b'SPRAVATO (esketamine) nasal spray, CIII SPRAVATO (esketamine) nasal spray, CIIImembers or caregivers of patients to monitor for changes in behavior and toEmbryo-fetal Toxicityalert the healthcare provider. Consider changing the therapeutic regimen,Based on published findings from pregnant animals treated with ketamine, including possibly discontinuing SPRAVATO and/or the concomitant oralthe racemic mixture of arketamine and esketamine, SPRAVATO may cause antidepressant, in patients whose depression is persistently worse, or whofetal harm when administered to pregnant women. Advise pregnant women are experiencing emergent suicidal thoughts or behaviors. of the potential risk to an infant exposed to SPRAVATO in utero. Advise Increase in Blood Pressure womenofreproductivepotentialtoconsiderpregnancyplanningand SPRAVATO causes increases in systolic and/or diastolic blood pressure (BP)prevention [see Use in Specific Populations].at all recommended doses. Increases in BP peak approximately 40 minutesADVERSE REACTIONSafter SPRAVATO administration and last approximately 4 hours [see AdverseThefollowingadversereactionsarediscussedinmoredetailinother Reactions]. sections of the labeling:Approximately 8% to 19% of SPRAVATO-treated patients and 1% to 4% ofSedation [see Warnings and Precautions]placebo-treated patients experienced an increase of greater than or equal toDissociation [see Warnings and Precautions]40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours afterIncrease in Blood Pressure [see Warnings and Precautions]administration at least once during the first 4 weeks of treatment. A substantialCognitive Impairment [see Warnings and Precautions]increase in blood pressure could occur after any dose administered even if Impaired Ability to Drive and Operate Machinery [see Warnings and smaller blood pressure effects were observed with previous administrations.Precautions]SPRAVATOiscontraindicatedinpatientsforwhomanincreaseinBPUlcerative or Interstitial Cystitis [see Warnings and Precautions]orintracranialpressureposesaseriousrisk(e.g.,aneurysmalvascularEmbryo-fetal Toxicity [see Warnings and Precautions]disease, arteriovenous malformation, history of intracerebral hemorrhage) [see Contraindications]. Before prescribing SPRAVATO, patients with otherClinical Trials Experiencecardiovascular and cerebrovascular conditions should be carefully assessedBecauseclinicaltrialsareconductedunderwidelyvaryingconditions, to determine whether the potential benefits of SPRAVATO outweigh its risks. adverse reaction rates observed in the clinical trials of a drug cannot be Assess BP prior to administration of SPRAVATO. In patients whose BP isdirectly compared to rates in the clinical trials of another drug and may not elevated prior to SPRAVATO administration (as a general guide: 140/90 mmHg) reflect the rates observed in clinical practice.a decision to delay SPRAVATO therapy should take into account the balance ofTreatment-Resistant Depressionbenefit and risk in individual patients. SPRAVATO was evaluated for safety in 1709 adults diagnosed with treatment-BP should be monitored for at least 2 hours after SPRAVATO administrationresistant depression (TRD) [see Clinical Studies (14.1) in Full Prescribing [see Dosage and Administration (2.1, 2.4) in Full Prescribing Information].Information] from five Phase 3 studies (3 short-term and 2 long-term studies) Measure blood pressure around 40 minutes post-dose and subsequentlyand one Phase 2 dose-ranging study. Of all SPRAVATO-treated patients as clinically warranted until values decline. If BP remains high, promptlyin the completed Phase 3 studies, 479 (30%) received at least 6 months of seek assistance from practitioners experienced in BP management. Refertreatment, and 178 (11%) received at least 12 months of treatment.patients experiencing symptoms of a hypertensive crisis (e.g., chest pain,Adverse Reactions Leading to Discontinuation of Treatmentshortness of breath) or hypertensive encephalopathy (e.g., sudden severeIn short-term studies in adults 65 years old (Study 1 pooled with another headache, visual disturbances, seizures, diminished consciousness or focal4-weekstudy),theproportionofpatientswhodiscontinuedtreatment neurological deficits) immediately for emergency care. becauseofanadversereactionwas4.6%inpatientswhoreceived Closely monitor blood pressure with concomitant use of SPRAVATO withSPRAVATO plus oral AD compared to 1.4% for patients who received placebo psychostimulantsormonoamineoxidaseinhibitors(MAOIs)[seeDrugnasal spray plus oral AD. For adults65 years old, the proportions were Interactions]. 5.6% and 3.1%, respectively. In Study 2, a long-term maintenance study, In patients with history of hypertensive encephalopathy, more intensivethe discontinuation rates because of an adverse reaction were similar for monitoring,includingmorefrequentbloodpressureandsymptompatients receiving SPRAVATO plus oral AD and placebo nasal spray plus assessment, is warranted because these patients are at increased risk fororal AD in the maintenance phase, at 2.6% and 2.1%, respectively. Across all developing encephalopathy with even small increases in blood pressure. Phase 3 studies, adverse reactions leading to SPRAVATO discontinuation in Cognitive Impairment more than 2 patients were (in order of frequency): anxiety (1.2%), depression Short-Term Cognitive Impairment (0.9%), blood pressure increased (0.6%), dizziness (0.6%), suicidal ideation (0.5%), dissociation (0.4%), nausea (0.4%), vomiting (0.4%), headache (0.3%), In a study in healthy volunteers, a single dose of SPRAVATO caused cognitivemuscular weakness (0.3%), vertigo (0.2%), hypertension (0.2%), panic attack performance decline 40 minutes post-dose. Compared to placebo-treated(0.2%) and sedation (0.2%).subjects, SPRAVATO-treated subjects required a greater effort to completeMost Common Adverse Reactionscognitive tests at 40 minutes post-dose. Cognitive performance and mentalThe most commonly observed adverse reactions in patients treated with effort were comparable between SPRAVATO and placebo at 2 hours post- SPRAVATO plus oral AD (incidence 5% and at least twice that of placebo dose. Sleepiness was comparable after 4 hours post-dose. nasal spray plus oral AD) were dissociation, dizziness, nausea, sedation, Long-Term Cognitive Impairment vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, Long-termcognitiveandmemoryimpairmenthavebeenreportedwithand feeling drunk. repeated ketamine misuse or abuse. No adverse effects of SPRAVATO nasalTable 2 shows the incidence of adverse reactions that occurred in patients spray on cognitive functioning were observed in a one-year open-labeltreated with SPRAVATO plus oral AD at any dose and greater than patients safety study; however, the long-term cognitive effects of SPRAVATO havetreated with placebo nasal spray plus oral AD.not been evaluated beyond one year.Impaired Ability to Drive and Operate Machinery Table 2:Adverse Reactions Occurring in 2% of Adult TRD Patients Treated Two placebo-controlled studies were conducted to assess the effects ofwith SPRAVATO + Oral AD at Any Dose and at a Greater Rate than SPRAVATO on the ability to drive [see Clinical Studies (14.3) in Full PrescribingPatients Treated with Placebo Nasal Spray + Oral ADInformation]. The effects of SPRAVATO 84 mg were comparable to placebo atSPRAVATO + Oral AD Placebo + Oral AD6 hours and 18 hours post-dose. However, two SPRAVATO-treated subjects in(N=346) (N=222)one of the studies discontinued the driving test at 8 hours post-dose becauseCardiac disordersof SPRAVATO-related adverse reactions. Tachycardia* 6 (2%) 1 (0.5%)BeforeSPRAVATOadministration,instructpatientsnottoengageinEar and labyrinth disorderspotentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery,Vertigo* 78 (23%) 6 (3%)until the next day following a restful sleep. Patients will need to arrangeGastrointestinal disorderstransportation home following treatment with SPRAVATO. Nausea 98 (28%) 19 (9%)Ulcerative or Interstitial Cystitis Vomiting 32 (9%) 4 (2%)Cases of ulcerative or interstitial cystitis have been reported in individualsDiarrhea 23 (7%) 13 (6%)with long-term off-label use or misuse/abuse of ketamine. In clinical studiesDry mouth 19 (5%) 7 (3%)with SPRAVATO nasal spray, there was a higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) inConstipation11 (3%) 3 (1%)SPRAVATO-treated patients than in placebo-treated patients [see AdverseGeneral disorders and administration site conditionsReactions].Nocasesofesketamine-relatedinterstitialcystitiswereFeeling drunk 19 (5%) 1 (0.5%)observed in any of the studies, which included treatment for up to a year. Feeling abnormal 12 (3%) 0 (0%)Monitorforurinarytractandbladdersymptomsduringthecourseof treatment with SPRAVATO, and refer to an appropriate healthcare providerInvestigationsas clinically warranted. Blood pressure increased* 36 (10%) 6 (3%)1641587-CHAESK_Journal AD_Mech AP1_Rv8.indd 5 11/24/20 10:38 AM'