Midostaurin

Registered South African indications:

• Newly diagnosed acute myeloid leukaemia (AML) who are FLT3 mutation-positive
• Aggressive systemic mastocytosis (ASM)
• Systemic mastocytosis with associated haematological neoplasm (SM-AHN)
• Mast cell leukaemia (MCL)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Concomitant administration of potent CYP3A4 inducers, e.g. rifampicin, St. John’s Wort (Hypericum perforatum), carbamazepine, enzalutamide, phenytoin
• Cardiovascular disorders:
  • Congestive cardiac failure NYHA class III or IV
  • Left ventricular ejection fraction (LVEF) <50%
  • Myocardial infarction within the previous 6 months
  • Heart block of any degree
  • Congenital or acquired prolongation of QT time
  • Poorly controlled hypertension
• Pregnancy
• Lactation

Cautions

• Females of reproductive potential
• Severe renal impairment or ESRD
• Severe hepatic impairment
• Serious infection
• Symptomatic congestive cardiac failure
• Risk factors for cardiac dysfunction
• Risk of QT prolongation
• Electrolyte imbalances
• Alcohol-related problems
• Epilepsy
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

Used for the treatment of

• Newly diagnosed acute myeloid leukaemia (AML) who are FLT3 mutation-positive 
  - In combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response followed by midostaurin single agent maintenance therapy
• Aggressive systemic mastocytosis (ASM)
• Systemic mastocytosis with associated haematological neoplasm (SM-AHN)
• Mast cell leukaemia (MCL)

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Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

• Contraindicated

Breastfeeding

• Contraindicated

Fertility

• There are no data on the effect of midostaurin on human fertility. Animal studies with midostaurin have shown impaired fertility

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available
  Clinical experience in patients with severe renal impairment is limited and no data are available in patients with end-stage renal disease

Hepatic Impairment

• Mild or moderate (Child-Pugh Classes A & B): No dose adjustment recommended
• Severe (Child-Pugh Class C): Caution; no information available

Elderly

• No dose adjustment recommended
  There is limited experience in AML patients aged 60-70 years and no experience in AML patients above 70 years. In patients aged ≥60 years, midostaurin should be used only in patients eligible to receive intensive induction chemotherapy with adequate performance status and without significant comorbidities

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Headache
• Syncope
• Tremor
• Dizziness
• Disturbance in attention
• Fatigue

Cardiovascular Disorders

• Hypotension
• Sinus tachycardia
• Hypertension
• Pericardial effusion
• Haematoma
• Peripheral oedema
• Oedema
• QT prolongation

Respiratory Disorders

• Upper respiratory tract infection
• Epistaxis
• Laryngeal pain
• Dyspnoea
• Pleural effusion
• Nasopharyngitis
• Acute respiratory distress syndrome
• Pneumonia
• Bronchitis
• Sinusitis
• Cough
• Oropharyngeal pain

Gastrointestinal Disorders

• Nausea and vomiting
• Stomatitis
• Upper abdominal pain
• Haemorrhoids
• Anorectal discomfort
• Abdominal discomfort
• Oral herpes
• Constipation
• Dyspepsia
• Gastrointestinal haemorrhage

Hepatobiliary Disorders

• Increased alanine aminotransferase
• Increased aspartate aminotransferase 
• Increased total bilirubin
• Increased lipase
• Increased amylase

Genitourinary Disorders

• Urinary tract infection
• Cystitis

Endocrine and Metabolic Disorders

• Hyperuricaemia
• Increased weight
• Hypokalaemia
• Hyperglycaemia (non-fasting)
• Hypernatraemia
• Hypercalcaemia

Musculoskeletal Disorders

• Back pain
• Arthralgia
• Bone pain
• Pain in extremity
• Neck pain

Skin and Subcutaneous Tissue Disorders

• Exfoliative dermatitis
• Hyperhidrosis
• Dry skin
• Keratitis
• Erysipelas
• Petechiae

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Anaphylactic shock
• Neutropenic sepsis
• Febrile neutropenia
• Petechiae
• Lymphopenia
• Decreased haemoglobin
• Decreased absolute neutrophil count
• Prolonged activated partial thromboplastin time
• Sepsis
• Herpes zoster
• Chills
• Decreased absolute lymphocyte
• Contusion
• Fever

Sensory Disorders

• Eyelid oedema
• Vertigo

Others

• Device-related infection
• Catheter-related thrombosis
• Falls

• Strong CYP3A4 inducers
• Rifampicin
• St. John's Wort (Hypericum perforatum)
• Carbamazepine
• Enzalutamide
• Phenytoin
• Strong CYP3A4 inhibitors
• Antifungals
• Ketoconazole
• Antivirals
• Ritonavir
• Macrolide antibiotics
• Clarithromycin
• Nefazodone
• CYP1A2 substrates
• Tizandine
• CYP2D6 substrates
• Codeine
• CYP2C8 substrates
• Paclitaxel
• CYP2C9 substrates
• Warfarin
• CYP2C19 substrates
• Omeprazole
• CYP2E1 substrates
• Chlorzoxazone
• CYP3A4/5 substrates
• Tacrolimus
• CYP2B6 substrates
• Efavirenz
• P-glycoprotein substrates
• BCRP substrates
• Atorvastatin
• OATP1B1 substrates
• Digoxin
• QTc prolonging agents

• Full blood count with differential
• FLT3 mutation status

None routine. Specific cases may require 

• ECG
• Pregnancy status

Midostaurin inhibits multiple receptor tyrosine kinases, including FLT3 and KIT kinase. Midostaurin inhibits FLT3 receptor signalling and induces cell cycle arrest and apoptosis in leukaemic cells expressing FLT3 ITD or TKD mutant receptors or over-expressing FLT3 wild type receptors. Midostaurin interferes with aberrant KIT D816V-mediated signalling and inhibits mast cell proliferation, survival and histamine release. In addition, midostaurin inhibits several other receptor tyrosine kinases such as PDGFR (platelet-derived growth factor receptor) or VEGFR2 (vascular endothelial growth factor receptor 2), as well as members of the serine/threonine kinase family PKC (protein kinase C). Midostaurin binds to the catalytic domain of these kinases and inhibits the mitogenic signalling of the respective growth factors in cells, resulting in growth arrest. Midostaurin in combination with chemotherapeutic agents (cytarabine, doxorubicin, idarubicin and daunorubicin) resulted in synergistic growth inhibition in FLT3-ITD expressing AML cell lines.

Capsule 25mg

• Sotauric (Novartis) originator