VITRAKVI

Larotrectinib is a kinase inhibitor. VITRAKVI (larotrectinib) capsules and oral solution are formulated using larotrectinib sulfate. The molecular formula for larotrectinib sulfate is C 21 H 24 F 2 N 6 O 6 S and the molecular weight is 526.51 g/mol for the sulfate salt and 428.44 g/mol for the free base. The chemical name is (3 S )- N -{5-[(2 R )-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidinecarboxamide sulfate. Larotrectinib sulfate has the following chemical structure: Larotrectinib sulfate is an off-white to pinkish yellow solid that is not hygroscopic. The aqueous solubility of larotrectinib at 37°C is pH dependent (very soluble at pH 1.0 and freely soluble at pH 6.8, according to USP descriptive terms of solubility). VITRAKVI (larotrectinib) capsules and oral solution are for oral use. Each capsule contains 25 mg or 100 mg larotrectinib (30.7 mg and 123 mg larotrectinib sulfate, respectively) in a hard gelatin capsule. The capsule is composed of gelatin, titanium dioxide, and edible ink. The oral solution contains 20 mg/mL larotrectinib (24.6 mg/mL larotrectinib sulfate) and the following inactive ingredients: purified water, hydroxypropyl betadex, sucrose, glycerin, sorbitol, citric acid, sodium phosphate, sodium citrate dihydrate, propylene glycol and flavoring. Preserved with methylparaben and potassium sorbate. image of the chemical structure of VITRAKVI

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. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 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. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials ( 1 , 14 ).

• Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion ( 2.1 , 14 ). • Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of at Least 1.0 Meter-Squared: 100 mg orally twice daily ( 2.2 ) • Recommended Dosage in Pediatric Patients with Body Surface Area of Less Than 1.0 Meter-Squared: 100 mg/m 2 orally twice daily ( 2.2 ) 2.1 Patient Selection Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion in tumor specimens [see Clinical Studies ( 14 )] . An FDA-approved test for the detection of NTRK gene fusion is not currently available. 2.2 Recommended Dosage Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of at Least 1.0 Meter-Squared The recommended dosage of VITRAKVI is 100 mg orally twice daily, with or without food, until disease progression or until unacceptable toxicity. Recommended Dosage in Pediatric Patients with Body Surface Area Less Than 1.0 Meter-Squared The recommended dosage of VITRAKVI is 100 mg/m 2 orally twice daily, with or without food, until disease progression or until unacceptable toxicity. 2.3 Dosage Modifications for Adverse Reactions For Grade 3 or 4 adverse reactions: • Withhold VITRAKVI until adverse reaction resolves or improves to baseline or Grade 1. Resume at the next dosage modification if resolution occurs within 4 weeks. • Permanently discontinue VITRAKVI if an adverse reaction does not resolve within 4 weeks. The recommended dosage modifications for VITRAKVI for adverse reactions are provided in Table 1 . Table 1 Recommended Dosage Modifications for VITRAKVI for Adverse Reactions Dosage Modification Adult and Pediatric Patients with Body Surface Area of at Least 1.0 m 2 Pediatric Patients with Body Surface Area Less Than 1.0 m 2 First 75 mg orally twice daily 75 mg/m 2 orally twice daily Second 50 mg orally twice daily 50 mg/m 2 orally twice daily Third 100 mg orally once daily 25 mg/m 2 orally twice daily Permanently discontinue VITRAKVI in patients who are unable to tolerate VITRAKVI after three dose modifications. 2.4 Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration of a strong CYP3A4 inhibitor cannot be avoided, reduce the VITRAKVI dose by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the VITRAKVI dose taken prior to initiating the CYP3A4 inhibitor [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . 2.5 Dosage Modifications for Coadministration with Strong CYP3A4 Inducers Avoid coadministration of strong CYP3A4 inducers with VITRAKVI. If coadministration of a strong CYP3A4 inducer cannot be avoided, double the VITRAKVI dose. After the inducer has been discontinued for 3 to 5 elimination half-lives, resume the VITRAKVI dose taken prior to initiating the CYP3A4 inducer [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . 2.6 Dosage Modifications for Patients with Hepatic Impairment Reduce the starting dose of VITRAKVI by 50% in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . 2.7 Administration VITRAKVI capsule or oral solution may be used interchangeably. Do not make up a missed dose within 6 hours of the next scheduled dose. If vomiting occurs after taking a dose of VITRAKVI, take the next dose at the scheduled time. Capsules Swallow capsules whole with water. Do not chew or crush the capsules. Oral Solution • Store the glass bottle of VITRAKVI oral solution in the refrigerator. Discard any unused VITRAKVI oral solution remaining after 90 days of first opening the bottle. • Prior to preparing an oral dose for administration, refer to the Instructions for Use.

None. None. ( 4 )

The following clinically significant adverse reactions are described elsewhere in the labeling: • Neurotoxicity [see Warnings and Precautions ( 5.1 )] • Hepatotoxicity [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥ 20%) with VITRAKVI were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea. ( 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. Data in WARNINGS AND PRECAUTIONS and below reflects exposure to VITRAKVI in 176 patients, including 70 (40%) patients exposed for greater than 6 months and 35 (20%) patients exposed for greater than 1 year. VITRAKVI was studied in one adult dose-finding trial [LOXO-TRK-14001 (n = 70)], one pediatric dose-finding trial [SCOUT (n = 43)], and one single arm trial [NAVIGATE (n = 63)]. All patients had an unresectable or metastatic solid tumor and no satisfactory alternative treatment options or disease progression following treatment. Across these 176 patients, the median age was 51 years (range: 28 days to 82 years); 25% were 18 years or younger; 52% were male; and 72% were White, 11% were Hispanic/Latino, 8% were Black, and 3% were Asian. The most common tumors in order of decreasing frequency were soft tissue sarcoma (16%), salivary gland (11%), lung (10%), thyroid (9%), colon (8%), infantile fibrosarcoma (8%), primary central nervous system (CNS) (7%), or melanoma (5%). NTRK gene fusions were present in 60% of VITRAKVI-treated patients. Most adults (80%) received VITRAKVI 100 mg orally twice daily and 68% of pediatrics (18 years or younger) 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 Pediatric Use ( 8.4 )] . The most common adverse reactions (≥ 20%) in order of decreasing frequency were fatigue, nausea, dizziness, vomiting, anemia, increased AST, cough, increased ALT, constipation, and diarrhea. The most common serious adverse reactions (≥ 2%) were pyrexia, diarrhea, sepsis, abdominal pain, dehydration, cellulitis, and vomiting. Grade 3 or 4 adverse reactions occurred in 51% of patients; adverse reactions leading to dose interruption or reduction occurred in 37% of patients and 13% permanently discontinued VITRAKVI for adverse reactions. The most common adverse reactions (1-2% each) that resulted in discontinuation of VITRAKVI were brain edema, intestinal perforation, pericardial effusion, pleural effusion, small intestinal obstruction, dehydration, fatigue, increased ALT, increased AST, enterocutaneous fistula, increased amylase, increased lipase, muscular weakness, abdominal pain, asthenia, decreased appetite, dyspnea, hyponatremia, jaundice, syncope, vomiting, acute myeloid leukemia, and nausea. The most common adverse reactions (≥ 3%) resulting in dose modification (interruption or reduction) were increased ALT (6%), increased AST (6%), and dizziness (3%). Most (82%) adverse reactions leading to dose modification occurred during the first three months of exposure. Adverse reactions of VITRAKVI occurring in ≥ 10% of patients and laboratory abnormalities worsening from baseline in ≥ 5% of patients are summarized in Table 2 and Table 3 , respectively. Table 2 Adverse Reactions Occurring in ≥ 10% of Patients Treated with VITRAKVI Adverse Reaction VITRAKVI N = 176 All Grades National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03. (%) Grade 3-4 One Grade 4 adverse reaction of pyrexia. (%) General Fatigue 37 3 Pyrexia 18 1 Edema peripheral 15 0 Gastrointestinal Nausea 29 1 Vomiting 26 1 Constipation 23 1 Diarrhea 22 2 Abdominal pain 13 2 Nervous System Dizziness 28 1 Headache 14 0 Respiratory, Thoracic and Mediastinal Cough 26 0 Dyspnea 18 2 Nasal congestion 10 0 Investigations Increased weight 15 4 Musculoskeletal and Connective Tissue Arthralgia 14 1 Myalgia 14 1 Muscular weakness 13 0 Back pain 12 1 Pain in extremity 12 1 Metabolism and Nutrition Decreased appetite 13 2 Vascular Hypertension 11 2 Injury, Poisoning and Procedural Complications Fall 10 1 Table 3 Laboratory Abnormalities Occurring in ≥ 5% Patients Treated with VITRAKVI Laboratory Abnormality VITRAKVI Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 170 to 174 patients. All Grades NCI-CTCAE v 4.03. (%) Grade 3-4 (%) Chemistry Increased ALT 45 3 Increased AST 45 3 Hypoalbuminemia 35 2 Increased alkaline phosphatase 30 3 Hematology Anemia 42 10 Neutropenia 23 7

• Strong CYP3A4 Inhibitors: Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration cannot be avoided, reduce the VITRAKVI dose. ( 2.4 , 7.1 ) • Strong CYP3A4 Inducers: Avoid coadministration of strong CYP3A4 inducers with VITRAKVI. If coadministration cannot be avoided, increase the VITRAKVI dose. ( 2.5 , 7.1 ) • Sensitive CYP3A4 Substrates: Avoid coadministration of sensitive CYP3A4 substrates with VITRAKVI. ( 7.2 ) 7.1 Effects of Other Drugs on VITRAKVI Strong CYP3A4 Inhibitors Coadministration of VITRAKVI with a strong CYP3A4 inhibitor may increase larotrectinib plasma concentrations, which may result in a higher incidence of adverse reactions [see Clinical Pharmacology ( 12.3 )] . Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors, including grapefruit or grapefruit juice. If coadministration of strong CYP3A4 inhibitors cannot be avoided, modify VITRAKVI dose as recommended [see Dosage and Administration ( 2.4 )] . Strong CYP3A4 Inducers Coadministration of VITRAKVI with a strong CYP3A4 inducer may decrease larotrectinib plasma concentrations, which may decrease the efficacy of VITRAKVI [see Clinical Pharmacology ( 12.3 )] . Avoid coadministration of VITRAKVI with strong CYP3A4 inducers, including St. John’s wort. If coadministration of strong CYP3A4 inducers cannot be avoided, modify VITRAKVI dose as recommended [see Dosage and Administration ( 2.5 )] . 7.2 Effects of VITRAKVI on Other Drugs Sensitive CYP3A4 Substrates Coadministration of VITRAKVI with sensitive CYP3A4 substrates may increase their plasma concentrations, which may increase the incidence or severity of adverse reactions [see Clinical Pharmacology ( 12.3 )] . Avoid coadministration of VITRAKVI with sensitive CYP3A4 substrates. If coadministration of these sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.