Midostaurin oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of midostaurin.
Drugs List
Therapeutic Indications
Uses
Acute myeloid leukaemia with FLT3 mutation
Mast cell leukaemia
Systemic mastocytosis
As monotherapy in adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM-AHN) or mast cell leukaemia (MCL).
In combination with daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients with complete response followed by single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia (AML) who are FLT3 mutation-positive.
Dosage
Adults
AML
50mg twice daily on days 8 to 21 of induction and consolidation chemotherapy cycles. For patients in complete response, treatment may then be given every day until relapse for up to 12 cycles of 28 days.
ASM, SM-AHN and MCL
100mg twice daily. Continue until relapse or intolerable toxicity.
Additional Dosage Information
Missed dose
If a dose is missed or the patient vomits, the next dose should occur as per the normal dosing schedule.
Dose modifications for AML
Induction, consolidation and maintenance
Grade 3 or 4 pulmonary infiltrates
Interrupt midostaurin, and then resume at the same dose at the start of the next cycle, provided infiltrates have resolved to grade 1 or below.
Other grade 3 or 4 non-haematological toxicities
Interrupt midostaurin until any suspected or confirmed treatment-related non-haematological toxicities resolve to grade 2 or below, then resume midostaurin at the same dose.
QTc interval above 470 milliseconds, and below 500 milliseconds
Reduce dose to 50mg once daily for the remaining duration of the treatment cycle. If QTc interval resolves to less than or equal to 470 milliseconds, resume midostaurin at the initial dose at the start of the next cycle. If QTc does not resolve to less than or equal to 470 milliseconds, continue midostaurin at 50mg once daily.
QTc interval above 500 milliseconds
Interrupt midostaurin for the remaining duration of the treatment cycle. If QTc interval resolves to less than or equal to 470 milliseconds, resume midostaurin at the initial dose at the start of the next cycle. If QTc does not resolve to less than or equal to 470 milliseconds, withhold midostaurin for as many cycles as necessary until QTc improves.
Maintenance only
Grade 4 neutropenia (absolute neutrophil count of less than 0.5 times 10 to the power of 9 per litre)
Interrupt midostaurin until absolute neutrophil count resolves to 1 times 10 to the power of 9 per litre, or higher. Midostaurin may then be resumed at 50mg twice daily. If absolute neutrophil count remains below 1 times 10 to the power of 9 per litre for more than 2 weeks, discontinue midostaurin.
Any persistent grade 1 or 2 toxicity that the patient deems unacceptable
Interrupt midostaurin for up to 28 days.
Dose modifications for ASM, SM-AHN and MCL
Grade 4 neutropenia (absolute neutrophil count of less than 0.5 times 10 to the power of 9 per litre) in patients with baseline neutrophil count of 0.5 to 1.5 times 10 to the power of 9 per litre, or grade 3 neutropenia (absolute neutrophil count of less than 1 times 10 to the power of 9 per litre) in patients without MCL
Interrupt midostaurin until absolute neutrophil count resolves to 1 times 10 to the power of 9 per litre or more, then resume midostaurin at 50mg twice daily. If well tolerated, increase dose to 100mg twice daily. If absolute neutrophil count remains below 1 times 10 to the power of 9 per litre for more than 3 weeks, discontinue midostaurin.
Platelet count less than 25 times 10 to the power of 9 per litre in patients with a baseline platelet count of 25 to 75 times 10 to the power of 9 per litre, or platelet count of less than 50 times 10 to the power of 9 per litre in patients without MCL
Interrupt midostaurin until absolute platelet count resolves to 50 times 10 to the power of 9 per litre or more, then resume midostaurin at 50mg twice daily. If well tolerated, increase dose to 100mg twice daily. If platelet count remains below 50 times 10 to the power of 9 per litre for more than 3 weeks, discontinue midostaurin.
Haemoglobin less than 8 grams per decilitre in patients without MCL, or life-threatening anaemia in patients with baseline a haemoglobin value of 8 to 10 grams per decilitre
Interrupt midostaurin until haemoglobin resolves to 8g per decilitre or higher, then resume midostaurin at 50mg twice daily. If well tolerated, increase dose to 100mg twice daily. If haemoglobin remains below 8 grams per decilitre for more than 3 weeks, discontinue midostaurin.
Grade 3 or 4 nausea or vomiting despite optimal anti-emetic treatment
Interrupt midostaurin for 3 days, then resume midostaurin at 50mg twice daily. If well tolerated, increase dose to 100mg twice daily.
Other grade 3 or 4 non-haematological toxicities
Interrupt midostaurin until toxicity resolves to grade 2 or lower, then resume midostaurin at 50mg twice daily. If well tolerated, increase dose to 100mg twice daily. If toxicity remains at grade 3 or above for 3 weeks, or severe toxicity recurs at a reduced dose of midostaurin, discontinue midostaurin.
Contraindications
Children under 18 years
Uncontrolled systemic infection
Breastfeeding
Long QT syndrome
Pregnancy
Torsade de pointes
Precautions and Warnings
Family history of long QT syndrome
Females of childbearing potential
Patients over 60 years
Risk of cardiac failure
Electrolyte imbalance
History of torsade de pointes
Severe hepatic impairment
Severe renal impairment
Correct electrolyte disorders before treatment
Advise patient that dizziness/vertigo may affect ability to drive
Confirm FLT3 mutation status prior to treatment
Pre-medicate with antiemetics & continue according to local protocol
Treat and control infections prior to commencing therapy
Treatment to be initiated by specialist
Contains alcohol
Some formulations contain castor oil polyoxyl which may cause diarrhoea
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Ensure negative pregnancy test in week preceding initiation of treatment
Monitor differential WBC count before and during therapy
Monitor LVEF in patients at risk of cardiac failure
Consider dose reduction if QTc interval greater than 470msec
Consider interrupting treatment if QTc > 500msec
Consider monitoring ECG in patients at risk of QT prolongation
Monitor for signs and symptoms of interstitial lung disease
Monitor for signs and symptoms of pneumonitis
Monitor hepatic function in patients with severe hepatic impairment
Monitor patient for signs of serious infection
Monitor patients with severe renal impairment for adverse effects
Monitor serum electrolytes
Suspend/reduce dose if grade 3 nausea despite anti-emetic treatment
Discontinue if evidence of interstitial lung disease
Discontinue treatment if grade 3 or greater pneumonitis occurs
Interrupt if haemoglobin falls below 8 g/dL
Suspend therapy &/or reduce dose if platelets below 50 x 10 to power 9/L
Suspend treatment and reduce dose if grade 4 neutropenia occurs
Suspend treatment and/or reduce dose in grade 3 non-haematological toxicity
Suspend treatment if grade 3 or greater pulmonary infiltrates occurs
Consider interrupting treatment if infection occurs
Advise patient not to take St John's wort concurrently
Female: Effect of hormonal contraceptive may be reduced
Female:Barrier contraception required during & for 4 months after treatment
Breastfeeding: Do not breastfeed during & for 4 months after treatment
Midostaurin has not been studied in patients with acute promyelocytic leukaemia, and as such the manufacturer states that midostaurin is not recommended for use in this patient group.
In patients receiving a haematopoietic stem cell transplant (SCT), midostaurin should be discontinued 48 hours prior to the conditioning regimen for SCT.
Discontinue the Midostaurin 48 hours prior to the conditioning regimen for stem cell transplant.
Pregnancy and Lactation
Pregnancy
Midostaurin in contraindicated during pregnancy.
The manufacturer does not recommend using midostaurin during pregnancy or in women of childbearing potential not using contraception. Animal studies have shown teratogenic effects. Human data is limited and as such a potential risk cannot be ruled out.
Lactation
Midostaurin in contraindicated during breastfeeding.
The manufacturer advises that the patient discontinues breastfeeding during treatment with midostaurin and for at least 4 months after stopping treatment. Animal data reports significant levels of midostaurin in the breast milk, however the presence in human breast milk is unknown.
Side Effects
Abdominal discomfort
Acute respiratory distress syndrome
Anaphylactic shock
Arthralgia
Asthenia
Attention disturbances
Back pain
Bone pain
Bronchitis
Chills
Constipation
Contusion
Cough
Cystitis
Diarrhoea
Dizziness
Dry skin
Dyspepsia
Dyspnoea
Elevated amylase levels
Elevated serum lipase
Epistaxis
Erysipelas
Exfoliative dermatitis
Eyelid oedema
Falls
Fatigue
Febrile neutropenia
Gastrointestinal bleeding
Haematoma
Haemoglobin decrease
Haemorrhoids
Headache
Herpes zoster
Hypercalcaemia
Hyperglycaemia
Hyperhidrosis
Hypernatraemia
Hypersensitivity reactions
Hypertension
Hyperuricaemia
Hypokalaemia
Hypotension
Increase in serum ALT/AST
Increased partial thromboplastin time
Insomnia
Keratitis
Laryngeal discomfort
Lymphopenia
Nasopharyngitis
Nausea
Neck pain
Neutropenic sepsis
Oedema
Oral herpes
Oropharyngeal pain
Painful extremities
Pericardial effusion
Peripheral oedema
Petechiae
Pleural effusion
Pneumonia
Pyrexia
Rectal discomfort
Reduced lymphocyte count
Reduced neutrophil count
Sepsis
Serum bilirubin increased
Sinus tachycardia
Sinusitis
Stomatitis
Syncope
Tremor
Upper abdominal pain
Upper respiratory tract infection
Urinary tract infections
Vertigo
Vomiting
Weight gain
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: December 2020
Reference Sources
Summary of Product Characteristics: Rydapt 25mg soft capsules. Novartis Pharmaceuticals Ltd. Revised April 2018.
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
FDB Disclaimer : FDB Multilex is intended for the use of healthcare professionals and is provided on the basis that the healthcare professionals will retain FULL and SOLE responsibility for deciding what treatment to prescribe or dispense for any particular patient or circumstance.