AYVAKYT

1). Posology for AdvSM The recommended starting dose of avapritinib is 200 mg orally once daily, on an empty stomach (see Method of administration). This once daily 200 mg dose is also the maximum recommended dose. Continue treatment until SM disease progression or unacceptable toxicity.

4). Concomitant use of avapritinib with strong or moderate CYP3A inhibitors should be avoided. 5). Posology for ISM For ISM, the recommended dose of avapritinib is 25 mg orally once daily, on an empty stomach (see Method of administration).

This once daily 25 mg dose is also the maximum recommended dose that must not be exceeded in patients with ISM. Treatment of ISM should be continued until disease progression or unacceptable toxicity occurs. 5). Dose modifications for adverse reactionsIrrespective of indication, interruption of treatment with or without dose reduction may be considered to manage adverse reactions based on severity and clinical presentation.

The dose should be adjusted as recommended, based on safety and tolerability. Dose reductions and modifications for adverse reactions are recommended in patients with AdvSM or ISM and are provided in Tables 1 and 2. Table 1. Recommended dose reductions for AYVAKYT for adverse reactions Dose reduction AdvSM (starting dose 200 mg) ISM (starting dose 25 mg)* First 100 mg once daily 25 mg once every other day Second 50 mg once daily - Third 25 mg once daily - * ISM patients requiring dose reduction below 25 mg once every other day must discontinue treatment.

Table 2. 4) All Grades Permanently discontinue AYVAKYT. 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. 4) 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. 4) Less than 50 x 109/L Interrupt dosing until platelet count is ≥ 50 x 109/L, then resume at reduced dose (see Table 1).

If platelet count does not recover above 50 x 109/L, consider platelet support. 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).

1). Advanced systemic mastocytosis The most common adverse reactions of any grade during treatment with avapritinib at a starting dose of 200 mg were periorbital oedema (38%), thrombocytopenia (37%), oedema peripheral (33%), and anaemia (22%).

Serious adverse reactions occurred in 12% of patients receiving avapritinib. The most common serious adverse reactions during treatment with avapritinib were subdural haematoma (2%), anaemia (2%), and haemorrhage (2%). 1% had adverse reactions leading to permanent treatment discontinuation.

6%), subdural haematoma occurred. 8% each). Adverse reactions leading to a dose reduction included thrombocytopenia, neutropenia, periorbital oedema, cognitive disorder, oedema peripheral, platelet count decreased, neutrophil count decreased, anaemia, asthenia, fatigue, arthralgia, blood alkaline phosphatase increased, blood bilirubin increased, and white blood cell count decreased.

Indolent systemic mastocytosis In Part 2 of PIONEER, the most common adverse reaction during treatment with avapritinib at the recommended dose of 25 mg was peripheral oedema (12%). Overall, the majority of oedema adverse reactions reported were Grade 1 (94% for peripheral oedema, 90% for face oedema); none were Grade ≥3 or led to treatment discontinuation.

No serious adverse reactions or fatal adverse reactions occurred in 141 patients receiving avapritinib at the recommended dose of 25 mg in Part 2 of PIONEER. Treatment discontinuation due to adverse reactions occurred in <1% of patients receiving avapritinib.

4 which are included regardless of frequency, according to the MedDRA System Organ Class and frequency. For patients with ISM, adverse reactions reported in Part 2 of the PIONEER study in ≥5% of patients are listed in Table 4. 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).

8). g. warfarin, phenprocoumon, rivaroxaban, dabigatran, apixaban and edoxaban) or other concomitant medicinal products that increase the risk of bleeding (including antiplatelet therapy). 8). Fatal events have occurred in <1% of patients across all doses.

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). Advanced systemic mastocytosis The incidence of intracranial haemorrhage was higher in patients with platelet counts <50 x 109/L and in patients with a starting dose of ≥300 mg. Considering the above, a platelet count must be performed prior to initiating therapy.

Avapritinib is not recommended in patients with platelet counts <50 x 109/L. Following treatment initiation, platelet counts must be performed every 2 weeks for the first 8 weeks regardless of baseline platelet count. After 8 weeks of treatment, monitor platelet counts every 2 weeks (or more frequently as clinically indicated) if values are less than 75 x 109/L, every 4 weeks if values are between 75 and 100 x 109/L, and as clinically indicated if values are greater than 100 x 109/L.

Manage platelet counts of <50 x 109/L by temporarily interrupting avapritinib. 2). Thrombocytopenia was generally reversible by reducing or interrupting avapritinib in clinical studies. The maximum dose for patients with AdvSM must not exceed 200 mg once daily.

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