AYVAKYT

Therapy should be initiated by a physician experienced in the administration of anticancer therapy. Posology for GIST Patient selection for treatment of unresectable or metastatic GIST harbouring the PDGFRA D842V mutation should be based on a validated test method.

The recommended starting dose of avapritinib is 300 mg orally once daily, on an empty stomach (see Method of administration). The dose should be adjusted based on safety and tolerability. Treatment should be continued until disease progression or unacceptable toxicity.

Concomitant use of avapritinib with strong or moderate CYP3A inhibitors should be avoided. 5). Dose modifications for adverse reactions Interruption of treatment with or without dose reduction may be considered to manage adverse reactions based on severity and clinical presentation.

Patients may have their dose reduced by 100 mg increments to a minimum dose of 100 mg once daily. The dose should be adjusted as recommended, based on safety and tolerability. Dose reductions and modifications for adverse reactions are recommended in patients with GIST and are provided in Tables 1 and 2.

Table 1. Recommended dose reductions for AYVAKYT for adverse reactions Dose reduction GIST (starting dose 300 mg) First 200 mg once daily Second 100 mg once daily Table 2. 4) All Grades Permanently discontinue AYVAKYT. 4) Grade 1 Continue at the same dose, reduce dose or interrupt until improvement to baseline or resolution.

Resume at the same dose or at a reduced dose. Grade 2 or Grade 3 Interrupt therapy until improved to baseline, Grade 1, or resolution. Resume at the same dose or at a reduced dose. Grade 4 Permanently discontinue AYVAKYT. 8) Grade 3 or Grade 4 Interrupt therapy until less than or equal to Grade 2.

Resume at the same dose or at a reduced dose, if warranted. 0 ** Adverse reactions with impact on Activities of Daily Living (ADLs) for Grade 2 or higher adverse reactions Missed doses If a dose of avapritinib is missed, the patient should make up for the missed dose unless the next scheduled dose is within 8 hours (see Method of administration).

If the dose has not been taken at least 8 hours prior to the next dose, then that dose should be omitted and the patient should resume treatment with the next scheduled dose. If vomiting occurs after taking a dose of avapritinib, the patient should not take an additional dose but continue with the next scheduled dose.

2). 0 times ULN and any AST). A modified starting dose of avapritinib is recommended for patients with severe hepatic impairment (Child-Pugh Class C). 2). Renal impairment No dose adjustment is recommended for patients with mild and moderate renal impairment (creatinine clearance [CLcr] 30-89 mL/min estimated by Cockcroft- Gault).

2). Paediatric population The safety and efficacy of AYVAKYT in children aged 0 to 18 years have not yet been established. No data are available. Method of administration AYVAKYT is for oral use. 2). Patients should swallow the tablet(s) whole with a glass of water.

1. The most common adverse reactions of any grade during treatment with avapritinib at a starting dose of 300 mg or 400 mg were nausea (45%), fatigue (40%), anaemia (39%), periorbital oedema (33%), face oedema (27%), hyperbilirubinaemia (28%), diarrhoea (26%), vomiting (24%), oedema peripheral (23%), lacrimation increased (22%), decreased appetite (21%) and memory impairment (20%).

Serious adverse reactions occurred in 23% of patients receiving avapritinib. The most common serious adverse reactions during treatment with avapritinib were anaemia (6%), and pleural effusion (1%). The most common adverse reactions leading to permanent treatment discontinuation were fatigue, encephalopathy and intracranial haemorrhage (< 1% each).

Adverse reactions leading to a dose reduction included anaemia, fatigue, neutrophil count decreased, blood bilirubin increased, memory impairment, cognitive disorder, periorbital oedema, nausea and face oedema. 4 which are included regardless of frequency, according to the MedDRA System Organ Class and frequency.

Frequencies are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3. 3 - Intracranial haemorrhage (including Cerebral haemorrhage, Haemorrhage intracranial, Subdural haematoma, Cerebral haematoma) 2Mental impairment (including Disturbance in attention, Mental impairment, Mental status changes, Dementia) 3Ocular haemorrhage (including Eye haemorrhage, Retinal haemorrhage, Vitreous haemorrhage) 4Gastrointestinal haemorrhage (including Gastric haemorrhage, Gastrointestinal haemorrhage, Upper gastrointestinal haemorrhage, Rectal haemorrhage, Melaena) 5Oedema (including Periorbital oedema, Oedema peripheral, Face oedema, Eyelid oedema, Fluid retention, Generalised oedema, Orbital oedema, Eye oedema, Oedema, Peripheral swelling, Swelling face, Eye swelling, Conjunctival oedema, Laryngeal oedema, Localised oedema, Lip swelling) -: no adverse reactions reported with Grades ≥3 Description of […]

Haemorrhages Avapritinib has been associated with an increased incidence of haemorrhagic adverse reactions, including serious and severe adverse reactions, like gastrointestinal haemorrhage and intracranial haemorrhage, in patients with unresectable or metastatic GIST.

8). g. warfarin, phenprocoumon, rivaroxaban, dabigatran, apixaban and edoxaban) or other concomitant medicinal products that increase the risk of bleeding (including antiplatelet therapy). 8). The exact mechanism is unknown. Before initiating avapritinib at any dose the risk for intracranial haemorrhage should be carefully considered in patients with risk factors such as concomitant use of anticoagulants, severe thrombocytopenia, a history of vascular aneurysm, intracranial haemorrhage, cerebrovascular accident or transient ischaemic attack within the prior year.

g. severe headache, vision problems, somnolence, or focal weakness) during treatment with avapritinib should interrupt treatment and inform their healthcare professional immediately. Brain imaging by magnetic resonance imaging (MRI) or computed tomography (CT) may be performed at the discretion of the physician based on severity and the clinical presentation.

2). There is no clinical study experience using avapritinib in patients with brain metastases. 8). These include, but are not limited to, memory impairment, cognitive disorder, confusional state, and encephalopathy. The mechanism of the cognitive effects is not known.

It is recommended that patients are clinically monitored for signs and symptoms of cognitive events such as new or increased forgetfulness, confusion, or difficulty with cognitive functioning. Patients should notify their healthcare professional immediately if they experience new or worsening cognitive symptoms.

2). In clinical studies conducted in patients with GIST, dose reductions or interruptions improved Grade ≥2 cognitive effects compared to no action. Fluid retention Occurrences of fluid retention, including severe cases of localised oedema (facial, periorbital, peripheral oedema and/or pleural effusion), generalised oedemas and ascites, have been reported with a frequency category of at least common in patients with unresectable or metastatic GIST taking avapritinib.

8). Therefore, it is recommended that patients be evaluated for these adverse reactions including regular assessment of weight and respiratory symptoms. An unexpected rapid weight gain or respiratory symptoms indicating fluid retention should be carefully investigated and appropriate supportive care and therapeutic measures, such as diuretics, should be undertaken.

For patients presenting with ascites, it is recommended to evaluate the aetiology of ascites. 1). QT interval prolongation may induce an increased risk of ventricular arrhythmias, including Torsade de pointes. g. due to concomitant medicinal products that can prolong QT interval such as amiodarone, citalopram, escitalopram, ondansetron; pre-existing cardiac disease; and/or electrolyte disturbances).

5). 2 for dose modification instructions. Interval assessments of QT by electrocardiogram (ECG) should be considered if avapritinib is taken concurrently with medicinal products that can prolong QT interval. 8). Patients who present with diarrhoea, nausea and vomiting should be evaluated to exclude disease-related aetiologies.

Supportive care for gastrointestinal adverse reactions requiring treatment may include medicinal products with antiemetic, antidiarrheal, or antacid properties. The hydration status of patients experiencing gastrointestinal adverse reactions must be closely monitored and treated as per standard clinical practice.

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