SOTAURIC (RYDAPT CAPSULE

Indications

• Acute myeloid leukaemia (specialist use only)
• Aggressive systemic mastocytosis (specialist use only)
• Systemic mastocytosis with associated haematological neoplasm (specialist use only)
• Mast cell leukaemia (specialist use only)

Dosage

Adults: 50 mg twice daily on days 8–21 of induction and after the last treatment; after consolidation chemotherapy, adjust dosage based on side effects. For aggressive systemic mast

Mechanism of action

Midostaurin potently inhibits multiple receptor tyrosine kinases, including protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR, and both wild-type and mutant FLT3 tyrosine kinases. This inhibition leads to the induction of apoptosis in target leukemia cells and mast cells, as well as antiproliferative effects on various cancer cell lines. Additionally, midostaurin interacts with organic anion transporter (OATP) 1A1 and multidrug resistance protein (MRP)-2.

Pharmacodynamics

Midostaurin targets both wild-type and mutated kinases that, when activated, cause aberrant signaling cascades associated with malignancies such as AML and ASM. The drug is also noted for prolonging QTc intervals, although this effect was not clinically significant compared to placebo in patients with advanced systemic mastocytosis or acute myeloid leukaemia. It is beneficial as a combination therapy for patients undergoing chemotherapy.

Pharmacokinetics

Midostaurin is absorbed orally and undergoes extensive metabolism, primarily via cytochrome P450 enzymes. It has a half-life that allows for twice-daily dosing, and its pharmacokinetic profile can be influenced by various drug interactions, particularly those involving CYP450 enzymes. Monitoring of serum cholesterol, triglycerides, lipase, and amylase levels is recommended during treatment.

Contra-indications

• Severe hepatic impairment
• Severe renal impairment
• Active severe infection

Adverse effects

• Anaemia
• Anxiety
• Arthralgia
• Asthenia
• Behavioural abnormality
• Cognitive disorder
• Decreased concentration
• Constipation
• Cough
• Cystitis
• Diarrhoea
• Dizziness
• Dyspepsia
• Dyspnoea
• Febrile neutropenia
• Fever
• Haemorrhage
• Headache
• Hyperglycaemia
• Hypotension
• Increased risk of infection
• Nausea
• Oedema
• Oropharyngeal pain
• QT interval prolongation

Interactions

• St. John's Wort (decreases exposure)
• Rifampicin (decreases exposure)
• Dronedarone (unknown, increases exposure)
• Antifungal azoles (unknown, increases exposure)
• Active metabolite of bupropion (unknown, decreases exposure)
• Ciclosporin (unknown, increases concentration)
• Cobicistat (unknown, increases exposure)
• Crizotinib (unknown, increases exposure)
• Dabrafenib (unknown, decreases exposure)
• Bosentan (unknown, decreases exposure)

Precautions

• Elderly patients (limited experience)
• Patients at risk of congestive heart failure
• Monitor serum cholesterol and triglycerides before starting treatment and at weeks 2, 4, 8, and regularly thereafter
• Monitor for lipase and amylase elevations before starting treatment and regularly thereafter
• Monitor ECG before starting treatment and monthly thereafter

Pregnancy

Manufacturer advises avoid due to potential toxicity in animal studies.

Breast-feeding

Manufacturer advises avoid during treatment and for 7 days after last treatment.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Midostaurin 50 mg tablets
• Midostaurin 100 mg tablets

Mechanism of action

It potently inhibits multiple receptor tyrosine kinases. Midostaurin and its major active metabolites CGP62221 and CGP52421 inhibit the activity of protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and WT and/or mutant FLT3 tyrosine kinases. Inhibition of FLT3 receptor signalling cascades induces apoptosis of target leukemia cells expressing target receptors and mast cells, in addition to its antiproliferative activity toward multiple cancer cell lines. Midostaurin also interacts with organic anion transporter (OATP) 1A1 and multidrug resistance protein (MRP)-2 according to preliminary in vitro studies.

Pharmacodynamics

It targets multiple WT and mutated kinases that, when activated, constitutively stimulate aberrant signalling cascades that lead to malignancies such as AML and ASM. Alternative pharmacodynamic effect of midostaurin in prolonging QTc intervals was not clinically significant in patients with advanced SM or AML when compared to placebo. Midostaurin is therapeutically beneficial as a combination therapy for patients undergoing chemotherapy.