VITRAKVI

VITRAKVI- larotrectinib capsule
VITRAKVI- larotrectinib solution
Loxo Oncology, Inc.

1 INDICATIONS AND USAGE

VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that:

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have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation,

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are metastatic or where surgical resection is likely to result in severe morbidity, and

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have no satisfactory alternative treatments or that have progressed following treatment.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion in tumor specimens [see Clinical Studies (14)]. An FDA-approved test for the detection of NTRK gene fusion is not currently available.

2.2 Recommended Dosage

Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of at Least 1.0 Meter-Squared

The recommended dosage of VITRAKVI is 100 mg orally twice daily, with or without food, until disease progression or until unacceptable toxicity.

Recommended Dosage in Pediatric Patients with Body Surface Area Less Than 1.0 Meter-Squared

The recommended dosage of VITRAKVI is 100 mg/m² orally twice daily, with or without food, until disease progression or until unacceptable toxicity.

2.3 Dosage Modifications for Adverse Reactions

For Grade 3 or 4 adverse reactions:

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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.

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Permanently discontinue VITRAKVI if an adverse reaction does not resolve within 4 weeks.

The recommended dosage modifications for VITRAKVI for adverse reactions are provided in Table 1.

Table 1 Recommended Dosage Modifications for VITRAKVI for Adverse Reactions

Dosage Modification	Adult and Pediatric Patients with Body Surface Area of at Least 1.0 m2	Pediatric Patients with Body Surface Area Less Than 1.0 m2
First	75 mg orally twice daily	75 mg/m2 orally twice daily
Second	50 mg orally twice daily	50 mg/m2 orally twice daily
Third	100 mg orally once daily	25 mg/m2 orally twice daily

Permanently discontinue VITRAKVI in patients who are unable to tolerate VITRAKVI after three dose modifications.

2.4 Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors

Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration of a strong CYP3A4 inhibitor cannot be avoided, reduce the VITRAKVI dose by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the VITRAKVI dose taken prior to initiating the CYP3A4 inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.5 Dosage Modifications for Coadministration with Strong CYP3A4 Inducers

Avoid coadministration of strong CYP3A4 inducers with VITRAKVI. If coadministration of a strong CYP3A4 inducer cannot be avoided, double the VITRAKVI dose. After the inducer has been discontinued for 3 to 5 elimination half-lives, resume the VITRAKVI dose taken prior to initiating the CYP3A4 inducer [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.6 Dosage Modifications for Patients with Hepatic Impairment

Reduce the starting dose of VITRAKVI by 50% in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.7 Administration

VITRAKVI capsule or oral solution may be used interchangeably.

Do not make up a missed dose within 6 hours of the next scheduled dose.

If vomiting occurs after taking a dose of VITRAKVI, take the next dose at the scheduled time.

Capsules

Swallow capsules whole with water. Do not chew or crush the capsules.

Oral Solution

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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.

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Prior to preparing an oral dose for administration, refer to the Instructions for Use.

3 DOSAGE FORMS AND STRENGTHS

Capsules

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25 mg: white opaque hard gelatin capsule, size 2, with blue printing of “LOXO” and “LARO 25 mg” on body of capsules. 25 mg larotrectinib is equivalent to 30.7 mg larotrectinib sulfate.

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100 mg: white opaque hard gelatin capsule, size 0, with blue printing of “LOXO” and “LARO 100 mg” on body of capsule. 100 mg larotrectinib is equivalent to 123 mg larotrectinib sulfate.

Oral Solution

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20 mg/mL: clear yellow to orange solution. 20 mg/mL larotrectinib is equivalent to 24.6 mg/mL larotrectinib sulfate.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Neurotoxicity

Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively [see Adverse Reactions (6.1)]. The majority (65%) of neurologic adverse reactions occurred within the first three months of treatment (range: 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%).

Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed [see Dosage and Administration (2.3)].

5.2 Hepatotoxicity

Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients [see Adverse Reactions (6.1)]. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed [see Dosage and Administration (2.3)].