USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oLactation: Advise not to breastfeed. (8.2)oHepatic Impairment: Reduce the starting dose of VITRAKVI in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment. (2.6, 8.7). oLactation: Advise not to breastfeed. (8.2). oHepatic Impairment: Reduce the starting dose of VITRAKVI in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment. (2.6, 8.7). 8.1 Pregnancy. Risk SummaryBased 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 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 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.DataHuman DataPublished 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 DataLarotrectinib 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 SummaryThere 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 week after the final dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating VITRAKVI [see Use in Specific Populations (8.1)].ContraceptionVITRAKVI can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].FemalesAdvise female patients of reproductive potential to use effective contraception during treatment with VITRAKVI and for at least week after the final dose.MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with VITRAKVI and for week after the final dose.InfertilityFemalesBased on histopathological findings in the reproductive tracts of female rats in 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 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 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 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 increased ALT and Grade 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 DataLarotrectinib was administered in juvenile toxicity study in rats at twice daily doses of 0.2, and 7.5 mg/kg from postnatal day (PND) to 27 and at twice daily doses of 0.6, 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 times the human exposure at the clinical dose of 100 mg twice daily) resulted in mortality between PND to 99; 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 maze swim test occurred in females at exposures of approximately 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 reduction in pregnancy rate occurred at the high-dose of 7.5/22.5 mg/kg twice daily (approximately 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 (2.6)].. 8.7 Renal Impairment. No dose adjustment is recommended for patients with renal impairment of any severity [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oCentral Nervous System (CNS) Effects: Advise patients and caretakers of the risk of CNS adverse reactions including dizziness, cognitive impairment, mood disorders, and sleep disturbances. Advise patients not to drive or operate hazardous machinery if experiencing neurotoxicity. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity. (2.3, 5.1)oSkeletal Fractures: Promptly evaluate patients with signs or symptoms of fractures. (5.2) oHepatotoxicity: Monitor liver tests including ALT and AST every 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, 5.3)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. (5.4, 8.3). oCentral Nervous System (CNS) Effects: Advise patients and caretakers of the risk of CNS adverse reactions including dizziness, cognitive impairment, mood disorders, and sleep disturbances. Advise patients not to drive or operate hazardous machinery if experiencing neurotoxicity. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity. (2.3, 5.1). oSkeletal Fractures: Promptly evaluate patients with signs or symptoms of fractures. (5.2) oHepatotoxicity: Monitor liver tests including ALT and AST every 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, 5.3). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. (5.4, 8.3). 5.1 Central Nervous System Effects Central nervous system (CNS) adverse reactions occurred in patients receiving VITRAKVI, including dizziness, cognitive impairment, mood disorders, and sleep disturbances.In patients who received VITRAKVI, all grades CNS effects including cognitive impairment, mood disorders, dizziness and sleep disorders were observed in 42% with Grades 3-4 in 3.9% of patients. Cognitive impairment occurred in 11% of patients. The median time to onset of cognitive impairment was 5.6 months (range: days to 41 months). Cognitive impairment occurring in >= 1% of patients included memory impairment (3.6%), confusional state (2.9%), disturbance in attention (2.9%), delirium (2.2%), cognitive disorders (1.4%), and Grade cognitive adverse reactions occurred in 2.5% of patients. Among the 30 patients with cognitive impairment, 7% required dose modification, and 20% required dose interruption.Mood disorders occurred in 14% of patients. The median time to onset of mood disorders was 3.9 months (range: day to 40.5 months). Mood disorders occurring in >= 1% of patients included anxiety (5%), depression (3.9%), agitation (2.9%), and irritability (2.9%). Grade mood disorders occurred in 0.4% of patients. Dizziness occurred in 27% of patients, and Grade dizziness occurred in 1.1% of patients. Among the 74 patients who experienced dizziness, 5% of patients required dose modification, and 5% required dose interruption.Sleep disturbances occurred in 10% of patients. Sleep disturbances included insomnia (7%), somnolence (2.5%), and sleep disorder (0.4%). There were no Grade 3-4 sleep disturbances. Among the 28 patients who experienced sleep disturbances, patient each (3.6%) required dose modification or dose interruption.Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed [see Dosage and Administration (2.3)].. 5.2 Skeletal Fractures Among 187 adult patients who received VITRAKVI across clinical trials, fractures were reported in 7% and among 92 pediatric patients, fractures were reported in 9% (N=279; 8%). Median time to fracture was 11.6 months (range 0.9 to 45.8 months) in patients followed per fracture. Fractures of the femur, hip or acetabulum were reported in patients (3 adult, pediatric). Most fractures were associated with minimal or moderate trauma. Some fractures were associated with radiologic abnormalities suggestive of local tumor involvement. VITRAKVI treatment was interrupted due to fracture in 1.4% patients. Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity). There are no data on the effects of VITRAKVI on healing of known fractures or risk of future fractures.. 5.3 Hepatotoxicity. In patients who received VITRAKVI, increased AST of any grade occurred in 52% of patients and increased ALT of any grade occurred in 45%. Grade 3-4 increased AST or ALT occurred in 3.1% and 2.5% of patients, respectively [see Adverse Reactions (6.1)]. The median time to onset of increased AST was 2.1 months (range: day to 4.3 years). The median time to onset of increased ALT was 2.3 months (range: day to 4.2 years). Increased AST and ALT leading to dose modifications occurred in 1.4% and 2.2% of patients, respectively. Increased AST or ALT led to permanent discontinuation in (1.1%) of patients.Monitor liver tests, including ALT and AST, every 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)].. 5.4 Embryo-Fetal Toxicity. Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, VITRAKVI can cause fetal harm when administered to 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 fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for week after the final dose of VITRAKVI [see Use in Specific Populations (8.1, 8.3)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:The following clinically significant adverse reactions are described elsewhere in the labeling:oCentral Nervous System Effects [see Warnings and Precautions (5.1)]oSkeletal Fractures [see Warnings and Precautions (5.2)]oHepatotoxicity [see Warnings and Precautions (5.3)]. oCentral Nervous System Effects [see Warnings and Precautions (5.1)]. oSkeletal Fractures [see Warnings and Precautions (5.2)]. oHepatotoxicity [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.. 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 months and 30% patients exposed for greater than 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/m2 twice daily up to 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/m2 twice daily to 120 mg/m2 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 or 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 and Table 3, respectively. Table Adverse Reactions Occurring in >= 10% of Patients Treated with VITRAKVIAdverse Reaction VITRAKVIN 279All Grades(%)Grade 3-4(%)Musculoskeletal and Connective Tissue Musculoskeletal Pain1423.9 Muscular weakness100.7General Fatigue2362.5 Pyrexia241.8 Edema3190.7Respiratory, Thoracic and Mediastinal Cough4320.4 Dyspnea5173 Upper respiratory tract infection130 Nasal congestion110Nervous System Dizziness6271.1 Headache150.4 Cognitive Impairment7112.5Gastrointestinal Constipation270.4 Diarrhea271.4 Nausea250.7 Vomiting250.7 Abdominal pain8212.2Skin and Subcutaneous Tissue Disorders Rash9 190.4Psychiatric Mood disorders10140.4 Sleep Disturbance11100Investigations Increased weight143.6Metabolism and Nutrition Decreased appetite 121.4Infections and Infestations Urinary tract infection12121.4 The adverse reaction identifies composite term:1Includes: arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, and pain in extremity2Includes: fatigue, asthenia3Includes: face edema, generalized edema, lip edema, localized edema, edema, edema genital, edema peripheral, periorbital edema, and swelling4Includes: cough, productive cough, and upper-airway cough syndrome5Includes: dyspnea, and dyspnea exertional6Includes: dizziness, dizziness postural, and vertigo7Includes: amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucinations, memory impairment, mental impairment, mental status changes8Includes: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain9Includes: 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 pustular10Includes: agitation, anxiety, depression, depressed mood, euphoric mood, irritability11Includes: insomnia, sleep disorder, somnolence12Includes: cystitis, escherichia urinary tract infection, pyelonephritis acute, and urinary tract infection National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) 4.03. One Grade adverse reaction of pyrexia.Clinically relevant adverse reactions occurring in <= 10% of patients include fractures (8%). Table Laboratory Abnormalities Occurring in >= 20% Patients Treated with VITRAKVILaboratory AbnormalityVITRAKVIAll Grades(%)Grade 3-4(%)Chemistry Increased AST523.1 Increased ALT452.5 Hypoalbuminemia361.9 Increased alkaline phosphatase341.9 Hypocalcemia252.6Hematology Anemia4210 Neutropenia3614 Leukopenia281.9 Lymphopenia226 Based on NCI CTCAE v4.03 Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available which ranged from 272 to 277 patients.. 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/m2 twice daily up to 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/m2 twice daily to 120 mg/m2 twice daily in pediatrics [see Use in Specific Populations (8.4)]. Musculoskeletal Pain1. Muscular weakness. Fatigue2. Pyrexia. Edema3. Cough4. Dyspnea5. Upper respiratory tract infection. Nasal congestion. Dizziness6. Headache. Cognitive Impairment7. Constipation. Diarrhea. Nausea. Vomiting. Abdominal pain8. Rash9 Mood disorders10. Sleep Disturbance11. Increased weight. Decreased appetite. Urinary tract infection12. Increased AST. Increased ALT. Hypoalbuminemia. Increased alkaline phosphatase. Hypocalcemia. Anemia. Neutropenia. Leukopenia. Lymphopenia.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, and TRKC with IC50 values between 5-11 nM. One other kinase TNK2 was inhibited at approximately 100-fold higher concentration. TRKA, B, and 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 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 ElectrophysiologyAt 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 single dose of VITRAKVI capsules, systemic exposure (Cmax and AUC) of larotrectinib was dose proportional over the dose range of 100 mg to 400 mg (1 to times the recommended adult dose) and slightly greater than proportional at doses of 600 mg to 900 mg (6 to times the recommended adult dose). In adult patients who received VITRAKVI capsules 100 mg twice daily in Study LOXO-TRK-14001, peak plasma levels (Cmax) of larotrectinib were achieved at approximately hour after dosing and steady-state was reached within days. Mean steady-state larotrectinib [coefficient of variation (CV%)] for Cmax was 788 (81%) ng/mL and AUC0-24hr was 4351 (97%) ngh/mL.AbsorptionThe 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 Cmax was 36% higher with the oral solution.Effect of FoodThe AUC of larotrectinib was similar and the Cmax was reduced by 35% after oral administration of single 100 mg capsule of VITRAKVI to healthy subjects taken with high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the Cmax and AUC in the fasted state.DistributionThe mean (CV%) volume of distribution (Vss) of larotrectinib is 48 (38%) 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.EliminationThe 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.MetabolismLarotrectinib is metabolized predominantly by CYP3A4. Following oral administration of single [14C] 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.ExcretionFollowing oral administration of single [14C] 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 PopulationsAge (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 PatientsIn pediatric patients, the larotrectinib geometric mean (%CV) AUC0-24hr by age subgroup was: 3348 (66%) ngh/mL in patients month to 2 years (n 9), 4135 (36%) ngh/mL in patients to 12 years (n 15), and 3108 (69%) ngh/mL and in patients 12 to 18 years (n 9).Patients with Renal ImpairmentFollowing oral administration of single 100 mg dose of VITRAKVI capsules in subjects with end-stage renal disease (e.g., subjects who required dialysis), the AUC0-INF of larotrectinib increased 1.5-fold and Cmax 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 ImpairmentFollowing oral administration of single 100 mg dose of VITRAKVI capsules, the AUC0-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 Cmax was similar in subjects with mild and moderate hepatic impairment and the Cmax 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 (2.6), Use in Specific Populations (8.6)].Drug Interaction StudiesClinical StudiesEffect of Strong CYP3A Inhibitors: Coadministration of single 100 mg dose of VITRAKVI capsules with strong CYP3A inhibitor (itraconazole) 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 (2.4), Drug Interactions (7.1)]. The effects of CYP3A moderate and weak inhibitors on the pharmacokinetics of larotrectinib have not been studied.Effect of Strong CYP3A Inducers: Coadministration of single 100 mg dose of VITRAKVI capsules with strong CYP3A inducer (rifampin) decreased the AUC0-INF of larotrectinib by 81% and of Cmax by 71% as compared to VITRAKVI administered alone [see Dosage and Administration (2.5), Drug Interactions (7.1)]. The effects of CYP3A weak and moderate inducers on the pharmacokinetics of larotrectinib have not been studied.Effect of Strong P-glycoprotein (P-gp) Inhibitors: Coadministration of single 100 mg dose of VITRAKVI capsules with P-gp inhibitor (rifampin) increased the AUC0-INF of larotrectinib by 1.7-fold and the Cmax 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 sensitive CYP3A4 substrate (midazolam) increased both the AUC0-INF and Cmax of midazolam by 1.7-fold as compared to midazolam administered alone. The AUC0-INF and Cmax 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 StudiesEffect of Transporter on Larotrectinib: Larotrectinib is substrate for P-gp and BCRP. Larotrectinib is not 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of VITRAKVI was evaluated in pediatric and adult patients with unresectable or metastatic solid tumors with 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/m2 up to 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 documented ETV6 translocation identified by FISH. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by 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 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 (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 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%). total of 50 patients had NTRK gene fusions detected by NGS and patients had NTRK gene fusions detected by FISH. Efficacy results are summarized in Tables 4, 5, and 6. Table 4Efficacy Results for Patients with Solid Tumors Harboring NTRK Gene FusionsEfficacy ParameterVITRAKVIN 55Overall response rate (95% CI)75% (61%, 85%) Complete response rate25% Partial response rate49%Duration of response (DOR)N 41 Median DOR32.9 (14.8, NE) Range (months)1.6+, 50.6+ with Observed DOR 12 months63% with Observed DOR 24 months49%+ Denotes ongoing response. 5% were pathological complete response. Patients undergoing 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 estimatesNE: Not evaluableTable Efficacy Results by Tumor TypeTumor TypePatients (N=55)ORRDOR%95% CIRange (months)Salivary gland1283%(52%, 98%)7.7, 44.7+Soft tissue sarcoma1191%(59%, 100%)3.6+, 50.6+Infantile fibrosarcoma7100%(59%, 100%)1.6+, 28.6+Thyroid5100%(48%, 100%)3.7, 32.9Lung475%(19%, 99%)8.2, 36.8+Melanoma450%NA1.9+, 23.2+ Colon425%NA5.6 Gastrointestinal stromal tumor3100%(29%, 100%)9.5, 31.1+Cholangiocarcinoma2SD, NENANAAppendix1SDNANABreast1PDNANAPancreas1SDNANANA 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 range.Table Efficacy Results by NTRK Fusion PartnerNTRK Partner Patients(N=55)ORRDOR%95% CIRange(months)ETV6-NTRK32584% (64%, 96%)3.7, 44.7+TPM3-NTRK1956%(21%, 86%)3.7, 27.5+LMNA-NTRK1540%(5%, 85%)5.6, 50.6+Inferred ETV6-NTRK33100%(29%, 100%)1.6+, 28.6+ IRF2BP2-NTRK12CR, PRNA3.7, 36.8+SQSTM1-NTRK12pCR, PRNA9.9, 12.9+PDE4DIP-NTRK11PRNA3.6+ PPL-NTRK11CRNA28.2+ STRN-NTRK21PRNA5.6 TPM4-NTRK31pCRNA25.6+ TPR-NTRK11PRNA8.2 TRIM63-NTRK11PRNA1.9+ CTRC-NTRK11SDNANAGON4L-NTRK11NENANAPLEKHA6-NTRK11SDNANACR 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 range.. Table 4Efficacy Results for Patients with Solid Tumors Harboring NTRK Gene Fusions. Complete response rate. Partial response rate. Median DOR. Range (months). with Observed DOR 12 months. with Observed DOR 24 months. 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oSelect patients for treatment with VITRAKVI based on the presence of NTRK gene fusion (2.1, 14).oRecommended Dosage in Adult and Pediatric Patients with Body Surface Area of at Least 1.0 Meter-Squared: 100 mg orally twice daily (2.2)oRecommended Dosage in Pediatric Patients with Body Surface Area of Less Than 1.0 Meter-Squared: 100 mg/m2 orally twice daily (2.2). oSelect patients for treatment with VITRAKVI based on the presence of NTRK gene fusion (2.1, 14).. oRecommended Dosage in Adult and Pediatric Patients with Body Surface Area of at Least 1.0 Meter-Squared: 100 mg orally twice daily (2.2). oRecommended Dosage in Pediatric Patients with Body Surface Area of Less Than 1.0 Meter-Squared: 100 mg/m2 orally twice daily (2.2). 2.1 Patient Selection. Select patients for treatment with VITRAKVI based on the presence of 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 1.0 Meter-SquaredThe 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-SquaredThe recommended dosage of VITRAKVI is 100 mg/m2 orally twice daily, with or without food, until disease progression or until unacceptable toxicity.. 2.3 Dosage Modifications for Adverse Reactions. For Grade or adverse reactions:oWithhold VITRAKVI until adverse reaction resolves or improves to baseline or Grade 1. Resume at the next dosage modification if resolution occurs within weeks.oPermanently discontinue VITRAKVI if an adverse reaction does not resolve within weeks.The recommended dosage modifications for VITRAKVI for adverse reactions are provided in Table 1.Table Recommended Dosage Modifications for VITRAKVI for Adverse ReactionsDosageModificationAdult andPediatric Patients with BodySurface Area of at Least 1.0 m2 Pediatric Patients with BodySurface Area Less Than 1.0 m2 First75 mg orally twice daily75 mg/m2 orally twice dailySecond50 mg orally twice daily50 mg/m2 orally twice dailyThird100 mg orally once daily25 mg/m2 orally twice daily a Pediatric patients on 25 mg/m2 orally twice daily should remain on this dosage even if body surface area becomes greater than 1.0 m2 during the treatment. Maximum dose should be 25 mg/m2 orally twice daily at the third dosage modification.Permanently discontinue VITRAKVI in patients who are unable to tolerate VITRAKVI after three dose modifications.. oWithhold VITRAKVI until adverse reaction resolves or improves to baseline or Grade 1. Resume at the next dosage modification if resolution occurs within weeks.. oPermanently discontinue VITRAKVI if an adverse reaction does not resolve within weeks.. 2.4 Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors. Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration of strong CYP3A4 inhibitor cannot be avoided, reduce the VITRAKVI dose by 50%. After the inhibitor has been discontinued for to 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 strong CYP3A4 inducer cannot be avoided, double the VITRAKVI dose. After the inducer has been discontinued for to 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 missed dose within hours of the next scheduled dose.If vomiting occurs after taking dose of VITRAKVI, take the next dose at the scheduled time.CapsulesSwallow capsules whole with water. Do not chew or crush the capsules.Oral SolutionoStore 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.oPrior to preparing an oral dose for administration, refer to the Instructions for Use.. oStore 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.. oPrior to preparing an oral dose for administration, refer to the Instructions for Use.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEVITRAKVI (vi trak vee)(larotrectinib)oral solutionRead this Instructions for Use before you take or give dose of VITRAKVI oral solution for the first time and each time you get 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 dose for the first time. Important information about measuring VITRAKVI oral solution: oAlways use the oral syringes provided with VITRAKVI to make sure that you correctly measure the prescribed dose.oWhen you receive VITRAKVI oral solution from your healthcare provider or pharmacist, you will get box that contains glass bottle of VITRAKVI oral solution and bottle adaptor. You may receive more than box of VITRAKVI oral solution.oYou will receive five mL or 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 7-day period. Do not use household teaspoon to measure the dose.Supplies needed to take or give dose of VITRAKVI oral solutionHow to prepare dose of VITRAKVI oral solution:Step 1: Remove the VITRAKVI oral solution bottle from the box. Place the bottle on 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 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 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 dose of VITRAKVI oral solution by mouth:Step 8: Place the tip of the oral syringe into the childs 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.oThe child should be kept in an upright position for few minutes right after giving dose of VITRAKVI.oIf the child spits up 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 syringesFollow the instructions below for cleaning the oral syringe (Step 10 through Step 16). After days of use, throw away the oral syringe in your household trash. Use new oral syringe for the next 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 clean, dry paper towel to dry.Step 16: Repeat step 12 to assemble the oral syringe and store in clean place until the next use.Replace the oral syringe after days of use, or if:othere is any damage to the barrel, plunger, or tipothe dosage marking is no longer clearly recognizable oroit becomes difficult to move the plungerHow should store VITRAKVI oral solutionoStore VITRAKVI oral solution in refrigerator between 36 to 46 (2 to C). Do not freeze.oThrow away any unused medicine 90 days after the date of first opening. Write the date that you opened the bottle of VITRAKVI oral solution on the bottle. See Figure Q.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 07981Revised: 3/2021. oAlways use the oral syringes provided with VITRAKVI to make sure that you correctly measure the prescribed dose.. oWhen you receive VITRAKVI oral solution from your healthcare provider or pharmacist, you will get box that contains glass bottle of VITRAKVI oral solution and bottle adaptor. You may receive more than box of VITRAKVI oral solution.. oYou will receive five mL or 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 7-day period. Do not use household teaspoon to measure the dose.. oThe child should be kept in an upright position for few minutes right after giving dose of VITRAKVI.. oIf the child spits up dose or you are not sure the entire dose was given, do not give another dose. Wait until the next scheduled dose.. othere is any damage to the barrel, plunger, or tip. othe dosage marking is no longer clearly recognizable or. oit becomes difficult to move the plunger. oStore VITRAKVI oral solution in refrigerator between 36 to 46 (2 to C). Do not freeze.. oThrow away any unused medicine 90 days after the date of first opening. Write the date that you opened the bottle of VITRAKVI oral solution on the bottle. See Figure Q.. image of supplies needed to take or give 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 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 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.

PEDIATRIC USE SECTION.

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 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 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 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 increased ALT and Grade 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 DataLarotrectinib was administered in juvenile toxicity study in rats at twice daily doses of 0.2, and 7.5 mg/kg from postnatal day (PND) to 27 and at twice daily doses of 0.6, 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 times the human exposure at the clinical dose of 100 mg twice daily) resulted in mortality between PND to 99; 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 maze swim test occurred in females at exposures of approximately 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 reduction in pregnancy rate occurred at the high-dose of 7.5/22.5 mg/kg twice daily (approximately times the human exposure at the clinical dose of 100 mg twice daily).

PHARMACOKINETICS SECTION.

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 single dose of VITRAKVI capsules, systemic exposure (Cmax and AUC) of larotrectinib was dose proportional over the dose range of 100 mg to 400 mg (1 to times the recommended adult dose) and slightly greater than proportional at doses of 600 mg to 900 mg (6 to times the recommended adult dose). In adult patients who received VITRAKVI capsules 100 mg twice daily in Study LOXO-TRK-14001, peak plasma levels (Cmax) of larotrectinib were achieved at approximately hour after dosing and steady-state was reached within days. Mean steady-state larotrectinib [coefficient of variation (CV%)] for Cmax was 788 (81%) ng/mL and AUC0-24hr was 4351 (97%) ngh/mL.AbsorptionThe 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 Cmax was 36% higher with the oral solution.Effect of FoodThe AUC of larotrectinib was similar and the Cmax was reduced by 35% after oral administration of single 100 mg capsule of VITRAKVI to healthy subjects taken with high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the Cmax and AUC in the fasted state.DistributionThe mean (CV%) volume of distribution (Vss) of larotrectinib is 48 (38%) 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.EliminationThe 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.MetabolismLarotrectinib is metabolized predominantly by CYP3A4. Following oral administration of single [14C] 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.ExcretionFollowing oral administration of single [14C] 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 PopulationsAge (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 PatientsIn pediatric patients, the larotrectinib geometric mean (%CV) AUC0-24hr by age subgroup was: 3348 (66%) ngh/mL in patients month to 2 years (n 9), 4135 (36%) ngh/mL in patients to 12 years (n 15), and 3108 (69%) ngh/mL and in patients 12 to 18 years (n 9).Patients with Renal ImpairmentFollowing oral administration of single 100 mg dose of VITRAKVI capsules in subjects with end-stage renal disease (e.g., subjects who required dialysis), the AUC0-INF of larotrectinib increased 1.5-fold and Cmax 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 ImpairmentFollowing oral administration of single 100 mg dose of VITRAKVI capsules, the AUC0-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 Cmax was similar in subjects with mild and moderate hepatic impairment and the Cmax 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 (2.6), Use in Specific Populations (8.6)].Drug Interaction StudiesClinical StudiesEffect of Strong CYP3A Inhibitors: Coadministration of single 100 mg dose of VITRAKVI capsules with strong CYP3A inhibitor (itraconazole) 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 (2.4), Drug Interactions (7.1)]. The effects of CYP3A moderate and weak inhibitors on the pharmacokinetics of larotrectinib have not been studied.Effect of Strong CYP3A Inducers: Coadministration of single 100 mg dose of VITRAKVI capsules with strong CYP3A inducer (rifampin) decreased the AUC0-INF of larotrectinib by 81% and of Cmax by 71% as compared to VITRAKVI administered alone [see Dosage and Administration (2.5), Drug Interactions (7.1)]. The effects of CYP3A weak and moderate inducers on the pharmacokinetics of larotrectinib have not been studied.Effect of Strong P-glycoprotein (P-gp) Inhibitors: Coadministration of single 100 mg dose of VITRAKVI capsules with P-gp inhibitor (rifampin) increased the AUC0-INF of larotrectinib by 1.7-fold and the Cmax 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 sensitive CYP3A4 substrate (midazolam) increased both the AUC0-INF and Cmax of midazolam by 1.7-fold as compared to midazolam administered alone. The AUC0-INF and Cmax 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 StudiesEffect of Transporter on Larotrectinib: Larotrectinib is substrate for P-gp and BCRP. Larotrectinib is not 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.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONVITRAKVI (vi trak vee)(larotrectinib)capsules and oral solutionWhat is VITRAKVIVITRAKVI is prescription medicine that is used to treat adults and children with solid tumors (cancer) that:oare caused by certain abnormal NTRK genes andohave spread or if surgery to remove their cancer is likely to cause severe complications, andothere is no acceptable treatment option or the cancer grew or spread on other treatment.Your healthcare provider will perform test to make sure that VITRAKVI is right for you.It is not known if VITRAKVI is safe and effective in children younger than 28 days of age.Before taking VITRAKVI, tell your healthcare provider about all of your medical conditions, including if you:ohave liver problemsohave nervous system (neurological) problemsoare pregnant or plan to become pregnant. VITRAKVI can harm your unborn baby. You should not become pregnant during treatment with VITRAKVI.oIf you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with VITRAKVI.oFemales who are able to become pregnant should use effective birth control (contraception) during treatment and for at least week after the final dose of VITRAKVI. Talk to your healthcare provider about birth control methods that may be right for you.oMales with female partners who are able to become pregnant should use effective birth control during treatment with VITRAKVI and for at least week after the final dose of VITRAKVI.oare breastfeeding or plan to breastfeed. It is not known if VITRAKVI passes into your breast milk. Do not breastfeed during treatment and for week after the final dose of VITRAKVI.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Certain other medicines may affect how VITRAKVI works and VITRAKVI may affect how other medicines work. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take VITRAKVIoTake VITRAKVI exactly as your healthcare provider tells you.oYour healthcare provider may stop treatment or change your dose of VITRAKVI if you have side effects. Do not change your dose or stop taking VITRAKVI unless your healthcare provider tells you.oVITRAKVI comes in capsules and as an oral solution.oIf your healthcare provider prescribes VITRAKVI oral solution:oYour healthcare provider will provide you with the VITRAKVI oral solution and oral syringes or send you to pharmacy that can provide you with VITRAKVI oral solution and oral syringes.oYour healthcare provider should show you how to correctly measure and give dose of VITRAKVI oral solution.oSee the detailed Instructions for Use that comes with VITRAKVI oral solution for information about the correct way to measure and give dose of VITRAKVI oral solution. If you have any questions, talk to your healthcare provider or pharmacist.oVITRAKVI is usually taken by mouth times day.oSwallow VITRAKVI capsules whole with water. Do not chew or crush the capsules.oTake VITRAKVI with or without food.oIf you vomit after taking dose of VITRAKVI, wait and take the next dose at your scheduled timeoIf you miss dose of VITRAKVI, take it as soon as you remember. If your next scheduled dose is due within hours, skip the missed dose and take your next dose at your regular time.oIf you take too much VITRAKVI, call your healthcare provider or go to the nearest hospital emergency room right away.What should avoid while taking VITRAKVIoVITRAKVI can make you feel dizzy. Do not drive or operate machinery until you know how VITRAKVI affects you.oAvoid taking St. Johns wort, eating grapefruit, or drinking grapefruit juice during treatment with VITRAKVI.What are the possible side effects of VITRAKVIVITRAKVI may cause serious side effects, including: oCentral nervous system (CNS) problems. VITRAKVI may cause dizziness, confusion, problems with concentration, attention, and memory, changes in your mood, and sleep problems. Tell your healthcare provider if you develop any of these symptoms or they get worse. Your healthcare provider may temporarily stop treatment, decrease your dose, or permanently stop VITRAKVI if you develop central nervous system symptoms with VITRAKVI. oBone fractures. Bone fractures can happen with VITRAKVI. Tell your healthcare provider if you develop pain, changes in your ability to move around, or bone abnormalities. oLiver problems. Increased liver enzymes in blood tests are common in people who take VITRAKVI. Increased liver enzymes can sometimes lead to liver problems which can become serious. Your healthcare provider will do blood tests to check your liver function every weeks during the first month of treatment with VITRAKVI, then monthly, as needed. Tell your healthcare provider right away if you develop symptoms of liver problems including: loss of appetite, nausea or vomiting, or pain on the upper right side of your stomach area. Your healthcare provider may temporarily stop treatment, decrease your dose, or permanently stop VITRAKVI if you develop liver problems with VITRAKVI.The most common side effects of VITRAKVI include:olow red blood cell and white blood cell countsomuscle and bone painotirednessolow levels of protein called albumin in the bloodoincreased levels of enzyme called alkaline phosphatase in the blood (test for liver or bone problems)ocoughoconstipationodiarrheaodizzinessolow levels of calcium in the bloodonauseaovomitingofeverostomach (abdomen) painVITRAKVI may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is concern for you.These are not all the possible side effects with VITRAKVI. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store VITRAKVIoStore VITRAKVI capsules at room temperature between 68F to 77F (20C to 25C).oStore VITRAKVI oral solution in the refrigerator between 36 to 46 (2 to C). Do not freeze.oThrow away (dispose of) any unused VITRAKVI oral solution remaining after 90 days of first opening the bottle.Keep VITRAKVI and all medicines out of the reach of children.General information about the safe and effective use of VITRAKVI.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use VITRAKVI for condition for which it was not prescribed. Do not give VITRAKVI to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about VITRAKVI that is written for health professionals.What are the ingredients in VITRAKVIActive ingredient: larotrectinib Inactive ingredients: Capsule: gelatin, titanium dioxide and edible ink Oral Solution: purified water, hydroxypropyl betadex, sucrose, glycerin, sorbitol, citric acid, sodium phosphate, sodium citrate dihydrate, propylene glycol and flavoring. Preserved with methylparaben and potassium sorbate. Manufactured for Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981For more information, go to www.VITRAKVI.com or call 1-888-842-2937This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 7/2019. oare caused by certain abnormal NTRK genes and. ohave spread or if surgery to remove their cancer is likely to cause severe complications, and. othere is no acceptable treatment option or the cancer grew or spread on other treatment.. ohave liver problems. ohave nervous system (neurological) problems. oare pregnant or plan to become pregnant. VITRAKVI can harm your unborn baby. You should not become pregnant during treatment with VITRAKVI.oIf you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with VITRAKVI.oFemales who are able to become pregnant should use effective birth control (contraception) during treatment and for at least week after the final dose of VITRAKVI. Talk to your healthcare provider about birth control methods that may be right for you.oMales with female partners who are able to become pregnant should use effective birth control during treatment with VITRAKVI and for at least week after the final dose of VITRAKVI.. oIf you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with VITRAKVI.. oFemales who are able to become pregnant should use effective birth control (contraception) during treatment and for at least week after the final dose of VITRAKVI. Talk to your healthcare provider about birth control methods that may be right for you.. oMales with female partners who are able to become pregnant should use effective birth control during treatment with VITRAKVI and for at least week after the final dose of VITRAKVI.. oare breastfeeding or plan to breastfeed. It is not known if VITRAKVI passes into your breast milk. Do not breastfeed during treatment and for week after the final dose of VITRAKVI.. oTake VITRAKVI exactly as your healthcare provider tells you.. oYour healthcare provider may stop treatment or change your dose of VITRAKVI if you have side effects. Do not change your dose or stop taking VITRAKVI unless your healthcare provider tells you.. oVITRAKVI comes in capsules and as an oral solution.. oIf your healthcare provider prescribes VITRAKVI oral solution:oYour healthcare provider will provide you with the VITRAKVI oral solution and oral syringes or send you to pharmacy that can provide you with VITRAKVI oral solution and oral syringes.oYour healthcare provider should show you how to correctly measure and give dose of VITRAKVI oral solution.oSee the detailed Instructions for Use that comes with VITRAKVI oral solution for information about the correct way to measure and give dose of VITRAKVI oral solution. If you have any questions, talk to your healthcare provider or pharmacist.. oYour healthcare provider will provide you with the VITRAKVI oral solution and oral syringes or send you to pharmacy that can provide you with VITRAKVI oral solution and oral syringes.. oYour healthcare provider should show you how to correctly measure and give dose of VITRAKVI oral solution.. oSee the detailed Instructions for Use that comes with VITRAKVI oral solution for information about the correct way to measure and give dose of VITRAKVI oral solution. If you have any questions, talk to your healthcare provider or pharmacist.. oVITRAKVI is usually taken by mouth times day.. oSwallow VITRAKVI capsules whole with water. Do not chew or crush the capsules.. oTake VITRAKVI with or without food.. oIf you vomit after taking dose of VITRAKVI, wait and take the next dose at your scheduled time. oIf you miss dose of VITRAKVI, take it as soon as you remember. If your next scheduled dose is due within hours, skip the missed dose and take your next dose at your regular time.. oIf you take too much VITRAKVI, call your healthcare provider or go to the nearest hospital emergency room right away.. oVITRAKVI can make you feel dizzy. Do not drive or operate machinery until you know how VITRAKVI affects you.. oAvoid taking St. Johns wort, eating grapefruit, or drinking grapefruit juice during treatment with VITRAKVI.. oCentral nervous system (CNS) problems. VITRAKVI may cause dizziness, confusion, problems with concentration, attention, and memory, changes in your mood, and sleep problems. Tell your healthcare provider if you develop any of these symptoms or they get worse. Your healthcare provider may temporarily stop treatment, decrease your dose, or permanently stop VITRAKVI if you develop central nervous system symptoms with VITRAKVI.. oBone fractures. Bone fractures can happen with VITRAKVI. Tell your healthcare provider if you develop pain, changes in your ability to move around, or bone abnormalities. oLiver problems. Increased liver enzymes in blood tests are common in people who take VITRAKVI. Increased liver enzymes can sometimes lead to liver problems which can become serious. Your healthcare provider will do blood tests to check your liver function every weeks during the first month of treatment with VITRAKVI, then monthly, as needed. Tell your healthcare provider right away if you develop symptoms of liver problems including: loss of appetite, nausea or vomiting, or pain on the upper right side of your stomach area. Your healthcare provider may temporarily stop treatment, decrease your dose, or permanently stop VITRAKVI if you develop liver problems with VITRAKVI.. olow red blood cell and white blood cell counts. omuscle and bone pain. otiredness. olow levels of protein called albumin in the blood. oincreased levels of enzyme called alkaline phosphatase in the blood (test for liver or bone problems). ocough. oconstipation. odiarrhea. odizziness. olow levels of calcium in the blood. onausea. ovomiting. ofever. ostomach (abdomen) pain. oStore VITRAKVI capsules at room temperature between 68F to 77F (20C to 25C).. oStore VITRAKVI oral solution in the refrigerator between 36 to 46 (2 to C). Do not freeze.. oThrow away (dispose of) any unused VITRAKVI oral solution remaining after 90 days of first opening the bottle.