Vitrakvi Drug Information

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.

Patient 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.

Recommended 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.

Dosage Modifications for Adverse Reactions For Grade 2 and higher liver function test abnormalities, refer to Section 2.4, Table 2, Dosage Modifications for Hepatotoxicity. For all other Grade 3 or 4 adverse reactions: Withhold VITRAKVI until adverse reaction resolves or improves to baseline or Grade 1. Resume at the next dosage modification if resolution occurs within 4 weeks.

Permanently discontinue VITRAKVI if an adverse reaction does not resolve within 4 weeks. The recommended dosage reductions for VITRAKVI for adverse reactions are provided in Table 1. Table 1 Recommended Permanently discontinue VITRAKVI in patients who are unable to tolerate VITRAKVI after three dose modifications.

Dosage Modifications for Hepatotoxicity

The recommended dosage modifications for VITRAKVI liver function test abnormalities are provided in Table 2. For CTCAE Grade 2 ALT and/or AST elevation, monitor liver function frequently as clinically indicated, to establish whether a dose interruption or reduction is required. 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 4.03 Dosage 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.

AST or ALT > 3 × ULN with total bilirubin > 2 × ULN in the absence of alternative causes Permanently discontinue VITRAKVI.

Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration of a strong CYP3A4 inhibitor cannot be avoided, reduce the VITRAKVI dose by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the VITRAKVI dose that was used prior to initiating the CYP3A4 inhibitor.

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.

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.

Administration

VITRAKVI capsule or oral solution may be used interchangeably. Do not make up a missed dose within 6 hours of the next scheduled dose. If vomiting occurs after taking a dose of VITRAKVI, take the next dose at the scheduled time.

Capsules Swallow capsules whole with water. Do not chew or crush the capsules. Oral Solution packaged in one bottle containing 100 mL Store the glass bottle of VITRAKVI oral solution in the refrigerator.

Discard any unused VITRAKVI oral solution remaining after 90 days of first opening the bottle. Prior to preparing an oral dose for administration, refer to the Instructions for Use. Oral Solution packaged in two bottles each containing 50 mL Store the glass bottles of VITRAKVI oral solution in the refrigerator.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. VITRAKVI was studied in one adult dose-finding trial, one pediatric dose-finding trial, and one single arm trial. All patients had an unresectable or metastatic solid tumor and no satisfactory alternative treatment options or disease progression following treatment.

The most common serious adverse reactions (≥ 2%) were pneumonia, pyrexia, and dyspnea. The most common adverse reactions (1% each) that resulted in permanent discontinuation of VITRAKVI were increased ALT and increased AST. 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. Table 4 Laboratory Abnormalities Occurring in ≥ 20% Patients Treated with VITRAKVI

Effects of Other Drugs on VITRAKVI Strong and Moderate CYP3A4 Inhibitors Coadministration of VITRAKVI with a strong or moderate CYP3A4 inhibitor may increase larotrectinib plasma concentrations, which may result in a higher incidence of adverse reactions. Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors, including grapefruit or grapefruit juice. If coadministration of strong CYP3A4 inhibitors cannot be avoided, modify VITRAKVI dose as recommended.

In patients coadministered a moderate CYP3A4 inhibitor with VITRAKVI, monitor for adverse reactions more frequently and reduce the VITRAKVI dosage based on the severity of emergent adverse reactions. Strong and Moderate CYP3A4 Inducers Coadministration of VITRAKVI with a strong or moderate CYP3A4 inducer may decrease larotrectinib plasma concentrations, which may decrease the efficacy of VITRAKVI. Avoid coadministration of VITRAKVI with strong CYP3A4 inducers, including St.

John's wort. For coadministration with moderate CYP3A4 inducers, modify VITRAKVI dose as recommended.

Effects of VITRAKVI on Other Drugs Sensitive CYP3A4 Substrates Coadministration of VITRAKVI with sensitive CYP3A4 substrates may increase their plasma concentrations, which may increase the incidence or severity of adverse reactions. Avoid coadministration of VITRAKVI with sensitive CYP3A4 substrates. If coadministration of these sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.

Pregnancy Risk Summary Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on VITRAKVI use in pregnant women. Administration of larotrectinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily (see Data ).

Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 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 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. 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).

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. The efficacy of VITRAKVI was evaluated in 131 pediatric patients and is described in the Clinical Studies section. The safety of VITRAKVI was evaluated in 154 pediatric patients who received VITRAKVI.

The median duration of exposure was 14.8 months (range: 0.4 months to 87.4 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. The pharmacokinetics of VITRAKVI in the pediatric population were similar to those seen in adults.

The dosing period was equivalent to human pediatric populations from newborn to adulthood. The main findings were transient central nervous system-related signs including head flick, tremor, and circling in both sexes. An increase in the number of errors in a maze swim test occurred in females at exposures of approximately 4 times the human exposure (AUC) at the clinical dose of 100 mg twice daily.

Decreased growth and delays in sexual development occurred in the mid- and high-dose groups. Mating was normal in treated animals, but a reduction in pregnancy rate occurred at the high-dose of 7.5/22.5 mg/kg twice daily (approximately 4 times the human exposure at the clinical dose of 100 mg twice daily).