AYVAKYT Film-coated tablet Ref.[27915] Active ingredients: Avapritinib

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 and AdvSM. Gastrointestinal haemorrhagic adverse reactions were the most commonly reported haemorrhagic adverse reactions during avapritinib treatment of unresectable or metastatic GIST patients, while hepatic and tumour haemorrhage also occurred in GIST patients (see section 4.8).

Routine surveillance of haemorrhagic adverse reactions in patients with GIST or AdvSM must include physical examination. Complete blood counts, including platelets, and coagulation parameters must be monitored in patients with GIST or AdvSM, 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.

Intracranial haemorrhages

Adverse reactions of intracranial haemorrhage occurred in GIST and AdvSM patients who received avapritinib.

Before initiating avapritinib 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 avapritinib must interrupt dosing of avapritinib 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 avapritinib in any indication, regardless of severity grade, avapritinib must be permanently discontinued (see section 4.2).

Unresectable or metastatic GIST

Serious adverse reactions of intracranial haemorrhage were reported in patients with unresectable or metastatic GIST receiving avapritinib (see section 4.8). The exact mechanism is unknown.

There is no clinical study experience using avapritinib in patients with brain metastases.

Advanced systemic mastocytosis

Serious adverse reactions of intracranial haemorrhage were reported in patients with AdvSM receiving avapritinib (see section 4.8). 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. 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. Platelet support may be necessary, and the recommended dose modification in Table 2 must be followed (see section 4.2). 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.

Cognitive effects

Cognitive effects, such as memory impairment, cognitive disorder, confusional state, and encephalopathy, can occur in patients receiving avapritinib (see section 4.8). The mechanism of the cognitive effects is not known.

It is recommended that patients with GIST or AdvSM 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 GIST or AdvSM must notify their healthcare professional immediately if they experience new or worsening cognitive symptoms.

For GIST or AdvSM patients with observed cognitive effects related to treatment with avapritinib, the recommended dose modification in Table 2 must be followed (see section 4.2). In clinical studies conducted in patients with GIST and AdvSM, dose reductions or interruptions improved Grade ≥2 cognitive effects compared to no action.

In patients with ISM, cognitive effects can be one of the disease symptoms. Patients with ISM must notify their healthcare professional if they experience new or worsening cognitive symptoms.

Fluid retention

Occurrences of fluid retention, including severe cases of localised oedema (facial, periorbital, peripheral oedema and/or pleural effusion) or generalised oedemas, have been reported with a frequency category of at least common in patients with unresectable or metastatic GIST taking avapritinib. Other localised oedemas (laryngeal oedema and/or pericardial effusion) have been reported uncommonly (see section 4.8).

In patients with AdvSM, 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 (see section 4.8). Other localised oedemas (laryngeal oedema) have been reported uncommonly.

Therefore, it is recommended that patients with GIST or AdvSM 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 GIST or AdvSM patients presenting with ascites, it is recommended to evaluate the aetiology of ascites.

In patients with ISM, localised (peripheral, facial) oedemas have been reported with a frequency category of at least common (see section 4.8).

QT interval prolongation

Prolongation of QT interval has been observed in patients with unresectable or metastatic GIST and AdvSM treated with avapritinib in clinical studies (see section 4.8 and 5.1). QT interval prolongation may induce an increased risk of ventricular arrhythmias, including Torsade de pointes.

Avapritinib should be used with caution in GIST or AdvSM 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 (see section 4.5). If concomitant use of moderate CYP3A4 inhibitors cannot be avoided, see section 4.2 for dose modification instructions.

In patients with GIST or AdvSM, interval assessments of QT by electrocardiogram (ECG) should be considered if avapritinib is taken concurrently with medicinal products that can prolong QT interval.

In patients with ISM, QT interval assessments by ECG should be considered, in particular in patients with concurrent factors that could prolong QT (e.g. age, pre-existing heart rhythm disorders, etc.).

Gastrointestinal disorders

Diarrhoea, nausea and vomiting were the most commonly reported gastrointestinal adverse reactions in patients with unresectable or metastatic GIST and AdvSM (see section 4.8). GIST or AdvSM 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 GIST or AdvSM patients experiencing gastrointestinal adverse reactions must be closely monitored and treated as per standard clinical practice.

Laboratory tests

Treatment with avapritinib in patients with unresectable or metastatic GIST and AdvSM is associated with anaemia, neutropenia and/or thrombocytopenia. Complete blood counts must be performed on a regular basis during the treatment with avapritinib in patients with GIST or AdvSM. See also intracranial haemorrhages above in this section and in section 4.8.

Treatment with avapritinib is associated in patients with unresectable or metastatic GIST and AdvSM with elevations in bilirubin and liver transaminases (see section 4.8). Liver function (transaminases and bilirubin) should be monitored regularly in patients with GIST or AdvSM receiving avapritinib.

CYP3A4 inhibitors and inducers

Co-administration with strong or moderate CYP3A inhibitors should be avoided because it may increase the plasma concentration of avapritinib (see sections 4.2 and 4.5).

Co-administration with strong or moderate CYP3A inducers should be avoided because it may decrease the plasma concentrations of avapritinib (see section 4.5).

Photosensitivity reaction

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

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially "sodium-free".

Active substances that may have an effect on avapritinib

Strong and moderate CYP3A inhibitors

Co-administration of avapritinib with a strong CYP3A inhibitor increased avapritinib plasma concentrations and may result in increased adverse reactions. Co-administration of itraconazole (200 mg twice daily on Day 1 followed by 200 mg once daily for 13 days) with a single 200 mg dose of avapritinib on Day 4 in healthy subjects increased avapritinib C_max by 1.4-fold and AUC_0-inf by 4.2-fold, relative to a 200 mg dose of avapritinib administered alone.

Concomitant use of avapritinib with strong or moderate CYP3A inhibitors (such as antifungals including ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides such as erythromycin, clarithromycin and telithromycin; active substances to treat human immunodeficiency virus infections/acquired immunodeficiency syndrome (HIV/AIDS) such as cobicistat, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir; as well as conivaptan for hyponatremia and boceprevir to treat hepatitis) including grapefruit or grapefruit juice should be avoided. If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the starting dose of avapritinib should be reduced from 300 mg to 100 mg orally once daily for patients with GIST, and from 200 mg to 50 mg orally once daily for patients with AdvSM. For patients with ISM, concomitant use of avapritinib with strong or moderate CYP3A inhibitors must be avoided (see sections 4.2 and 4.4).

Strong and moderate CYP3A inducers

Co-administration of avapritinib with a strong CYP3A inducer decreased avapritinib plasma concentrations and may result in decreased efficacy of avapritinib. Co-administration of rifampicin (600 mg once daily for 18 days) with a single 400 mg dose of avapritinib on Day 9 in healthy subjects decreased avapritinib C_max by 74% and AUC_0-inf by 92%, relative to a 400 mg dose of avapritinib administered alone.

Co-administration of avapritinib with strong and moderate CYP3A inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone, bosentan, efavirenz, etravirine, modafinil, dabrafenib, nafcillin or Hypericum perforatum, also known as St. John's wort) should be avoided.

Effect of avapritinib on other active substances

In vitro studies demonstrated that avapritinib is a direct inhibitor of CYP3A and a time-dependent inhibitor of CYP3A. Therefore, avapritinib may have the potential to increase plasma concentrations of co-administered medicinal products that are substrates of CYP3A.

In vitro studies indicated that avapritinib is an inducer of CYP3A. Therefore, avapritinib may have the potential to decrease plasma concentrations of co-administered medicinal products that are substrates of CYP3A.

Caution must be exercised with co-administration of avapritinib with narrow therapeutic index CYP3A substrates as their plasma concentrations may be altered.

Avapritinib is an inhibitor of P-gp, BCRP, MATE1, MATE2-K, and BSEP in vitro. Therefore, avapritinib has the potential to alter concentrations of co-administered substrates of these transporters.

Women of childbearing potential / Contraception in males and females

Women of childbearing potential must be informed that avapritinib may cause foetal harm (see section 5.3).

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

There are no data from the use of avapritinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

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.

Breast-feeding

It is unknown whether avapritinib/metabolites are excreted in human milk.

A risk to the newborns/infants cannot be excluded.

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

Fertility

There are no data on the effect of AYVAKYT on human fertility. However, based on nonclinical findings in animals, male and female fertility may be compromised by treatment with avapritinib (see section 5.3).

AYVAKYT may cause adverse reactions such as cognitive effects that may influence the ability to drive and use machines.

Patients should be made aware of the potential for adverse reactions that affect their ability to concentrate and react. Patients who experience these adverse effects must take special care when driving a car or operating machinery.

Summary of the safety profile

The safety database includes a total of 585 patients with GIST (all doses), of which 550 patients received avapritinib at a starting dose of 300 mg or 400 mg; 193 patients enrolled in studies for AdvSM (all doses), of which 126 patients received avapritinib at a starting dose of 200 mg, and 246 patients with ISM (doses 25 mg – 100 mg), of which 141 patients received avapritinib at the recommended dose of 25 mg in Part 2, pivotal part of the PIONEER study (see section 5.1).

Unresectable or metastatic GIST

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.

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%).

In AdvSM patients treated at 200 mg, 7.1% had adverse reactions leading to permanent treatment discontinuation. In two patients (1.6%), subdural haematoma occurred. Cognitive disorder, depressed mood, diarrhoea, disturbance in attention, haemoglobin decreased, hair colour changes, libido decreased, nausea, neutropenia, premature menopause and thrombocytopenia occurred in one patient (0.8% 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.

Tabulated list of adverse reactions

Adverse reactions that were reported in clinical studies in ≥1% of patients with GIST are listed below (Table 3) except for adverse reactions mentioned in the section 4.4 which are included regardless of frequency, according to the MedDRA System Organ Class and frequency. For patients with AdvSM, adverse reactions that were reported in clinical studies in ≥3% of patients are listed below (Table 4). For patients with ISM, adverse reactions reported in Part 2 of the PIONEER study in ≥5% of patients are listed in Table 5.

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.

Unresectable or metastatic GIST

Table 3. Adverse reactions reported in clinical studies in patients with unresectable or metastatic GIST treated with avapritinib:

¹ Intracranial haemorrhage (including Cerebral haemorrhage, Haemorrhage intracranial, Subdural haematoma, Cerebral haematoma)
² Mental impairment (including Disturbance in attention, Mental impairment, Mental status changes, Dementia)
³ Ocular haemorrhage (including Eye haemorrhage, Retinal haemorrhage, Vitreous haemorrhage)
⁴ Gastrointestinal haemorrhage (including Gastric haemorrhage, Gastrointestinal haemorrhage, Upper gastrointestinal haemorrhage, Rectal haemorrhage, Melaena)
⁵ Oedema (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

Advanced systemic mastocytosis

Table 4. Adverse reactions reported in clinical studies in patients with advanced systemic mastocytosis treated with avapritinib starting at 200 mg:

¹ Neuropathy peripheral (including Paraesthesia, Neuropathy peripheral, Hypoaesthesia)
² Intracranial haemorrhage (including Haemorrhage intracranial, Subdural haematoma)
³ Gastrointestinal haemorrhage (including Gastric haemorrhage, Gastrointestinal haemorrhage, Melaena)
⁴ Oedema (including Periorbital oedema, Oedema peripheral, Face oedema, Eyelid oedema, Fluid retention, Generalised oedema, Oedema, Peripheral swelling, Swelling face, Eye swelling, Conjunctival oedema, Laryngeal oedema, Localised oedema)
^* Comprises pooled terms representing similar medical concepts.
-: no adverse reactions reported

Indolent systemic mastocytosis

Table 5. Adverse reactions reported in clinical studies in patients with indolent systemic mastocytosis:

¹ Peripheral oedema (including oedema peripheral and peripheral swelling)
-: no adverse reactions reported

Description of selected adverse reactions

Intracranial haemorrhage

Unresectable or metastatic GIST

Intracranial haemorrhage occurred in 10 (1.7%) of the 585 patients with GIST (all doses) and in 9 (1.6%) of the 550 patients with GIST who received avapritinib at a starting dose of 300 mg or 400 mg once daily (see section 4.4).

Events of intracranial haemorrhage (all grades) occurred in a range from 8 weeks to 84 weeks after initiating avapritinib, with a median time to onset of 22 weeks. The median time to improvement and resolution was 25 weeks for intracranial haemorrhage of Grade ≥2.

Advanced systemic mastocytosis

Intracranial haemorrhage occurred in a total (regardless of causality) of 4 (3.2%) of the 126 patients with AdvSM who received avapritinib at a starting dose of 200 mg once daily regardless of platelet count prior to initiation of therapy. In 3 of these 4 patients, the event was assessed as related to avapritinib (2.4%). The risk of intracranial haemorrhagic events is higher in patients with platelet counts <50 x 10⁹/L. Intracranial haemorrhage occurred in a total (regardless of causality) of 3 (2.5%) of the 121 patients with AdvSM who received a starting dose of 200 mg once daily and had a platelet count ≥50 x 10⁹/L prior to initiation of therapy (see section 4.4). In 2 of the 3 patients, the event was assessed as related to avapritinib (1.7 %). Of 126 patients treated with the recommended starting dose of 200 mg once daily, 5 had platelet counts <50 x 10⁹/L prior to initiation of therapy, of which one patient experienced an intracranial haemorrhage.

Events of intracranial haemorrhage (all grades) occurred in a range from 12.0 weeks to 15.0 weeks after initiating avapritinib, with a median time to onset of 12.1 weeks.

In clinical studies with avapritinib, the incidence of intracranial haemorrhage was higher in patients who received a starting dose of ≥300 mg once daily, as compared to patients who received the recommended starting dose of 200 mg once daily. Of the 50 patients who received a starting dose of ≥300 mg once daily, 8 (16.0%) experienced an event (regardless of causality) of intracranial bleeding regardless of platelet count prior to initiation of therapy. In 6 of the 8 patients, the event was assessed as related to avapritinib (12.0%). Of these 50 patients, 7 had platelet counts <50 x 10⁹/L prior to initiation of therapy, of which 4 patients experienced an intracranial haemorrhage, that were assessed as related to avapritinib in 3 of 4 cases. Four of 43 patients with platelet counts ≥50 x 10⁹/L prior to initiation of therapy experienced an intracranial haemorrhage, which were assessed as related to avapritinib in 3 of 4 cases.

Fatal events of intracranial haemorrhage have occurred in less than 1% of patients with AdvSM (all doses).

The maximum dose for patients with AdvSM must not exceed 200 mg once daily.

Indolent systemic mastocytosis

No intracranial haemorrhages were reported in 141 patients with ISM receiving 25 mg of avapritinib during the 24-week duration of Part 2 of the PIONEER study.

Cognitive effects

A broad spectrum of cognitive effects that are generally reversible (with intervention) can occur in patients receiving avapritinib. Cognitive effects were managed with dose interruption and/or reduction, and 2.7% led to permanent discontinuation of avapritinib treatment in patients with GIST and AdvSM.

Unresectable or metastatic GIST

Cognitive effects occurred in 194 (33%) of the 585 patients with GIST (all doses) and in 182 (33%) of the 550 patients with GIST who received avapritinib at starting doses of either 300 or 400 mg once daily (see section 4.4). In the patients who had an event (any grade), the median time to onset was 8 weeks.

Most cognitive effects were Grade 1, with Grade ≥2 occurring in 11% of 550 patients. Among patients who experienced a cognitive effect of Grade ≥2 (impacting activities of daily living) the median time to improvement was 15 weeks.

Memory impairment occurred in 20% of patients, <1% of these events were Grade 3. Cognitive disorder occurred in 12% of patients; <1% of these events were Grade 3. Confusional state occurred in 5% of patients; <1% of these events were Grade 3. Encephalopathy occurred in <1% of patients; <1% of these events were Grade 3. Serious adverse reactions of cognitive effects were reported for 9 of 585 (1.5%) of the GIST patients (all doses), of which 7 of the 550 (1.3%) patients were observed in the GIST group receiving a starting dose of either 300 or 400 mg once daily.

Overall, 1.3% of patients required permanent discontinuation of avapritinib for a cognitive effect.

Cognitive effects occurred in 37% of the patients aged ≥65 years receiving a starting dose of either 300 or 400 mg once daily.

Advanced systemic mastocytosis

Cognitive effects occurred in 51 (26%) of the 193 patients with AdvSM (all doses) and in 23 (18%) of the 126 patients with AdvSM who received avapritinib at a starting dose of 200 mg (see section 4.4). In the patients with AdvSM treated at a starting dose of 200 mg who had an event (any grade), the median time to onset was 12 weeks (range: 0.1 weeks to 108.1 weeks).

Most cognitive effects were Grade 1, with Grade ≥2 occurring in 7% of 126 patients treated at a starting dose of 200 mg. Among patients who experienced a cognitive effect of Grade ≥2 (impacting activities of daily living) the median time to improvement was 6 weeks.

For patients with AdvSM treated at a starting dose of 200 mg, cognitive disorder occurred in 12% of patients, memory impairment occurred in 6% of patients and confusional state occurred in 2% of patients. None of these events were Grade 4.

Serious adverse reactions of cognitive effects were reported for 1 of 193 (<1%) AdvSM patients (all doses), none were observed in the AdvSM group receiving a starting dose of 200 mg once daily.

Overall, 1.6% of AdvSM patients (all doses) required permanent discontinuation of avapritinib for a cognitive adverse reaction, 8% required a dose interruption, and 9% required dose reduction.

Cognitive effects occurred in 20% of the patients aged ≥65 years receiving a starting dose of 200 mg once daily.

Indolent systemic mastocytosis

In Part 2 of the PIONEER study, cognitive effects occurred in 2.8% of patients with ISM who received 25 mg of avapritinib (see section 4.4); all cognitive effects were Grade 1 or 2. Overall, none of the patients who received avapritinib in Part 2 of PIONEER required permanent treatment discontinuation for cognitive effects.

Anaphylactic adverse reactions

Indolent systemic mastocytosis

Anaphylaxis is a common clinical manifestation of ISM. In Part 2 of the PIONEER study, patients who received 25 mg of avapritinib had fewer episodes of anaphylaxis over time (5% during the ~8-week screening period versus 1% during Part 2).

Elderly

Unresectable or metastatic GIST

In NAVIGATOR and VOYAGER (N=550) (see section 5.1), 39% of patients were 65 years of age and older, and 9% were 75 years of age and older. Compared with younger patients (<65), more patients ≥65 years old had reported adverse reactions that led to dose reductions (55% versus 45%) and dose discontinuation (18% versus 4%). The types of adverse reactions reported were similar regardless of age. Older patients reported more Grade 3 or higher adverse reactions compared to younger patients (63% versus 50%).

Advanced systemic mastocytosis

In patients treated at 200 mg in EXPLORER and PATHFINDER (N=126) (see section 5.1), 63% of patients were 65 years of age or older, and 21% were 75 years of age and older. Compared with younger patients (<65), more patients ≥65 years old reported adverse reactions that led to dose reductions (62% versus 73%). A similar fraction of patients reported adverse reactions that led to dose discontinuation (9% versus 6%). The types of adverse reactions reported were similar regardless of age. Older patients reported more Grade 3 or higher adverse reactions (63.3%) compared to younger patients (53.2%).

Indolent systemic mastocytosis

In Part 2 of PIONEER (N=141) (see section 5.1), 9 (6%) patients were 65 years of age or older, and 1 (<1%) patient was 75 years of age or older. No patients over the age of 84 were included. Overall, no meaningful differences in safety were observed between patients ≥65 years and those <65 years.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.