oxicity was observedat doses ≥ 15 mg/kg/day. In addition, a dose-dependent delay in the age of attainment of Preyerresponse reflex was observed in pups at all doses during the preweaning period. Thissensory/motor developmental measure was tested starting on postnatal day (PND) 9, and theeffect normalized by PND 19 in treatment groups as compared with PND 14 for the majority of
the control animals. There is no NOAEL for this delay in sensory/motor response observed inpups during the preweaning period. During the postweaning period, a decrease in motor activitywas observed at doses ≥ 15 mg/kg which is 0.5-times the human exposure at the MRHD of84 mg/day. The NOAEL for maternal toxicity and decreased motor activity during thepostweaning period was 4.5 mg/kg/day which was associated with a plasma exposure (AUC) thatwas 0.07-times the AUC exposure at MRHD of 84 mg/day.
8.2 Lactation
Risk Summary
Esketamine is present in human milk. There are no data on the effects of SPRAVATO on thebreastfed infant or on milk production. Published studies in juvenile animals report neurotoxicity(see Data). Because of the potential for neurotoxicity, advise patients that breast-feeding is notrecommended during treatment with SPRAVATO.
Data
Published juvenile animal studies demonstrate that the administration of drugs that block NMDAreceptors, such as ketamine, during the period of rapid brain growth or synaptogenesis, results inwidespread neuronal and oligodendrocyte cell loss in the developing brain and alterations insynaptic morphology and neurogenesis. Based on comparisons across species, the window ofvulnerability to these changes is believed to correlate with exposures in the third trimester ofgestation through the first several months of life, but this window may extend out toapproximately 3 years of age in humans.
8.3 Females and Males of Reproductive Potential
Contraception
Based on published animal reproduction studies, SPRAVATO may cause embryo-fetal harmwhen administered to a pregnant woman [see Warnings and Precautions (5.10) and Use inSpecific Populations (8.1)]. However, it is not clear how these animal findings relate to femalesof reproductive potential treated with the recommended clinical dose. Consider pregnancyplanning and prevention for females of reproductive potential during treatment withSPRAVATO.
8.4 Pediatric Use
The safety and effectiveness of SPRAVATO in pediatric patients have not been established.
8.5 Geriatric Use
Of the total number of patients in Phase 3 clinical studies exposed to SPRAVATO, (N=1601),194 (12%) were 65 years of age and older, and 25 (2%) were 75 years of age and older. Nooverall differences in the safety profile were observed between patients 65 years of age and olderand patients younger than 65 years of age.
The mean esketamine Cmax and AUC values were higher in elderly patients compared withyounger adult patients [see Clinical Pharmacology (12.3)].
The efficacy of SPRAVATO for the treatment of TRD in geriatric patients was eva luated in a4-week, randomized, double-blind study comparing flexibly-dosed intranasal SPRAVATO plusa newly initiated oral antidepressant compared to intranasal placebo plus a newly initiated oralantidepressant in patients ≥ 65 years of age. SPRAVATO was initiated at 28 mg twice weeklyand could be titrated to 56 mg or 84 mg administered twice-weekly. At the end of four weeks,
there was no statistically significant difference between groups on the primary efficacy |
