events were defined as failure to obtain complete remission at any time during induction therapy (assigned as an event beginning on study day 1), relapse, or death from any cause was conducted.1, 10 In this exploratory analysis, median event-free survival also was prolonged in midostaurin-treated patients compared with placebo recipients (10.6 versus 5.6 months; hazard ratio: 0.72).1, 10 Median disease-free survival also was prolonged in midostaurin-treated patients compared with placebo recipients (26.7 versus 15.5 months).2 Subgroup analysis according to Flt-3 mutation subtype suggested that the favorable overall survival benefit of midostaurin in combination with chemotherapy was consistent across these subgroups; however, overall survival did not differ significantly between midostaurin-treated patients and placebo recipients within these subgroups.2 In a post-hoc analysis, the cumulative incidence of relapse (which included AML relapse, death related to AML, and transplantation) was reduced with use of midostaurin compared to standard chemotherapy.15 However, a reduction in AML relapse and deaths alone were not significantly reduced with midostaurin compared to standard chemotherapy.15
The intensive induction chemotherapy regimen consisting of midostaurin, cytabarine, and an anthracycline is recommended by the National Cancer Institute (NCI) as one of several combination regimens that may be used for the treatment of newly diagnosed acute myeloid leukemia (AML).3015 The addition of midostaurin to cytabarine and an anthracycline has been shown to improve survival in patients withFLT3-mutated AML.3015 In patients who may not be able to tolerate intensive induction chemotherapy (e.g., older adults or patients with significant comorbid conditions), NCI and other experts state that less-intensive chemotherapy regimens may be considered.3015, 3016
NCI includes midostaurin as a treatment option for postremission therapy† in patients with FLT3-mutated AML.3015 While maintenance therapy (longer-term therapy at lower doses) has not been shown to benefit AML, there is some evidence indicating that midostaurin or oral azacitadine may improve outcomes.3015
Midostaurin is used for the treatment of aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematologic neoplasm (SM-AHN; also known as systemic mastocytosis with an associated hematologic non-mast-cell-lineage disease [SM-AHNMD]4, 14 ), and mast cell leukemia;1, 4 midostaurin has been designated an orphan drug by FDA for the treatment of these conditions.3 Systemic mastocytosis is characterized by multifocal infiltrates of neoplastic mast cells in various internal organs, including the bone marrow, spleen, liver, and GI tract; symptoms are related to release of vasoactive mediators and to organ damage resulting from neoplastic mast cell infiltration.4, 14 In 2 open-label, noncomparative, phase 2 studies in patients with advanced systemic mastocytosis, overall responses (major plus partial responses) were observed in 52-60% of evaluable patients.1, 4, 10, 16
The first study enrolled 116 adults with advanced systemic mastocytosis whose disease had relapsed or progressed following 0-2 prior therapies for systemic mastocytosis; 89 of these patients had at least one measurable clinical finding (C-finding) related to organ damage caused by infiltrating neoplastic mast cells (i.e., transfusion-independent and transfusion-dependent anemia or thrombocytopenia, hypoalbuminemia, neutropenia, liver function test abnormalities, weight loss)4 and were evaluable for response in the primary efficacy analysis.1, 4 Patients enrolled in the study were required to have adequate renal and hepatic function (i.e., serum creatinine concentrations not exceeding 2 mg/dL; total bilirubin concentrations not exceeding 1.5 times the upper limit of normal [ULN] or 3 times the ULN if disease related and aminotransferase concentrations not exceeding 2.5 times the ULN or 5 times the ULN if disease related).1, 4 This study excluded patients with corrected QT (QTc) intervals exceeding 450 msec, cardiovascular disease (e.g., left ventricular ejection fraction less than 50%, recent myocardial infarction, poorly controlled hypertension), or evidence of pulmonary infiltrates, and those with acute-stage or life-threatening SM-AHN.1, 4, 10 All patients received midostaurin 100 mg orally twice daily in continuous 28-day cycles until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.1, 4 The median duration of treatment was 11 months; however, 17% of patients were still receiving midostaurin therapy at the time of analysis.1
In this study, the primary measure of efficacy was overall response rate (major plus partial responses) occurring within the first 6 treatment cycles and lasting at least 8 weeks as assessed by the study steering committee using modified Valent response criteria;4, 10 major response was defined as complete resolution of at least one C-finding, and partial response was defined as improvement of at least one C-finding by greater than 20%.4 Subtypes of major response included complete remission (absence of mast cell organ infiltration and organomegaly and a reduction in serum tryptase concentrations, an indicator of disease burden, to less than 20 ng/mL), incomplete remission (greater than 50% reduction in mast cell organ infiltration and/or organomegaly and/or serum tryptase concentrations), and pure clinical response (no more than 50% reduction in serum tryptase concentrations but no substantial change in mast cell organ infiltration and organomegaly).4 Patients receiving concomitant high-dose corticosteroid therapy were excluded from the primary efficacy analysis.1, 4 The median age of response-evaluable patients was 64 years; 97% of these patients were Caucasian, 64% of patients were male, 36% had received prior therapy for systemic mastocytosis, and 82% of the patients had D816V c-Kit mutation at baseline.1, 4
The overall response rate in this study was 60% in the primary efficacy population and 46% in the intent-to-treat population.4 In the primary efficacy population, major response was achieved in 45% of patients, generally within the first 3 months of therapy.4 The complete plus incomplete remission rate was 21% in the primary efficacy population, with incomplete remission reported in 38, 16, or 25% of patients with ASM, SM-AHN, or mast cell leukemia, respectively; there were no complete remissions.1, 4 The median time to incomplete remission was 0.5 months.1 At the time of analysis, responses were ongoing, with a median response duration of at least 24.1 months in the primary efficacy population.4 In the primary efficacy population, median progression-free survival was 17 months and the preliminary estimate of median overall survival was 26.8 months.10 In a post-hoc analysis, median overall survival was substantially prolonged in patients who achieved a response compared with those who did not achieve a response (44.4 versus 15.4 months).4 Results of a subgroup analysis (based on age, gender, exposure to prior therapy, and presence of D816V c-Kit mutation) suggested that the effects of midostaurin on response rates were consistent across all subgroups.4, 10
A post-hoc analysis of this study using the more-stringent International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus response criteria was conducted in 115 evaluable patients.1, 10 In this post-hoc analysis, overall responses lasting at least 12 weeks were achieved in 17% of patients; complete remission was achieved in 2% of patients.1 Among patients with ASM, SM-AHN, or mast cell leukemia, overall response rates were 31, 11, or 19%, respectively.1 Overall response rates were 17% in patients with D816V c-Kit mutation at baseline as well as in those who had received prior therapy for systemic mastocytosis.1 Although the overall response rate and depth of response were lower using the IWG-MRT-ECNM response criteria, responses were durable, lasting at least 6 months.1, 10
In a second similarly designed trial, 26 patients with previously treated or untreated advanced systemic mastocytosis received midostaurin (100 mg orally twice daily after meals) in 28-day cycles for up to 12 cycles;1, 10 however, 3 patients were not evaluable for response because the subtype of systemic mastocytosis was not confirmed.1, 10 An overall response (as assessed by the investigators using Valent response criteria10 ) that occurred within the first 2 cycles and lasted for at least 8 weeks was achieved in 52% of evaluable patients, including 10 of 17 patients with SM-AHN and 2 of 6 patients with mast cell leukemia; however, patients receiving concomitant corticosteroid therapy were included in the response assessment.1, 10 At the time of analysis, responses were ongoing, with a median response duration of at least 29.3 months.1, 10 At a median follow-up of 10 years, median overall survival was 40 months.16 Two patients achieved complete remission with midostaurin.16 Treatment achieved over 50% reduction in mast cell burden.16
Midostaurin is administered orally twice daily, at intervals of approximately 12 hours, with food.1 The capsules should be swallowed whole and should not be opened or crushed.1
If a dose is missed or vomited, do not make up the dose; take the next dose at the usual scheduled time.1
Store the capsules in the original container to protect from moisture at 20-25°C (excursions permitted between 15-30°C).1
For use in conjunction with cytarabine and daunorubicin as a component of induction therapy followed by use in conjunction with high-dose cytarabine as a component of consolidation therapy for newly diagnosed AML with Flt-3 mutation, the recommended adult dosage of midostaurin is 50 mg twice daily on days 8-21 of each cycle.1
In the RATIFY study, patients who received midostaurin as a component of induction and consolidation therapy also received post-consolidation therapy† with midostaurin (50 mg twice daily continuously) for up to 12 additional 28-day cycles.1, 2
For the treatment of aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), or mast cell leukemia, the recommended adult dosage of midostaurin is 100 mg twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity in Systemic Mastocytosis
In the principal efficacy studies evaluating midostaurin in patients with advanced systemic mastocytosis, adverse effects resulting in dosage modifications occurred, generally within the initial 5 months of therapy, in 56% of patients receiving midostaurin.1, 10 The median time to first dosage modification for toxicity was 1.6 months.1
Patients should be monitored for adverse effects at least weekly for the first 4 weeks of therapy, every other week for the following 8 weeks of therapy, and then monthly thereafter.1
If ANC decreases to less than 1000/mm3 in patients with systemic mastocytosis (except in patients with mast cell leukemia) or ANC decreases to less than 500/mm3 in patients who have a baseline ANC of 500-1500/mm3, midostaurin therapy should be withheld.1 When ANC reaches or exceeds 1000/mm3, midostaurin may be resumed at a reduced dosage of 50 mg twice daily.1 If a reduced dosage of 50 mg twice daily is tolerated, the midostaurin dosage may be returned to 100 mg twice daily.1
If platelet count decreases to less than 50,000/mm3 in patients with systemic mastocytosis (except in patients with mast cell leukemia) or platelet count decreases to less than 25,000/mm3 in patients who have a baseline platelet count of 25,000-75,000/mm3, midostaurin therapy should be withheld.1 When platelet count reaches or exceeds 50,000/mm3, midostaurin may be resumed at a reduced dosage of 50 mg twice daily.1 If a reduced dosage of 50 mg twice daily is tolerated, the midostaurin dosage may be returned to 100 mg twice daily.1
If hemoglobin concentration decreases to less than 8 g/dL in patients with systemic mastocytosis (except in patients with mast cell leukemia) or life-threatening anemia occurs in patients who have a baseline hemoglobin concentration of 8-10 g/dL, midostaurin therapy should be withheld.1 When hemoglobin concentration reaches or exceeds 8 g/dL, midostaurin may be resumed at a reduced dosage of 50 mg twice daily.1 If a reduced dosage of 50 mg twice daily is tolerated, the midostaurin dosage may be returned to 100 mg twice daily.1
If prolonged treatment-related neutropenia, thrombocytopenia, or anemia (i.e., lasting more than 21 days) occurs, midostaurin therapy should be discontinued.1
If grade 3 or 4 nausea and/or vomiting occurs in patients with systemic mastocytosis despite optimal antiemetic therapy, midostaurin therapy should be withheld for 3 days (6 doses).1 Upon resumption of therapy, the dosage of midostaurin should be reduced to 50 mg twice daily.1 If a reduced dosage of 50 mg twice daily is tolerated, the midostaurin dosage may be returned to 100 mg twice daily.1
If other grade 3 or 4 nonhematologic toxicity occurs in patients with systemic mastocytosis, midostaurin therapy should be withheld until the toxicity resolves to grade 2 or less.1 Upon resumption of therapy, the dosage of midostaurin should be reduced to 50 mg twice daily.1 If a reduced dosage of 50 mg twice daily is tolerated, the midostaurin dosage may be returned to 100 mg twice daily.1
The manufacturer makes no special population dosage recommendations at this time.1
The manufacturer makes no special population dosage recommendations at this time.1
The manufacturer makes no special population dosage recommendations at this time.1
Patients with known hypersensitivity to the drug or any ingredient in the formulation.1
Fetal/Neonatal Morbidity and Mortality
There are no adequate and well-controlled studies of midostaurin in pregnant women; however, based on its mechanism of action and animal findings, midostaurin may cause fetal harm.1 Embryofetal toxicity (i.e., decreased fetal weight, fetal growth retardation, abortion) have been demonstrated in animals receiving midostaurin at exposure levels of approximately 0.01 times the human exposure at the recommended dosage.1 Late embryofetal death also has been demonstrated in animals receiving midostaurin at exposure levels of approximately 0.004 times the human exposure at the recommended dosage.1
Pregnancy should be avoided during midostaurin therapy.1 The manufacturer states that confirmation of pregnancy status must be obtained no more than 7 days prior to initiation of midostaurin therapy, and women of childbearing potential and men who are partners of such women should be advised to use effective contraceptive methods during and for at least 4 months after discontinuance of the drug.1 Patients should be apprised of the potential hazard to the fetus if midostaurin is used during pregnancy.1
Interstitial lung disease (ILD) and pneumonitis, sometimes fatal, have occurred in patients receiving midostaurin as monotherapy or in combination with chemotherapy.1
Patients receiving midostaurin should be monitored for pulmonary symptoms suggestive of ILD or pneumonitis.1 Midostaurin should be discontinued in patients who experience manifestations of ILD or pneumonitis without an infectious etiology.1
Risk of Prolonged Severe Neutropenia and Thrombocytopenia in Pediatric Patients Treated with Combination Chemotherapy
Prolonged Grade 4 neutropenia and thrombocytopenia have been reported with use of an unapproved formulation of midostaurin in combination with anthracyclines, fludarabine, and cytarabine in 2 pediatric patients with acute myeloid leukemia (AML).1 Both patients also received an azole antifungal (strong cytochrome P-450 [CYP] 3A4 inhibitor), which can increase midostaurin concentrations and risk of toxicity.1 The safety and effectiveness of midostaurin have not been established in pediatric patients.1, 1
Midostaurin may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 Females who may have been exposed to midostaurin during pregnancy directly or through a male partner while receiving midostaurin should report the exposure to Novartis' pregnancy exposure registry at 1-888-669-6682.1
Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating treatment.1
Midostaurin and its metabolites are distributed into milk in rats; it is not known whether the drug or its metabolites are distributed into milk in humans.1 Because of the potential for serious adverse reactions to midostaurin in nursing infants, women should be advised to discontinue nursing during midostaurin therapy.1 Women may begin nursing 4 months after discontinuance of therapy.1 The effects of the drug on nursing infants or on milk production are unknown.1
Females and Males of Reproductive Potential
Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating treatment.1
Women of childbearing potential and men who are partners of such women should be advised to use effective contraceptive methods during and for at least 4 months after discontinuance of the drug.1
Results of animal studies suggest that midostaurin may impair male and female fertility.1 It is not known whether these effects are reversible.1
Safety and efficacy of midostaurin have not been established in pediatric patients.1
In phase 3 clinical trials evaluating midostaurin in patients with advanced systemic mastocytosis, 45% of patients were 65 years of age or older, while 11% were 75 years of age or older.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults, but greater sensitivity in some older patients cannot be ruled out.1
Clinical studies evaluating midostaurin in patients with AML did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1
The manufacturer states that midostaurin should be used with caution in geriatric patients, considering the patient's eligibility for concomitant chemotherapy and the greater frequency of concomitant disease and drug therapy observed in this age group.1
Analysis of population pharmacokinetic data indicates that the pharmacokinetics of midostaurin and its metabolites are not influenced by mild (total bilirubin concentration between 1-1.5 times the upper limit of normal [ULN] or AST concentration exceeding the ULN) or moderate (total bilirubin concentration between 1.5-3 times the ULN with any AST concentration) hepatic impairment.1 The effects of severe hepatic impairment (total bilirubin concentration exceeding 3 times the ULN with any AST concentration) on the pharmacokinetics of midostaurin have not been established.1
Analysis of population pharmacokinetic data indicates that the pharmacokinetics of midostaurin and its metabolites are not influenced by mild to moderate renal impairment (creatinine clearance of 30 mL/minute or greater).1 The effects of severe renal impairment (creatinine clearance 15-29 mL/minute) on the pharmacokinetics of midostaurin have not been established.1
The most common adverse effects (≥20%) in patients with AML include febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, prolonged QT interval, and upper respiratory tract infection.1
The most common adverse effects (≥20%) in patients with ASM, SM-AHN, or MCL include nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.1
Midostaurin and its active metabolites (CGP-52421 and CGP-62221) are metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1, 6 In vitro studies indicate that midostaurin inhibits CYP isoenzymes 1A2 and 2E1 and induces CYP isoenzyme 1A2.1 In vitro, CGP-62221 inhibits and induces CYP1A2 and in vitro, CGP-52421 induces CYP1A2.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of midostaurin with potent inhibitors of CYP3A may result in increased systemic exposure to midostaurin and its active metabolites (CGP-52421 and CGP-62221) and an increased incidence of adverse effects.1, 5 The extent of the pharmacokinetic interaction appears to be dependent on the duration of midostaurin dosing,6 such that the increase in midostaurin concentrations may be larger and the potential for adverse effects greater when potent CYP3A inhibitors are administered during the first week of midostaurin therapy.1 In healthy individuals, the potent CYP3A4 inhibitor ketoconazole (400 mg daily for 10 days) increased the area under the concentration-time curve (AUC) and peak plasma concentrations of midostaurin (single 50-mg dose) by 10.4- and 1.8-fold, respectively,1, 5 and prolonged the elimination half-life of midostaurin from 23.3 hours to 90.6 hours.5 In addition, the AUCs of CGP-62221 and CGP-52421 were increased by 3.5- and 1.2-fold, respectively;1, 5 however, peak plasma concentrations of these active metabolites were decreased by twofold.5 When itraconazole (100 mg twice daily on days 22-28) was administered concomitantly with midostaurin (100 mg twice daily on days 1-2 followed by 50 mg twice daily on days 3-28) in patients with acute myeloid leukemia (AML), trough plasma concentrations of midostaurin, CGP-62221, and CGP-52421 were increased by 2.1-, 1.2-, and 1.3-fold, respectively, on day 28.1, 6
In a post-hoc analysis of a phase 3 randomized controlled study (RATIFY), midostaurin exposure and safety in patients who received a concomitant strong CYP3A4 inhibitor were compared to the exposure and safety in patients who did not receive such concomitant therapy.17 Exposure to midosturin and its weak metabolite (CGP-5421) increased by 1.44-fold and 1.11-fold, respectively, with concomitant CYP3A4 inhibitor use.17 No difference in exposure was observed with the more active metabolite (CGP-62221) in combination with a CYP3A4 inhibitor.17 Although the frequency of grade 3/4 infection-related adverse events was higher in patients who received midostaurin with a strong CYP3A4 inhibitor compared to midostaurin without a strong CYP3A4 inhibitor, the frequency was similar in patients who received placebo with or without a CYP3A4 inhibitor.17
Because of the potential for strong CYP3A inhibitors (e.g., clarithromycin; cobicistat; conivaptan; diltiazem; ritonavir-boosted elvitegravir; grapefruit products; idelalisib; ritonavir-boosted indinavir; itraconazole; ketoconazole; the fixed combination of lopinavir and ritonavir [lopinavir/ritonavir]; nefazodone; nelfinavir; the fixed combination of ombitasvir, paritaprevir, and ritonavir [with or without dasabuvir]; posaconazole; ritonavir; ritonavir-boosted saquinavir; ritonavir-boosted tipranavir; voriconazole) to increase exposure to midostaurin and its active metabolites, consider selecting an alternative drug with less CYP3A inhibition potential.1 Alternatively, monitor patients for adverse effects, especially during the first week of midostaurin therapy (including the first week of midostaurin therapy in each cycle when used in combination with chemotherapy).1
Concomitant use of midostaurin with strong inducers of CYP3A may result in decreased systemic exposure to midostaurin, CGP-52421, and CGP-62221, and reduced midostaurin efficacy.1 When the potent CYP3A4 inducer rifampin (600 mg daily for 14 days) was administered concomitantly with midostaurin (single 50-mg dose) in healthy individuals, the AUCs of midostaurin, CGP-52421, and CGP-62221 were decreased by 96, 59, and 92%, respectively.1, 6
Concomitant use with strong CYP3A4 inducers (e.g., carbamazepine, enzalutamide, mitotane, phenytoin, rifampin) should be avoided.1 Although the CYP3A4 induction potential of St. John's wort [ Hypericum perforatum ] varies among preparations, St. John's wort is generally considered a strong CYP3A4 inducer and concomitant use should be avoided.1 Some clinicians also recommend avoiding concomitant use with moderate CYP3A4 inducers.5
Drugs Affected by Hepatic Microsomal Enzymes or Transport Proteins
Substrates of CYP2B6, Breast Cancer Resistance Protein (BCRP), or Organic Anion Transporter Polypeptide (OATP)1B1
Concentrations of CYP2B6 or BCRP/OATP1B1 substrates are likely to be affected by midostaurin.1 Dosage adjustment of the coadministered substrate may be necessary.1
Following coadministration of midostaurin (50 mg twice daily) at steady state with a single dose of bupropion (a CYP2B6 substrate), the AUC of bupropion and hydroxybupropion decreased by 48% and 65%, respectively.1 Dose adjustment of bupropion may be necessary if used concomitantly with midostaurin.1
Coadministration of a single 100 mg dose of midostaurin with a single dose of rosuvastatin (a BCRP and OATP1B1 substrate) increased the AUC of rosuvastatin by 48%.1 At steady-state, midostaurin 50 mg twice daily is predicted to increase the AUC of an OATP1B1 substrate by 2-fold, with an unknown effect on a BCRP substrate.1
Substrates of CYP3A, CYP2C8, CYP2D6, and P-glycoprotein (P-gP)
Concentrations of CYP3A, CYP2C8, CYP2D6, and P-gp substrates are not likely to be affected by multiple doses of midostaurin, but concentrations have not been evaluated during the first week of midostaurin use (when concentrations are the highest).1
Coadministration of multiple doses of midostaurin (50 mg twice daily) at steady-state with single doses of midazolam or pioglitazone (CYP3A substrates) did not affect the AUC of midazolam (a sensitive CYP3A substrate) or pioglitazone (a moderate sensitive CYP2C8 substrate).1 The effect on these substrates is unknown during the first week of midostaurin use (when trough concentrations are the highest).1
Coadministration of a single 100 mg dose of midostaurin with a single dose of dextromethorphan (a sensitive CYP2D6 substrate) did not affect the AUC of dextromethorphan.1 The effect of multiple doses of midostaurin on dextromethorphan is unknown.1
Coadministration of multiple doses of midostaurin (50 mg twice daily) at steady-state with a single dose of a hormonal contraceptive containing ethinyl estradiol and levonorgestrel (CYP3A4 substrates) increased the AUC of ethinyl estradiol by 10% and levonorgestrel by 42%.1 The effect of midostaurin on these substrates is unknown during the first week of midostaurin use (when trough concentrations are the highest).1
Coadministration of a single 100 mg dose of midostaurin with a single dose of digoxin (a sensitive P-gp substrate) did not affect the AUC of digoxin.1 The effect of multiple doses of midostaurin on digoxin is unknown.1
Drugs that Prolong the QT Interval
In a placebo- and active-controlled study of the effects of midostaurin on the QT interval, clinically important QT-interval prolongation was not observed when midostaurin was administered at a dosage of 75 mg twice daily for 3 days, and no relationship between change in QT interval and plasma concentrations of the drug and its active metabolites was observed.1 However, the duration of the study was not adequate to determine whether the active metabolite CGP-52421 prolongs the QT interval at steady-state exposures.1, 10 In clinical studies evaluating use of midostaurin in patients with advanced systemic mastocytosis, prolongation of the QT interval (corrected for heart rate using Fridericia's formula [QTcF]) by more than 60 msec from baseline occurred in 6.3% of midostaurin-treated patients and the QTcF interval exceeded 480 or 500 msec in 4.7% or 0%, respectively, of midostaurin-treated patients.1 In a randomized study evaluating use of midostaurin in patients with acute myeloid leukemia (AML), prolongation of the QTcF interval by more than 60 msec from baseline occurred in 18.4% of patients receiving midostaurin compared with 10.7% of those receiving placebo,1, 10 and the QTcF interval exceeded 480 or 500 msec in 10.1% or 6.2%, respectively, of midostaurin-treated patients compared with 5.7% or 2.6%, respectively, of patients receiving placebo.1
Although studies of the effects of midostaurin on the QT interval did not reveal clinically important effects, some patients receiving the drug during clinical trials have experienced QT-interval prolongation.1 Therefore, the manufacturer states that periodic monitoring of ECGs should be considered in patients receiving midostaurin concomitantly with other drugs that are known to prolong the QT interval.1
Although the CYP3A inhibition potential of grapefruit juice may be influenced by the concentration, dose, and specific preparation, grapefruit juice is generally considered to be a strong CYP3A inhibitor.1 Patients receiving midostaurin should be advised to avoid consuming grapefruit products.1
Midostaurin, an inhibitor of multiple receptor tyrosine kinases including fms-like tyrosine kinase 3 (Flt-3), is an antineoplastic agent.1 Receptor tyrosine kinases are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.8, 9 Midostaurin has been shown to inhibit Flt-3 signaling resulting in inhibition of Flt-3-induced cell proliferation.1 The drug also induced apoptosis in leukemic cells expressing Flt-3 mutations (i.e., internal tandem duplications [ITD], tyrosine kinase domain [TKD] point mutations) or overexpressing wild-type Flt-3 and platelet-derived growth factor receptors (PDGFR).1 In vitro, midostaurin or its active metabolites (CGP-62221 and CGP-52421) exhibit inhibitory activity against wild-type Flt-3, mutant Flt-3, vascular endothelial growth factor receptor 2 (VEGFR-2), PDGFR-α, PDGFR-β, and members of the protein kinase C (PKC) family of tyrosine kinases.1 The drug also has demonstrated inhibition of stem cell factor receptor (c-Kit) signaling resulting in apoptosis in mast cells and inhibition of c-Kit-induced cell proliferation and histamine release.1
Following repeated administration of midostaurin, trough concentrations of midostaurin and its metabolites (CGP-62221 and CGP-52421) exhibit time-dependent pharmacokinetics and there is a lack of proportionality between dosage and systemic exposure, possibly because of autoinduction of its own metabolism.1, 6, 10, 12 Maximum trough concentrations of both midostaurin and CGP-62221 are achieved in 8 days and then decline substantially (by about 50-60%) to steady-state values by day 28; however, plasma concentrations of CGP-52421 continue to increase until day 28.1, 6, 12 Maximum trough and steady-state concentrations of midostaurin, CGP-62221, and CGP-52421 achieved at a midostaurin dosage of 50 mg twice daily (given with food) are similar to those achieved at a dosage of 100 mg twice daily (also given with food).1, 6
Following oral administration in a fasted state, midostaurin is rapidly absorbed with peak plasma concentrations occurring within 1-3 hours.1 Administration of a single 50-mg dose of midostaurin with a high-fat, high-calorie meal (900-1000 calories with 50% of calories from fat) increased the area under the concentration-time curve (AUC) of midostaurin by 1.6-fold and decreased peak plasma concentrations of the drug by 27% compared with administration in the fasted state.1, 6 When the drug was administered with a standard meal (450 calories with 25% of calories from fat), the AUC of midostaurin was increased by 1.2-fold and peak plasma concentrations were decreased by 20% compared with administration in the fasted state.1, 6 Following oral administration with a standard or high-fat meal, the median time to peak plasma concentrations of midostaurin ranged from 2.5-3 hours.1
Midostaurin and its metabolites are highly bound (greater than 99.8%) to plasma proteins (mainly to α1-acid glycoprotein) in vitro.1
Midostaurin is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1 Major metabolites of the drug include active hydroxyl (CGP-52421) and O -demethylated (CGP-62221) derivatives.1, 6, 7 CGP-52421 and CGP-62221 also are metabolized by CYP3A4 and account for approximately 38 and 28%, respectively, of total plasma concentrations of the drug.1, 6 The terminal half-lives of midostaurin, CGP-62221, and CGP-52421 are 19, 32, and 482 hours, respectively.1 Following oral administration of midostaurin, 95% of the recovered dose is excreted in feces (4% as unchanged drug and 91% as metabolites) and 5% is eliminated in urine.1
Data from a population pharmacokinetic analysis indicate that age (20-94 years), gender, and race do not have clinically important effects on the pharmacokinetics of midostaurin.1
Instruct patients to read the manufacturer's patient information before initiating midostaurin therapy.1
If a dose is missed or vomited, administer the next dose at the regularly scheduled time; an additional dose should not be administered to make up for a missed dose.1
Risk of interstitial lung disease or pneumonitis.1 Advise patients to inform clinician immediately if new or worsening cough, chest pain, or shortness of breath occurs.1
Risk of diarrhea, nausea, or vomiting.1 Advise patients to inform clinician if any of these symptoms occur or persist despite optimal supportive therapy.1
Inform patients of the risk of impaired fertility in men and women.1
Risk of fetal harm.1 Advise females of child-bearing potential and men who are partners of such females that they should use an effective method of contraception while receiving the drug and for at least 4 months after discontinuance of therapy.1 Advise women to inform clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1
Advise women to avoid breast-feeding while receiving the drug and for at least 4 months after discontinuance of therapy.1
Advise patients of the importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Advise patients of other important precautionary information.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Midostaurin can only be obtained through designated specialty pharmacies.18 Contact the manufacturer for specific availability information.18
1. Novartis Pharmaceuticals. Rydapt® (midostaurin) capsules prescribing information. East Hanover, NJ; 2023 May.
2. Stone RM, Mandrekar SJ, Sanford BL et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med . 2017; 377:454-464. [PubMed 28644114]
3. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2017 Jul 12. [Web]
4. Gotlib J, Kluin-Nelemans HC, George TI et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med . 2016; 374:2530-41. [PubMed 27355533]
5. Dutreix C, Munarini F, Lorenzo S et al. Investigation into CYP3A4-mediated drug-drug interactions on midostaurin in healthy volunteers. Cancer Chemother Pharmacol . 2013; 72:1223-34. [PubMed 24085261]
6. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 207997Orig1s000, 207997Orig2s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]
7. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 207997Orig1s000, 207997Orig2s000: Pharmacology review(s). From FDA website. [Web]
8. Escudier B, Gore M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R D . 2011; 11:113-26. [PubMed 21679004]
9. Hu-Lowe DD, Zou HY, Grazzini ML et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res . 2008; 14:7272-83. [PubMed 19010843]
10. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 207997Orig1s000, 207997Orig2s000: Medical review(s). From FDA website. [Web]
12. Fischer T, Stone RM, Deangelo DJ et al. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol . 2010; 28:4339-45. [PubMed 20733134]
13. Stone RM, Fischer T, Paquette R et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia . 2012; 26:2061-8. [PubMed 22627678]
14. Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood . 2017; 129:1420-1427. [PubMed 28031180]
15. Larson RA, Mandrekar SJ, Huebner LJ, et al. Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial. Leukemia. 2021;35(9):2539-2551.
16. DeAngelo DJ, George TI, Linder A, et al. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia. 2018;32(2):470-478.
17. Sechaud R, Sinclair K, Grosch K, Ouatas T, Pathak D. Evaluation of drug-drug interactions between midostaurin and strong CYP3A4 inhibitors in patients with FLT-3-mutated acute myeloid leukemia (AML). Cancer Chemother Pharmacol. 2022 Jul;90(1):19-27.
18. Oncology Medications: Limited Distribution Medications. Onco 360: Oncology Pharmacy website. Accessed August 8, 2022. [Web]
3015. PDQ® Adult Treatment Editorial Board. PDQ Acute Myeloid Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated June 10, 2022. Accessed July 18, 2022 [Web]
3016. Sekeres MA, Guyatt G, Abel G, et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv. 2020 11;4(15):3528-3549.