Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Blueprint Medicines (Netherlands) B.V., Gustav Mahlerplein 2, 1082 MA Amsterdam, Netherlands
AYVAKYT is indicated as monotherapy for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) harbouring the platelet-derived growth factor receptor alpha (PDGFRA) D842V mutation.
AYVAKYT is indicated as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated haematological neoplasm (SM-AHN) or mast cell leukaemia (MCL), after at least one systemic therapy.
AYVAKYT is indicated for the treatment of adult patients with indolent systemic mastocytosis (ISM) with moderate to severe symptoms inadequately controlled on symptomatic treatment (see section 5.1).
Therapy should be initiated by a healthcare professional experienced in the diagnosis and treatment of conditions for which avapritinib is indicated (see section 4.1).
For GIST, the recommended starting dose of avapritinib is 300 mg orally once daily, on an empty stomach (see Method of administration). Treatment should be continued until disease progression or unacceptable toxicity occurs.
Patient selection for treatment of unresectable or metastatic GIST harbouring the PDGFRA D842V mutation should be based on a validated test method.
Concomitant use of avapritinib with strong or moderate CYP3A inhibitors should be avoided. If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the starting dose of avapritinib must be reduced from 300 mg to 100 mg orally once daily (see section 4.5).
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 that must not be exceeded by patients with AdvSM. Treatment should be continued until disease progression or unacceptable toxicity occurs.
Treatment with avapritinib is not recommended in patients with platelet count <50 x 109/L (see Table 2 and section 4.4).
Concomitant use of avapritinib with strong or moderate CYP3A inhibitors should be avoided. If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the starting dose of avapritinib must be reduced from 200 mg to 50 mg orally once daily (see section 4.5).
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.
Concomitant use of avapritinib with strong or moderate CYP3A inhibitors must be avoided (see section 4.5).
Irrespective 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 GIST, AdvSM or ISM 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) | AdvSM (starting dose 200 mg) | ISM (starting dose 25 mg)* |
|---|---|---|---|
| First | 200 mg once daily | 100 mg once daily | 25 mg once every other day |
| Second | 100 mg once daily | 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. Recommended dose modifications for AYVAKYT for adverse reactions:
| Adverse reaction | Severity* | Dose modification |
|---|---|---|
| Patients with GIST, AdvSM or ISM | ||
| Intracranial haemorrhage (see section 4.4) | All Grades | Permanently discontinue AYVAKYT. |
| Cognitive effects** (see section 4.4) | 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. | |
| Other adverse reactions (also see section 4.4 and section 4.8) | 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. |
| Patients with AdvSM | ||
| Thrombocytopenia (see section 4.4) | 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. |
* The severity of adverse reactions graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0
** Adverse reactions with impact on Activities of Daily Living (ADLs) for Grade 2 or higher adverse reactions
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 must be omitted and the patient should resume treatment with the next scheduled dose.
If vomiting occurs after taking a dose of avapritinib, the patient must not take an additional dose but continue with the next scheduled dose.
No dose adjustment is recommended for patients aged 65 years and above (see section 5.2). Clinical data in ISM patients aged 75 years and above is limited (see section 5.1).
No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase (AST) > ULN or total bilirubin greater than 1 to 1.5 times ULN and any AST) and moderate hepatic impairment (total bilirubin >1.5 to 3.0 times ULN and any AST). A modified starting dose of avapritinib is recommended for patients with severe hepatic impairment (Child-Pugh Class C). The starting dose of avapritinib should be reduced from 300 mg to 200 mg orally once daily for patients with GIST, from 200 mg to 100 mg orally once daily for patients with AdvSM, and from 25 mg orally once daily to 25 mg orally every other day for patients with ISM (see section 5.2).
No dose adjustment is recommended for patients with mild and moderate renal impairment (creatinine clearance [CLcr] 30-89 mL/min estimated by Cockcroft-Gault). Avapritinib has not been studied in patients with severe renal impairment (CLcr 15-29 mL/min) or end-stage renal disease (CLcr <15 mL/min), therefore its use in patients with severe renal impairment or end-stage renal disease cannot be recommended (see section 5.2).
The safety and efficacy of AYVAKYT in children aged 0 to 18 years have not yet been established. No data are available.
AYVAKYT is for oral use.
The tablets must be taken on an empty stomach at least 1 hour before or at least 2 hours after a meal (see section 5.2).
Patients must swallow the tablets whole with a glass of water.
There is limited experience with cases of overdose reported in clinical studies with avapritinib. The maximum dose of avapritinib studied clinically is 600 mg orally once daily. Adverse reactions observed at this dose were consistent with the safety profile at 300 mg or 400 mg once daily (see section 4.8).
There is no known antidote for avapritinib overdose. In the event of suspected overdose, avapritinib should be interrupted and supportive care instituted. Based on the large volume of distribution of avapritinib and extensive protein binding, dialysis is unlikely to result in significant removal of avapritinib.
4 years.
This medicinal product does not require any special storage conditions.
High-density polyethylene (HDPE) bottle with child-resistant cap (polypropylene) with foiled induction seal liner (pulp backed heat induction foil) and a desiccant in canister.
Each carton contains one bottle with 30 film-coated tablets.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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