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 any known acquired resistance mutation,
• are metastatic or where surgical removal is likely to cause severe morbidity, and
• have no suitable alternative treatment options or have progressed after prior therapy.

Larotrectinib is a selective inhibitor of tropomyosin receptor kinases (TRK), including TRKA, TRKB, and TRKC. In enzyme assays, it inhibits TRKA, TRKB, and TRKC with IC50 values ranging from 5 to 11 nM, while another kinase (TNK2) is inhibited at significantly higher concentrations. TRKA, TRKB, and TRKC are encoded by the NTRK1, NTRK2, and NTRK3 genes. Chromosomal rearrangements involving these genes can produce TRK fusion proteins, which are constitutively active and function as oncogenic drivers by promoting tumor cell growth and survival.

Absorption: The average absolute bioavailability of Larotrectinib capsules is approximately 34% (range: 32% to 37%).

Distribution: The mean volume of distribution (Vss) is 48 L (38%) following intravenous administration in healthy individuals. Larotrectinib shows about 70% binding to plasma proteins, independent of its concentration, and has a blood-to-plasma ratio of 0.9.

Elimination: The mean clearance (CL/F) is 98 L/h (44%), and the elimination half-life is approximately 2.9 hours after oral administration.

Metabolism: Larotrectinib is mainly metabolized by CYP3A4. After administration of a radiolabeled dose, unchanged Larotrectinib accounts for 19% of circulating drug components, while an O-linked glucuronide metabolite accounts for 26%.

Excretion: Following oral administration of a radiolabeled dose, about 58% of the administered dose is excreted in feces (5% unchanged) and 39% in urine (20% unchanged).

Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of at Least 1 m²: The usual recommended dose of Larotrectinib is 100 mg taken orally twice daily, with or without food, continued until disease progression or unacceptable toxicity occurs.

Recommended Dosage in Pediatric Patients with Body Surface Area Less Than 1 m²: The recommended dose of Larotrectinib is 100 mg/m² orally twice daily, with or without food, until disease progression or unacceptable toxicity. Capsules should be swallowed whole with water and must not be chewed or crushed. If a dose is missed, it should not be taken within 6 hours of the next scheduled dose. If vomiting occurs after taking a dose, the next dose should be taken at the regular scheduled time, or as advised by a registered physician.

Effects of Other Drugs on Larotrectinib: Strong CYP3A4 Inhibitors: Coadministration of Larotrectinib with strong CYP3A4 inhibitors may increase its plasma concentration, leading to a higher risk of adverse reactions. Such combinations, including grapefruit or grapefruit juice, should generally be avoided. If unavoidable, the Larotrectinib dose should be adjusted as recommended.

Strong CYP3A4 Inducers: Coadministration with strong CYP3A4 inducers may reduce Larotrectinib plasma concentrations and decrease its therapeutic effectiveness. These combinations, including St. John’s wort, should be avoided whenever possible. If unavoidable, dose modification is recommended.

Effects of Larotrectinib on Other Drugs: Sensitive CYP3A4 Substrates: Larotrectinib may increase the plasma concentrations of sensitive CYP3A4 substrates, potentially increasing the risk or severity of adverse reactions. Concomitant use should be avoided when possible. If unavoidable, patients should be carefully monitored for adverse effects.

Larotrectinib is contraindicated in patients with known hypersensitivity to Larotrectinib or any of its components.

Common side effects of Larotrectinib include neurotoxicity and hepatotoxicity.

Larotrectinib may cause harm to the developing fetus if used during pregnancy. There are no adequate data in pregnant women, so pregnant women should be informed about the possible risk to the unborn baby. It is not known whether Larotrectinib or its metabolites pass into human breast milk. Because of the potential for serious adverse effects in breastfed infants, breastfeeding should be avoided during treatment and for at least 1 week after the last dose.

Neurotoxicity: Among 176 patients treated with Larotrectinib, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 events in 6% and 0.6% of patients, respectively. Most neurologic events (65%) appeared within the first three months (range: 1 day to 2.2 years). Grade 3 events included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) was reported in one patient. Neurologic reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%). Patients should be informed about these risks and advised not to drive or operate hazardous machinery if symptoms occur. Depending on severity, treatment should be withheld or discontinued, and dose adjustment considered upon resumption.

Hepatotoxicity: Among 176 patients, increased transaminases occurred in 45%, including Grade 3 AST or ALT elevations in 6%. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of elevated AST was 2 months (range: 1 month to 2.6 years), and for ALT also 2 months (range: 1 month to 1.1 years). Dose modification due to increased AST and ALT occurred in 4% and 6% of patients, respectively, and permanent discontinuation in 2%. Liver function tests (ALT and AST) should be monitored every 2 weeks during the first month, then monthly, or as clinically indicated. Treatment should be withheld or discontinued based on severity, and dose adjusted when resumed.

Embryo-Fetal Toxicity: Based on human reports, animal studies, and its mechanism of action, Larotrectinib may cause fetal harm if administered during pregnancy. Women should be informed of the potential risk and advised to use effective contraception during treatment and for at least 1 week after the last dose.

Females: Women of reproductive potential should use effective contraception during treatment and for at least 1 week after the last dose.
Males: Men with female partners of reproductive potential should also use effective contraception during treatment and for 1 week after the final dose.
Pediatric Use: The safety and effectiveness of Larotrectinib have been established in pediatric patients aged 28 days and older.
Geriatric Use: There is not enough data in patients aged 65 years and older to determine whether they respond differently from younger adults.

Cytotoxic Chemotherapy.

Store below 30°C in a cool and dry place, away from sunlight. Keep out of the reach of children.