s, 27% were 1 month to < 2years (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% hadreceived 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 5.4months (range: 9 days to 1.9 years).
Due to the small number of pediatric and adult patients, the single arm design of clinical studiesof VITRAKVI, and confounding factors such as differences in susceptibility to infectionsbetween pediatric and adult patients, it is not possible to determine whether differences in theincidence of adverse reactions to VITRAKVI are related to patient age or other factors. Adversereactions 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 patientswere increased weight (11% vs. 2%) and neutropenia (20% vs. 2%). One of the 44 pediatric
patients discontinued VITRAKVI due to an adverse reaction (Grade 3 increased ALT).
The pharmacokinetics of VITRAKVI in the pediatric population were similar to those seen inadults [see Clinical Pharmacology (12.3)].
Juvenile Animal Toxicity DataLarotrectinib 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 and22.5mg/kg between PND 28 and 70. The dosing period was equivalent to human pediatricpopulations from newborn to adulthood. The doses of 2/6 mg/kg twice daily [approximately0.7 times the human exposure (AUC) at the clinical dose of 100 mg twice daily] and 7.5/22.5mg/kg twice daily (approximately 4 times the human exposure at the clinical dose of 100 mgtwice 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 testoccurred in females at exposures of approximately 4 times the human exposure (AUC) at theclinical dose of 100 mg twice daily. Decreased growth and delays in sexual developmentoccurred in the mid- and high-dose groups. Mating was normal in treated animals, but areduction 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 VITRAKVI, 22% of patients were≥ 65 years of age and 5% of patients were ≥ 75 years of age. Clinical studies of VITRAKVI didnot include sufficient numbers of subjects aged 65 and over to determine whether they responddifferently 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 (12.3)]. Reduce VITRAKVIdose as recommended [see Dosage and Administration (2.6)].
8.7 Renal Impairment
No dose adjustment is recommended for patients with renal impairment of any severity[see Clinical Pharmacology (12.3) |
