Midostaurin


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Acute myeloid leukaemia with FTL3 mutation Combined with standard cytarabine and daunorubicin induction or high dose cytarabine consolidation chemotherapy: 50 mg bid on days 8-21 of chemotherapy cycles. Maintenance: As monotherapy for patient in complete response: 50 mg once daily until relapsed for up to 12 cycles of 28 days cycles. Aggressive systemic mastocytosis; Systemic mastocytosis with associated haematological neoplasm; Mast cell leukaemia 100 mg bid continued until disease progression or unacceptable toxicity occurs. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Dosage Details
Oral
Acute myeloid leukaemia with FTL3 mutation
Adult: In combination with standard cytarabine and daunorubicin induction and high dose cytarabine consolidation chemotherapy: 50 mg bid on days 8-21 of chemotherapy cycles. Maintenance: As monotherapy for patient in complete response: 50 mg once daily until relapsed for up to 12 cycles of 28 days cycles. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).

Oral
Aggressive systemic mastocytosis, Mast cell leukaemia, Systemic mastocytosis with associated haematological neoplasm
Adult: 100 mg bid continued until disease progression or unacceptable toxicity occurs. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Administration
Liquid Filled Cap: Should be taken with food. Take approx 12 hr intervals. Swallow whole, do not open/crush.
Contraindications
Concomitant administration with potent CYP3A4 inducers.
Special Precautions
Patient with cardiac dysfunction, risk of QTc prolongation. Severe renal and hepatic impairment. Pregnancy and lactation.
Adverse Reactions
Significant: Bone marrow suppression (e.g. neutropenia, leukopenia); gastrointestinal toxicity (e.g. nausea, vomiting, diarrhoea, abdominal pain, constipation, mucositis); decreased LVEF, QTc prolongation; hypersensitivity reaction (e.g. analphylactic shock, angioedema).
Blood and lymphatic system disorders: Hyperbilirubinaemia.
Cardiac disorders: Dyspnoea.
Gastrointestinal disorders: Increased serum lipase/amylase, gastrointestinal haemorrhage.
General disorders and administration site conditions: Fatigue, pyrexia.
Infections and infestations: Localised infection.
Investigations: Increased serum creatinine, increased gamma-glutamyl transferase, increased serum alkaline phosphatase, increased ALT/AST.
Metabolism and nutrition disorders: Peripheral oedema, hypokalaemia, hyperkalaemia, hyperglycaemia, hyponatraemia, hypernatraemia, hypocalcaemia, hyperuricaemia, hypoalbuminemia, hypophosphataemia, hypomagnasemia.
Musculoskeletal and connective tissue disorders: Musculoskeletal pain, arthralgia.
Nervous system disorders: Headache, dizziness.
Psychiatric disorders: Insomnia.
Renal and urinary disorders: UTI, renal insufficiency.
Respiratory, thoracic and mediastinal disorders: Upper respiratory tract infection, pleural effusion.
Skin and subcutaneous tissue disorders: Hyperhidrosis, rash.
Vascular disorders: Haemorrhoids, epistaxis, hypotension, hypertension.
Potentially Fatal: CHF, interstitial lung disease (ILD), pneumonitis.
Patient Counseling Information
This drug may cause dizziness and vertigo, if affected do not drive or operate machinery.
MonitoringParameters
Perform confirmatory test of FLT3 mutation (internal tandem duplication or tyrosine kinase domain) prior to initiation of therapy for acute myeloid leukaemia. Monitor WBC at treatment initiation and regularly thereafter. Assess LVEF at baseline and during treatment or when clinically indicated. Monitor CBC with differential in systemic mastocytosis at least weekly for 4 weeks, then every other week for next 8 weeks, then monthly thereafter or when clinically indicated. Monitor for pulmonary symptoms indicative of ILD or pneumonitis; signs and symptoms of infection. Perform pregnancy test within 7 days of therapy.
Drug Interactions
Increased plasma concentration with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, clarithromycin, nefazodone). Increased risk of QT prolongation with QT prolonging drugs (e.g. chloroquine).
Potentially Fatal: Decreased plasma concentration with strong CYP3A4 inducers (e.g. carbamazepine, rifampicin, enzalutamide, phenytoin).
Food Interaction
Increased absorption with food. Decreased serum concentrations with St. John’s wort.
Action
Description: Midostaurin is a multikinase inhibitor effective against tyrosine kinase, protein kinase C family, and multiple receptors including growth factors (e.g. vascular endothelial growth factor, platelet-derived growth factor). It inhibits FLT3 receptor signaling and cell proliferation, inducing apoptosis in mutant expressing leukemic cells and in cells overexpressing wild type FLT3 and PDGFR. It may also inhibit KIT signaling, cell proliferation, and histamine release and induces apoptosis in mast cells.
Pharmacokinetics:
Absorption: Rapidly absorb from the gastrointestinal tract. Food, particularly high fat meal, increases absorption. Time to peak plasma concentration: 1-3 hours.
Distribution: Distributed mainly in plasma. Volume of distribution: 95.2 L. Plasma protein-binding: >99.8% mainly to α1-acid glycoprotein.
Metabolism: Metabolised mainly in the liver by CYP3A4 via oxidative pathways to active metabolites, CGP62221 and CGP52421.
Excretion: Via urine (5%); faeces (95%, 91% as metabolites, 4% as unchanged drug). Elimination half-life: 19 hours.
Chemical Structure

Chemical Structure Image
Midostaurin

Source: National Center for Biotechnology Information. PubChem Database. Midostaurin, CID=9829523, https://pubchem.ncbi.nlm.nih.gov/compound/Midostaurin (accessed on Jan. 22, 2020)

Storage
Store at 25°C.
ATC Classification
L01XE39 - midostaurin ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.
References
Anon. Midostaurin. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 20/03/2019.

Buckingham R (ed). Midostaurin. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 20/03/2019.

Rydapt (Novartis Pharmaceuticals Corporation). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 20/03/2019.

Disclaimer: This information is independently developed by MIMS based on Midostaurin from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in