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.
