In embryo-fetal development toxicity studies in rats and rabbits, embryo-lethality was noted at the highest doses (128- and 174-fold the human AUC₂₄ at the human therapeutic dose for rats and rabbits, respectively). The no observed adverse effect level (NOAEL) for embryo-fetal development was 50 mg/kg/day in rats and 45 mg/kg/day in rabbits (62- and 16-fold the human AUC₂₄ at the human therapeutic dose for rats and rabbits, respectively). Fezolinetant showed no effects on fertility and early embryonic development in rats.^L46422

In the pre-and post-natal development study in rats, the NOAEL for maternal and fetal toxicity was 30 mg/kg/day (36-fold the human AUC₂₄ at the human therapeutic dose) based on delayed parturition and embryo-lethality at 100 mg/kg/day. The NOAEL for F1 generation development was determined to be 100 mg/kg/day for females (204-fold the human AUC₂₄ at the human therapeutic dose) and 10 mg/kg/day for males (11-fold the human AUC₂₄ at the human therapeutic dose).^L46422

In the pre-and post-natal development study in rats, the F1 male showed incomplete balanopreputial separation at doses greater than or equal to 30 mg/kg/day (36-fold the human AUC₂₄ at the human therapeutic dose), which delayed male reproductive maturation and affected fertility. These effects were not observed following dosing at 10 mg/kg/day (11-fold the human AUC₂₄ at the human therapeutic dose).^L46422

Repeat dose toxicity studies were conducted in intact female rats and cynomolgus monkeys. In female rats, daily administration of fezolinetant for 26 weeks at doses equal to or greater than 30 mg/kg/day (56-fold the human AUC₂₄ at the human therapeutic dose) showed uterine atrophy and epithelial mucification of the vagina and cervix. In female cynomolgus monkeys, daily administration for 39 weeks at doses equal to or greater than 10 mg/kg/day (19-fold the human AUC₂₄ at the human therapeutic dose) showed reduced ovarian activity.^L46422

Fezolinetant is contraindicated in individuals with severe (eGFR 15 to less than 30 mL/min/1.73 m²) renal impairment or end-stage renal disease (eGFR less than 15 mL/min/1.73 m²). No dose adjustment of fezolinetant is recommended for individuals with mild (eGFR 60 to less than 90 mL/min/1.73 m²) or moderate (eGFR 30 to less than 60 mL/min/1.73 m²) renal impairment.^L46422

Child-Pugh Class A or B hepatic impairment increased the exposure to fezolinetant. Fezolinetant has not been studied in individuals with Child-Pugh Class C hepatic impairment.^L46422

In a 2-year female rat carcinogenicity study and a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 186-fold and 47-fold the human AUC₂₄ at the human therapeutic dose of 45 mg, respectively.^L46422

Fezolinetant showed no genotoxic potential by the bacterial reverse mutation test, chromosomal aberration test, or in vivo micronucleus test.^L46422

Treatment of overdose consists of discontinuation of fezolinetant therapy with the institution of appropriate symptomatic care.^L46422