b'SPRAVATOSPRAVATO (esketamine) nasal spray, CIII(esketamine) nasal spray, CIIIBrief Summary Becauseoftherisksofdissociation,patientsmustbemonitoredbya BEFOREPRESCRIBINGSPRAVATO,PLEASESEEFULLPRESCRIBINGhealthcare provider for at least 2 hours at each treatment session, followed by INFORMATION, INCLUDING BOXED WARNING. an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Dosage and Administration WARNING: SEDATION; DISSOCIATION; ABUSE AND MISUSE; and(2.4) in Full Prescribing Information].SUICIDAL THOUGHTS AND BEHAVIORS SPRAVATO is available only through a restricted program under a REMS [see Sedation Warnings and Precautions]. Patients are at risk for sedation after administration of SPRAVATO [seeAbuse and MisuseWarnings and Precautions]. SPRAVATO contains esketamine, a Schedule III controlled substance (CIII), Dissociation and may be subject to abuse and diversion. Assess each patients risk forPatientsareatriskfordissociativeorperceptualchangesafterabuse or misuse prior to prescribing SPRAVATO and monitor all patients administration of SPRAVATO [see Warnings and Precautions]. receiving SPRAVATO for the development of these behaviors or conditions, Becauseoftherisksofsedationanddissociation,patientsmustbeincludingdrug-seekingbehavior,whileontherapy.Contactlocalstate monitored for at least 2 hours at each treatment session, followed by anprofessional licensing board or state-controlled substances authority for assessment to determine when the patient is considered clinically stableinformation on how to prevent and detect abuse or diversion of SPRAVATO. and ready to leave the healthcare setting [see Warnings and Precautions]. Individuals with a history of drug abuse or dependence are at greater Abuse and Misuse risk; therefore, use careful consideration prior to treatment of individualsSPRAVATO has the potential to be abused and misused. Consider thewith a history of substance use disorder and monitor for signs of abuse or risks and benefits of prescribing SPRAVATO prior to use in patients atdependence [see Drug Abuse and Dependence].higher risk of abuse. Monitor patients for signs and symptoms of abuseSPRAVATO is available only through a restricted program under a REMS [see and misuse [see Warnings and Precautions]. Warnings and Precautions].Because of the risks of serious adverse outcomes resulting from sedation,SPRAVATO Risk Evaluation and Mitigation Strategy (REMS)dissociation, and abuse and misuse, SPRAVATO is only available throughSPRAVATO is available only through a restricted program under a REMS a restricted program under a Risk Evaluation and Mitigation StrategycalledtheSPRAVATOREMSbecauseoftherisksofseriousadverse (REMS) called the SPRAVATO REMS [see Warnings and Precautions]. outcomes from sedation, dissociation, and abuse and misuse [see Boxed Suicidal Thoughts and Behaviors Warning and Warnings and Precautions].Antidepressants increased the risk of suicidal thoughts and behaviorImportant requirements of the SPRAVATO REMS include the following:inpediatricandyoungadultpatientsinshort-termstudies.Closely Healthcare settings must be certified in the program and ensure that monitor all antidepressant-treated patients for clinical worsening, andSPRAVATO is:for emergence of suicidal thoughts and behaviors. SPRAVATO is notOnly dispensed and administered in healthcare settings.approved for use in pediatric patients [see Warnings and Precautions]. Patients treated in outpatient settings (e.g. medical offices and clinics) INDICATIONS AND USAGE must be enrolled in the program.SPRAVATO is indicated, in conjunction with an oral antidepressant, for theAdministered by patients under the direct observation of a healthcare treatment of: provider and that patients are monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO [see Dosage and Treatment-resistant depression (TRD) in adults Administration (2.4) in Full Prescribing Information]. Depressive symptoms in adults with major depressive disorder (MDD) PharmaciesmustbecertifiedintheREMSandmustonlydispense with acute suicidal ideation or behavior SPRAVATO to healthcare settings that are certified in the program.Limitations of Use: Further information, including a list of certified pharmacies is available at The effectiveness of SPRAVATO in preventing suicide or in reducing suicidalwww.SPRAVATOrems.com or 1-855-382-6022.ideation or behavior has not been demonstrated [see Clinical Studies (14.2)Suicidal Thoughts and Behaviors in Adolescents and Young Adultsin Full Prescribing Information]. Use of SPRAVATO does not preclude theInpooledanalysesofplacebo-controlledtrialsofantidepressantdrugs need for hospitalization if clinically warranted, even if patients experience(SSRIs and other antidepressant classes) that included approximately 77,000 improvement after an initial dose of SPRAVATO. adult patients and 4,500 pediatric patients (SPRAVATO is not approved inSPRAVATOisnotapprovedasananestheticagent.Thesafetypediatricpatients),theincidenceofsuicidalthoughtsandbehaviorsin andeffectivenessofSPRAVATOasananestheticagenthavenot patients age 24 years and younger was greater than in placebo-treated been established. patients. There was considerable variation in risk of suicidal thoughts and CONTRAINDICATIONS behaviors among drugs, but there was an increased risk identified in young SPRAVATO is contraindicated in patients with: patients for most drugs studied. There were differences in absolute risk ofAneurysmalvasculardisease(includingthoracicandabdominalsuicidal thoughts and behaviors across the different indications, with the aorta,intracranial,andperipheralarterialvessels)orarteriovenoushighest incidence in patients with major depressive disorder (MDD). The malformation [see Warnings and Precautions] drug-placebo differences in the number of cases of suicidal thoughts and History of intracerebral hemorrhage [see Warnings and Precautions] behaviors per 1000 patients treated are provided in Table 1.Hypersensitivity to esketamine, ketamine, or any of the excipients. Table 1:RiskDifferencesoftheNumberofPatientswithSuicidal WARNINGS AND PRECAUTIONS Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Sedation Antidepressants in Pediatric* and Adult PatientsIn clinical trials, 48% to 61% of SPRAVATO-treated patients developed sedationAge Range (Years) Drug-Placebo Difference in Number of Patients based on the Modified Observers Assessment of Alertness/Sedation scalewith Suicidal Thoughts or Behaviors per(MOAA/S) [see Adverse Reactions], and 0.3% to 0.4% of SPRAVATO-treated1000 Patients Treatedpatients experienced loss of consciousness (MOAA/S score of 0). Increases Compared to PlaceboBecause of the possibility of delayed or prolonged sedation, patients must18 14 additional patientsbe monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered18-24 5 additional patientsclinically stable and ready to leave the healthcare setting [see Dosage andDecreases Compared to PlaceboAdministration (2.4) in Full Prescribing Information]. 25-64 1 fewer patientClosely monitor for sedation with concomitant use of SPRAVATO with CNS65 6 fewer patientsdepressants [see Drug Interaction].SPRAVATO is available only through a restricted program under a REMS [see* SPRAVATO is not approved in pediatric patients.Warnings and Precautions]. It is unknown whether the risk of suicidal thoughts and behaviors in children, Dissociation adolescents, and young adults extends to longer-term use, i.e., beyond four The most common psychological effects of SPRAVATO were dissociativemonths. However, there is substantial evidence from placebo-controlled or perceptual changes (including distortion of time, space and illusions),maintenance studies in adults with MDD that antidepressants delay the derealizationanddepersonalization(61%to84%ofSPRAVATO-treatedrecurrence of depression and that depression itself is a risk factor for patients developed dissociative or perceptual changes based on the Clinician- suicidal thoughts and behaviors.AdministeredDissociativeStatesScale)[seeAdverseReactions].GivenMonitorallantidepressant-treatedpatientsforclinicalworseningand its potential to induce dissociative effects, carefully assess patients withemergence of suicidal thoughts and behaviors, especially during the initial psychosis before administering SPRAVATO; treatment should be initiated onlyfew months of drug therapy and at times of dosage changes. Counsel family if the benefit outweighs the risk.1641587-CHAESK_Journal AD_Mech AP1_Rv8.indd 4 11/24/20 10:38 AM'