b'SPRAVATO (esketamine) nasal spray, CIII SPRAVATO (esketamine) nasal spray, CIIITable 2:Adverse Reactions Occurring in 2% of Adult TRD Patients TreatednasalsprayplusoralAD)weredissociation,dizziness,sedation,blood with SPRAVATO + Oral AD at Any Dose and at a Greater Rate thanpressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo. Patients Treated with Placebo Nasal Spray + Oral AD (continued) Table 3 shows the incidence of adverse reactions that occurred in patients SPRAVATO + Oral AD Placebo + Oral AD treated with SPRAVATO plus oral AD and greater than patients treated with placebo nasal spray plus oral AD.(N=346) (N=222)Nervous system disorders Table 3:Adverse Reactions Occurring in 2% of Adult Patients with MDD and Dizziness* 101 (29%) 17 (8%) Acute Suicidal Ideation or Behavior Treated with SPRAVATO + Oral Sedation* 79 (23%) 21 (9%) AD and at a Greater Rate than Patients Treated with Placebo Nasal Spray + Oral ADHeadache* 70 (20%) 38 (17%) SPRAVATO + Oral ADPlacebo + Oral AD Dysgeusia* 66 (19%) 30 (14%) (N=227) (N=225)Hypoesthesia* 63 (18%) 5 (2%) Cardiac disordersLethargy* 37 (11%) 12 (5%) Tachycardia* 8 (4%) 2 (1%)Dysarthria* 15 (4%) 0 (0%) Ear and labyrinth disordersTremor 12 (3%) 2 (1%) Vertigo 14 (6%) 1 (0.4%)Mental impairment 11 (3%) 2 (1%) Gastrointestinal disordersPsychiatric disorders Nausea 61 (27%) 31 (14%)Dissociation* 142 (41%) 21 (9%) Vomiting 26 (11%) 12 (5%)Anxiety* 45 (13%) 14 (6%) Constipation22 (10%) 14 (6%)Insomnia 29 (8%) 16 (7%) Dry mouth 8 (4%) 6 (3%)Euphoric mood 15 (4%) 2 (1%) Toothache 5 (2%) 2 (1%)Renal and urinary disorders General disorders and administration site conditionsPollakiuria 11 (3%) 1 (0.5%) Feeling drunk 8 (4%) 1 (0.4%)Respiratory, thoracic and mediastinal disorders Feeling of relaxation 5 (2%) 3 (1%)Nasal discomfort* 23 (7%) 11 (5%) InvestigationsThroat irritation 23 (7%) 9 (4%) Blood pressure34 (15%) 14 (6%)Oropharyngeal pain 9 (3%) 5 (2%) increased*Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disordersHyperhidrosis 14 (4%) 5 (2%) Myalgia 5 (2%) 1 (0.4%)* The following terms were combined: Nervous system disordersAnxietyincludes:agitation;anticipatoryanxiety;anxiety;fear;feelingDizziness* 103 (45%) 34 (15%)jittery; irritability; nervousness; panic attack; tension Sedation* 66 (29%) 27 (12%)Blood pressure increased includes: blood pressure diastolic increased; blood pressure increased; blood pressure systolic increased; hypertension Dysgeusia* 46 (20%) 29 (13%)Dissociation includes: delusional perception; depersonalization/derealizationHypoesthesia* 30 (13%) 4 (2%)disorder; derealization; diplopia; dissociation; dysesthesia; feeling cold; feelingLethargy* 10 (4%) 4 (2%)hot; feeling of body temperature change; hallucination; hallucination, auditory;Confusional state 5 (2%) 0 (0%)hallucination, visual; hyperacusis; illusion; ocular discomfort; oral dysesthesia; paresthesia;paresthesiaoral;pharyngealparesthesia;photophobia;timePsychiatric disordersperception altered; tinnitus; vision blurred; visual impairment Dissociation* 108 (48%) 30 (13%)Dizzinessincludes:dizziness;dizzinessexertional;dizzinesspostural;Anxiety* 34 (15%) 20 (9%)procedural dizzinessDysarthria includes: dysarthria; slow speech; speech disorder Euphoric mood 17 (7%) 1 (0.4%)Dysgeusia includes: dysgeusia; hypogeusia Intentional self-injury 7 (3%) 3 (1%)Headache includes: headache; sinus headache Dysphoria 5 (2%) 0 (0%)Hypoesthesiaincludes:hypoesthesia;hypoesthesiaoral,hypoesthesiaRenal and urinary disordersteeth, pharyngeal hypoesthesiaLethargy includes: fatigue; lethargy Pollakiuria* 5 (2%) 2 (1%)Nasal discomfort includes: nasal crusting; nasal discomfort; nasal dryness;Respiratory, thoracic and mediastinal disordersnasal pruritus Oropharyngeal pain 10 (4%) 3 (1%)Sedation includes: altered state of consciousness; hypersomnia; sedation;Throat irritation 9 (4%) 5 (2%)somnolenceTachycardia includes: extrasystoles; heart rate increased; tachycardia Skin and subcutaneous tissue disordersVertigo includes: vertigo; vertigo positional Hyperhidrosis* 11 (5%) 5 (2%)DepressiveSymptomsinPatientswithMajorDepressiveDisorderwith* The following terms were combined:Acute Suicidal Ideation or BehaviorSPRAVATOwasevaluatedforsafetyin262adultsforthetreatmentofAnxietyincludes:agitation;anxiety;anxietydisorder;fear;irritability; depressivesymptomsinadultswithmajordepressivedisorder(MDD)nervousness; panic attack; psychomotor hyperactivity; tensionwith acute suicidal ideation or behavior [see Clinical Studies (14.2) in FullBlood pressure increased includes: blood pressure diastolic increased; Prescribing Information] from two Phase 3 studies (Study 3 and Study 4) andblood pressure increased; blood pressure systolic increased; hypertensionone Phase 2 study. Of all SPRAVATO-treated patients in the completed PhaseDissociationincludes:depersonalization/derealizationdisorder; 3 studies, 184 (81%) received all eight doses over a 4-week treatment period. derealization; diplopia; dissociation; dysesthesia; feeling cold; feeling hot; hallucination; hallucination, auditory; hallucination, visual; hallucinations, Adverse Reactions Leading to Discontinuation of Treatment mixed; hyperacusis; paresthesia; paresthesia oral; pharyngeal paresthesia; In short-term studies in adults (pooled Study 3 and Study 4), the proportionphotophobia; time perception altered; tinnitus; vision blurredof patients who discontinued treatment because of an adverse reaction wasDizziness includes: dizziness; dizziness exertional; dizziness postural6.2% for patients who received SPRAVATO plus oral AD compared to 3.6% forDysgeusia includes: dysgeusia; hypogeusiapatients who received placebo nasal spray plus oral AD. Adverse reactionsHyperhidrosis includes: cold sweat; hyperhidrosisleading to SPRAVATO discontinuation in more than 1 patient were (in orderHypoesthesiaincludes:hypoesthesia;hypoesthesiaoral;intranasal of frequency): dissociation-related events (2.6%), blood pressure increasedhypoesthesia; pharyngeal hypoesthesia(0.9%), dizziness-related events (0.9%), nausea (0.9%), and sedation-relatedLethargy includes: fatigue; lethargy; psychomotor retardationevents (0.9%). Pollakiuria includes: micturition urgency; pollakiuriaMost Common Adverse Reactions Sedation includes: sedation; somnolence; stupor The most commonly observed adverse reactions in patients treated withTachycardia includes: heart rate increased; sinus tachycardia; tachycardiaSPRAVATO plus oral AD (incidence 5% and at least twice that of placebo 1641587-CHAESK_Journal AD_Mech AP1_Rv8.indd 6 11/24/20 10:38 AM'