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. Select patients for therapy based on an FDA-approved test . 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 )

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 Recommended Dosage in Pediatric Patients with Body Surface Area of Less Than 1 Meter-Squared: 100 mg/m 2 orally twice daily

2.1Patient Selection Select

patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion in tumor specimens . In patients with secretory breast cancer, mammary analogue secretory cancer (MASC), congenital mesoblastic nephroma (CMN), or infantile fibrosarcoma, consider treatment without confirmation of NTRK rearrangements in tumor specimens. Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics.

2.2Recommended Dosage Recommended Dosage in Adult

and Pediatric Patients with Body Surface Area of 1 Meter-Squared or greater 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.

2.3Dosage 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 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.

2.4Dosage 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 . Table 2 Recommended Dosage Modifications for VITRAKVI for Hepatotoxicity Severity Grading defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version

4.03Dosage Modification

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal AST or ALT ≥ 5 × ULN with bilirubin ≤ 2 × ULN 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.

2.5Dosage 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 .

2.6Dosage 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 .

2.7Dosage 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 .

2.8Administration

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.

Central Nervous System (CNS) Effects: Advise patients and caretakers of the risk of CNS adverse reactions including dizziness, cognitive impairment, mood disorders, and sleep disturbances. Advise patients not to drive or operate hazardous machinery if experiencing neurotoxicity. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity. ( 2.3 , 5.1 ) Skeletal Fractures: Promptly evaluate patients with signs or symptoms of fractures. Hepatotoxicity: Obtain liver function tests (ALT, AST, ALP and bilirubin) before initiation of VITRAKVI and every 2 weeks during the first 2 months of treatment, then monthly thereafter or as clinically indicated. Temporarily withhold, reduce dose, or permanently discontinue VITRAKVI based on severity. ( 2.4 , 5.3 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. ( 5.4 , 8.3 )

5.1Central Nervous System Effects Central

nervous system (CNS) adverse reactions occurred in patients receiving VITRAKVI, including dizziness, cognitive impairment, mood disorders, and sleep disturbances. In patients who received VITRAKVI (n=444), all grades CNS effects including cognitive impairment, mood disorders, dizziness and sleep disorders were observed in 40.3% with Grades 3-4 in 3.8% of patients. Cognitive impairment occurred in 11% of patients.

The median time to onset of cognitive impairment was 6 months (range: 2 days to 56 months). Cognitive impairment occurring in ≥ 1% of patients included memory impairment (4.1%), disturbance in attention (3.6%), confusional state (2.3%), cognitive disorder (1.6%), delirium (1.4%), and hallucination (1.1%). Grade 3 cognitive adverse reactions occurred in 1.8% of patients and Grade 4 cognitive adverse reactions in 0.2% of patients.

Among the 49 patients with cognitive impairment, 6% required a dose modification, and 18% required dose interruption. Mood disorders occurred in 14% of patients. The median time to onset of mood disorders was 3.3 months (range: 1 day to 65 months). Mood disorders occurring in ≥ 1% of patients included anxiety (5%), agitation (3.2%), depression (3.2%), irritability (2.3%), and restlessness (1.1%).

Grade 3 mood disorders occurred in 0.9% of patients. Among the 63 patients who experienced mood disorders, no patient required a dose modification, and 1.6% required dose interruption. Dizziness occurred in 22% of patients, and Grade 3 dizziness occurred in 0.9% of patients. Among the 96 patients who experienced dizziness, 6% of patients required a dose modification, and 5% required dose interruption.

Sleep disturbances occurred in 12% of patients. Sleep disturbances included insomnia (9%), somnolence (3.4%), and sleep disorder (0.5%). Grade 3 sleep disturbances occurred in 0.2% of patients. Among the 54 patients who experienced sleep disturbances, no patient required a dose modification, and 3.7% required dose interruption.

Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed .

5.2Skeletal Fractures Skeletal

fractures can occur in patients taking VITRAKVI. Among 444 patients who received VITRAKVI across clinical trials, fractures occurred in 7% of patients; 6% of 290 adult patients and 10% of 154 pediatric patients. Median time to first fracture was 13 months (range 27 days to 73 months) in patients followed per fracture. The most common fractures were of the rib (1.4%), fibula, foot, or wrist (0.7% each).

Most fractures were associated with minimal or moderate trauma. Some fractures were associated with radiologic abnormalities suggestive of local tumor involvement. VITRAKVI treatment was interrupted due to fracture in 1.4% patients. Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity).

There are no data on the effects of VITRAKVI on healing of known fractures or risk of future fractures.

5.3Hepatotoxicity Hepatotoxicity

including drug-induced liver injury (DILI) has occurred in patients taking VITRAKVI. In patients who received VITRAKVI (n=444), increased AST of any grade occurred in 62% of patients and increased ALT of any grade occurred in 61%. Grade 3-4 increased AST or ALT occurred in 7% and 8% of patients, respectively . The median time to onset of increased AST was 1.9 months (range: 4 days to 3.8 years). The median time to onset of increased ALT was 1.9 months (range: 1 day to 4.9 years). Increased AST and ALT leading to dose modifications occurred in 1.6% and 3.2% of patients, respectively.

Increased AST or ALT led to permanent discontinuation in 4 (0.9%) patients. There have been reports from clinical studies and postmarketing cases of Grade ≥ 2 increases in ALT and/or AST with increases in bilirubin ≥ 2 × ULN. Obtain liver function tests (ALT, AST, ALP and bilirubin) before initiation of VITRAKVI and monitor every 2 weeks during the first 2 months of treatment, then monthly thereafter, or more frequently following the occurrence of Grade 2 or greater AST or ALT elevation. Temporarily withhold, reduce the dose, or permanently discontinue VITRAKVI based on severity .

5.4Embryo-Fetal Toxicity Based on

literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus.

Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the last dose of VITRAKVI .

None. None.

8.1Pregnancy 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 , 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 . 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).

The following clinically significant adverse reactions are described elsewhere in the labeling: Central Nervous System Effects Skeletal Fractures Hepatotoxicity The most common (≥ 20%) adverse reactions, including laboratory abnormalities, with VITRAKVI were increased AST, increased ALT, anemia, hypoalbuminemia, musculoskeletal pain, increased alkaline phosphatase, leukopenia, lymphopenia, neutropenia, hypocalcemia, fatigue, vomiting, cough, constipation, pyrexia, diarrhea, nausea, abdominal pain, dizziness, and rash. 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 .

6.1Clinical Trial Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Unless noted, data in WARNINGS AND PRECAUTIONS and below reflects exposure to VITRAKVI in 444 patients, including 62% patients exposed for greater than 6 months, 44% patients exposed for greater than 1 year, and 30% patients exposed for greater than 2 years. VITRAKVI was studied in one adult dose-finding trial [LOXO-TRK-14001 (n = 75)], one pediatric dose-finding trial [SCOUT (n = 154)], and one single arm trial [NAVIGATE (n = 215)].

All patients had an unresectable or metastatic solid tumor and no satisfactory alternative treatment options or disease progression following treatment. Across these 444 patients, the median age was 44 years (range: 18 days to 90 years); 35% were younger than 18 years; 53% were female; 59% were White, 24% were Asian and, 4% were Black; and 7% were Hispanic/Latino. Most adults (91%) received VITRAKVI 100 mg orally twice daily and 91% of pediatrics (< 18 years) received VITRAKVI 100 mg/m 2 twice daily up to a maximum dose of 100 mg twice daily.

The dose ranged from 50 mg daily to 200 mg twice daily in adults and 9.6 mg/m 2 twice daily to 120 mg/m 2 twice daily in pediatrics . The most common serious adverse reactions (≥ 2%) were pneumonia, pyrexia, and dyspnea. Grade 3 or 4 adverse reactions occurred in 60% of patients; adverse reactions leading to dose interruption or modification occurred in 45% and 11% of patients, respectively, and 12% permanently discontinued VITRAKVI for adverse reactions. The most common adverse reactions (1% each) that resulted in permanent discontinuation of VITRAKVI were increased ALT and increased AST. The most common adverse reactions (≥ 3%) resulting in dose interruption were increased ALT (6%), increased AST (5%), neutrophil count decreased (4.7%), pyrexia (4.3%), and vomiting (3.2%).

Most (64%) adverse reactions leading to dose interruption occurred during the first three months of exposure. The most common adverse reactions (≥ 20%), including laboratory abnormalities, in order of decreasing frequency were increased AST, increased ALT, anemia, hypoalbuminemia, musculoskeletal pain, increased alkaline phosphatase, leukopenia, lymphopenia, neutropenia, hypocalcemia, fatigue, vomiting, cough, constipation, pyrexia, diarrhea, nausea, abdominal pain, dizziness, and rash. Adverse reactions of VITRAKVI occurring in ≥ 10% of patients and laboratory abnormalities worsening from baseline in ≥ 20% of patients are summarized in Table 3 and Table 4, respectively.

Table 3 Adverse Reactions Occurring in ≥ 10% of Patients Treated with VITRAKVI Adverse Reaction The adverse reaction identifies a composite term: VITRAKVI N = 444 All Grades National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03. (%) Grade 3-4 Grade 4 adverse reaction: 1 of cognitive impairment, 1 of pyrexia. (%) Musculoskeletal and Connective Tissue Musculoskeletal Pain Includes: arthralgia, back pain, bone pain, flank pain, groin pain, growing pains, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw, and tendon pain 41

3.6General Fatigue Includes:

fatigue, asthenia 31

2.5Pyrexia

26

2.3Edema Includes:

face edema, generalized edema, lip edema, localized edema, edema, edema genital, edema peripheral, periorbital edema, and swelling 17

0.7Respiratory, Thoracic and Mediastinal Cough Includes:

cough, productive cough, and upper-airway cough syndrome 29

0.5Dyspnea Includes:

dyspnea, and dyspnea exertional 17

2.7Nasal

congestion 10 0 Nervous System Dizziness Includes: dizziness, dizziness postural, and vertigo 22

0.9Headache

17

0.9Cognitive Impairment Includes:

amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucination, hallucination visual, memory impairment, mental impairment, mental status changes 11 2 Gastrointestinal Vomiting 30

1.1Constipation

27

0.5Diarrhea

26

2.9Nausea

25

0.5Abdominal

pain Includes: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain 24

1.4Skin and Subcutaneous Tissue Disorders Rash

Includes: dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative generalized, eczema, eczema asteatotic, palmar-plantar erythrodysaesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular 21

0.2Psychiatric Mood

disorders Includes: agitation, anxiety, depression, depressed mood, euphoric mood, fear, feeling jittery, irritability, panic attack, psychomotor hyperactivity, restlessness 14

0.9Sleep Disturbance Includes:

insomnia, sleep disorder, somnolence 12

0.2Investigations Increased

weight 17

4.1Metabolism and Nutrition Decreased

appetite 14

1.1Infections and Infestations Upper

respiratory tract infection 18

0.7Urinary

tract infection Includes: cystitis, cystitis escherichia, escherichia urinary tract infection, kidney infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic, and urinary tract infection 14

1.8Nasopharyngitis

11 0 Clinically relevant adverse reactions occurring in ≤ 10% of patients include fractures (7%). Table 4 Laboratory Abnormalities Occurring in ≥ 20% Patients Treated with VITRAKVI Laboratory Abnormality VITRAKVI Based on NCI CTCAE v4.03 All Grades (%) Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 416 to 442 patients. Grade 3-4 (%) Chemistry Increased AST 62 7 Increased ALT 61 8 Hypoalbuminemia 44

2.7Increased

alkaline phosphatase 40 3 Hypocalcemia 32

3.1Hematology Anemia

45 8 Leukopenia 37

3.8Lymphopenia

35 11 Neutropenia 34 11