Adult: Monotherapy in patients harbouring the platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations: Initially, 300 mg once daily. Continue treatment until disease progression or unacceptable toxicity occurs. Dosing interruption with or without dose reduction and treatment discontinuation may be considered depending on the severity of adverse reactions and clinical presentation (refer to detailed product guidelines).
Oral Advanced systemic mastocytosis
Adult: Initially, 200 mg once daily. Continue treatment until disease progression or unacceptable toxicity occurs. Dosing interruption and dose reduction may be considered depending on the severity of adverse reactions (refer to detailed product guidelines).
Special Patient Group
Unresectable or metastatic gastrointestinal stromal tumour:
Patients concomitantly receiving moderate CYP3A4 inhibitors: Reduce initial dose to 100 mg once daily.
Advanced systemic mastocytosis:
Patients concomitantly receiving moderate CYP3A4 inhibitors: Reduce initial dose to 50 mg once daily.
Renal Impairment
Severe or ESRD: Not recommended.
Hepatic Impairment
Severe (Child-Pugh class C): Not recommended.
Administration
Should be taken on an empty stomach. Take on an empty stomach, at least 1 hr before or 2 hr after a meal.
Contraindications
Lactation.
Special Precautions
Patient with a condition predisposing to bleeding, increased risk of intracranial haemorrhage (e.g. thrombocytopenia, vascular aneurysm, history of intracranial haemorrhage within the previous year, history of CVA or TIA); known QT interval prolongation or at risk of prolongation (e.g. pre-existing cardiac disease and/or electrolyte disturbances). Patient receiving anticoagulant treatment or drugs that may increase bleeding risk; concomitantly receiving moderate CYP3A4 inhibitors. Avoid co-administration with strong CYP3A4 inhibitors and strong or moderate CYP3A4 inducers. Not recommended for the treatment of patients with advanced systemic mastocytosis with platelet counts of <50,000/mm3. Severe renal and hepatic impairment. Pregnancy.
Adverse Reactions
Significant: Gastrointestinal, hepatic, and tumour haemorrhages; cognitive effects (e.g. memory impairment, confusion, encephalopathy, disturbance in attention, mental status changes, amnesia, dementia, abnormal thinking); fluid retention including severe cases of local oedemas (periorbital, facial, peripheral oedema and/or pleural effusion) or generalised oedemas; QT interval prolongation, diarrhoea, nausea, vomiting; anaemia, neutropenia, thrombocytopenia; elevated bilirubin and liver transaminases; photosensitivity reaction. Ear and labyrinth disorders: Vertigo. Eye disorders: Conjunctivitis, increased lacrimation, blurred vision, conjunctival haemorrhage, photophobia, ocular haemorrhage. Gastrointestinal disorders: Abdominal pain, GERD, dry mouth, constipation, ascites, dysphagia, stomatitis, flatulence, salivary hypersecretion, taste altered. General disorders and administration site conditions: Fatigue, asthenia, malaise, pyrexia, feeling cold. Investigations: Decreased WBC and lymphocyte count, increased blood creatinine, creatine phosphokinase, and lactate dehydrogenase, decreased or increased weight. Metabolism and nutrition disorders: Decreased appetite, dehydration, hypophosphataemia, hypokalaemia, hypomagnesaemia, hypocalcaemia, hypoalbuminaemia, hyponatraemia. Musculoskeletal and connective tissue disorders: Arthralgia, back pain, myalgia, muscle spasms. Nervous system disorders: Dizziness, headache, somnolence, peripheral neuropathy, aphasia, hypokinesia, balance disorder, speech disorder, tremor. Psychiatric disorders: Anxiety, depression, insomnia. Renal and urinary disorders: Acute kidney injury, haematuria. Respiratory, thoracic and mediastinal disorders: Dyspnoea, cough, nasal congestion. Skin and subcutaneous tissue disorders: Rash, hair colour changes, palmar-plantar erythrodysaesthesia syndrome, skin hypopigmentation, alopecia, pruritus. Vascular disorders: Hypertension. Potentially Fatal: Intracranial haemorrhage.
PO: Z (No human data. Teratogenic and embryotoxic in animal studies. Not recommended during pregnancy.)
Patient Counseling Information
This drug may affect the ability to concentrate and react, if affected, do not drive or operate machinery. Avoid excessive exposure to sunlight, apply sunscreen or wear protective clothing when going outdoors. Women of reproductive potential and men with partners of reproductive potential must use effective contraception during treatment and for 6 weeks after the last dose.
Monitoring Parameters
Verify pregnancy status of women of childbearing potential before initiation of treatment. Evaluate PDGFRA exon 18 mutation status for use in patients with gastrointestinal stromal tumours. Regularly monitor blood counts, coagulation parameters, and LFTs (bilirubin, transaminases). In patients with advanced systemic mastocytosis, obtain platelet count before initiating treatment and routinely thereafter. Observe for signs and symptoms of cognitive events (e.g. difficulty with cognitive functioning, new or worsening forgetfulness, confusion) and intracranial haemorrhage (particularly in patients with risk factors).
Drug Interactions
Increased plasma concentration and risk of adverse reactions (e.g. QT prolongation and related arrhythmias) with moderate or strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, cobicistat, indinavir, ritonavir, nelfinavir, conivaptan, boceprevir). Reduced plasma concentration and efficacy with moderate or strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampicin, phenobarbital, primidone, efavirenz, etravirine, modafinil, nafcillin, dabrafenib, dexamethasone).
Food Interaction
Decreased plasma concentration and efficacy with St. John's wort; avoid concomitant use. Increased plasma concentration and risk of adverse reactions with grapefruit or grapefruit juice; avoid concomitant use. Increased exposure when given with high-calorie, high-fat meals as compared to fasting.
Action
Description: Mechanism of Action: Avapritinib is a strong tyrosine kinase inhibitor that targets platelet-derived growth factor receptor alpha (PDGFRA) D842V and KIT D816V mutants which are overexpressed in certain disorders. It blocks the signalling pathway of kinases for these mutations, thus preventing tumour and mast cell proliferation. Pharmacokinetics: Absorption: Increased exposure when given with high-calorie, high-fat meals (compared to fasting). Time to peak plasma concentration: 2-4.1 hours. Distribution: Volume of distribution: 1,200 L (300 mg dose); 1,900 L (200 mg dose). Plasma protein binding: 98.8%. Metabolism: Metabolised in the liver mainly by CYP3A4 and CYP3A5, and to a lesser extent by CYP2C9; the glucuronide metabolite (M690) is mainly catalysed by uridine diphosphate glucuronosyltransferase (UGT) 1A3. Excretion: Via faeces (70%; 11% as unchanged drug); urine (18%; <1% as unchanged drug). Elimination half-life: 32-57 hours.
Chemical Structure
Avapritinib Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 118023034, Avapritinib. https://pubchem.ncbi.nlm.nih.gov/compound/Avapritinib. Accessed Oct. 27, 2022.
Storage
Store between 20-25°C. Follow applicable procedures for receiving, handling, administration, and disposal.
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