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

Haemorrhages

In patients with unresectable or metastatic GIST, avapritinib has been associated with an increased incidence of haemorrhagic events, including serious and severe events, like gastrointestinal haemorrhage, hepatic, tumour and intracranial haemorrhages. Gastrointestinal haemorrhagic events were the most commonly reported haemorrhagic events during avapritinib treatment (see section 4.8).

Routine surveillance of haemorrhagic events should include physical examination, and blood counts and coagulation parameters should be monitored, 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

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.

Before initiating AYVAKYT the risk for intracranial haemorrhage should be carefully considered in patients with risk factors such as severe thrombocytopenia, and in patients with increased risk of intracranial haemorrhage such as those with a vascular aneurysm or a history of intracranial haemorrhage within the prior year, a history of a cerebrovascular accident or transient ischaemic attack. Patients who experience clinically relevant neurological signs and symptoms (e.g. severe headache, vision problems, somnolence, or focal weakness) during treatment with AYVAKYT should 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, regardless of Grade, avapritinib should be permanently discontinued (see section 4.2).

There is no clinical trial experience using AYVAKYT in patients with brain metastases.

Cognitive effects

Cognitive effects can occur in patients with unresectable or metastatic GIST receiving AYVAKYT (see section 4.8). These include 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.

For patients with observed cognitive effects related to treatment with AYVAKYT, the recommended dose modification in Table 1 should be followed (see section 4.2). In clinical trials, 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) 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).

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.

QT interval prolongation

Prolongation of QT interval has been observed in patients with unresectable or metastatic GIST treated with avapritinib in clinical trials. QT interval prolongation may induce an increased risk of ventricular arrhythmias, including Torsade de pointes.

AYVAKYT should be used with caution in 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 moderate or strong 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.

Interval assessments of QT by ECG should be considered if AYVAKYT is taken concurrently with medicinal products that can prolong QT interval.

Gastrointestinal disorders

Diarrhoea, nausea and vomiting were the most commonly reported gastrointestinal adverse reactions in patients with unresectable or metastatic GIST (see section 4.8). 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.

Laboratory tests

Treatment with avapritinib in patients with unresectable or metastatic GIST is associated with anaemia, neutropenia and thrombocytopenia (see section 4.8). Complete blood counts should be performed on a regular basis during the treatment with AYVAKYT. Treatment with avapritinib is associated in patients with unresectable or metastatic GIST with elevations in bilirubin and liver transaminases (see section 4.8). Liver function (transaminases, bilirubin) should be monitored regularly in patients receiving AYVAKYT.

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 should be avoided or minimised due to the risk of phototoxicity associated with AYVAKYT. Patients should 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 AYVAKYT

Strong and moderate CYP3A inhibitors

Co-administration of AYVAKYT 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 AYVAKYT should be reduced from 300 mg orally once daily to 100 mg orally once daily (see section 4.2 and 4.4).

Strong and moderate CYP3A inducers

Co-administration of AYVAKYT with a strong CYP3A inducer decreased avapritinib plasma concentrations and may result in decreased efficacy of avapritinib. Co-administration of rifampin (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 AYVAKYT 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 Worth) should be avoided.

Effect of AYVAKYT 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 should 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

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

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

Women of childbearing potential should use effective contraception during treatment and for 1 month after the last dose of AYVAKYT.

Patients should 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 should 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 should 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. No relevant effects on fertility were observed in a rat fertility study (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 should 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, see section 5.1.

The most frequently reported adverse reactions of any Grade during treatment with AYVAKYT 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.

Tabulated list of adverse reactions

Adverse reactions that were reported in clinical trials in ≥1% of patients are listed below (Table 2) 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.

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 2. Adverse reactions reported in clinical trials in patients treated with AYVAKYT:

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.

Description of selected adverse reactions

Intracranial haemorrhage

Intracranial haemorrhage (e.g., subdural hematoma, intracranial haemorrhage, cerebral haemorrhage, and cerebral haematoma) 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 AYVAKYT 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 AYVAKYT, 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.

Cognitive effects

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 AYVAKYT 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 AYVAKYT 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.

Elderly

In NAVIGATOR and VOYAGER (N=550), 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%).

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.