VITRAKVI

5 WARNINGS AND PRECAUTIONS Central Nervous System (CNS) Effects: Advise patients and caretakers of the risk of CNS adverse reactions including dizziness, cognitive impairment, mood disorders, and sleep disturbances. Advise patients not to drive or operate hazardous machinery if experiencing neurotoxicity. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity. ( 2.3 , 5.1 ) Skeletal Fractures: Promptly evaluate patients with signs or symptoms of fractures. ( 5.2 ) Hepatotoxicity: Obtain liver function tests (ALT, AST, ALP and bilirubin) before initiation of VITRAKVI and every 2 weeks during the first 2 months of treatment, then monthly thereafter or as clinically indicated. Temporarily withhold, reduce dose, or permanently discontinue VITRAKVI based on severity. ( 2.4 , 5.3 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. ( 5.4 , 8.3 ) 5.1 Central Nervous System Effects Central nervous system (CNS) adverse reactions occurred in patients receiving VITRAKVI, including dizziness, cognitive impairment, mood disorders, and sleep disturbances. In patients who received VITRAKVI (n=444), all grades CNS effects including cognitive impairment, mood disorders, dizziness and sleep disorders were observed in 40.3% with Grades 3-4 in 3.8% of patients. Cognitive impairment occurred in 11% of patients. The median time to onset of cognitive impairment was 6 months (range: 2 days to 56 months). Cognitive impairment occurring in ≥ 1% of patients included memory impairment (4.1%), disturbance in attention (3.6%), confusional state (2.3%), cognitive disorder (1.6%), delirium (1.4%), and hallucination (1.1%). Grade 3 cognitive adverse reactions occurred in 1.8% of patients and Grade 4 cognitive adverse reactions in 0.2% of patients. Among the 49 patients with cognitive impairment, 6% required a dose modification, and 18% required dose interruption. Mood disorders occurred in 14% of patients. The median time to onset of mood disorders was 3.3 months (range: 1 day to 65 months). Mood disorders occurring in ≥ 1% of patients included anxiety (5%), agitation (3.2%), depression (3.2%), irritability (2.3%), and restlessness (1.1%). Grade 3 mood disorders occurred in 0.9% of patients. Among the 63 patients who experienced mood disorders, no patient required a dose modification, and 1.6% required dose interruption. Dizziness occurred in 22% of patients, and Grade 3 dizziness occurred in 0.9% of patients. Among the 96 patients who experienced dizziness, 6% of patients required a dose modification, and 5% required dose interruption. Sleep disturbances occurred in 12% of patients. Sleep disturbances included insomnia (9%), somnolence (3.4%), and sleep disorder (0.5%). Grade 3 sleep disturbances occurred in 0.2% of patients. Among the 54 patients who experienced sleep disturbances, no patient required a dose modification, and 3.7% required dose interruption. Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed [see Dosage and Administration (2.3) ] . 5.2 Skeletal Fractures Skeletal fractures can occur in patients taking VITRAKVI. Among 444 patients who received VITRAKVI across clinical trials, fractures occurred in 7% of patients; 6% of 290 adult patients and 10% of 154 pediatric patients. Median time to first fracture was 13 months (range 27 days to 73 months) in patients followed per fracture. The most common fractures were of the rib (1.4%), fibula, foot, or wrist (0.7% each). Most fractures were associated with minimal or moderate trauma. Some fractures were associated with radiologic abnormalities suggestive of local tumor involvement. VITRAKVI treatment was interrupted due to fracture in 1.4% patients. Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity). There are no data on the effects of VITRAKVI on healing of known fractures or risk of future fractures. 5.3 Hepatotoxicity Hepatotoxicity including drug-induced liver injury (DILI) has occurred in patients taking VITRAKVI. In patients who received VITRAKVI (n=444), increased AST of any grade occurred in 62% of patients and increased ALT of any grade occurred in 61%. Grade 3-4 increased AST or ALT occurred in 7% and 8% of patients, respectively [see Adverse Reactions (6.1) ] . The median time to onset of increased AST was 1.9 months (range: 4 days to 3.8 years). The median time to onset of increased ALT was 1.9 months (range: 1 day to 4.9 years). Increased AST and ALT leading to dose modifications occurred in 1.6% and 3.2% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 4 (0.9%) patients. There have been reports from clinical studies and postmarketing cases of Grade ≥ 2 increases in ALT and/or AST with increases in bilirubin ≥ 2 × ULN. Obtain liver function tests (ALT, AST, ALP and bilirubin) before initiation of VITRAKVI and monitor every 2 weeks during the first 2 months of treatment, then monthly thereafter, or more frequently following the occurrence of Grade 2 or greater AST or ALT elevation. Temporarily withhold, reduce the dose, or permanently discontinue VITRAKVI based on severity [see Dosage and Administration (2.4) ] . 5.4 Embryo-Fetal Toxicity Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the last dose of VITRAKVI [see Use in Specific Populations (8.1 , 8.3) ] .

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) ] Skeletal Fractures [see Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] 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 Clinically relevant adverse reactions occurring in ≤ 10% of patients include fractures (7%). 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

<table width="80%"><caption>Table 3 Adverse Reactions Occurring in &#x2265; 10% of Patients Treated with VITRAKVI</caption><col width="34%" align="left" valign="middle"/><col width="33%" align="center" valign="middle"/><col width="33%" align="center" valign="middle"/><thead><tr styleCode="botrule"><th styleCode="Lrule Rrule" rowspan="2">Adverse Reaction<footnote>The adverse reaction identifies a composite term:</footnote></th><th styleCode="Rrule" colspan="2">VITRAKVI N = 444</th></tr><tr><th styleCode="Rrule" align="center">All Grades<footnote>National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03.</footnote> (%)</th><th styleCode="Rrule" align="center">Grade 3-4<footnote>Grade 4 adverse reaction: 1 of cognitive impairment, 1 of pyrexia. </footnote> (%)</th></tr></thead><tbody><tr styleCode="botrule"><td styleCode="Lrule Rrule">Musculoskeletal and Connective Tissue </td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Musculoskeletal Pain<footnote>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</footnote></td><td styleCode="Rrule">41</td><td styleCode="Rrule">3.6</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">General</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Fatigue<footnote>Includes: fatigue, asthenia</footnote></td><td styleCode="Rrule">31</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">26</td><td styleCode="Rrule">2.3</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Edema<footnote>Includes: face edema, generalized edema, lip edema, localized edema, edema, edema genital, edema peripheral, periorbital edema, and swelling</footnote></td><td styleCode="Rrule">17</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Respiratory, Thoracic and Mediastinal </td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Cough<footnote>Includes: cough, productive cough, and upper-airway cough syndrome</footnote></td><td styleCode="Rrule">29</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Dyspnea<footnote>Includes: dyspnea, and dyspnea exertional</footnote></td><td styleCode="Rrule">17</td><td styleCode="Rrule">2.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Nasal congestion</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Nervous System </td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Dizziness<footnote>Includes: dizziness, dizziness postural, and vertigo</footnote></td><td styleCode="Rrule">22</td><td styleCode="Rrule">0.9</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">17</td><td styleCode="Rrule">0.9</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Cognitive Impairment<footnote>Includes: amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucination, hallucination visual, memory impairment, mental impairment, mental status changes</footnote></td><td styleCode="Rrule">11</td><td styleCode="Rrule">2</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Gastrointestinal </td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">30</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">27</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">26</td><td styleCode="Rrule">2.9</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">25</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Abdominal pain<footnote>Includes: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain</footnote></td><td styleCode="Rrule">24</td><td styleCode="Rrule">1.4</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Skin and Subcutaneous Tissue Disorders</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Rash<footnote>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</footnote></td><td styleCode="Rrule">21</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Psychiatric</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Mood disorders<footnote>Includes: agitation, anxiety, depression, depressed mood, euphoric mood, fear, feeling jittery, irritability, panic attack, psychomotor hyperactivity, restlessness</footnote></td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.9</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Sleep Disturbance<footnote>Includes: insomnia, sleep disorder, somnolence</footnote></td><td styleCode="Rrule">12</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Investigations</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Increased weight</td><td styleCode="Rrule">17</td><td styleCode="Rrule">4.1</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Metabolism and Nutrition </td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Rrule">14</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Infections and Infestations </td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Upper respiratory tract infection</td><td styleCode="Rrule">18</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Urinary tract infection<footnote>Includes: cystitis, cystitis escherichia, escherichia urinary tract infection, kidney infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic, and urinary tract infection</footnote></td><td styleCode="Rrule">14</td><td styleCode="Rrule">1.8</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Nasopharyngitis</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="80%"><caption>Table 4 Laboratory Abnormalities Occurring in &#x2265; 20% Patients Treated with VITRAKVI</caption><col width="34%" align="left" valign="middle"/><col width="33%" align="center" valign="middle"/><col width="33%" align="center" valign="middle"/><thead><tr styleCode="botrule"><th styleCode="Lrule Rrule" rowspan="2">Laboratory Abnormality</th><th styleCode="Rrule" colspan="2" align="center">VITRAKVI<footnote>Based on NCI CTCAE v4.03</footnote></th></tr><tr><th styleCode="Lrule Rrule" align="center" valign="top">All Grades (%)<footnote ID="t42">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.</footnote></th><th styleCode="Rrule" valign="top">Grade 3-4 (%)<footnoteRef IDREF="t42"/></th></tr></thead><tbody><tr styleCode="botrule"><td styleCode="Lrule Rrule">Chemistry</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Increased AST</td><td styleCode="Rrule">62</td><td styleCode="Rrule">7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Increased ALT</td><td styleCode="Rrule">61</td><td styleCode="Rrule">8</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Hypoalbuminemia</td><td styleCode="Rrule">44</td><td styleCode="Rrule">2.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Increased alkaline phosphatase</td><td styleCode="Rrule">40</td><td styleCode="Rrule">3</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Hypocalcemia</td><td styleCode="Rrule">32</td><td styleCode="Rrule">3.1</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Hematology</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Anemia</td><td styleCode="Rrule">45</td><td styleCode="Rrule">8</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Leukopenia</td><td styleCode="Rrule">37</td><td styleCode="Rrule">3.8</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Lymphopenia</td><td styleCode="Rrule">35</td><td styleCode="Rrule">11</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Neutropenia</td><td styleCode="Rrule">34</td><td styleCode="Rrule">11</td></tr></tbody></table>