Avapritinib

AYVAKIT is a kinase inhibitor indicated for: Gastrointestinal Stromal Tumor (GIST) the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. Advanced Systemic Mastocytosis (AdvSM) the treatment of adult patients with AdvSM. AdvSM includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). Limitations of Use: AYVAKIT is not recommended for the treatment of patients with AdvSM with platelet counts of less than 50 × 10 9 /L. Indolent Systemic Mastocytosis (ISM) the treatment of adult patients with ISM. Limitations of Use: AYVAKIT is not recommended for the treatment of patients with ISM with platelet counts of less than 50 × 10 9 /L

Avapritinib is a tyrosine kinase inhibitor that targets KIT D816V, PDGFRA and PDGFRA D842 mutants as well as multiple KIT exon 11, 11/17 and 17 mutants with half maximal inhibitory concentrations (IC 50s ) less than 25 nM in biochemical assays. Certain mutations in PDGFRA and KIT can result in the autophosphorylation and constitutive activation of these receptors which can contribute to tumor and mast cell proliferation. Other potential targets for avapritinib include wild type KIT, PDGFRB, and CSFR1. In cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V with an IC 50 of 4 nM, approximately 48-fold lower concentration than wild-type KIT. In cellular assays, avapritinib inhibited the proliferation in KIT mutant cell lines, including a murine mastocytoma cell line and a human mast cell leukemia cell line.

GIST: Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation. GIST: The recommended dosage is 300 mg orally once daily. AdvSM: The recommended dosage is 200 mg orally once daily. ISM: The recommended starting dosage is 25 mg orally once daily. Patients with severe hepatic impairment (Child-Pugh Class C): reduce dose of AYVAKIT.

None. None.

Intracranial Hemorrhage: Permanently discontinue for any occurrence of any grade. Cognitive Effects: A broad spectrum of cognitive adverse reactions can occur in patients receiving AYVAKIT. In patients with GIST, AdvSM, or ISM depending on the severity, continue AYVAKIT at same dose, withhold and then resume at same or reduced dose upon improvement, or permanently discontinue. Photosensitivity: May cause photosensitivity reactions. Advise patients to limit direct ultraviolet exposure. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception.

The following clinically significant adverse reactions are described elsewhere in the labeling: Intracranial hemorrhage Cognitive effects Photosensitivity The most common adverse reactions are: GIST (≥20% incidence): edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, increased lacrimation, abdominal pain, constipation, rash, dizziness, and hair color changes. AdvSM (≥20% incidence): edema, diarrhea, nausea, and fatigue/asthenia. ISM (≥10% incidence): eye edema, dizziness, peripheral edema and flushing.

Strong and Moderate CYP3A Inhibitors: Avoid coadministration of AYVAKIT with strong and moderate CYP3A inhibitors. If coadministration of AYVAKIT with a moderate inhibitor cannot be avoided, reduce dose of AYVAKIT in patients with GIST or AdvSM. Strong and Moderate CYP3A Inducers: Avoid coadministration of AYVAKIT with strong and moderate CYP3A inducers. Hormonal contraceptives containing ethinyl estradiol: See full prescribing information for dose-specific recommendations for concomitant use. CYP3A Substrates: Follow the recommendations in the approved product labeling for CYP3A substrates with a narrow therapeutic range when coadministered with AYVAKIT in patients with GIST

Store at 20°C to 25°C (68°F to 77°F), excursions are permitted from 15°C to 30°C (59°F to 86°F).