VITRAKVI

1 INDICATIONS AND USAGE VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that: • have a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion without a known acquired resistance mutation, • are metastatic or where surgical resection is likely to result in severe morbidity, and • have no satisfactory alternative treatments or that have progressed following treatment. 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 ).

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 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.

5 WARNINGS AND PRECAUTIONS • Neurotoxicity: Advise patients and caretakers of the risk of neurologic adverse reactions. 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 ) • Hepatotoxicity: Monitor liver tests including ALT and AST every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity. ( 2.6 , 5.2 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. ( 5.3 , 8.3 ) 5.1 Neurotoxicity Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively [see Adverse Reactions ( 6.1 )] . The majority (65%) of neurologic adverse reactions occurred within the first three months of treatment (range: 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%). 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 Hepatotoxicity Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients [see Adverse Reactions ( 6.1 )] . One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients. Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed [see Dosage and Administration ( 2.3 )] . 5.3 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 final dose of VITRAKVI [see Use in Specific Populations ( 8.1 , 8.3 )] .

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS • 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.

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 final dose.

6 ADVERSE REACTIONS 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. (%) …