b'SPRAVATO (esketamine) nasal spray, CIII SPRAVATO (esketamine) nasal spray, CIIISedation Table 6:IncreasesinBloodPressureinDouble-blind,Randomized, SedationwasevaluatedbyadverseeventreportsandtheModifiedPlacebo-Controlled, Short-Term Trials of SPRAVATO + Oral AD Observers Assessment of Alertness/Sedation (MOAA/S). In the MOAA/S,Compared to Placebo Nasal Spray + Oral AD in the Treatment of 5 means responds readily to name spoken in normal tone and 0 meansTRD in Adult Patientsno response after painful trapezius squeeze. Any decrease in MOAA/SPatients 65 years Patients 65 yearsfrom pre-dose is considered to indicate the presence of sedation, and such a decrease occurred in a higher number of patients on SPRAVATO thanSPRAVATO Placebo + SPRAVATO Placebo +placebo during the short-term TRD studies. Dose-related increases in the+ Oral ADOral AD + Oral AD Oral ADincidence of sedation (MOAA/S score 5) were observed in a fixed-doseN=346 N=222 N=72 N=65TRD study [see Warnings and Precautions]. Table 4 presents the incidenceSystolic blood pressureof sedation (MOAA/S score 5) in a fixed-dose study with adult patients 180 mmHg 9 (3%) - 2 (3%) 1 (2%)65 years of age with TRD and a flexible-dose study with patients 65 years of age with TRD. 40 mmHg increase 29 (8%) 1 (0.5%) 12 (17%) 1 (2%)Table 4:IncidenceofSedation(MOAA/SScore5)inDouble-Blind,Diastolic blood pressureRandomized, Placebo-Controlled Studies (Fixed-Dose Study with110 mmHg 13 (4%) 1 (0.5%) - -Adult Patients 65 Years of Age with TRD and Flexible-Dose Study25 mmHg increase 46 (13%) 6 (3%) 10 (14%) 2 (3%)with Patients 65 Years of Age with TRD) In studies for the treatment of depressive symptoms in adults with MDD Patients 65 years Patients 65 years with acute suicidal ideation or behavior, patients treated with SPRAVATO Placebo +SPRAVATO + Placebo +SPRAVATO +plusoralantidepressantsdemonstratedsimilarmeanplacebo-adjusted Oral AD Oral AD Oral AD Oral AD increases in SBP and DBP compared to patient with TRD, as well as similar 56 mg 84 mg 28 to 84 mg rates of increases to SBP 180 mmHg or 40 mmHg increases in SBP, and similar rates of increases to DBP 110 mmHg or 25 mmHg increases in DBP, Number of patients* N=112 N=114 N=114 N=63 N=72 compared to the TRD study results in Table 6.Sedation (MOAA/S11% 50% 61% 19% 49% Nausea and Vomitingscore 5) SPRAVATO can cause nausea and vomiting. Most of these events occurred *Patients who were evaluated with MOAA/S on the day of dosing and resolved the same day, with the median duration not exceeding 1 hour in most subjects across dosing sessions. Rates of reported In studies for the treatment of depressive symptoms in adults with MDDnausea and vomiting decreased over time across dosing sessions from the with acute suicidal ideation or behavior, there was a higher incidence offirst week of treatment in the short-term studies, as well as over time with sedation (MOAA/S score 5) in patients treated with SPRAVATO plus oral ADlong-term treatment. Table 7 presents the incidence and severity of nausea compared to patients treated with placebo plus oral AD, similar to the TRDand vomiting in a short-term study with patients with TRD.study results in Table 4.Dissociation/Perceptual Changes Table 7: I ncidenceandSeverityofNauseaandVomitinginaDouble-SPRAVATO can cause dissociative symptoms (including derealization andblind, Randomized, Placebo-Controlled, Fixed-Dose Study in Adult depersonalization) and perceptual changes (including distortion of time andPatients with TRDspace, and illusions). In clinical trials, dissociation was transient and occurredTreatment (+ Oral AD) Nausea Vomitingon the day of dosing. Dissociation was evaluated by adverse event reportsN All Severe All Severeand the Clinician-Administered Dissociative States Scale (CADSS). A CADSSSPRAVATO 56 mg 115 31 (27%) 0 7 (6%) 0total score of more than 4 indicates the presence of dissociative symptoms,SPRAVATO 84 mg 116 37 (32%) 4 (3%) 14 (12%) 3 (3%)and such an increase to a score of 4 or more occurred in a higher number of patients on SPRAVATO compared to placebo during the short-term TRDPlacebo Nasal Spray 113 12 (11%) 0 2 (2%) 0studies. Dose-related increases in the incidence of dissociative symptomsIn studies for the treatment of depressive symptoms in adults with MDD with (CADSS total score 4 and change 0) were observed in a fixed-dose TRDacute suicidal ideation or behavior, patients demonstrated similar incidence study [see Warnings and Precautions]. Table 5 presents the incidence ofand severity of reported nausea and vomiting compared to the TRD study dissociation (CADSS total score 4 and change 0) in a fixed-dose studyresults described above.with adult patients 65 years of age with TRD and a flexible-dose study withSense of Smellpatients 65 years of age with TRD. Senseofsmellwasassessedovertime;nodifferencewasobservedTable 5:Incidence of Dissociation (CADSS Total Score 4 and Change 0)between patients treated with SPRAVATO plus oral AD and those treated in Double-Blind, Randomized, Placebo-Controlled Studies (Fixed- with placebo nasal spray plus oral AD during the double-blind maintenance Dose Study with Adult Patients 65 Years of Age with TRD andphase of Study 2 [see Clinical Studies (14.1) in Full Prescribing Information].Flexible-Dose Study with Patients 65 Years of Age with TRD) DRUG INTERACTIONSPatients 65 years Patients 65 years Central Nervous System DepressantsPlacebo +SPRAVATO Placebo +SPRAVATO Concomitant use with CNS depressants (e.g., benzodiazepines, opioids, alcohol) Oral AD + Oral AD Oral AD + Oral AD may increase sedation [see Warnings and Precautions]. Closely monitor for 56 mg 84 mg 28 to 84 mg sedation with concomitant use of SPRAVATO with CNS depressants. Number of patients* N=113 N=113 N=116 N=65 N=72 PsychostimulantsCADSS total scoreConcomitant use with psychostimulants (e.g., amphetamines, methylphenidate, 4 and change 0 5% 61% 69% 12% 75% modafinil,armodafinil)mayincreasebloodpressure[seeWarningsand Precautions].Closelymonitorbloodpressurewithconcomitantuseof * Number of patients who were evaluated with CADSS SPRAVATO with psychostimulants.In studies for the treatment of depressive symptoms in adults with MDD withMonoamine Oxidase Inhibitors (MAOIs)acute suicidal ideation or behavior, patients treated with SPRAVATO plus oralConcomitant use with monoamine oxidase inhibitors (MAOIs) may increase AD also demonstrated a higher number (84%) with dissociation (CADSS totalbloodpressure[seeWarningsandPrecautions].Closelymonitorblood score 4 and change 0) compared to patients treated with placebo pluspressure with concomitant use of SPRAVATO with MAOIs.oral AD (16%). USE IN SPECIFIC POPULATIONSIncrease in Blood Pressure PregnancyThemeanplacebo-adjustedincreasesinsystolicanddiastolicbloodPregnancy Exposure Registrypressure (SBP and DBP) over time were about 7 to 9 mmHg in SBP and 4There is a pregnancy exposure registry that monitors pregnancy outcomes in to 6 mmHg in DBP at 40 minutes post-dose and 2 to 5 mmHg in SBP andwomen exposed to antidepressants, including SPRAVATO, during pregnancy. 1 to 3 mmHg in DBP at 1.5 hours post-dose in patients with TRD receivingHealthcare providers are encouraged to register patients by contacting SPRAVATO plus oral antidepressants [see Warnings and Precautions]. Tablethe National Pregnancy Registry for Antidepressants at 1-844-405-6185 or 6 presents increases in blood pressure in short-term trials with patients 65online at https://womensmentalhealth.org/clinical-and-research-programs/years of age and 65 years of age with TRD. pregnancyregistry/antidepressants/.1641587-CHAESK_Journal AD_Mech AP1_Rv8.indd 7 11/24/20 10:38 AM'