VITRAKVI

1 INDICATIONS AND USAGE VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that: have a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. Select patients for therapy based on an FDA-approved test [see Dosage and Administration (2.1) ]. VITRAKVI is a kinase inhibitor indicated for the treatment of adult and pediatric patients with solid tumors that: have a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. Select patients for therapy based on an FDA-approved test. ( 1 , 2.1 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Central Nervous System Effects [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] The most common (≥ 20%) adverse reactions, including laboratory abnormalities, with VITRAKVI were increased AST, increased ALT, anemia, hypoalbuminemia, musculoskeletal pain, increased alkaline phosphatase, leukopenia, lymphopenia, neutropenia, hypocalcemia, fatigue, vomiting, cough, constipation, pyrexia, diarrhea, nausea, abdominal pain, dizziness, and rash ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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. Unless noted, data in WARNINGS AND PRECAUTIONS and below reflects exposure to VITRAKVI in 444 patients, including 62% patients exposed for greater than 6 months, 44% patients exposed for greater than 1 year, and 30% patients exposed for greater than 2 years. VITRAKVI was studied in one adult dose-finding trial [LOXO-TRK-14001 (n = 75)], one pediatric dose-finding trial [SCOUT (n = 154)], and one single arm trial [NAVIGATE (n = 215)]. All patients had an unresectable or metastatic solid tumor and no satisfactory alternative treatment options or disease progression following treatment. Across these 444 patients, the median age was 44 years (range: 18 days to 90 years); 35% were younger than 18 years; 53% were female; 59% were White, 24% were Asian and, 4% were Black; and 7% were Hispanic/Latino. Most adults (91%) received VITRAKVI 100 mg orally twice daily and 91% of pediatrics (< 18 years) received VITRAKVI 100 mg/m 2 twice daily up to a maximum dose of 100 mg twice daily. The dose ranged from 50 mg daily to 200 mg twice daily in adults and 9.6 mg/m 2 twice daily to 120 mg/m 2 twice daily in pediatrics [see Use in Specific Populations (8.4) ] . The most common serious adverse reactions (≥ 2%) were pneumonia, pyrexia, and dyspnea. Grade 3 or 4 adverse reactions occurred in 60% of patients; adverse reactions leading to dose interruption or modification occurred in 45% and 11% of patients, respectively, and 12% permanently discontinued VITRAKVI for adverse reactions. The most common adverse reactions (1% each) that resulted in permanent discontinuation of VITRAKVI were increased ALT and increased AST. The most common adverse reactions (≥ 3%) resulting in dose interruption were increased ALT (6%), increased AST (5%), neutrophil count decreased (4.7%), pyrexia (4.3%), and vomiting (3.2%). Most (64%) adverse reactions leading to dose interruption occurred during the first three months of exposure. The most common adverse reactions (≥ 20%), including laboratory abnormalities, in order of decreasing frequency were increased AST, increased ALT, anemia, hypoalbuminemia, musculoskeletal pain, increased alkaline phosphatase, leukopenia, lymphopenia, neutropenia, hypocalcemia, fatigue, vomiting, cough, constipation, pyrexia, diarrhea, nausea, abdominal pain, dizziness, and rash. Adverse reactions of VITRAKVI occurring in ≥ 10% of patients and laboratory abnormalities worsening from baseline in ≥ 20% of patients are summarized in Table 3 and Table 4, respectively. Table 3 Adverse Reactions Occurring in ≥ 10% of Patients Treated with VITRAKVI Adverse Reaction The adverse reaction identifies a composite term: VITRAKVI N = 444 All Grades National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03. (%) Grade 3-4 Grade 4 adverse reaction: 1 of cognitive impairment, 1 of pyrexia. (%) Musculoskeletal and Connective Tissue Musculoskeletal Pain Includes: arthralgia, back pain, bone pain, flank pain, groin pain, growing pains, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw, and tendon pain 41 3.6 General Fatigue Includes: fatigue, asthenia 31 2.5 Pyrexia 26 2.3 Edema Includes: face edema, generalized edema, lip edema, localized edema, edema, edema genital, edema peripheral, periorbital edema, and swelling 17 0.7 Respiratory, Thoracic and Mediastinal Cough Includes: cough, productive cough, and upper-airway cough syndrome 29 0.5 Dyspnea Includes: dyspnea, and dyspnea exertional 17 2.7 Nasal congestion 10 0 Nervous System Dizziness Includes: dizziness, dizziness postural, and vertigo 22 0.9 Headache 17 0.9 Cognitive Impairment Includes: amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucination, hallucination visual, memory impairment, mental impairment, mental status changes 11 2 Gastrointestinal Vomiting 30 1.1 Constipation 27 0.5 Diarrhea 26 2.9 Nausea 25 0.5 Abdominal pain Includes: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain 24 1.4 Skin and Subcutaneous Tissue Disorders Rash Includes: dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative generalized, eczema, eczema asteatotic, palmar-plantar erythrodysaesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular 21 0.2 Psychiatric Mood disorders Includes: agitation, anxiety, depression, depressed mood, euphoric mood, fear, feeling jittery, irritability, panic attack, psychomotor hyperactivity, restlessness 14 0.9 Sleep Disturbance Includes: insomnia, sleep disorder, somnolence 12 0.2 Investigations Increased weight 17 4.1 Metabolism and Nutrition Decreased appetite 14 1.1 Infections and Infestations Upper respiratory tract infection 18 0.7 Urinary tract infection Includes: cystitis, cystitis escherichia, escherichia urinary tract infection, kidney infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic, and urinary tract infection 14 1.8 Nasopharyngitis 11 0 Table 4 Laboratory Abnormalities Occurring in ≥ 20% Patients Treated with VITRAKVI Laboratory Abnormality VITRAKVI Based on NCI CTCAE v4.03 All Grades (%) Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 416 to 442 patients. Grade 3-4 (%) Chemistry Increased AST 62 7 Increased ALT 61 8 Hypoalbuminemia 44 2.7 Increased alkaline phosphatase 40 3 Hypocalcemia 32 3.1 Hematology Anemia 45 8 Leukopenia 37 3.8 Lymphopenia 35 11 Neutropenia 34 11