Avapritinib

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) ] .

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 to less than or equal to Grade 2. Resume at same dose or reduced dose, as clinically appropriate. Patients with AdvSM Thrombocytopenia [see Warnings and Precautions (5.1) ] <50 × 10 9 /L Interrupt AYVAKIT until platelet count is ≥ 50 × 10 9 /L, then resume at reduced dose (per Table 1). If platelet counts do not recover above 50 × 10 9 /L, consider platelet support. 2.6 Concomitant Use of Strong and Moderate CYP3A Inhibitors Avoid concomitant use of AYVAKIT with strong or moderate CYP3A inhibitors. If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the starting dosage of AYVAKIT is as follows [see Drug Interactions (7.1) ] : GIST: 100 mg orally once daily AdvSM: 50 mg orally once daily For ISM, avoid concomitant use of AYVAKIT with strong or moderate CYP3A inhibitors. 2.7 Dosage Modifications for Severe Hepatic Impairment A modified starting dosage of AYVAKIT is recommended for patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7) ]: GIST: 200 mg orally once daily AdvSM: 100 mg orally once daily ISM: 25 mg orally every other day

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 impairment, vomiting, decreased appetite, diarrhea, increased lacrimation, abdominal pain, constipation, rash, dizziness, and hair color changes. Table 5 summarizes the adverse reactions observed in NAVIGATOR. Table 5. Adverse Reactions (≥ 10%) in Patients with GIST Receiving AYVAKIT in NAVIGATOR Adverse Reactions Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0 AYVAKIT N=204 All Grades % Grade ≥ 3 % General Edema Edema includes face swelling, conjunctival edema, eye edema, eyelid edema, orbital edema, periorbital edema, face edema, mouth edema, pharyngeal edema, peripheral edema, edema, generalized edema, localized edema, peripheral swelling, testicular edema. 72 2 Fatigue/asthenia 61 9 Pyrexia 14 0.5 Gastrointestinal Nausea 64 2.5 Vomiting 38 2 Diarrhea 37 4.9 Abdominal pain Abdominal pain includes abdominal pain, upper abdominal pain, abdominal discomfort, lower abdominal pain, abdominal tenderness, and epigastric discomfort. 31 6 Constipation 23 1.5 Dyspepsia 16 0 Nervous System Cognitive impairment Cognitive impairment includes memory impairment, cognitive disorder, confusional state, disturbance in attention, amnesia, mental impairment, mental status changes, encephalopathy, dementia, abnormal thinking, mental disorder, and retrograde amnesia. 48 4.9 Dizziness 22 0.5 Headache 17 0.5 Sleep disorders Sleep disorders includes insomnia, somnolence, and sleep disorder. 16 0 Taste effects Taste effects include dysgeusia and ageusia. 15 0 Mood disorders Mood disorders includes agitation, anxiety, depression, depressed mood, dysphoria, irritability, mood altered, nervousness, personality change, and suicidal ideation. 13 1 Metabolism and nutrition Decreased appetite 38 2.9 Eye Increased lacrimation 33 0 Skin and subcutaneous tissue Rash Rash includes rash, rash maculo-papular, rash erythematous, rash macular, rash generalized, and rash papular. 23 2.1 Hair color changes 21 0.5 Alopecia 13 0 Respiratory, thoracic and mediastinal Dyspnea 17 2.5 Pleural effusion 12 2 Investigations Weight decreased 13 1 Clinically relevant adverse reactions occurring in <10% of patients were: Vascular: hypertension (8%) Endocrine: thyroid disorders (hyperthyroid, hypothyroid) (3%) Skin and subcutaneous: palmar-plantar erythrodysesthesia (1%) Table 6 summarizes the laboratory abnormalities observed in NAVIGATOR. Table 6. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with GIST Receiving AYVAKIT in NAVIGATOR Laboratory Abnormality AYVAKIT The denominator used to calculate the rate varied from 154 to 201 based on the number of patients with a baseline value and at least one post-treatment value. N=204 All Grades (%) Grade ≥ 3 (%) Hematology Decreased hemoglobin 81 28 Decreased leukocytes 62 5 Decreased neutrophils 43 6 Decreased platelets 27 0.5 Increased INR 24 0.6 Increased activated partial thromboplastin time 13 0 Chemistry Increased bilirubin 69 9 Increased aspartate aminotransferase 51 1.5 Decreased phosphate 49 13 Decreases potassium 34 6 Decreased albumin 31 2 Decreased magnesium 29 1 Increased creatinine 29 0 Decreased sodium 28 7 Increased alanine aminotransferase 19 0.5 Increased alkaline phosphatase 14 1 Advanced Systemic Mastocytosis The safety of AYVAKIT in patients with AdvSM was evaluated in EXPLORER and PATHFINDER [see Clinical Studies (14.2) ] . Patients received a starting dose of AYVAKIT ranging from 30 mg to 400 mg orally once daily (n = 131), including 80 patients who received the recommended starting dose of 200 mg once daily. Among patients receiving AYVAKIT, 70% were treated for 6 months or longer and 37% were exposed for greater than one year. The median age of patients who received AYVAKIT was 68 years (range: 31 to 88 years), 38% were <65 years, 57% were male, and 88% were White. Serious adverse reactions occurred in 34% of patients receiving the recommended starting dose of 200 mg once daily and in 50% of patients receiving AYVAKIT at all doses. Serious adverse reactions occurring in ≥1% of patients who received AYVAKIT were anemia (5%), subdural hematoma (4%), pleural effusion, ascites and pneumonia (3% each), acute kidney injury, gastrointestinal hemorrhage, intracranial hemorrhage, encephalopathy, gastric hemorrhage, large intestine perforation, pyrexia, and vomiting (2% each). Fatal adverse reactions occurred in 2.5% of patients receiving the recommended starting dose of 200 mg once daily and in 5.3% of patients receiving AYVAKIT at all doses. No specific adverse reaction leading to death was reported in more than one patient. Permanent discontinuation due to adverse reactions occurred in 10% of patients receiving the recommended starting dose of 200 mg once daily and in 15% of patients who received AYVAKIT at all doses. Of patients receiving 200 mg once daily, subdural hematoma was the only adverse reaction requiring permanent discontinuation in more than one patient. Dosage interruptions due to an adverse reaction occurred in 60% of patients receiving the recommended starting dose of 200 mg once daily and in 67% of patients who received AYVAKIT at all doses. Adverse reactions requiring dosage interruption in >2% of patients who received AYVAKIT at 200 mg once daily were thrombocytopenia, neutropenia, neutrophil count decreased, platelet count decreased, anemia, white blood cell decreased, cognitive disorder, blood alkaline phosphatase increased, and edema peripheral. Dose reduction due to an adverse reaction occurred in 68% of patients receiving the recommended starting dose of 200 mg once daily and 70% of patients who received AYVAKIT at all doses. Median time to dose reduction was 1.7 months. Adverse reactions requiring dosage reduction in more than 2% of patients who received AYVAKIT at 200 mg once daily were thrombocytopenia, neutropenia, edema peripheral, neutrophil count decreased, platelet count decreased, periorbital edema, cognitive disorder, anemia, fatigue, arthralgia, blood alkaline phosphatase increased, and white blood cell count decreased. The most common adverse reactions (≥ 20%) at all doses were edema, diarrhea, nausea, and fatigue/asthenia. Table 7 summarizes the adverse reactions observed in EXPLORER and PATHFINDER. Table 7. Adverse Reactions (≥ 10%) in Patients with AdvSM Receiving AYVAKIT in EXPLORER and PATHFINDER Adverse Reactions Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0 AYVAKIT (200 mg once daily) N=80 All Grades % Grade ≥ 3 % General Edema Edema includes face swelling, eyelid edema, orbital edema, periorbital edema, face edema, peripheral edema, edema, generalized edema, and peripheral swelling. 79 5 Fatigue/asthenia 23 4 Gastrointestinal Diarrhea 28 1 Nausea 24 1 Vomiting 18 3 Abdominal pain Abdominal pain includes abdominal pain, upper abdominal pain, and abdominal discomfort. 14 1 Constipation 11 0 Nervous system Headache 15 0 Cognitive effects Cognitive effects include memory impairment, cognitive disorder, confusional state, delirium, and disorientation. 14 1 Taste effects Taste effects include dysgeusia. 13 0 Dizziness 13 0 Musculoskeletal and connective tissue Arthralgia 10 1 Respiratory, thoracic and mediastinal Epistaxis 11 0 Clinically relevant adverse reactions occurring in <10% of patients were: Cardiac : cardiac failure (2.5%), and cardiac failure congestive (1.3%) Gastrointestinal: ascites (5%), gastrointestinal hemorrhage (1.3%), and large intestine perforation (1.3%) Hepatobiliary: cholelithiasis (1.3%) Infections and infestations: upper respiratory tract infection (6%), urinary tract infection (6%), and herpes zoster (2.5%) Vascular: flushing (3.8%), hypertension (3.8%), hypotension (3.8%), and hot flush (2.5%) Nervous : insomnia (6%) Musculoskeletal and connective tissue : pain in extremity (6%) Respiratory, thoracic and mediastinal : dyspnea (9%), and cough (2.5%) Skin and subcutaneous tissue : rash Grouped terms (8%), alopecia (9%), pruritus (8%), and hair color changes (6%) Metabolism and nutrition : decreased appetite (8%) Eye : lacrimation increased (9%) Laboratory abnormality: decreased phosphate (9%) Rash includes rash and rash maculo-papular Table 8 summarizes the laboratory abnormalities observed in EXPLORER and PATHFINDER. Table 8. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with AdvSM Receiving AYVAKIT in EXPLORER and PATHFINDER Laboratory Abnormality AYVAKIT (200 mg once daily) N=80 All Grades (%) Grade ≥ 3 (%) Hematology Decreased platelets 64 21 Decreased hemoglobin 55 23 Decreased neutrophils 54 25 Decreased lymphocytes 34 11 Increased activated partial thromboplastin time 14 1 Increased lymphocytes 10 0 Chemistry Decreased calcium 50 3 Increased bilirubin 41 3 Increased aspartate aminotransferase 38 1 Decreased potassium 26 4 Increased alkaline phosphatase 24 5 Increased creatinine 20 0 Increased alanine aminotransferase 18 1 Decreased sodium 18 1 Decreased albumin 15 1 Decreased magnesium 14 1 Increased potassium 11 0 Other Clinically Relevant Adverse Reactions in <10% of patients In the pooled GIST and AdvSM safety populations, photosensitivity occurred in 2.5% of patients [see Warnings and Precautions (5.3) ]. Indolent Systemic Mastocytosis The safety of AYVAKIT in patients with ISM was evaluated in PIONEER [see Clinical Studies (14.3) ] . Patients received AYVAKIT 25 mg orally once daily with best supportive care (n = 141) or placebo once daily with best supportive care (n = 71). Serious adverse reactions occurred in 1 patient (0.7%) who received AYVAKIT due to pelvic hematoma. Permanent discontinuation of AYVAKIT due to an adverse reaction occurred in 1 patient (0.7%) due to dyspnea and dizziness. Dosage interruptions of AYVAKIT due to an adverse reaction occurred in 5% of patients. Adverse reactions which required dosage interruption included dizziness, blood alkaline phosphatase increased, dyspnea, face edema, pelvic hematoma, liver transaminase increased and respiratory tract infection (1 patient each). Table 9 summarizes the frequency of adverse reactions in the PIONEER study. The most common adverse reactions (≥ 10%) in the AYVAKIT group were eye edema, dizziness, peripheral edema and flushing. Of all adverse reactions, 55% were Grade 1, 38% were Grade 2 and 7% were Grade 3. Among patients with edema adverse reactions, 95% were Grade 1 and 5% were Grade 2. Among patients with hemorrhage adverse reactions, 86% were Grade 1 and 14% were Grade 2. Table 9. Adverse Reactions Occurring in AYVAKIT-Treated Patients with Indolent Systemic Mastocytosis During PIONEER Trial Adverse Reactions Adverse reactions that occurred in ≥5% of AYVAKIT-treated patients and ≥2% more than placebo-treated patients. , Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 AYVAKIT (25 mg once daily) + BSC N=141 % Placebo + BSC N=71 % Abbreviations: BSC=best supportive care Eye edema Eye edema includes periorbital edema, eye edema, swelling of eyelid, orbital edema, eye swelling, eyelid edema and eyelid ptosis. 13 7 Dizziness Term includes several similar terms. 13 10 Peripheral edema 12 6 Flushing 11 4 Respiratory tract infection Respiratory tract infection includes pneumonia, upper respiratory tract infection, bronchitis and respiratory tract infection. 8 1 Face edema 7 1 Rash 6 4 Liver transaminase increased 6 3 Insomnia 6 3 Hematoma Hematoma includes contusion, hematoma and pelvic hematoma. 6 1 Blood alkaline phosphatase increased 6 1 Hemorrhage Hemorrhage includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, retinal hemorrhage. 5 3 Clinically relevant adverse reactions occurring in <5% of patients were: Skin and subcutaneous tissue: photosensitivity (2.8%)

12.3 Pharmacokinetics Avapritinib C max and AUC increased approximately proportionally over the dose range of 25 mg to 400 mg once daily. Steady state concentrations of avapritinib were reached prior to day 15 following daily dosing. Steady state pharmacokinetic parameters per recommended dosing regimen are described in Table 10. Table 10. Steady State Pharmacokinetic Parameters of AYVAKIT Following Different Dosing Regimen Pharmacokinetic Parameters 25 mg once daily (ISM) 200 mg once daily (AdvSM) 300 mg once daily (GIST) Abbreviations: CV%=coefficient of variation C max (ng/mL) Geometric Mean (CV%) 70.2 (47.8 %, n=9) 377 (62%, n=18) 813 (52%, n=110) AUC 0-24h (h∙ng/mL) Geometric Mean (CV%) 1330 (49.5 %, n = 9) 6600 (54%, n=16) 15400 (48%, n=110) Mean accumulation ratio of AUC 0-24h 4.06 (n=9) 6.41 (n=9) 3.82 (n=34) Absorption The median time to peak concentration (T max ) ranged from 2 to 4 hours following single doses of avapritinib. Effect of Food The C max of avapritinib was increased by 59% and the AUC 0-INF was increased by 29% when AYVAKIT was taken with a high-calorie, high-fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to those in the fasted state. Distribution The mean (CV %) apparent volume of distribution of avapritinib is 1310 L (51.5%) at 300 mg in patients with GIST, 1900 L (43.2%) at 200 mg in patients with AdvSM, and 1400 L (59.1%) at 25 mg in patients with ISM. In vitro protein binding of avapritinib is 98.8% and is independent of concentration. The blood-to-plasma ratio is 0.95. Elimination The mean plasma elimination half-life of avapritinib was 32 to 57 hours in patients with GIST, 20 to 39 hours in patients with AdvSM, and 38 to 45 hours in patients with ISM. The steady state mean (CV%) apparent oral clearance of avapritinib is 21.8 L/h (54.9%) at 300 mg in patients with GIST, 40.3 L/h (86.0%) at 200 mg in patients with AdvSM, and 21.6 L/h (58.1%) at 25 mg in patients with ISM. Metabolism Avapritinib is primarily metabolized by CYP3A4, CYP3A5 and to a lesser extent by CYP2C9 in vitro. Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, unchanged avapritinib (49%) and its metabolites M690 (hydroxy glucuronide; 35%) and M499 (oxidative deamination; 14%) were the major circulating compounds. The formation of the glucuronide M690 is catalyzed mainly by UGT1A3. Following oral administration of AYVAKIT 300 mg once daily in patients, the steady state AUC of M499 is approximately 80% of the AUC of avapritinib. M499 is not likely to contribute to efficacy at the recommended dose of avapritinib. Excretion Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, 70% of the radioactive dose was recovered in feces (11% unchanged) and 18% in urine (0.23% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of avapritinib were observed based on age (18 to 90 years), sex, race (White, Black, or Asian), body weight (39.5 to 156.3 kg), mild to moderate (CL cr 30 to 89 mL/min estimated by Cockcroft-Gault) renal impairment, or mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST) to moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment. In a dedicated hepatic impairment study following a single oral dose administration of 100 mg avapritinib, the mean unbound AUC was 61% higher in subjects with severe hepatic impairment (Child-Pugh Class C) as compared to matched healthy subjects with normal hepatic function. The effect of severe renal impairment (CL cr 15 to 29 mL/min) and end-stage renal disease (CL cr < 15 mL/min) on the pharmacokinetics of avapritinib is unknown. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Strong and Moderate CYP3A Inhibitors on Avapritinib: Coadministration of AYVAKIT 300 mg once daily with itraconazole 200 mg once daily (a strong CYP3A inhibitor) is predicted to increase avapritinib AUC by 600% at steady state. Coadministration of AYVAKIT 300 mg once daily with fluconazole 200 mg once daily (a moderate CYP3A inhibitor) is predicted to increase avapritinib AUC by 210% at steady state [see Dosage and Administration (2.6) , Drug Interactions (7.1) ] . Effect of Strong and Moderate CYP3A Inducers on Avapritinib: Coadministration of AYVAKIT 400 mg as a single dose with rifampin 600 mg once daily (a strong CYP3A inducer) decreased avapritinib C max by 74% and AUC 0-INF by 92% . Coadministration of AYVAKIT 300 mg once daily with efavirenz 600 mg once daily (a moderate CYP3A inducer) is predicted to decrease avapritinib C max by 55% and AUC by 62% at steady state [see Drug Interactions (7.1) ]. Effect of Acid-Reducing Agents on Avapritinib: No clinically significant differences in the pharmacokinetics of avapritinib were identified when coadministered with gastric acid reducing agents. Hormonal Contraceptives : In a drug-drug interaction study of 15 subjects, coadministration of AYVAKIT 25 mg once daily with an 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 C max ratio of 1.46 (90% CI: 1.17, 1.81) relative to participants administered the oral contraceptive alone. This increase in ethinyl estradiol C max may lead to an increased risk of ethinyl estradiol-related adverse events. In Vitro Studies Cytochrome P450 (CYP) Enzymes: In vitro studies indicate that avapritinib is a time-dependent inhibitor as well as an inducer of CYP3A at clinically relevant concentrations. Avapritinib is an inhibitor of CYP2C9 at clinically relevant concentrations. Avapritinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C19, or CYP2D6 at clinically relevant concentrations. Avapritinib is not an inducer of CYP1A2 or CYP2B6. Avapritinib is a substrate of CYP3A. M499 is an inhibitor of CYP3A, CYP2C8, or CYP2C9 at clinically relevant concentrations. M499 is not an inhibitor of CYP1A2, CYP2B6, CYP2C19, or CYP2D6 at clinically relevant concentrations. Transporter Systems: Avapritinib is an inhibitor of P-glycoprotein (P-gp), intestinal BCRP, MATE1, MATE2-K, and BSEP, but not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2. Avapritinib is not a substrate of P-gp or BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K and BSEP. The effect of M499 on transporter systems is unknown.