b'SPRAVATO (esketamine) nasal spray, CIII SPRAVATO (esketamine) nasal spray, CIIIRisk Summary postnatal day (PND) 9, and the effect normalized by PND 19 in treatment SPRAVATO is not recommended during pregnancy. There are insufficient datagroups as compared with PND 14 for the majority of the control animals. on SPRAVATO use in pregnant women to draw conclusions about any drug- There is no NOAEL for this delay in sensory/motor response observed in pups associated risk of major birth defects, miscarriage, or adverse maternal or fetalduring the preweaning period. During the postweaning period, a decrease outcomes. Based on published findings from pregnant animals treated within motor activity was observed at doses15 mg/kg which is 0.5-times ketamine, the racemic mixture of arketamine and esketamine, SPRAVATO maythe human exposure at the MRHD of 84 mg/day. The NOAEL for maternal cause fetal harm when administered to pregnant women (see Data). Advisetoxicity and decreased motor activity during the postweaning period waspregnant women of the potential risk to an infant exposed to SPRAVATOi n utero.4.5 mg/kg/day which was associated with a plasma exposure (AUC) that was There are risks to the mother associated with untreated depression in pregnancy0.07-times the AUC exposure at MRHD of 84 mg/day.(see Clinical Considerations). If a woman becomes pregnant while being treatedLactationwith SPRAVATO, treatment with esketamine should be discontinued and theRisk Summarypatient should be counseled about the potential risk to the fetus. Esketamine is present in human milk. There are no data on the effects of Published studies in pregnant primates demonstrate that the administration ofSPRAVATO on the breastfed infant or on milk production. Published studies drugs that block N-methyl-D-aspartate (NMDA) receptors during the period of in juvenile animals report neurotoxicity (see Data). Because of the potential peak brain development increases neuronal apoptosis in the developing for neurotoxicity, advise patients that breast-feeding is not recommended brain of the offspring. There are no data on pregnancy exposures in primatesduring treatment with SPRAVATO.corresponding to periods prior to the third trimester in humans [see Use inDataSpecific Populations]. Publishedjuvenileanimalstudiesdemonstratethattheadministrationof In an embryo-fetal reproduction study in rabbits, skeletal malformationsdrugs that block NMDA receptors, such as ketamine, during the period of werenotedatmaternallytoxicdoseswhenketaminewasintranasallyrapid brain growth or synaptogenesis, results in widespread neuronal and administered with a No Observed Adverse Effect Level (NOAEL) at estimatedoligodendrocyte cell loss in the developing brain and alterations in synaptic esketamine exposures 0.3 times the exposures at the maximum recommendedmorphologyandneurogenesis.Basedoncomparisonsacrossspecies, human dose (MRHD) of 84 mg/day. In addition, intranasal administration ofthe window of vulnerability to these changes is believed to correlate with esketamine to pregnant rats during pregnancy and lactation at exposuresexposures in the third trimester of gestation through the first several months of that were similar to those at the MRHD resulted in a delay in sensorimotorlife, but this window may extend out to approximately 3 years of age in humans.development in pups during the preweaning period and a decrease in motorFemales and Males of Reproductive Potentialactivity in the post-weaning period.The estimated background risk of major birth defects and miscarriage for theContraceptionindicated population is unknown. All pregnancies have a background risk ofBasedonpublishedanimalreproductionstudies,SPRAVATOmaycause birth defect, loss, or other adverse outcomes. In the U.S. general population,embryo-fetal harm when administered to a pregnant woman [see Warnings the estimated background risk of major birth defects and miscarriage inand Precautions and Use in Specific Populations]. However, it is not clear how clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. these animal findings relate to females of reproductive potential treated with Clinical Considerations the recommended clinical dose. Consider pregnancy planning and prevention for females of reproductive potential during treatment with SPRAVATO.Disease-Associated Maternal and/or Embryo-Fetal Risk Pediatric UseAprospective,longitudinalstudyfollowed201pregnantwomenwithThe safety and effectiveness of SPRAVATO in pediatric patients have not ahistoryofmajordepressivedisorderwhowereeuthymicandtakingbeen established. Clinical studies of SPRAVATO in pediatric patients have antidepressants at the beginning of pregnancy. The women who discontinuednot been conducted.antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. ConsiderGeriatric Usethe risk of untreated depression when discontinuing or changing treatmentOfthetotalnumberofpatientsinPhase3clinicalstudiesexposedto with antidepressant medication during pregnancy and postpartum. SPRAVATO, (N=1601), 194 (12%) were 65 years of age and older, and 25 (2%) Data were 75 years of age and older. No overall differences in the safety profile Animal Data were observed between patients 65 years of age and older and patients Based on published data, when female monkeys were treated intravenouslyyounger than 65 years of age.with racemic ketamine at anesthetic dose levels in the third trimester ofThe mean esketamine C maxand AUC values were higher in elderly patients pregnancy, neuronal cell death was observed in the brains of their fetuses.compared with younger adult patients [see Clinical Pharmacology (12.3) in This period of brain development translates into the third trimester of humanFull Prescribing Information].pregnancy. The clinical significance of these findings is not clear; however,The efficacy of SPRAVATO for the treatment of TRD in geriatric patients was studies in juvenile animals suggest neuroapoptosis correlates with long-termevaluated in a 4-week, randomized, double-blind study comparing flexibly-cognitive deficits. dosedintranasalSPRAVATOplusanewlyinitiatedoralantidepressant Racemic ketamine was administered intranasally to pregnant rats duringcompared to intranasal placebo plus a newly initiated oral antidepressant the period of organogenesis at doses of 15, 50, and 150 mg/kg/day. The Noin patients65 years of age. SPRAVATO was initiated at 28 mg twice weekly Observed Adverse Effect Level (NOAEL) for embryo-fetal toxicity in rats wasand could be titrated to 56 mg or 84 mg administered twice-weekly. At the the highest dose of 150 mg/kg/day. Estimating 50% of the exposure to be fromend of four weeks, there was no statistically significant difference between esketamine, the NOAEL associated with esketamine plasma exposure (AUC)groups on the primary efficacy endpoint of change from baseline to Week 4 is 12-times the AUC exposure at the MRHD of 84 mg/day. In pregnant rabbits,on the Montgomery-sberg Depression Rating Scale (MADRS).racemic ketamine was administered intranasally from gestational day 6 to 18Hepatic Impairmentat doses of 10, 30, and 100 mg/kg/day. The high dose was lowered from 100ThemeanesketamineAUCandt 1/2 valueswerehigherinpatientswith to 50 mg/kg after 5 days of dosing due to excessive mortality in the pregnantmoderate hepatic impairment compared to those with normal hepatic function rabbits.Skeletalmalformationswereobservedatdoses30mg/kg/day, [see Clinical Pharmacology (12.3) in Full Prescribing Information]. SPRAVATO-which were maternally toxic. The NOAEL for skeletal malformations wastreated patients with moderate hepatic impairment may need to be monitored associated with a plasma esketamine exposure (AUC) that was 0.3 times thefor adverse reactions for a longer period of time.AUC exposure at MRHD of 84 mg/day. SPRAVATO has not been studied in patients with severe hepatic impairment Administration of esketamine to pregnant rats during pregnancy and lactation(Child-Pugh class C). Use in this population is not recommended [see Clinical at intranasal doses equivalent to 4.5, 15, and 45 mg/kg/day (based on a 200-gramPharmacology (12.3) in Full Prescribing Information].rat) produced AUC exposures 0.07, 0.5, and 0.7 times the MRHD of 84 mg/day, DRUG ABUSE AND DEPENDENCErespectively.Maternaltoxicitywasobservedatdoses15mg/kg/day. Controlled SubstanceIn addition, a dose-dependent delay in the age of attainment of PreyerSPRAVATO contains esketamine hydrochloride, the (S)-enantiomer of ketamine response reflex was observed in pups at all doses during the preweaningand a Schedule III controlled substance under the Controlled Substances Act.period. This sensory/motor developmental measure was tested starting on 1641587-CHAESK_Journal AD_Mech AP1_Rv8.indd 8 11/24/20 10:38 AM'