4.1. Therapeutic indications

Unresectable or metastatic gastrointestinal stromal tumour (GIST)

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.

Advanced systemic mastocytosis (AdvSM)

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).

4.2. Posology and method of administration

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).

Posology for GIST

Patient selection for treatment of unresectable or metastatic GIST harbouring the PDGFRA D842V mutation should be based on a validated test method.

The recommended starting dose of avapritinib is 300 mg orally once daily, on an empty stomach (see Method of administration). The dose should be adjusted based on safety and tolerability.

Treatment should be continued until disease progression or unacceptable toxicity.

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 should be reduced from 300 mg orally to 100 mg orally once daily (see section 4.5).

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.

Treatment with avapritinib is not recommended in patients with a platelet count of less than 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).

Dose modifications for adverse reactions

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 and AdvSM 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)

First

200 mg once daily

100 mg once daily

Second

100 mg once daily

50 mg once daily

Third

-

25 mg once daily

Table 2. Recommended dose modifications for AYVAKYT for adverse reactions

Adverse reaction

Severity*

Dose modification

Patients with GIST or AdvSM

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

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). If the dose has not been taken at least 8 hours prior to the next dose, then that dose should be omitted and the patient should resume treatment with the next scheduled dose.

If vomiting occurs after taking a dose of avapritinib, the patient should not take an additional dose but continue with the next scheduled dose.

Special populations

Elderly

No dose adjustment is recommended for patients aged 65 years and above (see section 5.2).

Hepatic impairment

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, and from 200 mg to 100 mg orally once daily for patients with AdvSM (see section 5.2).

Renal impairment

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).

Paediatric population

The safety and efficacy of AYVAKYT in children aged 0 to 18 years have not yet been established. No data are available.

Method of administration

AYVAKYT is for oral use.

The tablets should be taken on an empty stomach at least 1 hour before or at least 2 hours after a meal (see section 5.2).

Patients should swallow the tablet(s) whole with a glass of water.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

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 (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, phenprocoumon, rivaroxaban, dabigatran, apixaban and edoxaban) or other concomitant medicinal products that increase the risk of bleeding (including antiplatelet therapy).

Intracranial haemorrhages

Serious adverse reactions of intracranial haemorrhage were reported in patients with unresectable or metastatic GIST or AdvSM receiving avapritinib (see section 4.8). 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.

Patients who experience clinically relevant neurological signs and symptoms (e.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.

For patients with observed intracranial haemorrhage during treatment with avapritinib, in any indication, regardless of severity grade, avapritinib should 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).

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 in clinical studies (see section 4.8). Fatal events have occurred in <1% of patients. 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 can occur in patients with unresectable or metastatic GIST or AdvSM receiving avapritinib (see section 4.8). These include, but are not limited to, memory impairment, cognitive disorder, confusional state, and encephalopathy. 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, or difficulty with cognitive functioning. Patients with GIST or AdvSM should 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 should 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.

Fluid retention

Occurrences of fluid retention, including severe cases of localised oedema (facial, periorbital, peripheral oedema and/or pleural effusion), generalised oedemas and ascites, have been reported with a frequency category of at least common in patients with unresectable or metastatic GIST or AdvSM 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. For patients presenting with ascites, it is recommended to evaluate the aetiology of ascites.

QT interval prolongation

Prolongation of QT interval has been observed in patients with unresectable or metastatic GIST or 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 patients with known QT interval prolongation or at risk of QT interval prolongation (e.g. due to concomitant medicinal products that can prolong QT interval such as amiodarone, citalopram, escitalopram, ondansetron; 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.

Interval assessments of QT by electrocardiogram (ECG) should be considered if avapritinib 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 or AdvSM (see section 4.8). 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 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 (see section 4.8). Complete blood counts should be performed on a regular basis during the treatment with avapritinib in patients with GIST or AdvSM (see also the guidance under intracranial haemorrhages above in this section).

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, 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 should be avoided or minimised due to the risk of phototoxicity associated with avapritinib. 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”.

4.5. Interaction with other medicinal products and other forms of interaction

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 Cmax by 1.4-fold and AUC0-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 orally to 100 mg orally once daily for patients with GIST and from 200 mg to 50 mg orally once daily for patients with AdvSM (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 Cmax by 74% and AUC0-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

Co-administration of avapritinib 300 mg once daily with oral midazolam, a sensitive substrate for CYP3A4, increased the midazolam AUC and Cmax by 51% and 20%, respectively, in a clinical study. These results indicate that avapritinib 300 mg once daily is a weak inhibitor of CYP3A. Physiologically based pharmacokinetic simulations predict that avapritinib 200 mg once daily administered to patients with GIST is a weak inhibitor of CYP3A4. No inhibition is predicted in patients with AdvSM administered with the recommended dose of avapritinib.

Caution should be exercised with co-administration of avapritinib with medicinal products that can increase the risk of QT prolongation (e.g. amiodarone, citalopram, escitalopram, ondansetron).

In a drug-drug interaction study of 15 subjects, co-administration of avapritinib 25 mg once daily with a combined oral contraceptive (levonorgestrel 0.15 mg/ethinyl estradiol 0.03 mg) resulted in a mean ethinyl estradiol AUC ratio of 1.15 (90% confidence interval [CI]: 1.04, 1.28) and a mean ethinyl estradiol Cmax ratio of 1.46 (90% CI: 1.17, 1.81) relative to participants administered the combined oral contraceptive alone. This increase in ethinyl estradiol Cmax may lead to an increased risk of ethinyl estradiol-related adverse reactions in patients receiving avapritinib at doses greater than 25 mg once daily, such as headache, nausea and breast tenderness.

If the patient is unable to use or tolerate an effective nonhormonal contraceptive or an effective hormonal contraceptive without estrogen, use a formulation of ethinyl estradiol containing 20 mcg or less unless a higher dose is necessary.

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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

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 avapritinib treatment.

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

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

Pregnancy

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

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

If avapritinib is used during pregnancy or if the patient becomes pregnant while taking avapritinib, 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 avapritinib and for 2 weeks following the final dose.

Fertility

There are no data on the effect of avapritinib 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).

4.7. Effects on ability to drive and use machines

Avapritinib 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.

4.8. Undesirable effects

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, as well as 193 patients enrolled in studies for AdvSM (all doses), of which 126 patients received avapritinib at a starting dose of 200 mg, 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.

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).

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

System Organ Class / frequency category

Adverse reactions

All grades

%

Grades ≥3

%

Infections and infestations

Common

Conjunctivitis

2.0

-

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon

Tumour haemorrhage

0.2

0.2

Blood and lymphatic system disorders

Very common

Anaemia

White blood cell count decreased

Neutrophil count decreased

39.6

14.0

15.8

20.4

3.1

8.9

Common

Thrombocytopenia

Lymphocyte count decreased

8.4

4.7

0.9

2.2

Metabolism and nutrition disorders

Very common

Decreased appetite

21.1

0.5

Common

Hypophosphataemia

Hypokalaemia

Hypomagnesaemia

Hyponatraemia

Dehydration

Hypoalbuminaemia

Hypocalcaemia

8.9

6.0

3.8

1.3

1.8

2.4

2.2

2.5

0.9

0.4

0.7

0.5

-

0.4

Psychiatric disorders

Common

Confusional state

Depression

Anxiety

Insomnia

4.7

4.2

1.8

3.8

0.5

0.4

-

-

Nervous system disorders

Very common

Memory impairment

Cognitive disorder

Dizziness

Taste effect

22.7

11.8

10.5

12.7

0.9

0.9

0.2

-

Common

Intracranial haemorrhage1

Mental impairment2

Neuropathy peripheral

Somnolence

Aphasia

Hypokinesia

Headache

Balance disorder

Speech disorder

Tremor

1.6

5.6

8.5

1.8

1.8

1.3

8.0

1.6

4.5

2.2

1.1

0.7

0.4

-

-

0.2

0.2

-

-

0.2

Uncommon

Encephalopathy

0.9

0.5

Eye disorders

Very common

Lacrimation increased

22.2

-

Common

Ocular haemorrhage3

Vision blurred

Conjunctival haemorrhage

Photophobia

1.1

2.9

2.4

1.6

-

-

-

-

Ear and labyrinth disorders

Common

Vertigo

2.4

-

Cardiac disorders

Uncommon

Pericardial effusion

0.9

0.2

Vascular disorders

Common

Hypertension

3.3

1.1

Respiratory, thoracic and mediastinal disorders

Common

Pleural effusion

Dyspnoea

Nasal congestion

Cough

6.0

6.0

1.5

2.2

0.9

0.7

-

-

Gastrointestinal disorders

Very common

Abdominal pain

Vomiting

Diarrhoea

Nausea

Dryness

Gastrooesophageal reflux disease

10.9

24.2

26.4

45.1

10.9

12.9

1.1

0.7

2.7

1.5

0.2

0.5

Common

Gastrointestinal haemorrhage4

Ascites

Constipation

Dysphagia

Stomatitis

Flatulence

Salivary hypersecretion

2.2

7.5

5.8

2.4

2.4

1.6

1.5

1.6

1.3

-

0.4

-

-

-

Hepatobiliary disorders

Very common

Hyperbilirubinaemia

27.5

5.8

Uncommon

Hepatic haemorrhage

0.2

0.2

Skin and subcutaneous tissue disorders

Very common

Hair colour changes

Rash

15.3

12.7

0.2

1.6

Common

Palmar-plantar erythrodysaesthesia syndrome

Photosensitivity reaction

Skin hypopigmentation

Pruritus

Alopecia

1.3

1.1

1.1

2.9

9.6

-

-

-

-

-

Musculoskeletal and connective tissue disorders

Common

Myalgia

Arthralgia

Back pain

Muscle spasms

2.0

1.8

1.1

1.6

-

-

-

-

Renal and urinary disorders

Common

Acute kidney injury

Blood creatinine increased

Haematuria

2.0

4.4

1.1

0.9

-

-

General disorders and administration site conditions

Very common

Oedema5

Fatigue

70.2

39.6

4.7

5.3

Common

Asthenia

Pyrexia

Malaise

Feeling cold

7.8

1.8

2.5

2.9

1.6

0.2

0.2

-

Investigations

Very common

Transaminases increased

12.4

0.9

Common

Electrocardiogram QT prolonged

Blood creatine phosphokinase increased

Weight decreased

Weight increased

Blood lactate dehydrogenase increased

2.0

3.3

7.5

4.7

1.3

0.2

0.4

0.2

-

-

1Intracranial haemorrhage (including Cerebral haemorrhage, Haemorrhage intracranial, Subdural haematoma, Cerebral haematoma)

2Mental impairment (including Disturbance in attention, Mental impairment, Mental status changes, Dementia)

3Ocular haemorrhage (including Eye haemorrhage, Retinal haemorrhage, Vitreous haemorrhage)

4Gastrointestinal haemorrhage (including Gastric haemorrhage, Gastrointestinal haemorrhage, Upper gastrointestinal haemorrhage, Rectal haemorrhage, Melaena)

5Oedema (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

System Organ Class / frequency category

Adverse reactions

All grades

%

Grades ≥3

%

Blood and lymphatic system disorders

Very common

Thrombocytopenia*

46.8

23.0

Anaemia*

23.0

11.9

Neutropenia*

21.4

19.0

Common

Leukopenia*

8.7

2.4

Nervous system disorders

Very common

Cognitive effects1

18.3

1.6

Taste effect*

15.9

0.8

Common

Headache

7.9

-

Dizziness

5.6

-

Neuropathy peripheral2

4.8

-

Intracranial haemorrhage3

2.4

0.8

Eye disorders

Common

Lacrimation increased

6.3

-

Cardiac disorders

Uncommon

Pericardial effusion

0.8

-

Respiratory, thoracic and mediastinal disorders

Common

Epistaxis

5.6

-

Pleural effusion

2.4

-

Gastrointestinal disorders

Very common

Diarrhoea

14.3

1.6

Nausea

12.7

-

Common

Vomiting*

8.7

0.8

Gastroesophageal reflux disease*

4.8

-

Ascites*

4.0

0.8

Dryness*

4.0

-

Constipation

3.2

-

Abdominal pain*

3.2

-

Gastrointestinal haemorrhage4

2.4

1.6

Hepatobiliary disorders

Common

Hyperbilirubinaemia*

7.9

0.8

Skin and subcutaneous tissue disorders

Very common

Hair colour changes

15.1

-

Common

Rash*

7.9

0.8

Alopecia

7.1

-

Uncommon

Photosensitivity reaction

0.8

-

Musculoskeletal and connective tissue disorders

Common

Arthralgia

4.8

0.8

General disorders and administration site conditions

Very common

Oedema5

69.8

4.8

Fatigue*

18.3

2.4

Common

Pain

3.2

-

Investigations

Common

Weight increased

6.3

-

Blood alkaline phosphatase increased

4.8

1.6

Transaminases increased*

4.8

-

Electrocardiogram QT prolonged

1.6

0.8

Injury, poisoning and procedural complications

Common

Contusion

3.2

-

1Cognitive effects (including cognitive disorder, memory impairment and confusional state)

2Neuropathy peripheral (including Paraesthesia, Neuropathy peripheral, Hypoaesthesia)

3Intracranial haemorrhage (including Haemorrhage intracranial, Subdural haematoma)

4Gastrointestinal haemorrhage (including Gastric haemorrhage, Gastrointestinal haemorrhage, Melaena)

5Oedema (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

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

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

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 2.5% of the 121 patients with AdvSM with platelet counts of ≥50 x 109/L prior to initiation of therapy who received avapritinib at the recommended starting dose of 200 mg.

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

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; 1.6% of these events were Grade 3. Memory impairment occurred in 6% of patients; none of these events were Grade 3. Confusional state occurred in 2% of patients; none of these events were Grade 3. No Grade 4 and no fatal events were reported.

Of the 126 AdvSM patients treated at a starting dose of 200 mg one patient (<1%) required permanent discontinuation of avapritinib for a cognitive adverse reaction, 7% required a dose interruption, and 6% required dose reduction.

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

Elderly

Unresectable or metastatic GIST

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%).

Advanced systemic mastocytosis

Of the 126 patients with AdvSM who received avapritinib at a starting dose of 200 mg once daily in EXPLORER and in PATHFINDER, 63% were 65 years or older and 21% were 75 years of age or 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%).

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 Yellow Card Scheme at https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

There is limited experience with cases of overdoses 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 the recommended doses for both indications (see section 4.8).

Management

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.