Avapritinib
FDA Drug Information • Also known as: Ayvakit
- Brand Names
- Ayvakit
- Drug Class
- Kinase Inhibitor [EPC]
- Route
- ORAL
- Dosage Form
- TABLET, FILM COATED
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION Avapritinib is a kinase inhibitor with the chemical name ( S )-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1 H -pyrazol-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-yl)piperazin-yl)pyrimidin-5-yl)ethan-1-amine. The molecular formula is C 26 H 27 FN 10 , and the molecular weight is 498.57 g/mol. Avapritinib has the following chemical structure: The solubility of avapritinib in 0.1N HCl (pH 1.0) and buffer solutions at pH 2.5, 4.0, and 7.0 (at 25°C) is 3.6 mg/mL, 0.14 mg/mL, 0.07 mg/mL and <0.001 mg/mL respectively, indicating a decrease in solubility with increasing pH. AYVAKIT (avapritinib) film-coated tablets for oral use are supplied with five strengths that contain 25 mg, 50 mg, 100 mg, 200 mg or 300 mg of avapritinib. The tablets also contain inactive ingredients: copovidone, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablet coating consists of polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The blue printing ink, used only for avapritinib 100 mg, 200 mg and 300 mg strength tablets, contains ammonium hydroxide, black iron oxide, esterified shellac, FD&C blue 1, isopropyl alcohol, n-butyl alcohol, propylene glycol, and titanium dioxide. Chemical Structure
What Is Avapritinib Used For?
1 INDICATIONS AND USAGE 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. ( 1.1 , 2.2 ) 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). ( 1.2 ) Limitations of Use: AYVAKIT is not recommended for the treatment of patients with AdvSM with platelet counts of less than 50 × 10 9 /L ( 1.2 ) Indolent Systemic Mastocytosis (ISM) the treatment of adult patients with ISM. ( 1.3 ) Limitations of Use: AYVAKIT is not recommended for the treatment of patients with ISM with platelet counts of less than 50 × 10 9 /L ( 1.2 ) 1.1 PDGFRA Exon 18 Mutation-Positive Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST) AYVAKIT ® is indicated for 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 [see Dosage and Administration (2.2) ] . 1.2 Advanced Systemic Mastocytosis (AdvSM) AYVAKIT is indicated for the treatment of adult patients with advanced systemic mastocytosis (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 [see Warnings and Precautions (5.1) ] . 1.3 Indolent Systemic Mastocytosis (ISM) AYVAKIT is indicated for the treatment of adult patients with indolent systemic mastocytosis (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 [see Warnings and Precautions (5.1) ] .
Dosage and Administration
2 DOSAGE AND ADMINISTRATION GIST: Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation. ( 2.2 ) GIST: The recommended dosage is 300 mg orally once daily. ( 2.2 ) AdvSM: The recommended dosage is 200 mg orally once daily. ( 2.3 ) ISM: The recommended dosage is 25 mg orally once daily. ( 2.4 ) Patients with severe hepatic impairment (Child-Pugh Class C): reduce dose of AYVAKIT. ( 2.7 ) 2.1 Recommended Administration Administer AYVAKIT orally on an empty stomach, at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3) ] . Do not make up for a missed dose within 8 hours of the next scheduled dose. Do not repeat dose if vomiting occurs after AYVAKIT but continue with the next scheduled dose. 2.2 GIST Harboring PDGFRA Exon 18 Mutations Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation [see Clinical Studies (14.1) ] . An FDA-approved test for the detection of exon 18 mutations is not currently available. The recommended dosage of AYVAKIT is 300 mg orally once daily in patients with GIST . Continue treatment until disease progression or unacceptable toxicity. 2.3 Advanced Systemic Mastocytosis The recommended dosage of AYVAKIT is 200 mg orally once daily in patients with AdvSM. Continue treatment until disease progression or unacceptable toxicity. 2.4 Indolent Systemic Mastocytosis The recommended dosage of AYVAKIT is 25 mg orally once daily in patients with ISM. 2.5 Dosage Modifications for Adverse Reactions The recommended dosage reductions and modifications for adverse reactions are provided in Tables 1 and 2. Table 1: Recommended Dosage Reductions for AYVAKIT for Adverse Reactions Dose Reduction Level Dosage in patients with GIST Permanently discontinue AYVAKIT in patients with GIST who are unable to tolerate a dose of 100 mg once daily. Dosage in patients with AdvSM Permanently discontinue AYVAKIT in patients with AdvSM who are unable to tolerate a dose of 25 mg once daily. First dose reduction 200 mg once daily 100 mg once daily Second dose reduction 100 mg once daily 50 mg once daily Third dose reduction - 25 mg once daily Table 2: Recommended Dosage Modifications for AYVAKIT for Adverse Reactions Adverse Reaction Severity Severity as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 Dosage Modification Patients with GIST or AdvSM Intracranial Hemorrhage [see Warnings and Precautions (5.1) ] Any grade Permanently discontinue AYVAKIT. Cognitive Effects [see Warnings and Precautions (5.2) ] Grade 1 Continue AYVAKIT at same dose or reduced dose or withhold until improvement to baseline or resolution. Resume at same dose or reduced dose. Grade 2 or Grade 3 Withhold AYVAKIT until improvement to baseline, Grade 1, or resolution. Resume at same dose or reduced dose. Grade 4 Permanently discontinue AYVAKIT. Other [see Adverse Reactions (6.1) ] Grade 3 or Grade 4 Withhold AYVAKIT until improvement...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Intracranial hemorrhage [see Warnings and Precautions (5.1) ] Cognitive effects [see Warnings and Precautions (5.2) ] Photosensitivity [see Warnings and Precautions (5.3) ] 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. ( 6.1 ) AdvSM (≥20% incidence): edema, diarrhea, nausea, and fatigue/asthenia. ( 6.1 ) ISM (≥10% incidence): eye edema, dizziness, peripheral edema and flushing. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Blueprint Medicines Corporation at 1-888-258-7768 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the WARNINGS AND PRECAUTIONS reflect exposure to AYVAKIT at 25 mg to 600 mg orally once daily in 995 patients enrolled in one of five clinicals trials conducted in patients with advanced malignancies and systemic mastocytosis, including NAVIGATOR, EXPLORER, PATHFINDER and PIONEER [see Clinical Studies (14.1 , 14.2 , 14.3) ]. These patients included 601 patients with GIST, 148 patients with AdvSM and 246 patients with ISM. Among the 995 patients receiving AYVAKIT, 54% were exposed for 6 months or longer and 26% were exposed for greater than 1 year. Gastrointestinal Stromal Tumors Unresectable or Metastatic GIST The safety of AYVAKIT in patients with unresectable or metastatic GIST was evaluated in NAVIGATOR [see Clinical Studies (14.1) ] . The trial excluded patients with history of cerebrovascular accident or transient ischemic attacks, known risk of intracranial bleeding, and metastases to the brain. Patients received AYVAKIT 300 mg or 400 mg orally once daily (n = 204). Among patients receiving AYVAKIT, 56% were exposed for 6 months or longer and 44% were exposed for greater than one year. The median age of patients who received AYVAKIT was 62 years (range: 29 to 90 years), 60% were <65 years, 62% were male, and 69% were White. Patients had received a median of 3 prior kinase inhibitors (range: 0 to 7). Serious adverse reactions occurred in 52% of patients receiving AYVAKIT. Serious adverse reactions occurring in ≥1% of patients who received AYVAKIT were anemia (9%), abdominal pain (3%), pleural effusion (3%), sepsis (3%), gastrointestinal hemorrhage (2%), vomiting (2%), acute kidney injury (2%), pneumonia (1%), and tumor hemorrhage (1%). Fatal adverse reactions occurred in 3.4% of patients. Fatal adverse reactions that occurred in more than one patient were sepsis and tumor hemorrhage (1% each). Permanent discontinuation due to adverse reactions occurred in 16% of patients who received AYVAKIT. Adverse reactions requiring permanent discontinuation in more than one patient were fatigue, abdominal pain, vomiting, sepsis, anemia, acute kidney injury, and encephalopathy. Dosage interruptions due to an adverse reaction occurred in 57% of patients who received AYVAKIT. Adverse reactions requiring dosage interruption in >2% of patients who received AYVAKIT were anemia, fatigue, nausea, vomiting, hyperbilirubinemia, memory impairment, diarrhea, cognitive disorder, and abdominal pain. Dose reduction due to an adverse reaction occurred in 49% of patients who received AYVAKIT. Median time to dose reduction was 9 weeks. Adverse reactions requiring dosage reduction in more than 2% of patients who received AYVAKIT were fatigue, anemia, hyperbilirubinemia, memory impairment, nausea, and periorbital edema. The most common adverse reactions (≥ 20%) were edema, nausea, fatigue/asthenia, cognitive...
Drug Interactions
7 DRUG INTERACTIONS 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. ( 2.6 , 7.1 ) Strong and Moderate CYP3A Inducers : Avoid coadministration of AYVAKIT with strong and moderate CYP3A inducers. ( 7.1 ) Hormonal contraceptives containing ethinyl estradiol : See full prescribing information for dose-specific recommendations for concomitant use ( 7.2 ) 7.1 Effects of Other Drugs on AYVAKIT Strong and Moderate CYP3A Inhibitors Coadministration of AYVAKIT with a strong or moderate CYP3A inhibitor increases avapritinib plasma concentrations [see Clinical Pharmacology (12.3) ], which may increase the incidence and severity of adverse reactions of AYVAKIT. Avoid coadministration of AYVAKIT with strong or moderate CYP3A inhibitors. If coadministration of AYVAKIT with a moderate CYP3A inhibitor cannot be avoided, reduce the dose of AYVAKIT [see Dosage and Administration (2.6) ]. Strong and Moderate CYP3A Inducers Coadministration of AYVAKIT with a strong or moderate CYP3A inducer decreases avapritinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may decrease efficacy of AYVAKIT. Avoid coadministration of AYVAKIT with strong or moderate CYP3A inducers. 7.2 Effects of AYVAKIT on Other Drugs Coadministration of AYVAKIT with ethinyl estradiol-containing contraceptives may increase the exposure of ethinyl estradiol, which may lead to increased risk of ethinyl estradiol-associated adverse reactions [see Clinical Pharmacology (12.3) ] . 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.
Contraindications
4 CONTRAINDICATIONS None. None. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , AYVAKIT can cause fetal harm when administered to a pregnant woman. There are no available data on AYVAKIT use in pregnant women. Oral administration of avapritinib to pregnant rats during the period of organogenesis was teratogenic and embryotoxic at exposure levels approximately 31.4, 6.3 and 2.7 times the human exposure based on AUC at the 25 mg, 200 mg and 300 mg dose, respectively (see Data ) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In a reproductive toxicity study, administration of avapritinib to rats during the period of organogenesis resulted in decreased fetal body weights, post-implantation loss, and increases in visceral (hydrocephaly, septal defect, and stenosis of the pulmonary trunk) and skeletal (sternum) malformations at doses greater than or equal to 10 mg/kg/day (approximately 31.4, 6.3 and 2.7 times the human exposure based on AUC at the 25 mg, 200 mg and 300 mg dose, respectively).
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING AYVAKIT (avapritinib) tablets are supplied as follows: 25 mg, round, white film-coated tablet with debossed text. One side reads "BLU" and the other side reads "25"; available in bottles of 30 tablets (NDC 72064-125-30). 50 mg, round, white film-coated tablet with debossed text. One side reads "BLU" and the other side reads "50"; available in bottles of 30 tablets (NDC 72064-150-30). 100 mg, round, white film-coated tablet, printed with blue ink "BLU" on one side and "100" on the other side; available in bottles of 30 tablets (NDC 72064-110-30). 200 mg, capsule shaped, white film-coated tablet, printed with blue ink "BLU" on one side and "200" on the other side; available in bottles of 30 tablets (NDC 72064-120-30). 300 mg, capsule shaped, white film-coated tablet, printed with blue ink "BLU" on one side and "300" on the other side; available in bottles of 30 tablets (NDC 72064-130-30). 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) [see USP Controlled Room Temperature].
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.