Dosage guidance:
Clinical considerations: Midostaurin is associated with a moderate or high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Ref).
Acute myeloid leukemia (AML), FLT3 positive: Oral:
Induction: 50 mg twice daily on days 8 to 21 of each induction cycle (in combination with daunorubicin and cytarabine); administer a second induction cycle if there is definitive evidence of (clinically significant) residual leukemia (Ref).
Consolidation: 50 mg twice daily on days 8 to 21 of each 28-day consolidation cycle (in combination with high-dose cytarabine) for 4 consolidation cycles (Ref).
Maintenance (off- label): 50 mg twice daily on days 1 to 28 of each 28-day maintenance cycle for 12 cycles or until relapse, whichever occurs first (Ref).
Mast cell leukemia: Oral: 100 mg twice daily until disease progression or unacceptable toxicity (Ref).
Systemic mastocytosis (aggressive systemic mastocytosis or systemic mastocytosis with associated hematological neoplasm): Oral: 100 mg twice daily until disease progression or unacceptable toxicity (Ref).
Missed doses: If a dose is missed or vomited, do not make up the dose; take the next dose at the usually scheduled time.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, the pharmacokinetics of midostaurin and active metabolites were not significantly altered.
CrCl 15 to 29 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Mild (total bilirubin >1 to 1.5 times ULN or AST > ULN) or moderate (total bilirubin 1.5 to 3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, the pharmacokinetics of midostaurin and active metabolites were not significantly altered.
Severe impairment (total bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Systemic mastocytosis (aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, or mast cell leukemia):
Hematologic toxicity (attributed to midostaurin):
ANC <1,000/mm3 (in patients without mast cell leukemia) or ANC <500/mm3 (in patients with baseline ANC of 500 to 1,500/mm3): Interrupt midostaurin; when ANC has improved to ≥1,000/mm3, resume therapy at a reduced dose of 50 mg twice daily and if tolerated, may increase dose to 100 mg twice daily.
Persistently low ANC for >21 days (associated with midostaurin): Discontinue midostaurin
Platelets <50,000/mm3 (in patients without mast cell leukemia) or platelets <25,000/mm3 (in patients with baseline platelet count of 25,000 to 75,000/mm3): Interrupt midostaurin; when platelets have improved to ≥50,000/mm3, resume therapy at a reduced dose of 50 mg twice daily and if tolerated, may increase dose to 100 mg twice daily.
Persistently low platelet count for >21 days (associated with midostaurin): Discontinue midostaurin
Hemoglobin <8 g/dL (in patients without mast cell leukemia) or life-threatening anemia in patients with baseline hemoglobin of 8 to 10 g/dL: Interrupt midostaurin; when hemoglobin has improved to ≥8 g/dL, resume therapy at a reduced dose of 50 mg twice daily and if tolerated, may increase dose to 100 mg twice daily.
Persistently low hemoglobin for >21 days (associated with midostaurin): Discontinue midostaurin
Nonhematologic toxicity:
Nausea/vomiting, grade 3 or 4 (despite optimal antiemetic prophylaxis): Interrupt midostaurin for 3 days (6 doses), then resume therapy at a reduced dose of 50 mg twice daily. If tolerated, increase dose to 100 mg twice daily.
Other grade 3 or 4 toxicities: Interrupt midostaurin until improvement to ≤ grade 2, then resume therapy at a reduced dose of 50 mg twice daily. If tolerated, increase dose to 100 mg twice daily.
All indications: Pulmonary toxicity: Signs/symptoms of interstitial lung disease or pneumonitis without infectious etiology): Discontinue midostaurin.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Cardiovascular: Edema (40%), prolonged QT interval on ECG (11%)
Dermatologic: Skin rash (14%)
Endocrine & metabolic: Hyperglycemia (80%), hyperkalemia (23%), hyperuricemia (37%), hypoalbuminemia (27%), hypocalcemia (39%), hypokalemia (25%), hypomagnesemia (20%), hyponatremia (34%), hypophosphatemia (22%)
Gastrointestinal: Abdominal pain (34%), constipation (29%), diarrhea (54%), gastrointestinal hemorrhage (14%), increased serum amylase (20%), increased serum lipase (37%), nausea (82%), vomiting (68%)
Genitourinary: Urinary tract infection (16%)
Hematologic & oncologic: Anemia (60%; grades ≥3: 38%), leukopenia (61%; grades ≥3: 19%), lymphocytopenia (66%; grades ≥3: 42%), neutropenia (49%; grades ≥3: 22%), thrombocytopenia (50%; grades ≥3: 27%)
Hepatic: Hyperbilirubinemia (29%), increased gamma-glutamyl transferase (35%), increased serum alanine aminotransferase (31%), increased serum alkaline phosphatase (39%), increased serum aspartate aminotransferase (32%)
Nervous system: Dizziness (13%), fatigue (34%), headache (26%), insomnia (11%)
Neuromuscular & skeletal: Arthralgia (19%), musculoskeletal pain (35%)
Renal: Increased serum creatinine (25%), renal insufficiency (11%)
Respiratory: Cough (18%), dyspnea (23%), epistaxis (12%), pleural effusion (13%), upper respiratory tract infection (30%)
Miscellaneous: Fever (27%)
1% to 10%:
Cardiovascular: Acute myocardial infarction (≤4%), heart failure (6%), hypotension (9%), ischemia (≤4%), pericardial effusion (4%)
Dermatologic: Cellulitis (≤5%), erysipelas (≤5%)
Endocrine & metabolic: Weight gain (6%)
Gastrointestinal: Dyspepsia (6%), gastritis (3%)
Hematologic & oncologic: Bruise (6%), febrile neutropenia (8%), hematoma (6%)
Hypersensitivity: Hypersensitivity reaction (4%)
Infection: Herpes virus infection (10%), sepsis (9%)
Nervous system: Chills (5%), disturbance in attention (7%), mental status changes (4%), tremor (6%), vertigo (5%)
Respiratory: Bronchitis (6%), interstitial lung disease (1%), oropharyngeal pain (4%), pneumonia (10%), pulmonary edema (3%)
<1%: Respiratory: Pneumonitis
Postmarketing: Dermatologic: Sweet syndrome
Hypersensitivity to midostaurin or any component of the formulation
Concerns related to adverse effects:
• Bone marrow suppression: Lymphopenia, leukopenia, neutropenia, thrombocytopenia and anemia have been commonly observed in patients with systemic mastocytosis. Although the incidence of hematologic toxicity in acute myeloid leukemia (AML) may be confounded by concomitant chemotherapy, febrile neutropenia was reported at a slightly higher incidence in patients with AML receiving chemotherapy plus midostaurin (compared to chemotherapy plus placebo). Monitor blood counts.
• Hypersensitivity: Hypersensitivity reactions, including anaphylactic shock, angioedema, dyspnea, chest pain and flushing have been observed.
• QT prolongation: QT prolongation has been observed; consider ECG for QT interval assessment in patients on concurrent medications that may prolong the QT interval.
• Pulmonary toxicity: Interstitial lung disease and pneumonitis have been reported with midostaurin (either as monotherapy or in combination with other chemotherapy), some cases have been fatal. Monitor for pulmonary symptoms; discontinue in patients who develop signs/symptoms of interstitial lung disease or pneumonitis (without an infectious etiology).
Other warnings/precautions:
• FLT3 mutation positivity: In the treatment of acute myeloid leukemia, midostaurin is approved for use only in patients who are FLT3 mutation-positive (as detected by an approved test).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Rydapt: 25 mg [contains peg-40 hydrog castor oil(cremophor rh40)]
No
Capsules (Rydapt Oral)
25 mg (per each): $261.50
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Rydapt: 25 mg [contains corn oil]
Midostaurin is associated with a moderate or high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Ref).
Oral: Administer with food at approximately 12-hour intervals. Do not open or crush the capsules.
This medication is not on the NIOSH (2024) list; however, it may meet the criteria for a hazardous drug. Midostaurin may cause teratogenicity and reproductive toxicity.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Acute myeloid leukemia, FLT3-positive: Treatment of adult patients with newly diagnosed FLT3 mutation-positive (as detected by an approved test) acute myeloid leukemia (AML), in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy
Limitations of use: Not indicated as single-agent induction therapy for the treatment of patients with AML.
Mast cell leukemia: Treatment of adult patients with mast cell leukemia (MCL)
Systemic mastocytosis: Treatment of adult patients with aggressive systemic mastocytosis (ASM) or systemic mastocytosis with associated hematological neoplasm (SM-AHN)
Midostaurin may be confused with midodrine
Rydapt may be confused with Ryzolt
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
Substrate of CYP3A4 (Major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits BCRP, OATP1A2, OATP1B1/1B3; Induces CYP2B6 (Weak), MRP2;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Abrocitinib: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid
Alpelisib: BCRP/ABCG2 Inhibitors may increase serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Risk D: Consider Therapy Modification
Amisulpride (Oral): May increase QTc-prolonging effects of QT-prolonging Agents (Moderate Risk). Risk C: Monitor
Antidiabetic Agents: Hyperglycemia-Associated Agents may decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor
Antithymocyte Globulin (Equine): Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor
Antithyroid Agents: Myelosuppressive Agents may increase neutropenic effects of Antithyroid Agents. Risk C: Monitor
Atogepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Atogepant. Management: For episodic migraine, the recommended atogepant dose is 10 mg or 30 mg once daily if given with OATP1B1/1B3 inhibitors. For chronic migraine, the recommended atogepant dose is 30 mg once daily with OATP1B1/1B3 inhibitors. Risk D: Consider Therapy Modification
Atrasentan: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Atrasentan. Risk X: Avoid
Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Baricitinib. Risk X: Avoid
BCG Products: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of BCG Products. Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Brincidofovir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Brincidofovir. Management: Consider alternatives to OATP1B/1B3 inhibitors in patients treated with brincidofovir. If coadministration is required, administer OATP1B1/1B3 inhibitors at least 3 hours after brincidofovir and increase monitoring for brincidofovir adverse reactions. Risk D: Consider Therapy Modification
Brivudine: May increase adverse/toxic effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid
BuPROPion: CYP2B6 Inducers (Weak) may decrease serum concentration of BuPROPion. Risk C: Monitor
Chikungunya Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Chikungunya Vaccine (Live). Risk X: Avoid
Chloramphenicol (Ophthalmic): May increase adverse/toxic effects of Myelosuppressive Agents. Risk C: Monitor
Chloramphenicol (Systemic): Myelosuppressive Agents may increase myelosuppressive effects of Chloramphenicol (Systemic). Risk X: Avoid
Chloroquine: QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of Chloroquine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Cladribine. Risk X: Avoid
Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor
Clofazimine: QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of Clofazimine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Coccidioides immitis Skin Test: Coadministration of Immunosuppressants (Miscellaneous Oncologic Agents) and Coccidioides immitis Skin Test may alter diagnostic results. Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider Therapy Modification
Conivaptan: May increase serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and conivaptan if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Risk D: Consider Therapy Modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor
COVID-19 Vaccine (mRNA): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider Therapy Modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of COVID-19 Vaccine (Subunit). Risk C: Monitor
CYP3A4 Inducers (Moderate): May decrease serum concentration of Midostaurin. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of Midostaurin. Risk X: Avoid
CYP3A4 Inhibitors (Moderate): May increase serum concentration of Midostaurin. Risk C: Monitor
CYP3A4 Inhibitors (Strong): May increase serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and strong CYP3A4 inhibitors if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Risk D: Consider Therapy Modification
Dabrafenib: Midostaurin may increase QTc-prolonging effects of Dabrafenib. Dabrafenib may decrease serum concentration of Midostaurin. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Also monitor for decreased midostaurin efficacy. Risk C: Monitor
Deferiprone: Myelosuppressive Agents may increase neutropenic effects of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider Therapy Modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Dengue Tetravalent Vaccine (Live). Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Denosumab: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider Therapy Modification
Desmopressin: Hyponatremia-Associated Agents may increase hyponatremic effects of Desmopressin. Risk C: Monitor
Deucravacitinib: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid
Digoxin: Midostaurin may increase serum concentration of Digoxin. Risk C: Monitor
DilTIAZem: May increase serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and diltiazem if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Risk D: Consider Therapy Modification
Domperidone: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Domperidone. Risk X: Avoid
Elagolix, Estradiol, and Norethindrone: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Elagolix, Estradiol, and Norethindrone. Specifically, concentrations of elagolix may be increased. Risk X: Avoid
Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Elagolix. Risk X: Avoid
Elbasvir and Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid
Eluxadoline: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with OATP1B1/1B3 inhibitors and monitor patients for increased eluxadoline effects/toxicities. Risk D: Consider Therapy Modification
Encorafenib: May increase QTc-prolonging effects of Midostaurin. Encorafenib may decrease serum concentration of Midostaurin. Risk X: Avoid
Etrasimod: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid
Fexinidazole: Myelosuppressive Agents may increase myelosuppressive effects of Fexinidazole. Risk X: Avoid
Filgotinib: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid
Fluorouracil Products: QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Fusidic Acid (Systemic): May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification
Gadobenate Dimeglumine: QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of Gadobenate Dimeglumine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Grapefruit Juice: May increase serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and grapefruit juice if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions Risk D: Consider Therapy Modification
Halofantrine: QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of Halofantrine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Haloperidol: QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Inebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Inebilizumab. Risk C: Monitor
Influenza Virus Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider Therapy Modification
Lefamulin: May increase QTc-prolonging effects of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Risk X: Avoid
Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider Therapy Modification
Levoketoconazole: QT-prolonging CYP3A4 Substrates may increase QTc-prolonging effects of Levoketoconazole. Levoketoconazole may increase serum concentration of QT-prolonging CYP3A4 Substrates. Risk X: Avoid
Linezolid: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Lofexidine: QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of Lofexidine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Momelotinib: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Momelotinib. Risk C: Monitor
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Mumps- Rubella- or Varicella-Containing Live Vaccines. Mumps- Rubella- or Varicella-Containing Live Vaccines may increase adverse/toxic effects of Immunosuppressants (Miscellaneous Oncologic Agents). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Nadofaragene Firadenovec: Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid
Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Natalizumab. Risk X: Avoid
Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Ocrelizumab. Risk C: Monitor
Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Ofatumumab. Risk C: Monitor
Olaparib: Myelosuppressive Agents may increase myelosuppressive effects of Olaparib. Risk C: Monitor
Ondansetron: QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
PAZOPanib: Midostaurin may increase QTc-prolonging effects of PAZOPanib. Midostaurin may increase serum concentration of PAZOPanib. Risk X: Avoid
Pentamidine (Systemic): QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of Pentamidine (Systemic). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Pidotimod. Risk C: Monitor
Pimecrolimus: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid
Pimozide: May increase QTc-prolonging effects of QT-prolonging Agents (Moderate Risk). Risk X: Avoid
Piperaquine: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Piperaquine. Risk X: Avoid
Pneumococcal Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Pneumococcal Vaccines. Risk C: Monitor
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Poliovirus Vaccine (Live/Trivalent/Oral). Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may increase hypersensitivity effects of Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider Therapy Modification
Posaconazole: May increase serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Risk X: Avoid
Promazine: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
QT-prolonging Agents (Highest Risk): May increase QTc-prolonging effects of Midostaurin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider Therapy Modification
QT-prolonging Antidepressants (Moderate Risk): May increase QTc-prolonging effects of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-prolonging Antipsychotics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of QT-prolonging Class IC Antiarrhythmics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-Prolonging Inhalational Anesthetics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of QT-Prolonging Inhalational Anesthetics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-prolonging Kinase Inhibitors (Moderate Risk): Midostaurin may increase QTc-prolonging effects of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-prolonging Miscellaneous Agents (Moderate Risk): May increase QTc-prolonging effects of Midostaurin. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May increase QTc-prolonging effects of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-prolonging Quinolone Antibiotics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may increase QTc-prolonging effects of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): Midostaurin may increase QTc-prolonging effects of QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk). QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk) may increase serum concentration of Midostaurin. Management: Consider alternatives to this combination. If combined, monitor for midostaurin toxicities, QTc interval prolongation, and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider Therapy Modification
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May increase QTc-prolonging effects of Midostaurin. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase serum concentration of Midostaurin. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider Therapy Modification
Rabies Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider Therapy Modification
Resmetirom: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Resmetirom. Risk X: Avoid
Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase active metabolite exposure of Revefenacin. Risk X: Avoid
Ritlecitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Ritlecitinib. Risk X: Avoid
Ropeginterferon Alfa-2b: Myelosuppressive Agents may increase myelosuppressive effects of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider Therapy Modification
Rosuvastatin: BCRP/ABCG2 Inhibitors may increase serum concentration of Rosuvastatin. Risk C: Monitor
Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Ruxolitinib (Topical). Risk X: Avoid
Seladelpar: BCRP/ABCG2 Inhibitors may increase serum concentration of Seladelpar. Risk C: Monitor
Sertindole: May increase QTc-prolonging effects of QT-prolonging Agents (Moderate Risk). Risk X: Avoid
Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider Therapy Modification
Sphingosine 1-Phosphate (S1P) Receptor Modulators: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor
St John's Wort: May decrease serum concentration of Midostaurin. Risk X: Avoid
Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Tacrolimus (Topical). Risk X: Avoid
Talazoparib: BCRP/ABCG2 Inhibitors may increase serum concentration of Talazoparib. Risk C: Monitor
Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid
Taurursodiol: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Taurursodiol. Risk X: Avoid
Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Tertomotide. Risk X: Avoid
Thioridazine: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Thioridazine. Risk X: Avoid
Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Tofacitinib. Risk X: Avoid
Topotecan: BCRP/ABCG2 Inhibitors may increase serum concentration of Topotecan. Risk X: Avoid
Typhoid Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Typhoid Vaccine. Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Ublituximab: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Ublituximab. Risk C: Monitor
Ubrogepant: BCRP/ABCG2 Inhibitors may increase serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a BCRP inhibitor. Risk D: Consider Therapy Modification
Upadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Upadacitinib. Risk X: Avoid
Vaccines (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Vaccines (Live). Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Vaccines (Non-Live/Inactivated/Non-Replicating): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Vaccines (Non-Live/Inactivated/Non-Replicating). Management: Give non-live/inactivated/non-replicating vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before or during therapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider Therapy Modification
Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Voxilaprevir. Risk X: Avoid
Yellow Fever Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Yellow Fever Vaccine. Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Zavegepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Zavegepant. Risk X: Avoid
Zoster Vaccine (Live/Attenuated): Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Zoster Vaccine (Live/Attenuated). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Zoster Vaccine (Live/Attenuated). Risk X: Avoid
Grapefruit juice may increase midostaurin plasma concentration. Management: If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions.
Pregnancy status should be verified within 7 days prior to therapy initiation. Patients who may become pregnant and patients with partners who may become pregnant should use effective contraception during therapy and for 4 months after the last dose of midostaurin.
Outcome data following maternal use of midostaurin during pregnancy is limited (Ojha 2020). Based on the mechanism of action and data from animal reproduction studies, in utero exposure to midostaurin may cause fetal harm.
Data collection to monitor pregnancy outcomes following exposure to midostaurin is ongoing. Persons who may have been exposed to midostaurin during pregnancy (directly or through a partner receiving midostaurin) should contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://report.novartis.com.
It is not known if midostaurin is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for at least 4 months after the last midostaurin dose.
FLT3 mutation status (in AML); CBC with differential (in patients with systemic mastocytosis: at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter or as clinically indicated). Evaluate pregnancy status within 7 days of therapy initiation in women of reproductive potential. Consider ECG for QT interval assessment in patients on concurrent medications that may prolong the QT interval. Monitor for signs/symptoms of pulmonary toxicity (interstitial lung disease and pneumonitis). Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Midostaurin is a tyrosine kinase inhibitor which inhibits multiple receptors, such as wild type FLT3, FLT3 mutant kinases ITD and TKD, KIT (wild type and D816V mutant), PDGFRα/β, and members of the serine/threonine protein kinase C (PKC) family.
Midostaurin inhibits FLT3 receptor signaling and cell proliferation, and induces apoptosis in ITD- and TKD- mutant expressing leukemic cells, as well as in cells overexpressing wild type FLT3 and PDGFR. It also may inhibit KIT signaling, cell proliferation, and histamine release (and induces apoptosis) in mast cells.
Absorption: Exposure was increased 1.2- or 1.6-fold when administered with a standard or high-fat meal, respectively, compared to the fasted state. Midostaurin Cmax was reduced 20% and 27%, respectively, when administered with a standard or high-fat meal compared to a fasted state.
Distribution: 95.2 L
Protein binding: >99.8% bound to plasma proteins (parent drug, CGP62221, and CGP52421); midostaurin is mainly bound to α1-acid glycoprotein
Metabolism: Primarily hepatic via CYP3A4 to active metabolites CGP62221 and CGP52421
Half-life elimination: 19 hours (midostaurin); 32 hours (CGP62221); 482 hours (CGP52421)
Time to peak: 1 to 3 hours (fasted state); 2.5 to 3 hours (with standard or high-fat meal)
Excretion: Feces (95%; 91% as metabolites and 4% as unchanged drug); urine (5%)