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Larotrectinib Capsules and Oral Solution

TABLE OF CONTENTS

1. DESCRIPTION 7. DRUG INTERACTIONS
2. INDICATIONS AND USAGE 8. USE IN SPECIFIC POPULATIONS
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Larotrectinib is a kinase inhibitor. Larotrectinib capsules and oral solution are formulated using larotrectinib sulfate. The chemical name is (3S)-N-{5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidinecarboxamide sulfate. Larotrectinib sulfate has the following chemical structure:

Empirical formula: C21H24F2N6O6S

Molecular weight: 526.51 g/mol (sulfate salt), 428.44 g/mol (free base)

Larotrectinib sulfate is an off-white to pinkish yellow solid that is not hygroscopic. The aqueous solubility of larotrectinib at 37oC is pH dependent (very soluble at pH 1.0 and freely soluble at pH 6.8, according to USP descriptive terms of solubility).

Larotrectinib capsules and oral solution are for oral use. Each capsule contains 25 mg or 100 mg larotrectinib (30.7 mg and 123 mg larotrectinib sulfate, respectively) in a hard gelatin capsule. The capsule is composed of gelatin, titanium dioxide, and edible ink.

The oral solution contains 20 mg/mL larotrectinib (24.6 mg/mL larotrectinib sulfate) and the following inactive ingredients: purified water, hydroxypropyl betadex, sucrose, glycerin, sorbitol, citric acid, sodium phosphate, sodium citrate dihydrate, propylene glycol and flavoring. Preserved with methylparaben and potassium sorbate.

2. INDICATIONS AND USAGE

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

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

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

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

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

3. DOSAGE AND ADMINISTRATION

3.1 Patient Selection

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

3.2 Recommended Dosage

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

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

3.3 Dosage Modifications for Adverse Reactions

For Grade 3 or 4 adverse reactions:

• Withhold larotrectinib 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 larotrectinib if an adverse reaction does not resolve within 4 weeks.

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

Table 1: Recommended Dosage Modifications for Larotrectinib for Adverse Reactions

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

3.4 Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors

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

3.5 Dosage Modifications for Coadministration with Strong CYP3A4 Inducers

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

3.6 Dosage Modifications for Patients with Hepatic Impairment

Reduce the starting dose of larotrectinib 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].

3.7 Administration

Larotrectinib 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 larotrectinib, take the next dose at the scheduled time.

Capsules

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

Oral Solution

• Store the glass bottle of larotrectinib oral solution in the refrigerator. Discard any unused larotrectinib 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.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Neurotoxicity

Among the 176 patients who received larotrectinib, 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 larotrectinib. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue larotrectinib based on the severity. If withheld, modify the larotrectinib dosage when resumed [see Dosage and Administration (3.3)].

5.2 Hepatotoxicity

Among the 176 patients who received larotrectinib, 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 larotrectinib based on the severity. If withheld, modify the larotrectinib dosage when resumed [see Dosage and Administration (3.3)].

5.3 Embryo-Fetal Toxicity

Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, larotrectinib can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7- times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of larotrectinib [see Use in Specific Populations (8.1, 8.3)].

6. ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Neurotoxicity [see Warnings and Precautions (5.1)]

• Hepatotoxicity [see Warnings and Precautions (5.2)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Data in WARNINGS AND PRECAUTIONS and below reflects exposure to larotrectinib in 176 patients, including 70 (40%) patients exposed for greater than 6 months and 35 (20%) patients exposed for greater than 1 year. Larotrectinib was studied in one adult dose-finding trial [LOXO-TRK-14001 (n = 70)], one pediatric dose-finding trial [SCOUT (n = 43)], and one single arm trial [NAVIGATE (n = 63)]. All patients had an unresectable or metastatic solid tumor and no satisfactory alternative treatment options or disease progression following treatment.

Across these 176 patients, the median age was 51 years (range: 28 days to 82 years); 25% were 18 years or younger; 52% were male; and 72% were White, 11% were Hispanic/Latino, 8% were Black, and 3% were Asian. The most common tumors in order of decreasing frequency were soft tissue sarcoma (16%), salivary gland (11%), lung (10%), thyroid (9%), colon (8%), infantile fibrosarcoma (8%), primary central nervous system (CNS) (7%), or melanoma (5%). NTRK gene fusions were present in 60% of larotrectinib-treated patients. Most adults (80%) received larotrectinib 100 mg orally twice daily and 68% of pediatrics (18 years or younger) received larotrectinib 100 mg/m2 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/m2 twice daily to 120 mg/m2 twice daily in pediatrics [see Pediatric Use (8.4)].

The most common adverse reactions (≥ 20%) in order of decreasing frequency were fatigue, nausea, dizziness, vomiting, anemia, increased AST, cough, increased ALT, constipation, and diarrhea.

The most common serious adverse reactions (≥ 2%) were pyrexia, diarrhea, sepsis, abdominal pain, dehydration, cellulitis, and vomiting. Grade 3 or 4 adverse reactions occurred in 51% of patients; adverse reactions leading to dose interruption or reduction occurred in 37% of patients and 13% permanently discontinued larotrectinib for adverse reactions.

The most common adverse reactions (1-2% each) that resulted in discontinuation of larotrectinib were brain edema, intestinal perforation, pericardial effusion, pleural effusion, small intestinal obstruction, dehydration, fatigue, increased ALT, increased AST, enterocutaneous fistula, increased amylase, increased lipase, muscular weakness, abdominal pain, asthenia, decreased appetite, dyspnea, hyponatremia, jaundice, syncope, vomiting, acute myeloid leukemia, and nausea.

The most common adverse reactions (≥ 3%) resulting in dose modification (interruption or reduction) were increased ALT (6%), increased AST (6%), and dizziness (3%). Most (82%) adverse reactions leading to dose modification occurred during the first three months of exposure.

Adverse reactions of larotrectinib occurring in ≥ 10% of patients and laboratory abnormalities worsening from baseline in ≥ 5% of patients are summarized in Table 2 and Table 3, respectively.

Table 2: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Larotrectinib

* National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03.

** One Grade 4 adverse reaction of pyrexia.

Table 3: Laboratory Abnormalities Occurring in ≥ 5% Patients Treated with Larotrectinib

*Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 170 to 174 patients.

** NCI-CTCAE v 4.03.

7. DRUG INTERACTIONS

7.1 Effects of Other Drugs on Larotrectinib

Strong CYP3A4 Inhibitors

Coadministration of larotrectinib with a strong CYP3A4 inhibitor may increase larotrectinib plasma concentrations, which may result in a higher incidence of adverse reactions [see Clinical Pharmacology]. Avoid coadministration of larotrectinib with strong CYP3A4 inhibitors, including grapefruit or grapefruit juice. If coadministration of strong CYP3A4 inhibitors cannot be avoided, modify larotrectinib dose as recommended [see Dosage and Administration (3.4)].

Strong CYP3A4 Inducers

Coadministration of larotrectinib with a strong CYP3A4 inducer may decrease larotrectinib plasma concentrations, which may decrease the efficacy of larotrectinib [see Clinical Pharmacology]. Avoid coadministration of larotrectinib with strong CYP3A4 inducers, including St. John’s wort. If coadministration of strong CYP3A4 inducers cannot be avoided, modify larotrectinib dose as recommended [see Dosage and Administration (3.5)].

7.2 Effects of Larotrectinib on Other Drugs

Sensitive CYP3A4 Substrates

Coadministration of larotrectinib with sensitive CYP3A4 substrates may increase their plasma concentrations, which may increase the incidence or severity of adverse reactions [see Clinical Pharmacology]. Avoid coadministration of larotrectinib with sensitive CYP3A4 substrates. If coadministration of these sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.

Animal Data

Larotrectinib crosses the placenta in animals. Larotrectinib did not result in embryolethality at maternally toxic doses [up to 40 times the human exposure based on area under the curve (AUC) at the clinical dose of 100 mg twice daily] in embryo-fetal development studies in pregnant rats dosed during the period of organogenesis; however, larotrectinib was associated with fetal anasarca in rats from dams treated at twice-daily doses of 40 mg/kg [11 times the human exposure (AUC) at the clinical dose of 100 mg twice daily]. In pregnant rabbits, larotrectinib administration was associated with omphalocele at twice-daily doses of 15 mg/kg (0.7 times the human exposure at the clinical dose of 100 mg twice daily).

8.2 Lactation

Risk Summary

There are no data on the presence of larotrectinib or its metabolites in human milk and no data on its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with larotrectinib and for 1 week after the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating larotrectinib [see Use in Specific Populations (8.1)].

Contraception

Larotrectinib can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise female patients of reproductive potential to use effective contraception during treatment with larotrectinib and for at least 1 week after the final dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with larotrectinib and for 1 week after the final dose.

Infertility

Females

Based on histopathological findings in the reproductive tracts of female rats in a 1-month repeated-dose study, larotrectinib may reduce fertility [See Nonclinical Toxicology].

8.4 Pediatric Use

The safety and effectiveness of larotrectinib 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].

The efficacy of larotrectinib was evaluated in 12 pediatric patients and is described in the Clinical Studies section [see Clinical Studies]. The safety of larotrectinib was evaluated in 44 pediatric patients who received larotrectinib. Of these 44 patients, 27% were 1 month to < 2 years (n = 12), 43% were 2 years to < 12 years (n = 19), and 30% were 12 years to < 18 years (n = 13); 43% had metastatic disease and 57% had locally advanced disease; and 91% had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy. The most common cancers were infantile fibrosarcoma (32%), soft tissue sarcoma (25%), primary CNS tumors (20%), and thyroid cancer (9%). The median duration of exposure was 5.4 months (range: 9 days to 1.9 years).

Due to the small number of pediatric and adult patients, the single arm design of clinical studies of larotrectinib, 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 larotrectinib are related to patient age or other factors. Adverse reactions and laboratory abnormalities of Grade 3 or 4 severity occurring more frequently (at least a 5% increase in per-patient incidence) in pediatric patients compared to adult patients were increased weight (11% vs. 2%) and neutropenia (20% vs. 2%). One of the 44 pediatric patients discontinued larotrectinib due to an adverse reaction (Grade 3 increased ALT).

The pharmacokinetics of larotrectinib in the pediatric population were similar to those seen in adults [see Clinical Pharmacology].

Juvenile Animal Toxicity Data

Larotrectinib was administered in a juvenile toxicity study in rats at twice daily doses of 0.2, 2 and 7.5 mg/kg from postnatal day (PND) 7 to 27 and at twice daily doses of 0.6, 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 4 times the human exposure at the clinical dose of 100 mg twice daily) resulted in mortality between PND 9 to 99; a 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 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).

8.5 Geriatric Use

Of 176 patients in the overall safety population who received larotrectinib, 22% of patients were ≥ 65 years of age and 5% of patients were ≥ 75 years of age. Clinical studies of larotrectinib 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]. Reduce larotrectinib dose as recommended [see Dosage and Administration (3.6)].

8.7 Renal Impairment

No dose adjustment is recommended for patients with renal impairment of any severity [see Clinical Pharmacology].

10. MECHANISM OF ACTION

Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In a 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 C 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 a 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.

11. PHARMACODYNAMICS

Cardiac Electrophysiology

At a dose 9-fold higher than the recommended adult dose, larotrectinib does not prolong QTc intervals to any clinically relevant extent.

12. 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 a single dose of larotrectinib capsules, systemic exposure (Cmax and AUC) of larotrectinib was dose proportional over the dose range of 100 mg to 400 mg (1 to 4 times the recommended adult dose) and slightly greater than proportional at doses of 600 mg to 900 mg (6 to 9 times the recommended adult dose). In adult patients who received larotrectinib capsules 100 mg twice daily in Study LOXO-TRK-14001, peak plasma levels (Cmax) of larotrectinib were achieved at approximately 1 hour after dosing and steady-state was reached within 3 days. Mean steady-state larotrectinib [coefficient of variation (CV%)] for Cmax was 788 (81%) ng/mL and AUC0-24hr was 4351 (97%) ng*h/mL.

Absorption

The mean absolute bioavailability of larotrectinib capsules was 34% (range: 32% to 37%). In healthy subjects, the AUC of larotrectinib oral solution was similar to that of the capsules and the Cmax was 36% higher with the oral solution.

Effect of Food

The AUC of larotrectinib was similar and the Cmax was reduced by 35% after oral administration of a single 100 mg capsule of larotrectinib to healthy subjects taken with a 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.

Distribution

The mean (CV%) volume of distribution (Vss) of larotrectinib is 48 (38%) L 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.

Elimination

The mean (CV%) clearance (CL/F) of larotrectinib is 98 (44%) L/h and the half-life is 2.9 hours following oral administration of larotrectinib in healthy subjects.

Metabolism

Larotrectinib is metabolized predominantly by CYP3A4. Following oral administration of a 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.

Excretion

Following oral administration of a 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 Populations

Age (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 Patients

In pediatric patients, the larotrectinib geometric mean (%CV) AUC0-24hr by age subgroupwas: 3348 (66%) ng*h/mL in patients 1 month to < 2 years (n = 9), 4135 (36%) ng*h/mL in patients 2 to < 12 years (n = 15), and 3108 (69%) ng*h/mL and in patients 12 to < 18 years (n = 9).

Patients with Renal Impairment

Following oral administration of a single 100 mg dose of larotrectinib 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 larotrectinib in patients with moderate to severe renal impairment (creatinine clearance ≤ 60 mL/min) have not been studied.

Patients with Hepatic Impairment

Following oral administration of a single 100 mg dose of larotrectinib 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 (3.6), Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

Effect of Strong CYP3A Inhibitors: Coadministration of a single 100 mg dose of larotrectinib capsules with a strong CYP3A inhibitor (itraconazole) increased the AUC0-INF of larotrectinib by 4.3-fold and the Cmax by 2.8-fold as compared to larotrectinib administered alone [see Dosage and Administration (3.4), 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 a single 100 mg dose of larotrectinib capsules with a strong CYP3A inducer (rifampin) decreased the AUC0-INF of larotrectinib by 81% and of Cmax by 71% as compared to larotrectinib administered alone [see Dosage and Administration (3.5), 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 a single 100 mg dose of larotrectinib capsules with a P-gp inhibitor (rifampin) increased the AUC0-INF of larotrectinib by 1.7-fold and the Cmax by 1.8-fold as compared to larotrectinib administered alone.

Effect of Larotrectinib on CYP3A4 Substrates: Coadministration of larotrectinib capsules 100 mg twice daily with a 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 Studies

Effect of Transporter on Larotrectinib: Larotrectinib is a substrate for P-gp and BCRP. Larotrectinib is not a 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.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

VITRAKVI (larotrectinib) Capsules

25 mg: Hard gelatin opaque white capsule size #2 with blue printing of “LOXO” and “LARO 25 mg” on the body of the capsule.

• 60 count bottle NDC# 71777-390-01

100 mg: Hard gelatin opaque white capsule size #0 with blue printing of “LOXO” and “LARO 100 mg” on the body of the capsule.

• 60 count bottle NDC# 71777-391-01

VITRAKVI (larotrectinib) Oral Solution

20 mg/mL: Clear yellow to orange solution.

• 100 mL bottle NDC# 71777-392-01

Storage and Handling:

Capsules

Store capsules at room temperature 20°C to 25°C (68°F to 77°F); temperature excursions between 15°C and 30°C (59°F to 86°F) are permitted [see USP Controlled Room Temperature].

Oral Solution

Refrigerate oral solution at 2°C to 8°C (36°F to 46°F). Do not freeze.

Rx only

Rev 11/18