PATHFINDER
Safety Data

The safety of AYVAKYT was evaluated in patients with Advanced SM in EXPLORER and PATHFINDER

Patients received a starting dose ranging from 30 mg to 200 mg orally once daily, including 126 patients who received the recommended starting dose of 200 mg once daily:1–3

The majority of adverse reactions were Grade 1 or 2*

Serious adverse reactions occurred in 12% of patients receiving AYVAKYT. The most common serious adverse reactions were subdural haematoma (2%), anaemia (2%) and haemorrhage (2%)*

7.1% of patients permanently discontinued treatment due to any adverse reactions

The most common adverse reactions of any grade during treatment with AYVAKYT were periorbital oedema (38%), thrombocytopenia (37%), oedema peripheral (33%) and anaemia (22%)

*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.

AYVAKYT was generally well tolerated, with the majority of adverse reactions being Grade 1 or Grade 21,2

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Adverse reactions reported in clinical studies in patients with Advanced SM treated with AYVAKYT starting at 200 mg1

Please refer to the SmPC for a full list of adverse reactions

  • Adverse reactions in ≥10% of patients
  • Adverse reactions in <10% of patients

Adverse reactions occurring in ≥10% of patients1*

Adverse reactions All grades (%) Grades ≥3 (%)
Blood and lymphatic system disorders
Thrombocytopenia** 46.8 23.0
Anaemia** 23.0 11.9
Neutropenia** 21.4 19.0
General disorders
Oedema† 69.8 4.8
Fatigue** 18.3 2.4
Gastrointestinal disorders
Diarrhoea 14.3 1.6
Nausea 12.7 –
Nervous system disorders
Taste effect** 15.9 0.8
Cognitive disorder 11.9 1.6
Skin and subcutaneous tissue disorders
Hair colour changes 15.1 –

Adverse reactions occurring in <10% of patients1

  • Leukopenia (8.7%)**
  • Vomiting (8.7%)**
  • Headache (7.9%)
  • Hyperbilirubinaemia (7.9%)**
  • Rash (7.9%)**
  • Alopecia (7.1%)
  • Lacrimation increased (6.3%)
  • Weight increased (6.3%)
  • Memory impairment (5.6%)**
  • Dizziness (5.6 %)
  • Epistaxis (5.6 %)
  • Neuropathy peripheral (4.8%)‡
  • Blood alkaline phosphatase increased (4.8%)
  • Transaminases increased (4.8%)**
  • Gastroesophageal reflux disease (4.8%)**
  • Arthralgia (4.8%)
  • Ascites (4.0%)**
  • Dryness (4.0%)**
  • Constipation (3.2%)
  • Abdominal pain (3.2%)**
  • Pain (3.2%)
  • Contusion (3.2%)
  • Intracranial haemorrhage (ICH) (2.4%)§
  • Gastrointestinal haemorrhage (2.4%)‖
  • Pleural effusion (2.4%)
  • Electrocardiogram QT prolonged (1.6%)
  • Confusional state (1.6%)
  • Pericardial effusion (0.8%)
  • Photosensitivity reaction (0.8%)
  • Acute kidney injury (0.8%)**

*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.
**Comprises pooled terms representing similar medical concepts.
†Oedema (including periorbital oedema, oedema peripheral, facial oedema, eyelid oedema, fluid retention, generalised oedema, oedema, peripheral swelling, facial swelling, eye swelling, conjunctival oedema, laryngeal oedema, localised oedema).
‡Neuropathy peripheral (including paraesthesia, neuropathy peripheral, hypaesthesia).
§ICH (including haemorrhage intracranial, subdural haematoma).
‖Gastrointestinal haemorrhage (including gastric haemorrhage, gastrointestinal haemorrhage, melaena).

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Special warnings and precautions for use1

AYVAKYT has been associated with an increased incidence of haemorrhagic adverse reactions, including serious and severe adverse reactions, like gastrointestinal and intracranial haemorrhages in patients with Advanced SM.

Routine surveillance must include a physical examination. Complete blood counts, including platelets and coagulation parameters, must be monitored in patients with Advanced SM, particularly in patients with conditions predisposing to bleeding and in those treated with anticoagulants (e.g. warfarin and phenprocoumon) or other concomitant medicinal products that increase the risk of bleeding.

Adverse reactions of intracranial haemorrhage occurred patients with Advanced SM who received AYVAKYT.

Before initiating AYVAKYT at any dose the risk for intracranial haemorrhage should be carefully considered in patients with potential increased risk including those with a history of vascular aneurysm, intracranial haemorrhage, cerebrovascular accident within the prior year, concomitant use of anticoagulants or thrombocytopenia.

Patients who experience clinically relevant neurological signs and symptoms (e.g. severe headache, vision problems, somnolence, and/or focal weakness) during treatment with AYVAKYT must interrupt dosing of AYVAKYT 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.

For patients with observed intracranial haemorrhage during treatment with AYVAKYT in any indication, regardless of severity grade, AYVAKYT must be permanently discontinued.

Serious adverse reactions of intracranial haemorrhage were reported in patients with Advanced SM receiving AYVAKYT. The exact mechanism is unknown. 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. AYVAKYT 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 AYVAKYT. Platelet support may be necessary, and the recommended dose modification in Table 2 of the prescribing information must be followed. Thrombocytopenia was generally reversible by reducing or interrupting AYVAKYT in clinical studies. The maximum dose for patients with Advanced SM must not exceed 200 mg once daily.

Cognitive effects, such as memory impairment, cognitive disorder, confusional state, and encephalopathy, can occur in patients receiving AYVAKYT. The mechanism of the cognitive effects is not known.

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

For Advanced SM patients with observed cognitive effects related to treatment with AYVAKYT, the recommended dose modification in Table 2 of the prescribing information must be followed. In clinical studies conducted in patients with Advanced SM, dose reductions or interruptions improved Grade ≥2 cognitive effects compared to no action.

In patients with Advanced SM, localised (facial, periorbital, peripheral, pulmonary oedema, pericardial and/or pleural effusion) or generalised oedema, and ascites have been observed with a frequency category of at least common. Other localised oedemas (laryngeal oedema) have been reported uncommonly.

Therefore, it is recommended that patients with Advanced SM 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 must be carefully investigated and appropriate supportive care and therapeutic measures, such as diuretics, should be undertaken. For Advanced SM patients presenting with ascites, it is recommended to evaluate the aetiology of ascites.

Prolongation of QT interval has been observed in patients with Advanced SM treated with AYVAKYT in clinical studies. QT interval prolongation may induce an increased risk of ventricular arrhythmias, including Torsade de pointes.

AYVAKYT should be used with caution in Advanced SM patients with known QT interval prolongation or at risk of QT interval prolongation (e.g. due to concomitant medicinal products, pre-existing cardiac disease and/or electrolyte disturbances). Concomitant administration with strong or moderate CYP3A4 inhibitors should be avoided due to the increased risk of adverse reactions, including QT prolongation and related arrhythmias. If concomitant use of moderate CYP3A4 inhibitors cannot be avoided, see section 4.2 of the prescribing information for dose modification instructions.

In patients with Advanced SM, interval assessments of QT by electrocardiogram (ECG) should be considered if AYVAKYT is taken concurrently with medicinal products that can prolong QT interval.

Diarrhoea, nausea and vomiting were the most commonly reported gastrointestinal adverse reactions in patients with Advanced SM. Advanced SM 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 Advanced SM patients experiencing gastrointestinal adverse reactions must be closely monitored and treated as per standard clinical practice.

Treatment with AYVAKYT in patients with Advanced SM is associated with anaemia, neutropenia and/or thrombocytopenia. Complete blood counts must be performed on a regular basis during the treatment with AYVAKYT in patients with Advanced SM. See also intracranial haemorrhages above in this section and in section 4.8 of the prescribing information.

Treatment with AYVAKYT is associated in patients with Advanced SM with elevations in bilirubin and liver transaminases. Liver function (transaminases and bilirubin) should be monitored regularly in patients with Advanced SM receiving AYVAKYT.

Co-administration with strong or moderate CYP3A inhibitors should be avoided because it may increase the plasma concentration of AYVAKYT. Co-administration with strong or moderate CYP3A inducers should be avoided because it may decrease the plasma concentrations of AYVAKYT.

Exposure to direct sunlight must be avoided or minimised, due to the phototoxicity risk associated with AYVAKYT. Patients must be instructed to use measures such as protective clothing and sunscreen with a high sun protection factor (SPF).

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet; that is to say it is essentially ‘sodium-free’.

Women of childbearing potential/contraception in males and females

Women of childbearing potential must be informed that AYVAKYT may cause foetal harm.

The pregnancy status of women of reproductive potential must be verified prior to initiating AYVAKYT treatment.

Women of childbearing potential must use effective contraception during treatment and for 6 weeks after the last dose of AYVAKYT. Males with female partners of childbearing potential must use effective contraception during treatment and for 2 weeks after the last dose of AYVAKYT.

Patients must be advised to contact their healthcare professional immediately if they become pregnant, or if pregnancy is suspected, while taking AYVAKYT.

Pregnancy

AYVAKYT is not recommended during pregnancy and in women of childbearing potential not using contraception.

If AYVAKYT is used during pregnancy or if the patient becomes pregnant while taking AYVAKYT, the patient must be advised of the potential risk to the foetus.

Breastfeeding

Breastfeeding must be discontinued during treatment with AYVAKYT and for 2 weeks following the final dose.

The safety profile of AYVAKYT at a starting dose of 200 mg was generally well tolerated in this heavily pre-treated patient population, with only a few patients discontinuing treatment due to adverse reactions

Reporting of adverse events

To report suspected adverse reactions, contact Blueprint Medicines (Netherlands) B.V. by calling +31 85 064 4001 or via email at MedInfoEurope@blueprintmedicines.com

Access the recommended dosing instructions for AYVAKYT in Advanced SM

AYVAKYT Dosing for Advanced SM

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the product SmPC for how to report adverse reactions.

References

  1. AYVAKYT® (avapritinib). Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/ayvakyt-epar-product-information_en.pdf. Accessed February 2024.
  2. Gotlib J, et al. Nat Med. 2021;27(12):2192–2199.
  3. DeAngelo DJ, et al. Nat Med. 2021;27(12):2183–2191.

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