Description

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.

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. Coadministration of Larotrectinib should be avoided with strong CYP3A4 inhibitors, including grapefruit or grapefruit juice. If coadministration of strong CYP3A4 inhibitors cannot be avoided, Larotrectinib dose as recommended should be modified. Strong CYP3A4 Inducers: Coadministration of Larotrectinib with a strong CYP3A4 inducer may decrease Larotrectinib plasma concentrations, which may decrease the efficacy of Larotrectinib. Coadministration of Larotrectinib should be avoided with strong CYP3A4 inducers, including St. John’s wort. If coadministration of strong CYP3A4 inducers cannot be avoided, Larotrectinib dose as recommended should be modified. 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. Coadministration of Larotrectinib should be avoided with sensitive CYP3A4 substrates. If coadministration of these sensitive CYP3A4 substrates cannot be avoided, patients for increased adverse reactions of these drugs should be monitored.

Common side effects are Neurotoxicity, Hepatotoxicity.

Larotrectinib can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on Larotrectinib use in pregnant women. Pregnant women should be advised of the potential risk to a fetus. 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, women should be advised not to breastfeed during treatment with Larotrectinib and for 1 week after the final dose.

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. 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%). Patients and caretakers should be advised of these risks with Larotrectinib. Patients should be advised not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Larotrectinib should be withheld or permanently discontinued based on the severity. If withheld, Larotrectinib dosage should be modified when resumed. 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. 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. Liver tests should be monitored, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Larotrectinib should be withheld or permanently discontinued based on the severity. If withheld, Larotrectinib dosage should be modified when resumed. 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. Women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use an effective method of contraception during treatment and for 1 week after the final dose of Larotrectinib.

Females: Female patients of reproductive potential should be advised to use effective contraception during treatment with Larotrectinib and for at least 1 week after the final dose. Males: Males with female partners of reproductive potential should be advised to use effective contraception during treatment with Larotrectinib and for 1 week after the final dose. 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. Geriatric Use: Clinical studies of Larotrectinib did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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