VITRAKVI

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 musculoskeletal pain, fatigue, hypoalbuminemia, neutropenia, increased alkaline phosphatase, cough, leukopenia, constipation, diarrhea, dizziness, hypocalcemia, nausea, vomiting, pyrexia, lymphopenia, and abdominal pain ( 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 279 patients, including 54% patients exposed for greater than 6 months and 30% patients exposed for greater than 1 year. VITRAKVI was studied in one adult dose-finding trial [LOXO‑TRK-14001 (n = 75)], one pediatric dose-finding trial [SCOUT (n = 88)], and one single arm trial [NAVIGATE (n = 116)]. All patients had an unresectable or metastatic solid tumor and no satisfactory alternative treatment options or disease progression following treatment. Across these 279 patients, the median age was 46 years (range: 0.1 days to 84 years); 33% were younger than 18 years; 48% were male; and 74% were White, 9% were Hispanic/Latino, 7% were Asian and, 6% were Black. The most common tumors (≥3%) in order of decreasing frequency were soft tissue sarcoma (17%), thyroid (13%), infantile fibrosarcoma (12%), primary central nervous system (CNS) (11%), salivary gland (9%), lung (9%), colon (6%), breast (4%), or melanoma (3%). NTRK gene fusions were confirmed or inferred in 75% of VITRAKVI-treated patients. Most adults (86%) received VITRAKVI 100 mg orally twice daily and 85% 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 adverse reactions (≥ 20%), including laboratory abnormalities, in order of decreasing frequency were increased AST, increased ALT, anemia, musculoskeletal pain, fatigue, hypoalbuminemia, neutropenia, increased alkaline phosphatase, cough, leukopenia, constipation, diarrhea, dizziness, hypocalcemia, nausea, vomiting, pyrexia, lymphopenia, and abdominal pain. The most common serious adverse reactions (≥ 2%) were pneumonia and pyrexia. Grade 3 or 4 adverse reactions occurred in 53% of patients; adverse reactions leading to dose interruption or modification occurred in 39% and 8% of patients, respectively, and 9% permanently discontinued VITRAKVI for adverse reactions. The most common adverse reactions (1% each) that resulted in permanent discontinuation of VITRAKVI were increased ALT, increased AST, dehydration and fatigue. The most common adverse reactions (≥ 3%) resulting in dose interruption were increased ALT (4.7%), increased AST (4.3%), and neutrophil count decreased (4.3%). Most (70%) adverse reactions leading to dose interruption occurred during the first three months of exposure. 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* VITRAKVI N = 279 All Grades** (%) Grade 3-4*** (%) Musculoskeletal and Connective Tissue Musculoskeletal Pain 1 42 3.9 Muscular weakness 10 0.7 General Fatigue 2 36 2.5 Pyrexia 24 1.8 Edema 3 19 0.7 Respiratory, Thoracic and Mediastinal Cough 4 32 0.4 Dyspnea 5 17 3 Upper respiratory tract infection 13 0 Nasal congestion 11 0 Nervous System Dizziness 6 27 1.1 Headache 15 0.4 Cognitive Impairment 7 11 2.5 Gastrointestinal Constipation 27 0.4 Diarrhea 27 1.4 Nausea 25 0.7 Vomiting 25 0.7 Abdominal pain 8 21 2.2 Skin and Subcutaneous Tissue Disorders Rash 9 19 0.4 Psychiatric Mood disorders 10 14 0.4 Sleep Disturbance 11 10 0 Investigations Increased weight 14 3.6 Metabolism and Nutrition Decreased appetite 12 1.4 Infections and Infestations Urinary tract infection 12 12 1.4 * The adverse reaction identifies a composite term: 1 Includes: arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, and pain in extremity 2 Includes: fatigue, asthenia 3 Includes: face edema, generalized edema, lip edema, localized edema, edema, edema genital, edema peripheral, periorbital edema, and swelling 4 Includes: cough, productive cough, and upper-airway cough syndrome 5 Includes: dyspnea, and dyspnea exertional 6 Includes: dizziness, dizziness postural, and vertigo 7 Includes: amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucinations, memory impairment, mental impairment, mental status changes 8 Includes: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain 9 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 10 Includes: agitation, anxiety, depression, depressed mood, euphoric mood, irritability 11 Includes: insomnia, sleep disorder, somnolence 12 Includes: cystitis, escherichia urinary tract infection, pyelonephritis acute, and urinary tract infection ** National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03. *** One Grade 4 adverse reaction of pyrexia. Clinically relevant adverse reactions occurring in ≤ 10% of patients include fractures (8%). Table 4 Laboratory Abnormalities Occurring in ≥ 20% Patients Treated with VITRAKVI Laboratory Abnormality VITRAKVI* All Grades (%)** Grade 3-4 (%)** Chemistry Increased AST 52 3.1 Increased ALT 45 2.5 Hypoalbuminemia 36 1.9 Increased alkaline phosphatase 34 1.9 Hypocalcemia 25 2.6 Hematology Anemia 42 10 Neutropenia 36 14 Leukopenia 28 1.9 Lymphopenia 22 6 * Based on NCI CTCAE v4.03 ** Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 272 to 277 patients.

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION 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 37ᴼC 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 packaged in one bottle containing 100 mL 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. The oral solution packaged in two bottles each containing 50 mL contains 20 mg/mL larotrectinib (24.6 mg/mL larotrectinib sulfate) and the following inactive ingredients: purified water, hydroxypropyl betadex, sucralose, sodium citrate, strawberry flavor, and citric acid. Preserved with sodium benzoate. image of the chemical structure of VITRAKVI

2 DOSAGE AND ADMINISTRATION • 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 1 Meter-Squared or greater: 100 mg orally twice daily ( 2.2 ) • Recommended Dosage in Pediatric Patients with Body Surface Area of Less Than 1 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 )] . Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics. 2.2 Recommended Dosage Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of at Least 1 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 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 2 and higher liver function test abnormalities, refer to Section 2.4, Table 2, Dosage Modifications for Hepatotoxicity. For all other 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 reductions for VITRAKVI for adverse reactions are provided in Table 1 . Table 1 Recommended Dosage Reductions for VITRAKVI for Adverse Reactions Dosage Reduction Adult and Pediatric Patients with Body Surface Area of 1 m 2 or Greater Pediatric Patients with Body Surface Area Less Than 1 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 a a Pediatric patients on 25 mg/m 2 orally twice daily should remain on this dosage even if body surface area becomes greater than 1 m 2 during the treatment. Maximum dose should be 25 mg/m 2 orally twice daily at the third dosage modification. Permanently discontinue VITRAKVI in patients who are unable to tolerate VITRAKVI after three dose modifications. 2.4 Dosage Modifications for Hepatotoxicity The recommended dosage modifications for VITRAKVI liver function test abnormalities are provided in Table 2. For CTCAE Grade 2 ALT and/or AST elevation, monitor liver function frequently as clinically indicated, to establish whether a dose interruption or reduction is required [see Warnings and Precautions ( 5.3 )]. Table 2 Recommended Dosage Modifications for VITRAKVI for Hepatotoxicity Severitya Dosage Modification AST or ALT ≥ 5 x ULN with bilirubin ≤ 2 x ULN [see Warnings and Precautions (5.3)] • Withhold VITRAKVI until recovery to ≤ Grade 1 or return to baseline. • Resume VITRAKVI at the next lower dose level. • Permanently discontinue if a Grade 4 AST and/or ALT elevation occurs after resuming VITRAKVI. AST or ALT > 3 × ULN with total bilirubin > 2 × ULN in the absence of alternative causes • Permanently discontinue VITRAKVI. ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal aGrading defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 2.5 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 that was used prior to initiating the CYP3A4 inhibitor [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]. 2.6 Dosage Modifications for Coadministration with Strong or Moderate CYP3A4 Inducers Avoid coadministration of strong CYP3A4 inducers with VITRAKVI. If coadministration of a strong CYP3A4 inducer cannot be avoided, double the VITRAKVI dose. Additionally, for coadministration with a moderate CYP3A4 inducer, double the VITRAKVI dose. After the inducer has been discontinued for 3 to 5 elimination half-lives, resume the VITRAKVI dose that was used prior to initiating the CYP3A4 inducer [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]. 2.7 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 )] . 2.8 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 packaged in one bottle containing 100 mL • 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. Oral Solution packaged in two bottles each containing 50 mL • Store the glass bottles of VITRAKVI oral solution in the refrigerator. Discard any unused VITRAKVI oral solution remaining after 31 days of first opening the bottle. • Prior to preparing an oral dose for administration, refer to the Instructions for Use.

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 )]. 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. Select patients for therapy based on an FDA-approved test. ( 1 , 2.1 ) 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 ).

7 DRUG INTERACTIONS • Strong CYP3A4 Inhibitors: Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration cannot be avoided, reduce the VITRAKVI dose. ( 2.5 , 7.1 ) • Moderate CYP3A4 Inhibitors: Monitor for adverse reactions more frequently in patients coadministered a moderate CYP3A4 inhibitor with VITRAKVI and reduce the VITRAKVI dosage based on severity of adverse reactions. ( 7.1 ) • Strong CYP3A4 Inducers: Avoid coadministration of strong CYP3A4 inducers with VITRAKVI. If coadministration cannot be avoided, increase the VITRAKVI dose. ( 2.6 , 7.1 ) • Moderate CYP3A4 Inducers: Increase the VITRAKVI dose. ( 2.6 , 7.1 ) • Sensitive CYP3A4 Substrates: Avoid coadministration of sensitive CYP3A4 substrates with VITRAKVI. ( 7.2 ) 7.1 Effects of Other Drugs on VITRAKVI Strong and Moderate CYP3A4 Inhibitors Coadministration of VITRAKVI with a strong or moderate 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 ( 2.5 )]. In patients coadministered a moderate CYP3A4 inhibitor with VITRAKVI, monitor for adverse reactions more frequently and reduce the VITRAKVI dosage based on the severity of emergent adverse reactions [see Dosage and Administration ( 2.3 )]. Strong and Moderate CYP3A4 Inducers Coadministration of VITRAKVI with a strong or moderate 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. For coadministration with moderate CYP3A4 inducers, modify VITRAKVI dose as recommended [see Dosage and Administration ( 2.6 )]. 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In a broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, and TRKC with IC 50 values between 5-11 nM. One other kinase TNK2 was inhibited at approximately 100-fold higher concentration. TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3 . Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines. In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L. 12.2 Pharmacodynamics Cardiac Electrophysiology At a dose 9-fold higher than the recommended adult dose, VITRAKVI does not prolong QTc intervals to any clinically relevant extent. 12.3 Pharmacokinetics The pharmacokinetics of larotrectinib were studied in healthy subjects and adult and pediatric patients with locally advanced or metastatic solid tumors. In healthy subjects who received a single dose of VITRAKVI capsules, systemic exposure (C max and AUC) of larotrectinib was dose proportional over the dose range of 100 mg to 400 mg (1 to 4 times the recommended adult dose) and slightly greater than proportional at doses of 600 mg to 900 mg (6 to 9 times the recommended adult dose). In adult patients who received VITRAKVI capsules 100 mg twice daily in Study LOXO-TRK-14001, peak plasma levels (C max ) of larotrectinib were achieved at approximately 1 hour after dosing and steady-state was reached within 3 days. Mean steady-state larotrectinib [coefficient of variation (CV%)] for C max was 788 (81%) ng/mL and AUC 0-24hr was 4351 (97%) ng*h/mL. Absorption The mean absolute bioavailability of VITRAKVI capsules was 34% (range: 32% to 37%). In healthy subjects, the AUC of VITRAKVI oral solution was similar to that of the capsules and the C max was 36% higher with the oral solution. Effect of Food The AUC of larotrectinib was similar and the C max was reduced by 35% after oral administration of a single 100 mg capsule of VITRAKVI to healthy subjects taken with a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the C max and AUC in the fasted state. Distribution The mean (CV%) volume of distribution (V ss ) of larotrectinib is 48 (38%) L following intravenous administration of larotrectinib in healthy subjects. Larotrectinib is 70% bound to human plasma proteins in vitro and binding is independent of drug concentrations. The blood-to-plasma concentration ratio is 0.9. Elimination The mean (CV%) clearance (CL/F) of larotrectinib is 98 (44%) L/h and the half-life is 2.9 hours following oral administration of VITRAKVI in healthy subjects. Metabolism Larotrectinib is metabolized predominantly by CYP3A4. Following oral administration of a single [ 14 C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, unchanged larotrectinib constituted 19% and an O-linked glucuronide constituted 26% of the major circulating radioactive drug components in plasma. Excretion Following oral administration of a single [ 14 C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, 58% (5% unchanged) of the administered radioactivity was recovered in feces and 39% (20% unchanged) was recovered in urine. Specific Populations Age (range: 28 days to 82 years), sex, and body weight (range: 3.8 kg to 179 kg) had no clinically meaningful effect on the pharmacokinetics of larotrectinib. Pediatric Patients In pediatric patients, the larotrectinib geometric mean (%CV) AUC 0-24hr by age subgroup was: 3348 (66%) ng*h/mL in patients 1 month to < 2 years (n = 9), 4135 (36%) ng*h/mL in patients 2 to < 12 years (n = 15), and 3108 (69%) ng*h/mL and in patients 12 to < 18 years (n = 9). Patients with Renal Impairment Following oral administration of a single 100 mg dose of VITRAKVI capsules in subjects with end-stage renal disease (e.g., subjects who required dialysis), the AUC 0-INF of larotrectinib increased 1.5-fold and C max increased 1.3-fold as compared to that in subjects with normal renal function (creatinine clearance ≥ 90 mL/min as estimated by Cockcroft-Gault). The pharmacokinetics of VITRAKVI in patients with moderate to severe renal impairment (creatinine clearance ≤ 60 mL/min) have not been studied. Patients with Hepatic Impairment Following oral administration of a single 100 mg dose of VITRAKVI capsules, the AUC 0-INF of larotrectinib increased 1.3-fold in subjects with mild hepatic impairment (Child-Pugh A), 2-fold in subjects with moderate hepatic impairment (Child-Pugh B) and 3.2-fold in subjects with severe hepatic impairment (Child-Pugh C) as compared to that in subjects with normal hepatic function. The C max was similar in subjects with mild and moderate hepatic impairment and the C max of larotrectinib increased 1.5-fold in subjects with severe hepatic impairment as compared to that in subjects with normal hepatic function [see Dosage and Administration ( 2.7 ), Use in Specific Populations ( 8.6 )] . Drug Interaction Studies Clinical Studies Effect of CYP3A Inhibitors: Coadministration of a single 100 mg dose of VITRAKVI capsules with itraconazole (strong CYP3A inhibitor) increased the AUC0-INF of larotrectinib by 4.3-fold and the Cmax by 2.8-fold as compared to VITRAKVI administered alone [see Dosage and Administration ( 2.5 ), Drug Interactions ( 7.1 )]. Coadministration of VITRAKVI with fluconazole (moderate CYP3A4 inhibitor) is predicted to increase VITRAKVI steady state AUC by 2.7-fold and Cmax by 1.9-fold. Effect of CYP3A Inducers: Coadministration of a single 100 mg dose of VITRAKVI capsules with rifampin (strong CYP3A inducer) decreased the AUC0-INF of larotrectinib by 81% and the Cmax by 71% as compared to VITRAKVI administered alone [see Dosage and Administration ( 2.6 ), Drug Interactions ( 7.1 )]. Coadministration of VITRAKVI with efavirenz (moderate CYP3A4 inducer) is predicted to decrease steady state AUC of VITRAKVI by approximately 72% and Cmax by 60% compared to VITRAKVI administered alone [see Dosage and Administration ( 2.6 ), Drug Interactions ( 7.1 )]. Effect of Strong P-glycoprotein (P-gp) Inhibitors: Coadministration of a single 100 mg dose of VITRAKVI capsules with a P-gp inhibitor (rifampin) increased the AUC 0-INF of larotrectinib by 1.7-fold and the C max by 1.8-fold as compared to VITRAKVI administered alone. Effect of Larotrectinib on CYP3A4 Substrates: Coadministration of VITRAKVI capsules 100 mg twice daily with a sensitive CYP3A4 substrate (midazolam) increased both the AUC 0-INF and C max of midazolam by 1.7-fold as compared to midazolam administered alone. The AUC 0-INF and C max of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased 1.4-fold as compared to when midazolam was administered alone [see Drug Interactions ( 7.2 )] . In Vitro Studies Effect of Transporter on Larotrectinib: Larotrectinib is a substrate for P-gp and BCRP. Larotrectinib is not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3. Effect of Larotrectinib on Transporters: Larotrectinib is not an inhibitor of BCRP, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, MATE1 and MATE2-K at clinically relevant concentrations. Effect of Larotrectinib on CYP Substrates: Larotrectinib is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.

12.1 Mechanism of Action Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In a broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, and TRKC with IC 50 values between 5-11 nM. One other kinase TNK2 was inhibited at approximately 100-fold higher concentration. TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3 . Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines. In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.

12.2 Pharmacodynamics Cardiac Electrophysiology At a dose 9-fold higher than the recommended adult dose, VITRAKVI does not prolong QTc intervals to any clinically relevant extent.

12.3 Pharmacokinetics The pharmacokinetics of larotrectinib were studied in healthy subjects and adult and pediatric patients with locally advanced or metastatic solid tumors. In healthy subjects who received a single dose of VITRAKVI capsules, systemic exposure (C max and AUC) of larotrectinib was dose proportional over the dose range of 100 mg to 400 mg (1 to 4 times the recommended adult dose) and slightly greater than proportional at doses of 600 mg to 900 mg (6 to 9 times the recommended adult dose). In adult patients who received VITRAKVI capsules 100 mg twice daily in Study LOXO-TRK-14001, peak plasma levels (C max ) of larotrectinib were achieved at approximately 1 hour after dosing and steady-state was reached within 3 days. Mean steady-state larotrectinib [coefficient of variation (CV%)] for C max was 788 (81%) ng/mL and AUC 0-24hr was 4351 (97%) ng*h/mL. Absorption The mean absolute bioavailability of VITRAKVI capsules was 34% (range: 32% to 37%). In healthy subjects, the AUC of VITRAKVI oral solution was similar to that of the capsules and the C max was 36% higher with the oral solution. Effect of Food The AUC of larotrectinib was similar and the C max was reduced by 35% after oral administration of a single 100 mg capsule of VITRAKVI to healthy subjects taken with a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the C max and AUC in the fasted state. Distribution The mean (CV%) volume of distribution (V ss ) of larotrectinib is 48 (38%) L following intravenous administration of larotrectinib in healthy subjects. Larotrectinib is 70% bound to human plasma proteins in vitro and binding is independent of drug concentrations. The blood-to-plasma concentration ratio is 0.9. Elimination The mean (CV%) clearance (CL/F) of larotrectinib is 98 (44%) L/h and the half-life is 2.9 hours following oral administration of VITRAKVI in healthy subjects. Metabolism Larotrectinib is metabolized predominantly by CYP3A4. Following oral administration of a single [ 14 C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, unchanged larotrectinib constituted 19% and an O-linked glucuronide constituted 26% of the major circulating radioactive drug components in plasma. Excretion Following oral administration of a single [ 14 C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, 58% (5% unchanged) of the administered radioactivity was recovered in feces and 39% (20% unchanged) was recovered in urine. Specific Populations Age (range: 28 days to 82 years), sex, and body weight (range: 3.8 kg to 179 kg) had no clinically meaningful effect on the pharmacokinetics of larotrectinib. Pediatric Patients In pediatric patients, the larotrectinib geometric mean (%CV) AUC 0-24hr by age subgroup was: 3348 (66%) ng*h/mL in patients 1 month to < 2 years (n = 9), 4135 (36%) ng*h/mL in patients 2 to < 12 years (n = 15), and 3108 (69%) ng*h/mL and in patients 12 to < 18 years (n = 9). Patients with Renal Impairment Following oral administration of a single 100 mg dose of VITRAKVI capsules in subjects with end-stage renal disease (e.g., subjects who required dialysis), the AUC 0-INF of larotrectinib increased 1.5-fold and C max increased 1.3-fold as compared to that in subjects with normal renal function (creatinine clearance ≥ 90 mL/min as estimated by Cockcroft-Gault). The pharmacokinetics of VITRAKVI in patients with moderate to severe renal impairment (creatinine clearance ≤ 60 mL/min) have not been studied. Patients with Hepatic Impairment Following oral administration of a single 100 mg dose of VITRAKVI capsules, the AUC 0-INF of larotrectinib increased 1.3-fold in subjects with mild hepatic impairment (Child-Pugh A), 2-fold in subjects with moderate hepatic impairment (Child-Pugh B) and 3.2-fold in subjects with severe hepatic impairment (Child-Pugh C) as compared to that in subjects with normal hepatic function. The C max was similar in subjects with mild and moderate hepatic impairment and the C max of larotrectinib increased 1.5-fold in subjects with severe hepatic impairment as compared to that in subjects with normal hepatic function [see Dosage and Administration ( 2.7 ), Use in Specific Populations ( 8.6 )] . Drug Interaction Studies Clinical Studies Effect of CYP3A Inhibitors: Coadministration of a single 100 mg dose of VITRAKVI capsules with itraconazole (strong CYP3A inhibitor) increased the AUC0-INF of larotrectinib by 4.3-fold and the Cmax by 2.8-fold as compared to VITRAKVI administered alone [see Dosage and Administration ( 2.5 ), Drug Interactions ( 7.1 )]. Coadministration of VITRAKVI with fluconazole (moderate CYP3A4 inhibitor) is predicted to increase VITRAKVI steady state AUC by 2.7-fold and Cmax by 1.9-fold. Effect of CYP3A Inducers: Coadministration of a single 100 mg dose of VITRAKVI capsules with rifampin (strong CYP3A inducer) decreased the AUC0-INF of larotrectinib by 81% and the Cmax by 71% as compared to VITRAKVI administered alone [see Dosage and Administration ( 2.6 ), Drug Interactions ( 7.1 )]. Coadministration of VITRAKVI with efavirenz (moderate CYP3A4 inducer) is predicted to decrease steady state AUC of VITRAKVI by approximately 72% and Cmax by 60% compared to VITRAKVI administered alone [see Dosage and Administration ( 2.6 ), Drug Interactions ( 7.1 )]. Effect of Strong P-glycoprotein (P-gp) Inhibitors: Coadministration of a single 100 mg dose of VITRAKVI capsules with a P-gp inhibitor (rifampin) increased the AUC 0-INF of larotrectinib by 1.7-fold and the C max by 1.8-fold as compared to VITRAKVI administered alone. Effect of Larotrectinib on CYP3A4 Substrates: Coadministration of VITRAKVI capsules 100 mg twice daily with a sensitive CYP3A4 substrate (midazolam) increased both the AUC 0-INF and C max of midazolam by 1.7-fold as compared to midazolam administered alone. The AUC 0-INF and C max of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased 1.4-fold as compared to when midazolam was administered alone [see Drug Interactions ( 7.2 )] . In Vitro Studies Effect of Transporter on Larotrectinib: Larotrectinib is a substrate for P-gp and BCRP. Larotrectinib is not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3. Effect of Larotrectinib on Transporters: Larotrectinib is not an inhibitor of BCRP, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, MATE1 and MATE2-K at clinically relevant concentrations. Effect of Larotrectinib on CYP Substrates: Larotrectinib is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.

20231103

9

3 DOSAGE FORMS AND STRENGTHS Capsules • 25 mg: white opaque hard gelatin capsule, size 2, with blue printing of "BAYER" cross and "25 mg" on body of capsules. 25 mg larotrectinib is equivalent to 30.7 mg larotrectinib sulfate. • 100 mg: white opaque hard gelatin capsule, size 0, with blue printing of "BAYER" cross and "100 mg" on body of capsule. 100 mg larotrectinib is equivalent to 123 mg larotrectinib sulfate. Oral Solution packaged in one bottle containing 100 mL • 20 mg/mL: clear yellow to orange solution. 20 mg/mL larotrectinib is equivalent to 24.6 mg/mL larotrectinib sulfate. Oral Solution packaged in two bottles each containing 50 mL • 20 mg/mL: colorless to yellow or orange or red or brownish solution. 20 mg/mL larotrectinib is equivalent to 24.6 mg/mL larotrectinib sulfate. • Capsules: 25 mg, 100 mg ( 3 ) • Oral Solution: 20 mg/mL ( 3 )

VITRAKVI LAROTRECTINIB LAROTRECTINIB LAROTRECTINIB GELATIN, UNSPECIFIED TITANIUM DIOXIDE Opaque White BAYER;25mg VITRAKVI LAROTRECTINIB LAROTRECTINIB LAROTRECTINIB GELATIN, UNSPECIFIED TITANIUM DIOXIDE Opaque White BAYER;100mg VITRAKVI LAROTRECTINIB LAROTRECTINIB LAROTRECTINIB WATER SUCROSE GLYCERIN SORBITOL CITRIC ACID MONOHYDRATE SODIUM PHOSPHATE TRISODIUM CITRATE DIHYDRATE PROPYLENE GLYCOL METHYLPARABEN POTASSIUM SORBATE ADRABETADEX Clear Yellow to Orange Citrus Berry VITRAKVI LAROTRECTINIB LAROTRECTINIB LAROTRECTINIB CITRIC ACID MONOHYDRATE HYDROXYPROPYL BETADEX SODIUM BENZOATE SODIUM CITRATE, UNSPECIFIED FORM SUCRALOSE WATER

13.2 Animal Toxicology and/or Pharmacology In general toxicology studies conducted in rats and monkeys and in reproductive toxicology studies conducted in rats and rabbits, administration of larotrectinib led to increased food consumption and increased body weight at doses resulting in exposures 0.6 times the human exposure at the 100 mg twice daily clinical dose. Obesity has also been one phenotypic outcome of some human syndromes resulting from congenital mutations in NTRK2 resulting in altered TRK signaling.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with larotrectinib. Larotrectinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or in the in vitro mammalian mutagenesis assays, with or without metabolic activation. In vivo, larotrectinib was negative in the mouse micronucleus test. Fertility studies with larotrectinib have not been conducted. In a 3-month repeat-dose toxicity study in the rat, larotrectinib had no effects on spermatogenesis at 75 mg/kg/day (approximately 7 times the human exposure at the 100 mg twice daily dose). Additionally, larotrectinib had no histological effects on the male reproductive tract in rats or monkeys at doses resulting in exposures up to 10 times the human exposure (AUC 0-24hr ) at the 100 mg twice daily clinical dose. In a 1-month repeat-dose study in the rat, decreased uterine weight and uterine atrophy were seen at 200 mg/kg/day [approximately 45 times the human exposure (AUC) at the 100 mg twice daily dose]. Fewer corpora lutea and increased incidence of anestrus were also noted at doses ≥ 60 mg/kg/day (approximately 10 times the human exposure at the 100 mg twice daily dose). Decreased fertility occurred in a juvenile animal study [see Use in Specific Populations ( 8.4 )] . There were no findings in female reproductive organs in repeat-dose studies in monkeys at exposures up to 22 times the human exposure at the 100 mg twice daily dose.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with larotrectinib. Larotrectinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or in the in vitro mammalian mutagenesis assays, with or without metabolic activation. In vivo, larotrectinib was negative in the mouse micronucleus test. Fertility studies with larotrectinib have not been conducted. In a 3-month repeat-dose toxicity study in the rat, larotrectinib had no effects on spermatogenesis at 75 mg/kg/day (approximately 7 times the human exposure at the 100 mg twice daily dose). Additionally, larotrectinib had no histological effects on the male reproductive tract in rats or monkeys at doses resulting in exposures up to 10 times the human exposure (AUC 0-24hr ) at the 100 mg twice daily clinical dose. In a 1-month repeat-dose study in the rat, decreased uterine weight and uterine atrophy were seen at 200 mg/kg/day [approximately 45 times the human exposure (AUC) at the 100 mg twice daily dose]. Fewer corpora lutea and increased incidence of anestrus were also noted at doses ≥ 60 mg/kg/day (approximately 10 times the human exposure at the 100 mg twice daily dose). Decreased fertility occurred in a juvenile animal study [see Use in Specific Populations ( 8.4 )] . There were no findings in female reproductive organs in repeat-dose studies in monkeys at exposures up to 22 times the human exposure at the 100 mg twice daily dose. 13.2 Animal Toxicology and/or Pharmacology In general toxicology studies conducted in rats and monkeys and in reproductive toxicology studies conducted in rats and rabbits, administration of larotrectinib led to increased food consumption and increased body weight at doses resulting in exposures 0.6 times the human exposure at the 100 mg twice daily clinical dose. Obesity has also been one phenotypic outcome of some human syndromes resulting from congenital mutations in NTRK2 resulting in altered TRK signaling.

NDA210861

VITRAKVI

LAROTRECTINIB

50419-391

HUMAN PRESCRIPTION DRUG

ORAL

Package Label - 25 mg - 60 Capsules PRINCIPAL DISPLAY PANEL NDC 71777- 390 -01 VITRAKVI® (larotrectinib) capsules 25 mg Usual Dosage: See prescribing information. Rx only. 60 capsules. Keep out of reach of children. Store at 20°C to 25°C (68°F to 77°F). Excursions permitted from 15°C to 30°C (59° to 86°F). Manufactured for Loxo Omcology, Inc. Stamford, CT 06901 86579626 (01)10371777390012 Bayer LOXO Each capsule contains 25 mg larotrectinib (equivalent to 30.7 mg larotrectinib sulfate). image of 25 mg label principal panel - 60 capsules

Dosage and Administration ( 2.3 , 2.4 ) 11/2023 Dosage and Administration ( 2.6 ) 11/2022 Dosage and Administration ( 2.8 ) 12/2022 Warnings and Precautions ( 5.3 ) 11/2023

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Central Nervous System Effects Advise patients to notify their healthcare provider if they experience new or worsening neurotoxicity. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions [see Warnings and Precautions (5.1 ) ] . Skeletal Fractures Inform patients that bone fractures have been reported in patients taking VITRAKVI. Advise patients to report symptoms such as pain, changes in mobility, or deformity to their healthcare provider [see Warnings and Precautions ( 5.2 )]. Hepatotoxicity Advise patients that they will need to undergo laboratory tests to monitor liver function [see Warnings and Precautions ( 5.3 )] . Embryo-Fetal Toxicity Advise males and females of reproductive potential of the potential risk to a fetus [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.1 )]. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective contraception during the treatment with VITRAKVI and for 1 week after the last dose [see Use in Specific Populations ( 8.3 ) ] . Advise males with female partners of reproductive potential to use effective contraception during treatment with VITRAKVI and for 1 week after the last dose [see Use in Specific Populations ( 8.3 ) ] . Lactation Advise women not to breastfeed during treatment with VITRAKVI and for 1 week following the last dose [see Use in Specific Populations ( 8.2 ) ] . Infertility Advise females of reproductive potential that VITRAKVI may impair fertility [See Nonclinical Toxicology ( 13.1 )] . Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John’s wort, grapefruit or grapefruit juice while taking VITRAKVI [see Drug Interactions ( 7 .1, 7.2)]. Manufactured for Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981

INSTRUCTIONS FOR USE VITRAKVI (vi trak vee) (larotrectinib) oral solution Read this Instructions for Use before you take or give a dose of VITRAKVI oral solution for the first time and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. Your healthcare provider should show you how to correctly measure the prescribed dose of VITRAKVI oral solution before you take or give a dose for the first time. Important information about measuring VITRAKVI oral solution: • Always use the oral syringes provided with VITRAKVI to make sure that you correctly measure the prescribed dose. • When you receive VITRAKVI oral solution from your healthcare provider or pharmacist, you will get a box that contains VITRAKVI oral solution. You may receive more than 1 box of VITRAKVI oral solution. • Your healthcare provider or pharmacist will also provide you bottle adaptors and syringes. You will receive one bottle adaptor per bottle of VITRAKVI oral solution. After inserting the bottle adaptor into the bottle, do not remove the bottle adaptor. • You will receive five 1 mL or 5 mL oral syringes that are marked to help you correctly measure the prescribed dose of VITRAKVI oral solution. Each oral syringe may be used over a 7-day period. Do not use a household teaspoon to measure the dose. Supplies needed to take or give a dose of VITRAKVI oral solution How to prepare a dose of VITRAKVI oral solution: Step 1: Remove the VITRAKVI oral solution bottle from the box. Place the bottle on a flat work surface. Open the bottle by pushing down firmly on the child-resistant cap and turning it in the direction of the arrow (counter-clockwise) See Figure B. Do not throw away the child-resistant cap. Step 2: Insert the bottle adaptor by pressing it into the bottle neck and make sure it is secure. See Figure C. Do not remove the bottle adaptor. If the bottle adaptor is missing, talk to your healthcare provider. Step 3: Remove the oral syringe from the wrapper. Throw the wrapper away in your household trash. Look at the markings on the barrel of the oral syringe and find the marking that matches the VITRAKVI oral solution dose in mL prescribed by your healthcare provider. See Figure D . Step 4: With the bottle on your flat work surface, use 1 hand to hold the bottle upright. Using your other hand, push the air out of the oral syringe by pushing the plunger down. Then, insert the tip of the oral syringe into the bottle adaptor at the top of the bottle. See Figure E . The tip of the oral syringe should fit snugly into the hole of the bottle adaptor. Step 5: Use 1 hand to hold the oral syringe in place. With the other hand, turn the bottle upside down. Pull back on the plunger until the top of the plunger lines up with the marking on the barrel of the oral syringe that matches the dose of VITRAKVI oral solution prescribed by your healthcare provider. See Figure F . Your dose may be different than the dose shown in Figure F. Step 6: Check for air bubbles in the oral syringe. If you see air bubbles, push up gently on the plunger to push any large air bubbles back into the bottle. Then, pull back on the plunger to the prescribed dose. See Figure G . Step 7: Turn the bottle upright again and place it on your work surface. Remove the oral syringe from the bottle adaptor by gently pulling up on the syringe barrel. See Figure H. Do not push on the plunger during this step. The bottle adaptor should stay attached to the bottle. Giving a dose of VITRAKVI oral solution by mouth: Step 8: Place the tip of the oral syringe into the child’s mouth against the inside of the cheek. Slowly squirt VITRAKVI oral solution into the mouth by pressing down on the plunger and allow the child to swallow. See Figure I . • The child should be kept in an upright position for a few minutes right after giving a dose of VITRAKVI. • If the child spits up a dose or you are not sure the entire dose was given, do not give another dose. Wait until the next scheduled dose. Step 9: Replace the child-resistant cap on the bottle of VITRAKVI oral solution. Do not remove the bottle adaptor. Close the bottle by turning the bottle cap in the direction of the arrow (clockwise). See Figure J . Cleaning instructions for oral syringes Follow the instructions below for cleaning the oral syringe (Step 10 through Step 16). After 7 days of use, throw away the oral syringe in your household trash. Use a new oral syringe for the next 7 days. Step 10: Remove plunger from the barrel of the oral syringe. See Figure K . Step 11: Rinse the barrel and plunger in warm running water to help make sure that all of the medicine has been removed from the oral syringe. See Figure L. Do not boil the oral syringe. Step 12: Re-insert the plunger into the barrel of the oral syringe. See Figure M . Step 13: Draw warm water several times into the oral syringe and squirt out again until all of the medicine has been removed from the oral syringe. See Figure N . Step 14: Repeat steps 10 and 11 to rinse the barrel and plunger again with warm water. See Figure O . Step 15: Shake off excess water or wipe off the outside. See Figure P . Place the barrel and plunger on a clean, dry paper towel to dry. Step 16: Repeat step 12 to assemble the oral syringe and store in a clean place until the next use. Replace the oral syringe after 7 days of use, or if: • there is any damage to the barrel, plunger, or tip • the dosage marking is no longer clearly recognizable or • it becomes difficult to move the plunger How should I store VITRAKVI oral solution? • Store VITRAKVI oral solution in a refrigerator between 36° F to 46° F (2° C to 8° C). Do not freeze. • Write the date that you opened the bottle of VITRAKVI oral solution on the bottle. See Figure Q . • Throw away (dispose of) any unused VITRAKVI oral solution: • Bottle of 100 mL: remaining 90 days after first opening the bottle • Bottle of 50 mL: remaining 31 days after first opening the bottle Keep VITRAKVI oral solution and all medicines out of the reach of children. Talk to your healthcare provider if you have questions about how to use VITRAKVI oral solution. For more information, go to www.VITRAKVI.com or call 1-888-842-2937. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured for Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981 Revised: 12/2022 image of supplies needed to take or give a dose of VITRAKVI oral solution image of how to open the bottle image of how to insert the adaptor into the bottle image of the oral syringe and a close up of the markings in mL image of of how to insert the oral syringe into the bottle image of how to draw VITRAKVI into the oral syringe for proper dose image of how to expell air bubbles in the oral syringe image of how to remove the oral syringe from the bottle image of how to properly press the plunger to deliver the dose image of recapping the bottle image of removing the plunger from the barrel of the oral syringe image of rinsing the oral syringe (plunger and barrel) image of re-insertion of plunger into oral syringe barrel image of cleaning oral syringe using warm water image of rinsing the plunger and barrel of the oral syringe a 2nd time image of shaking excess water from the barrel and plunger image of where to write the date of when the bottle was opened

14 CLINICAL STUDIES The efficacy of VITRAKVI was evaluated in pediatric and adult patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of three multicenter, open-label, single-arm clinical trials: Study LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). All patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. Adult patients received VITRAKVI 100 mg orally twice daily and pediatric patients (18 years or younger) received VITRAKVI 100 mg/m 2 up to a maximum dose of 100 mg orally twice daily until unacceptable toxicity or disease progression. Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next generation sequencing (NGS) or fluorescence in situ hybridization (FISH). NTRK gene fusions were inferred in three patients with infantile fibrosarcoma who had a documented ETV6 translocation identified by FISH. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1. The assessment of efficacy was based on the first 55 patients with solid tumors with an NTRK gene fusion enrolled across the three clinical trials. Baseline characteristics were: median age 45 years (range 4 months to 76 years); 22% <18 years of age, and 78% ≥18 years of age; 53% male; 67% White; 7% Hispanic/Latino, 4% Asian, 4% Black; and ECOG performance status (PS) 0-1 (93%) or 2 (7%). Eighty-two percent of patients had metastatic disease, including patients with brain metastases, and 18% had locally advanced, unresectable disease. Ninety-eight percent of patients had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy. Of these, 82% (n = 45) received prior systemic therapy with a median of two prior systemic regimens and 35% (n = 19) received three or more prior systemic regimens. The most common cancers were salivary gland tumors (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%). A total of 50 patients had NTRK gene fusions detected by NGS and 5 patients had NTRK gene fusions detected by FISH. Efficacy results are summarized in Tables 5, 6, and 7. Table 5 Efficacy Results for Patients with Solid Tumors Harboring NTRK Gene Fusions Efficacy Parameter VITRAKVI N = 55 Overall response rate (95% CI) 75% (61%, 85%) Complete response rate 25% * Partial response rate 49% Duration of response (DOR) N = 41 Median DOR 32.9 ** (14.8, NE *** ) Range (months) 1.6+, 50.6+ % with Observed DOR > 12 months 63% % with Observed DOR > 24 months 49% + Denotes ongoing response. * 5% were pathological complete response. Patients undergoing a surgical resection whose post-operative pathologic assessment showed no viable tumor cells and negative margins were pathological complete responders provided that no other sites of disease were present. ** Kaplan-Meier estimates *** NE: Not evaluable Table 6 Efficacy Results by Tumor Type Tumor Type Patients (N=55) ORR DOR % 95% CI Range (months) Salivary gland 12 83% (52%, 98%) 7.7, 44.7+ Soft tissue sarcoma 11 91% (59%, 100%) 3.6+, 50.6+ Infantile fibrosarcoma 7 100% (59%, 100%) 1.6+, 28.6+ Thyroid 5 100% (48%, 100%) 3.7, 32.9 Lung 4 75% (19%, 99%) 8.2, 36.8+ Melanoma 4 50% NA 1.9+, 23.2+ * Colon 4 25% NA 5.6 * Gastrointestinal stromal tumor 3 100% (29%, 100%) 9.5, 31.1+ Cholangiocarcinoma 2 SD, NE NA NA Appendix 1 SD NA NA Breast 1 PD NA NA Pancreas 1 SD NA NA NA = not applicable due to small numbers or lack of response; CR = complete response; PR = partial response; NE = not evaluable; SD = stable disease; PD = progressive disease; NR = not reached. + Denotes ongoing response. * Observed values at data cutoff, not a range. Table 7 Efficacy Results by NTRK Fusion Partner NTRK Partner* Patients (N=55) ORR DOR % 95% CI Range (months) ETV6-NTRK3 25 84% (64%, 96%) 3.7, 44.7+ TPM3-NTRK1 9 56% (21%, 86%) 3.7, 27.5+ LMNA-NTRK1 5 40% (5%, 85%) 5.6, 50.6+ Inferred ETV6-NTRK3 3 100% (29%, 100%) 1.6+, 28.6+ ** IRF2BP2-NTRK1 2 CR, PR NA 3.7, 36.8+ SQSTM1-NTRK1 2 pCR, PR NA 9.9, 12.9+ PDE4DIP-NTRK1 1 PR NA 3.6+ *** PPL-NTRK1 1 CR NA 28.2+ *** STRN-NTRK2 1 PR NA 5.6 *** TPM4-NTRK3 1 pCR NA 25.6+ *** TPR-NTRK1 1 PR NA 8.2 *** TRIM63-NTRK1 1 PR NA 1.9+ *** CTRC-NTRK1 1 SD NA NA GON4L-NTRK1 1 NE NA NA PLEKHA6-NTRK1 1 SD NA NA CR = complete response; PR = partial response; pCR = pathological complete response; NE = not evaluable; SD = stable disease; NA = not applicable; NR = Not reached. + Denotes ongoing response. * Fusion partners identified in the primary analysis set (N=55) may not represent all potential fusion partners. ** Duration of response censored at the time of surgery for one pediatric patient with unresectable infantile fibrosarcoma who underwent resection following partial response and who remained disease-free at data cutoff. *** Observed values at data cutoff, not a range.

8.5 Geriatric Use Of 279 patients in the overall safety population who received VITRAKVI, 19% of patients were ≥ 65 years of age and 5% of patients were ≥ 75 years of age. Clinical studies of VITRAKVI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.2 Lactation Risk Summary There are no data on the presence of larotrectinib or its metabolites in human milk and no data on its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with larotrectinib and for 1 week after the last dose.

8.4 Pediatric Use The safety and effectiveness of VITRAKVI in pediatric patients was established based upon data from three multicenter, open-label, single-arm clinical trials in adult or pediatric patients 28 days and older [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14 )]. The efficacy of VITRAKVI was evaluated in 12 pediatric patients and is described in the Clinical Studies section [see Clinical Studies ( 14 )] . The safety of VITRAKVI was evaluated in 92 pediatric patients who received VITRAKVI. Of these 92 patients, 36% were <1 month to < 2 years (n = 33), 41% were 2 years to < 12 years (n = 38), and 23% were 12 years to < 18 years (n = 21); 29% had metastatic disease, 42% had locally advanced disease, and 27% had primary CNS; and 86% had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy. The most common cancers were infantile fibrosarcoma (37%), primary CNS tumors (27%), soft tissue sarcoma (24%), and thyroid cancer (7%). The median duration of exposure was 7.4 months (range: 0.4 months to 39 months). Due to the small number of pediatric and adult patients, the single arm design of clinical studies of VITRAKVI, and confounding factors such as differences in susceptibility to infections between pediatric and adult patients, it is not possible to determine whether differences in the incidence of adverse reactions to VITRAKVI are related to patient age or other factors. Adverse reactions occurring more frequently (at least a 10% increase in per-patient incidence) in pediatric patients compared to adult patients were pyrexia (45% versus 13%), vomiting (42% versus 17% in adults), diarrhea (35% versus 23% in adults), rash (28% versus 15% in adults), upper respiratory tract infection (23% versus 8% in adults), nasopharyngitis (16% versus 6% in adults), and otitis media and rhinitis (each 14% versus 0.5% in adults). Laboratory abnormalities occurring more frequently (at least a 10% increase in per-patient incidence) in pediatric patients compared to adult patients were AST increased (63% versus 49% in adults), neutrophil count decrease (60% versus 16% in adults), leukocyte count decrease (39% versus 27% in adults), hyperkalemia (36% versus 15%), and lymphocyte increase (24% versus 0.5%). Two of the 92 pediatric patients discontinued VITRAKVI due to an adverse reaction (Grade 3 increased ALT and Grade 3 decreased neutrophil count). The pharmacokinetics of VITRAKVI in the pediatric population were similar to those seen in adults [see Clinical Pharmacology ( 12.3 )]. Juvenile Animal Toxicity Data Larotrectinib was administered in a juvenile toxicity study in rats at twice daily doses of 0.2, 2 and 7.5 mg/kg from postnatal day (PND) 7 to 27 and at twice daily doses of 0.6, 6 and 22.5mg/kg between PND 28 and 70. The dosing period was equivalent to human pediatric populations from newborn to adulthood. The doses of 2/6 mg/kg twice daily [approximately 0.7 times the human exposure (AUC) at the clinical dose of 100 mg twice daily] and 7.5/22.5 mg/kg twice daily (approximately 4 times the human exposure at the clinical dose of 100 mg twice daily) resulted in mortality between PND 9 to 99; a definitive cause of death was not identified in the majority of cases. The main findings were transient central nervous system-related signs including head flick, tremor, and circling in both sexes. An increase in the number of errors in a maze swim test occurred in females at exposures of approximately 4 times the human exposure (AUC) at the clinical dose of 100 mg twice daily. Decreased growth and delays in sexual development occurred in the mid- and high-dose groups. Mating was normal in treated animals, but a reduction in pregnancy rate occurred at the high-dose of 7.5/22.5 mg/kg twice daily (approximately 4 times the human exposure at the clinical dose of 100 mg twice daily).

8.1 Pregnancy Risk Summary 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 [see Clinical Pharmacology ( 12.1 )] , VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on VITRAKVI use in pregnant women. Administration of larotrectinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily (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% to 4% and 15% to 20%, respectively. Data Human Data Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Animal Data Larotrectinib crosses the placenta in animals. Larotrectinib did not result in embryolethality at maternally toxic doses [up to 40 times the human exposure based on area under the curve (AUC) at the clinical dose of 100 mg twice daily] in embryo-fetal development studies in pregnant rats dosed during the period of organogenesis; however, larotrectinib was associated with fetal anasarca in rats from dams treated at twice-daily doses of 40 mg/kg [11 times the human exposure (AUC) at the clinical dose of 100 mg twice daily]. In pregnant rabbits, larotrectinib administration was associated with omphalocele at twice-daily doses of 15 mg/kg (0.7 times the human exposure at the clinical dose of 100 mg twice daily).

8 USE IN SPECIFIC POPULATIONS • Lactation: Advise not to breastfeed. ( 8.2 ) • Hepatic Impairment: Reduce the starting dose of VITRAKVI in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment. ( 2.7 , 8.7 ) 8.1 Pregnancy Risk Summary 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 [see Clinical Pharmacology ( 12.1 )] , VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on VITRAKVI use in pregnant women. Administration of larotrectinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily (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% to 4% and 15% to 20%, respectively. Data Human Data Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Animal Data Larotrectinib crosses the placenta in animals. Larotrectinib did not result in embryolethality at maternally toxic doses [up to 40 times the human exposure based on area under the curve (AUC) at the clinical dose of 100 mg twice daily] in embryo-fetal development studies in pregnant rats dosed during the period of organogenesis; however, larotrectinib was associated with fetal anasarca in rats from dams treated at twice-daily doses of 40 mg/kg [11 times the human exposure (AUC) at the clinical dose of 100 mg twice daily]. In pregnant rabbits, larotrectinib administration was associated with omphalocele at twice-daily doses of 15 mg/kg (0.7 times the human exposure at the clinical dose of 100 mg twice daily). 8.2 Lactation Risk Summary There are no data on the presence of larotrectinib or its metabolites in human milk and no data on its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with larotrectinib and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating VITRAKVI [see Use in Specific Populations ( 8.1 )] . Contraception VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Females Advise female patients of reproductive potential to use effective contraception during treatment with VITRAKVI and for 1 week after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with VITRAKVI and for 1 week after the last dose. Infertility Females Based on histopathological findings in the reproductive tracts of female rats in a 1-month repeated-dose study, VITRAKVI may reduce fertility [See Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of VITRAKVI in pediatric patients was established based upon data from three multicenter, open-label, single-arm clinical trials in adult or pediatric patients 28 days and older [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14 )]. The efficacy of VITRAKVI was evaluated in 12 pediatric patients and is described in the Clinical Studies section [see Clinical Studies ( 14 )] . The safety of VITRAKVI was evaluated in 92 pediatric patients who received VITRAKVI. Of these 92 patients, 36% were <1 month to < 2 years (n = 33), 41% were 2 years to < 12 years (n = 38), and 23% were 12 years to < 18 years (n = 21); 29% had metastatic disease, 42% had locally advanced disease, and 27% had primary CNS; and 86% had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy. The most common cancers were infantile fibrosarcoma (37%), primary CNS tumors (27%), soft tissue sarcoma (24%), and thyroid cancer (7%). The median duration of exposure was 7.4 months (range: 0.4 months to 39 months). Due to the small number of pediatric and adult patients, the single arm design of clinical studies of VITRAKVI, and confounding factors such as differences in susceptibility to infections between pediatric and adult patients, it is not possible to determine whether differences in the incidence of adverse reactions to VITRAKVI are related to patient age or other factors. Adverse reactions occurring more frequently (at least a 10% increase in per-patient incidence) in pediatric patients compared to adult patients were pyrexia (45% versus 13%), vomiting (42% versus 17% in adults), diarrhea (35% versus 23% in adults), rash (28% versus 15% in adults), upper respiratory tract infection (23% versus 8% in adults), nasopharyngitis (16% versus 6% in adults), and otitis media and rhinitis (each 14% versus 0.5% in adults). Laboratory abnormalities occurring more frequently (at least a 10% increase in per-patient incidence) in pediatric patients compared to adult patients were AST increased (63% versus 49% in adults), neutrophil count decrease (60% versus 16% in adults), leukocyte count decrease (39% versus 27% in adults), hyperkalemia (36% versus 15%), and lymphocyte increase (24% versus 0.5%). Two of the 92 pediatric patients discontinued VITRAKVI due to an adverse reaction (Grade 3 increased ALT and Grade 3 decreased neutrophil count). The pharmacokinetics of VITRAKVI in the pediatric population were similar to those seen in adults [see Clinical Pharmacology ( 12.3 )]. Juvenile Animal Toxicity Data Larotrectinib was administered in a juvenile toxicity study in rats at twice daily doses of 0.2, 2 and 7.5 mg/kg from postnatal day (PND) 7 to 27 and at twice daily doses of 0.6, 6 and 22.5mg/kg between PND 28 and 70. The dosing period was equivalent to human pediatric populations from newborn to adulthood. The doses of 2/6 mg/kg twice daily [approximately 0.7 times the human exposure (AUC) at the clinical dose of 100 mg twice daily] and 7.5/22.5 mg/kg twice daily (approximately 4 times the human exposure at the clinical dose of 100 mg twice daily) resulted in mortality between PND 9 to 99; a definitive cause of death was not identified in the majority of cases. The main findings were transient central nervous system-related signs including head flick, tremor, and circling in both sexes. An increase in the number of errors in a maze swim test occurred in females at exposures of approximately 4 times the human exposure (AUC) at the clinical dose of 100 mg twice daily. Decreased growth and delays in sexual development occurred in the mid- and high-dose groups. Mating was normal in treated animals, but a reduction in pregnancy rate occurred at the high-dose of 7.5/22.5 mg/kg twice daily (approximately 4 times the human exposure at the clinical dose of 100 mg twice daily). 8.5 Geriatric Use Of 279 patients in the overall safety population who received VITRAKVI, 19% of patients were ≥ 65 years of age and 5% of patients were ≥ 75 years of age. Clinical studies of VITRAKVI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). Larotrectinib clearance was reduced in subjects with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment [see Clinical Pharmacology ( 12.3 )] . Reduce VITRAKVI dose as recommended [see Dosage and Administration ( 2.7 )] . 8.7 Renal Impairment No dose adjustment is recommended for patients with renal impairment of any severity [see Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING Capsules 25 mg: Hard gelatin opaque white capsule size #2 with blue printing of "BAYER" cross and "25 mg" on the body of the capsule. • 60 count bottle NDC# 50419-390-01 100 mg: Hard gelatin opaque white capsule size #0 with blue printing of "BAYER" cross and "100 mg" on the body of the capsule. • 60 count bottle NDC# 50419-391-01 Store capsules at room temperature 20°C to 25°C (68°F to 77°F); temperature excursions between 15°C and 30°C (59°F to 86°F) are permitted [see USP Controlled Room Temperature]. Oral Solution Packaged in One Bottle Containing 100 mL 20 mg/mL: Clear yellow to orange solution. • One bottle containing 100 mL NDC# 50419-392-01 Refrigerate oral solution at 2°C to 8°C (36°F to 46°F). Do not freeze. Oral Solution Packaged in Two Bottles Each Containing 50 mL 20 mg/mL: Colorless to yellow or orange or red or brownish solution. • Two bottles each containing 50 mL NDC# 50419-393-03 Refrigerate oral solution at 2°C to 8°C (36°F to 46°F). Do not freeze.