Ayvakyt · 4.6 Fertility, pregnancy and lactation · 1

HOS-287867 · has-adverse-reaction-information · PDF-Seite 10

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%). 10 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

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HOS-287863 · has-contraindication-information · PDF-Seite 6

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

HOS-287862 · has-indication-information · PDF-Seite 3

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), after at least one systemic therapy. Indolent systemic mastocytosis (ISM) AYVAKYT is indicated for the treatment of adult patients with indolent systemic mastocytosis (ISM) with moderate to severe symptoms inadequately controlled on symptomatic treatment (see section 5.1).

HOS-287865 · has-interaction-information · PDF-Seite 9

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 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 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 increased the midazolam AUC and Cmax by 51% and 20%, respectively. These results indicate that avapritinib 300 mg o

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HOS-287866 · has-pregnancy-information · PDF-Seite 9

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. 9 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).

HOS-287864 · has-warning-information · PDF-Seite 6

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 adv

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