FDA label 309ff0be-81dc-4e85-9fe3-937e88e44e6e

WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Risk for sedation, dissociation, and respiratory depression after administration. Monitor patients for at least two hours after administration. ( 5.1 , 5.2 , 5.3 ) Potential for abuse and misuse. Consider the risks and benefits of prescribing SPRAVATO prior to using in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse. ( 5.4 ) SPRAVATO is only available through a restricted program called the SPRAVATO REMS. ( 5.5 ) Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. SPRAVATO is not approved for use in pediatric patients. ( 5.6 ) Sedation Patients are at risk for sedation after administration of SPRAVATO [see Warnings and Precautions (5.1) ]. Dissociation Patients are at risk for dissociative or perceptual changes after administration of SPRAVATO [see Warnings and Precautions (5.2) ]. Respiratory Depression Respiratory depression has been observed in postmarketing experience [see Warnings and Precautions (5.3) ] . Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Abuse and Misuse SPRAVATO has the potential to be abused and misused. Consider the risks and benefits of prescribing SPRAVATO prior to use in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse [see Warnings and Precautions (5.4) ] . Because of the risks of serious adverse outcomes resulting from sedation, dissociation, respiratory depression, abuse and misuse, SPRAVATO is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS [see Warnings and Precautions (5.5) ] . Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. SPRAVATO is not approved for use in pediatric patients [see Warnings and Precautions (5.6) ] .

5 WARNINGS AND PRECAUTIONS Increases in Blood Pressure: Patients with cardiovascular and cerebrovascular conditions and risk factors may be at an increased risk of associated adverse effects. ( 5.7 ) Cognitive Impairment: SPRAVATO may impair attention, judgment, thinking, reaction speed and motor skills. ( 5.8 ) Impaired Ability to Drive and Operate Machinery: Do not drive or operate machinery until the next day after a restful sleep. ( 5.9 ) Embryo-fetal Toxicity: May cause fetal harm. Consider pregnancy planning and prevention in females of reproductive potential. ( 5.11 , 8.1 , 8.3 ) 5.1 Sedation SPRAVATO may cause sedation or loss of consciousness. In some cases, patients may display diminished or less apparent breathing. In clinical trials, 48% to 61% of SPRAVATO-treated patients developed sedation based on the Modified Observer's Assessment of Alertness/Sedation scale (MOAA/S) [see Adverse Reactions (6.1) ] , and 0.3% to 0.4% of SPRAVATO-treated patients experienced loss of consciousness (MOAA/S score of 0). Because of the possibility of delayed or prolonged sedation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Dosage and Administration (2.5) ] . Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants [see Drug Interactions (7.1) ] . SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.5) ] . 5.2 Dissociation The most common psychological effects of SPRAVATO were dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization (61% to 84% of SPRAVATO-treated patients developed dissociative or perceptual changes based on the Clinician-Administered Dissociative States Scale) [see Adverse Reactions (6.1) ] . Given its potential to induce dissociative effects, carefully assess patients with psychosis before administering SPRAVATO; treatment should be initiated only if the benefit outweighs the risk. Because of the risks of dissociation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Dosage and Administration (2.5) ] . SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.5) ] . 5.3 Respiratory Depression In post marketing experience, respiratory depression was observed with the use of SPRAVATO. In addition, there were rare reports of respiratory arrest [see Adverse Reactions (6.2) ] . Because of the risks of respiratory depression, patients must be monitored for changes in respiratory status by a healthcare provider for at least 2 hours (including pulse oximetry) at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Dosage and Administration (2.5) ] . SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.5) ] . 5.4 Abuse and Misuse SPRAVATO contains esketamine, a Schedule III controlled substance (CIII), and may be subject to abuse and diversion. Assess each patient's risk for abuse or misuse prior to prescribing SPRAVATO and monitor all patients receiving SPRAVATO for the development of these behaviors or conditions, including drug-seeking behavior, while on therapy. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of SPRAVATO. Individuals with a history of drug abuse or dependence are at greater risk; therefore, use careful consideration prior to treatment of individuals with a history of substance use disorder and monitor for signs of abuse or dependence [see Drug Abuse and Dependence (9) ] . SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.5) ] . 5.5 SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) SPRAVATO is available only through a restricted program under a REMS called the SPRAVATO REMS because of the risks of serious adverse outcomes from sedation, dissociation, respiratory depression, abuse and misuse [see Boxed Warning and Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.4) ]. Important requirements of the SPRAVATO REMS include the following: Healthcare settings must be certified in the program and ensure that SPRAVATO is: – Only dispensed and administered in healthcare settings. – Patients treated in outpatient settings (e.g. medical offices and clinics) must be enrolled in the program. – Administered by patients under the direct observation of a healthcare provider and that patients are monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO [see Dosage and Administration (2.5) ]. Pharmacies must be certified in the REMS and must only dispense SPRAVATO to healthcare settings that are certified in the program. Further information, including a list of certified pharmacies is available at www.SPRAVATOrems.com or 1-855-382-6022. 5.6 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients (SPRAVATO is not approved in pediatric patients), the incidence of suicidal thoughts and behaviors in patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with major depressive disorder (MDD). The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2. Table 2: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric SPRAVATO is not approved in pediatric patients. and Adult Patients Age Range (Years) Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18–24 5 additional patients Decreases Compared to Placebo 25–64 1 fewer patient ≥65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing SPRAVATO and/or the concomitant oral antidepressant, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.7 Increase in Blood Pressure SPRAVATO causes increases in systolic and/or diastolic blood pressure (BP) at all recommended doses. Increases in BP peak approximately 40 minutes after SPRAVATO administration and last approximately 4 hours [see Adverse Reactions (6.1) ] . Approximately 3% to 19% of SPRAVATO-treated patients and 1% to 4% of placebo-treated patients experienced an increase of greater than or equal to 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A substantial increase in blood pressure could occur after any dose administered even if smaller blood pressure effects were observed with previous administrations. SPRAVATO is contraindicated in patients for whom an increase in BP or intracranial pressure poses a serious risk (e.g., aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage) [see Contraindications (4) ]. Before prescribing SPRAVATO, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of SPRAVATO outweigh its risks. Assess BP prior to administration of SPRAVATO. In patients whose BP is elevated prior to SPRAVATO administration (as a general guide: >140/90 mmHg) a decision to delay SPRAVATO therapy should take into account the balance of benefit and risk in individual patients. BP should be monitored for at least 2 hours after SPRAVATO administration [see Dosage and Administration (2.1 , 2.5) ] . Measure blood pressure around 40 minutes post-dose and subsequently as clinically warranted until values decline. If BP remains high, promptly seek assistance from practitioners experienced in BP management. Refer patients experiencing symptoms of a hypertensive crisis (e.g., chest pain, shortness of breath) or hypertensive encephalopathy (e.g., sudden severe headache, visual disturbances, seizures, diminished consciousness or focal neurological deficits) immediately for emergency care. Closely monitor blood pressure with concomitant use of SPRAVATO with psychostimulants or monoamine oxidase inhibitors (MAOIs) [see Drug Interactions (7.2 , 7.3) ] . In patients with history of hypertensive encephalopathy, more intensive monitoring, including more frequent blood pressure and symptom assessment, is warranted because these patients are at increased risk for developing encephalopathy with even small increases in blood pressure. 5.8 Cognitive Impairment Short-Term Cognitive Impairment In a study in healthy volunteers, a single dose of SPRAVATO caused cognitive performance decline 40 minutes post-dose. Compared to placebo-treated subjects, SPRAVATO-treated subjects required a greater effort to complete cognitive tests at 40 minutes post-dose. Cognitive performance and mental effort were comparable between SPRAVATO and placebo at 2 hours post-dose. Sleepiness was comparable after 4 hours post-dose. Long-Term Cognitive Impairment Long-term cognitive and memory impairment have been reported with repeated ketamine misuse or abuse. In 1-year and 3-year, long-term, open-label clinical trials in adults, the effect of SPRAVATO on cognitive functioning remained stable over time as evaluated by the Cogstate computerized battery and Hopkins Verbal Learning Test-Revised. 5.9 Impaired Ability to Drive and Operate Machinery Two placebo-controlled studies were conducted to assess the effects of SPRAVATO on the ability to drive [see Clinical Studies (14.3) ] . The effects of SPRAVATO 84 mg were comparable to placebo at 6 hours and 18 hours post-dose. However, two SPRAVATO-treated subjects in one of the studies discontinued the driving test at 8 hours post-dose because of SPRAVATO-related adverse reactions. Before SPRAVATO administration, instruct patients not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery, until the next day following a restful sleep. Patients will need to arrange transportation home following treatment with SPRAVATO. 5.10 Ulcerative or Interstitial Cystitis Cases of ulcerative or interstitial cystitis have been reported in individuals with long-term off-label use or misuse/abuse of ketamine. In clinical studies with SPRAVATO nasal spray, there was a higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in SPRAVATO-treated patients than in placebo-treated patients [see Adverse Reactions (6) ] . No cases of esketamine-related interstitial cystitis were observed in any of the studies, which included treatment for up to a year. Monitor for urinary tract and bladder symptoms during the course of treatment with SPRAVATO, and refer to an appropriate healthcare provider as clinically warranted. 5.11 Embryo-fetal Toxicity Based on published findings from pregnant animals treated with ketamine, the racemic mixture of arketamine and esketamine, SPRAVATO may cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to an infant exposed to SPRAVATO in utero . Advise women of reproductive potential to consider pregnancy planning and prevention [see Use in Specific Populations (8.1 , 8.3) ].

<table width="75%"><caption>Table 2: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric <footnote ID="K1795">SPRAVATO is not approved in pediatric patients.</footnote> and Adult Patients </caption><col align="center" valign="top" width="25%"/><col align="center" valign="top" width="75%"/><thead><tr><th styleCode="Lrule Rrule">Age Range (Years)</th><th styleCode="Rrule">Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"/><td styleCode="Rrule"><content styleCode="bold">Increases Compared to Placebo</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">&lt;18</td><td styleCode="Rrule">14 additional patients</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">18&#x2013;24</td><td styleCode="Rrule">5 additional patients</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"/><td styleCode="Rrule"><content styleCode="bold">Decreases Compared to Placebo</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">25&#x2013;64</td><td styleCode="Rrule">1 fewer patient</td></tr><tr><td styleCode="Lrule Rrule">&#x2265;65</td><td styleCode="Rrule">6 fewer patients</td></tr></tbody></table>

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Sedation [see Warnings and Precautions (5.1) ] Dissociation [see Warnings and Precautions (5.2) ] Respiratory Depression [see Warnings and Precautions (5.3) ] Increase in Blood Pressure [see Warnings and Precautions (5.7) ] Cognitive Impairment [see Warnings and Precautions (5.8) ] Impaired Ability to Drive and Operate Machinery [see Warnings and Precautions (5.9) ] Ulcerative or Interstitial Cystitis [see Warnings and Precautions (5.10) ] Embryo-fetal Toxicity [see Warnings and Precautions (5.11) ] The most commonly observed adverse reactions (incidence ≥5% and at least twice that of placebo): TRD: dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, feeling drunk, and headache. ( 6 ) Treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior: dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Treatment-Resistant Depression In Conjunction with an Oral Antidepressant SPRAVATO was evaluated for safety in 1709 adults diagnosed with treatment-resistant depression (TRD) [see Clinical Studies (14.1) ] from five Phase 3 studies (3 short-term and 2 long-term studies) and one Phase 2 dose-ranging study. Of all SPRAVATO-treated patients in the completed Phase 3 studies, 479 (30%) received at least 6 months of treatment, and 178 (11%) received at least 12 months of treatment. Adverse Reactions Leading to Discontinuation of Treatment In short-term studies in adults <65 years old (Study 1 pooled with another 4-week study), the proportion of patients who discontinued treatment because of an adverse reaction was 4.6% in patients who received SPRAVATO plus oral AD compared to 1.4% for patients who received placebo nasal spray plus oral AD. For adults ≥65 years old, the proportions were 5.6% and 3.1%, respectively. In Study 2, a long-term maintenance study, the discontinuation rates because of an adverse reaction were similar for patients receiving SPRAVATO plus oral AD and placebo nasal spray plus oral AD in the maintenance phase, at 2.6% and 2.1%, respectively. Across all Phase 3 studies, adverse reactions leading to SPRAVATO discontinuation in more than 2 patients were (in order of frequency): anxiety (1.2%), depression (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%), muscular weakness (0.3%), vertigo (0.2%), hypertension (0.2%), panic attack (0.2%) and sedation (0.2%). Most Common Adverse Reactions The most commonly observed adverse reactions in patients treated with SPRAVATO plus oral AD (incidence ≥5% and at least twice that of placebo nasal spray plus oral AD) were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk. Table 3 shows the incidence of adverse reactions that occurred in patients treated with SPRAVATO plus oral AD at any dose and greater than patients treated with placebo nasal spray plus oral AD. Table 3: Adverse Reactions Occurring in ≥2% of Adult TRD Patients Treated with SPRAVATO + Oral AD at Any Dose and at a Greater Rate than Patients Treated with Placebo Nasal Spray + Oral AD SPRAVATO + Oral AD (N=346) Placebo + Oral AD (N=222) Cardiac disorders Tachycardia The following terms were combined: Anxiety includes: agitation; anticipatory anxiety; anxiety; fear; feeling jittery; irritability; nervousness; panic attack; tension Blood pressure increased includes: blood pressure diastolic increased; blood pressure increased; blood pressure systolic increased; hypertension Dissociation includes: delusional perception; depersonalization/derealization disorder; derealization; diplopia; dissociation; dysesthesia; feeling cold; feeling hot; feeling of body temperature change; hallucination; hallucination, auditory; hallucination, visual; hyperacusis; illusion; ocular discomfort; oral dysesthesia; paresthesia; paresthesia oral; pharyngeal paresthesia; photophobia; time perception altered; tinnitus; vision blurred; visual impairment Dizziness includes: dizziness; dizziness exertional; dizziness postural; procedural dizziness Dysarthria includes: dysarthria; slow speech; speech disorder Dysgeusia includes: dysgeusia; hypogeusia Headache includes: headache; sinus headache Hypoesthesia includes: hypoesthesia; hypoesthesia oral, hypoesthesia teeth, pharyngeal hypoesthesia Lethargy includes: fatigue; lethargy Nasal discomfort includes: nasal crusting; nasal discomfort; nasal dryness; nasal pruritus Sedation includes: altered state of consciousness; hypersomnia; sedation; somnolence Tachycardia includes: extrasystoles; heart rate increased; tachycardia Vertigo includes: vertigo; vertigo positional 6 (2%) 1 (0.5%) Ear and labyrinth disorders Vertigo 78 (23%) 6 (3%) Gastrointestinal disorders Nausea 98 (28%) 19 (9%) Vomiting 32 (9%) 4 (2%) Diarrhea 23 (7%) 13 (6%) Dry mouth 19 (5%) 7 (3%) Constipation 11 (3%) 3 (1%) General disorders and administration site conditions Feeling drunk 19 (5%) 1 (0.5%) Feeling abnormal 12 (3%) 0 (0%) Investigations Blood pressure increased 36 (10%) 6 (3%) Nervous system disorders Dizziness 101 (29%) 17 (8%) Sedation 79 (23%) 21 (9%) Headache 70 (20%) 38 (17%) Dysgeusia 66 (19%) 30 (14%) Hypoesthesia 63 (18%) 5 (2%) Lethargy 37 (11%) 12 (5%) Dysarthria 15 (4%) 0 (0%) Tremor 12 (3%) 2 (1%) Mental impairment 11 (3%) 2 (1%) Psychiatric disorders Dissociation 142 (41%) 21 (9%) Anxiety 45 (13%) 14 (6%) Insomnia 29 (8%) 16 (7%) Euphoric mood 15 (4%) 2 (1%) Renal and urinary disorders Pollakiuria 11 (3%) 1 (0.5%) Respiratory, thoracic and mediastinal disorders Nasal discomfort 23 (7%) 11 (5%) Throat irritation 23 (7%) 9 (4%) Oropharyngeal pain 9 (3%) 5 (2%) Skin and subcutaneous tissue disorders Hyperhidrosis 14 (4%) 5 (2%) Monotherapy SPRAVATO used as monotherapy was evaluated for safety in 463 adults diagnosed with treatment-resistant depression (TRD) [see Clinical Studies (14.1) ] . Adverse Reactions Leading to Discontinuation of Treatment In the double-blind treatment phase of the short-term study in adults (Study 3), the proportion of patients who discontinued treatment because of an adverse reaction was 1% in patients who received SPRAVATO 56 mg and 4% in patients who received SPRAVATO 84 mg compared to 1% for patients who received placebo nasal spray. All of the adverse reactions leading to SPRAVATO discontinuation occurred in single subjects. Most Common Adverse Reactions The most common adverse reactions (≥5% and at least twice that of placebo nasal spray) were dissociation, nausea, dizziness, headache, anxiety, vomiting, feeling drunk, blood pressure increased, and sedation. Table 4 shows the incidence of adverse reactions that occurred in patients treated with SPRAVATO and greater than patients treated with placebo nasal spray. Table 4: Adverse Reactions Occurring in ≥2% of Adult TRD Patients Treated with SPRAVATO and at a Greater Rate than Patients Treated with Placebo Nasal Spray SPRAVATO 56mg + 84mg (N=226) Placebo (N=250) Ear and labyrinth disorders Vertigo 6 (3%) 0 (0%) Gastrointestinal disorders Nausea 56 (25%) 21 (8%) Vomiting 15 (7%) 1 (<1%) General disorders and administration site conditions Feeling drunk 16 (7%) 2 (<1%) Investigations Blood pressure increased The following terms were combined: Anxiety: anxiety, agitation, fear, feeling jittery, irritability, panic attack Blood pressure increased: blood pressure increased, hypertension Dissociation: depersonalization/derealization disorder, derealization, diplopia, dissociation, feeling hot, paresthesia, paresthesia oral, pharyngeal paresthesia, photophobia, tinnitus, vision blurred Dizziness: dizziness, dizziness postural Hypoesthesia: hypoesthesia, hypoesthesia oral, pharyngeal hypoesthesia Lethargy: fatigue, lethargy Sedation: sedation, somnolence 11 (5%) 4 (2%) Nervous system disorders Disturbance in attention 5(2%) 0 (0%) Dizziness 50 (22%) 18 (7%) Sedation 13 (6%) 4 (2%) Headache 43 (19%) 22 (9%) Dysgeusia 10 (4%) 9 (4%) Hypoesthesia 10 (4%) 1 (<1%) Lethargy 16 (7%) 12 (5%) Psychiatric disorders Dissociation 63 (28%) 11 (4%) Anxiety 22 (10%) 8 (3%) Insomnia 11 (5%) 9 (4%) Respiratory, thoracic, and mediastinal disorders Throat irritation 8 (4%) 2 (1%) Depressive Symptoms in Patients with Major Depressive Disorder with Acute Suicidal Ideation or Behavior SPRAVATO was evaluated for safety in 262 adults for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior [see Clinical Studies (14.2) ] from two Phase 3 studies (Study 4 and Study 5) and one Phase 2 study. Of all SPRAVATO-treated patients in the completed Phase 3 studies, 184 (81%) received all eight doses over a 4-week treatment period. Adverse Reactions Leading to Discontinuation of Treatment In short-term studies in adults (pooled Study 4 and Study 5), the proportion of patients who discontinued treatment because of an adverse reaction was 6.2% for patients who received SPRAVATO plus oral AD compared to 3.6% for patients who received placebo nasal spray plus oral AD. Adverse reactions leading to SPRAVATO discontinuation in more than 1 patient were (in order of frequency): dissociation-related events (2.6%), blood pressure increased (0.9%), dizziness-related events (0.9%), nausea (0.9%), and sedation-related events (0.9%). Most Common Adverse Reactions The most commonly observed adverse reactions in patients treated with SPRAVATO plus oral AD (incidence ≥5% and at least twice that of placebo nasal spray plus oral AD) were dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo. Table 5 shows the incidence of adverse reactions that occurred in patients treated with SPRAVATO plus oral AD and greater than patients treated with placebo nasal spray plus oral AD. Table 5: Adverse Reactions Occurring in ≥2% of Adult Patients with MDD and Acute Suicidal Ideation or Behavior Treated with SPRAVATO + Oral AD and at a Greater Rate than Patients Treated with Placebo Nasal Spray + Oral AD SPRAVATO + Oral AD (N=227) Placebo + Oral AD (N=225) Cardiac disorders Tachycardia The following terms were combined: Anxiety includes: agitation; anxiety; anxiety disorder; fear; irritability; nervousness; panic attack; psychomotor hyperactivity; tension Blood pressure increased includes: blood pressure diastolic increased; blood pressure increased; blood pressure systolic increased; hypertension Dissociation includes: depersonalization/derealization disorder; derealization; diplopia; dissociation; dysesthesia; feeling cold; feeling hot; hallucination; hallucination, auditory; hallucination, visual; hallucinations, mixed; hyperacusis; paresthesia; paresthesia oral; pharyngeal paresthesia; photophobia; time perception altered; tinnitus; vision blurred Dizziness includes: dizziness; dizziness exertional; dizziness postural Dysgeusia includes: dysgeusia; hypogeusia Hyperhidrosis includes: cold sweat; hyperhidrosis Hypoesthesia includes: hypoesthesia; hypoesthesia oral; intranasal hypoesthesia; pharyngeal hypoesthesia Lethargy includes: fatigue; lethargy; psychomotor retardation Pollakiuria includes: micturition urgency; pollakiuria Sedation includes: sedation; somnolence; stupor Tachycardia includes: heart rate increased; sinus tachycardia; tachycardia 8 (4%) 2 (1%) Ear and labyrinth disorders Vertigo 14 (6%) 1 (0.4%) Gastrointestinal disorders Nausea 61 (27%) 31 (14%) Vomiting 26 (11%) 12 (5%) Constipation 22 (10%) 14 (6%) Dry mouth 8 (4%) 6 (3%) Toothache 5 (2%) 2 (1%) General disorders and administration site conditions Feeling drunk 8 (4%) 1 (0.4%) Feeling of relaxation 5 (2%) 3 (1%) Investigations Blood pressure increased 34 (15%) 14 (6%) Musculoskeletal and connective tissue disorders Myalgia 5 (2%) 1 (0.4%) Nervous system disorders Dizziness 103 (45%) 34 (15%) Sedation 66 (29%) 27 (12%) Dysgeusia 46 (20%) 29 (13%) Hypoesthesia 30 (13%) 4 (2%) Lethargy 10 (4%) 4 (2%) Confusional state 5 (2%) 0 (0%) Psychiatric disorders Dissociation 108 (48%) 30 (13%) Anxiety 34 (15%) 20 (9%) Euphoric mood 17 (7%) 1 (0.4%) Intentional self-injury 7 (3%) 3 (1%) Dysphoria 5 (2%) 0 (0%) Renal and urinary disorders Pollakiuria 5 (2%) 2 (1%) Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 10 (4%) 3 (1%) Throat irritation 9 (4%) 5 (2%) Skin and subcutaneous tissue disorders Hyperhidrosis 11 (5%) 5 (2%) Sedation Sedation was evaluated by adverse event reports and the Modified Observer's Assessment of Alertness/Sedation (MOAA/S). In the MOAA/S, 5 means "responds readily to name spoken in normal tone" and 0 means "no response after painful trapezius squeeze." Any decrease in MOAA/S from pre-dose is considered to indicate the presence of sedation, and such a decrease occurred in a higher number of patients on SPRAVATO than placebo during the short-term TRD studies. Dose-related increases in the incidence of sedation (MOAA/S score <5) were observed in a fixed-dose TRD study [see Warnings and Precautions (5.1) ]. Table 6 presents the incidence of sedation (MOAA/S score <5) in a fixed-dose study with adult patients <65 years of age with TRD and a flexible-dose study with patients ≥65 years of age with TRD. Table 6: Incidence of Sedation (MOAA/S Score <5) in Double-Blind, Randomized, Placebo-Controlled Studies (Fixed-Dose Study with Adult Patients <65 Years of Age with TRD and Flexible-Dose Study with Patients ≥65 Years of Age with TRD) Patients <65 years Patients ≥65 years Placebo + Oral AD SPRAVATO + Oral AD Placebo + Oral AD SPRAVATO + Oral AD 56 mg 84 mg 28 to 84 mg Number of patients Patients who were evaluated with MOAA/S N=112 N=114 N=114 N=63 N=72 Sedation (MOAA/S score <5) 11% 50% 61% 19% 49% In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, there was a higher incidence of sedation (MOAA/S score <5) in patients treated with SPRAVATO plus oral AD compared to patients treated with placebo plus oral AD, similar to the TRD study results in Table 5. Dissociation/Perceptual Changes SPRAVATO can cause dissociative symptoms (including derealization and depersonalization) and perceptual changes (including distortion of time and space, and illusions). In clinical trials, dissociation was transient and occurred on the day of dosing. Dissociation was evaluated by adverse event reports and the Clinician-Administered Dissociative States Scale (CADSS). A CADSS total score of more than 4 indicates the presence of dissociative symptoms, 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 TRD studies. Dose-related increases in the incidence of dissociative symptoms (CADSS total score >4 and change >0) were observed in a fixed-dose TRD study [see Warnings and Precautions (5.2) ] . Table 7 presents the incidence of dissociation (CADSS total score >4 and change >0) in a fixed-dose study with adult patients <65 years of age with TRD and a flexible-dose study with patients ≥65 years of age with TRD. Table 7: Incidence of Dissociation (CADSS Total Score >4 and Change >0) in Double-Blind, Randomized, Placebo-Controlled Studies (Fixed-Dose Study with Adult Patients <65 Years of Age with TRD and Flexible-Dose Study with Patients ≥65 Years of Age with TRD) Patients <65 years Patients ≥65 years Placebo + Oral AD SPRAVATO + Oral AD Placebo + Oral AD SPRAVATO + Oral AD 56 mg 84 mg 28 to 84 mg Number of patients Number of patients who were evaluated with CADSS N=113 N=113 N=116 N=65 N=72 CADSS total score >4 and change >0 5% 61% 69% 12% 75% In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, patients treated with SPRAVATO plus oral AD also demonstrated a higher number (84%) with dissociation (CADSS total score >4 and change >0) compared to patients treated with placebo plus oral AD (16%). Increase in Blood Pressure The mean placebo-adjusted increases in systolic and diastolic blood pressure (SBP and DBP) over time were about 7 to 10 mmHg in SBP and 4 to 6 mmHg in DBP at 40 minutes post-dose and 2 to 5 mmHg in SBP and 1 to 3 mmHg in DBP at 1.5 hours post-dose in patients with TRD receiving SPRAVATO [see Warnings and Precautions (5.7) ] . Table 8 presents increases in blood pressure in short-term trials with patients <65 years of age and ≥65 years of age with TRD. Table 8: Increases in Blood Pressure in Double-blind, Randomized, Placebo-Controlled, Short-Term Trials of SPRAVATO Compared to Placebo Nasal Spray in the Treatment of TRD in Adult Patients SPRAVATO + Oral AD SPRAVATO Monotherapy Patients <65 years Patients ≥65 years Adult patients including those ≥65 years SPRAVATO + Oral AD N=346 Placebo + Oral AD N=222 SPRAVATO + Oral AD N=72 Placebo + Oral AD N=65 SPRAVATO N=226 Placebo N=250 Systolic blood pressure ≥180 mmHg 9 (3%) --- 2 (3%) 1 (2%) 2 (0.9%) 0 ≥40 mmHg increase 29 (8%) 1 (0.5%) 12 (17%) 1 (2%) 18 (8%) 5 (2%) Diastolic blood pressure ≥110 mmHg 13 (4%) 1 (0.5%) --- --- 3 (1%) 0 ≥25 mmHg increase 46 (13%) 6 (3%) 10 (14%) 2 (3%) 25 (11%) 6 (2%) In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, patients treated with SPRAVATO plus oral antidepressants demonstrated similar mean placebo-adjusted increases in SBP and DBP compared to patients with TRD, as well as similar 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, compared to the TRD study results in Table 8. Nausea and Vomiting SPRAVATO can cause nausea and vomiting. Most of these events occurred 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 nausea and vomiting decreased over time across dosing sessions from the first week of treatment in the short-term studies, as well as over time with long-term treatment. Table 9 presents the incidence and severity of nausea and vomiting in a short-term study with patients with TRD. Table 9: Incidence and Severity of Nausea and Vomiting in a Double-blind, Randomized, Placebo-Controlled, Fixed-Dose Study in Adult Patients with TRD Nausea Vomiting Treatment (+ Oral AD) N All Severe All Severe SPRAVATO 56 mg 115 31 (27%) 0 7 (6%) 0 SPRAVATO 84 mg 116 37 (32%) 4 (3%) 14 (12%) 3 (3%) Placebo Nasal Spray 113 12 (11%) 0 2 (2%) 0 In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, patients demonstrated similar incidence and severity of reported nausea and vomiting compared to the TRD study results described above. Sense of Smell Sense of smell was assessed over time; no difference was observed between patients treated with SPRAVATO plus oral AD and those treated with placebo nasal spray plus oral AD during the double-blind maintenance phase of Study 2 [see Clinical Studies (14.1) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SPRAVATO. Because these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac disorders: bradycardia Respiratory, thoracic and mediastinal disorders: respiratory depression (including respiratory arrest) Vascular disorders: hypotension

<table width="75%"><caption>Table 3: Adverse Reactions Occurring in &#x2265;2% of Adult TRD Patients Treated with SPRAVATO + Oral AD at Any Dose and at a Greater Rate than Patients Treated with Placebo Nasal Spray + Oral AD</caption><col width="60%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">SPRAVATO + Oral AD (N=346) </th><th styleCode="Rrule">Placebo + Oral AD (N=222) </th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Cardiac disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Tachycardia <footnote ID="t3f1">The following terms were combined: <content styleCode="bold">Anxiety includes:</content> agitation; anticipatory anxiety; anxiety; fear; feeling jittery; irritability; nervousness; panic attack; tension <content styleCode="bold">Blood pressure increased includes:</content> blood pressure diastolic increased; blood pressure increased; blood pressure systolic increased; hypertension <content styleCode="bold">Dissociation includes:</content> delusional perception; depersonalization/derealization disorder; derealization; diplopia; dissociation; dysesthesia; feeling cold; feeling hot; feeling of body temperature change; hallucination; hallucination, auditory; hallucination, visual; hyperacusis; illusion; ocular discomfort; oral dysesthesia; paresthesia; paresthesia oral; pharyngeal paresthesia; photophobia; time perception altered; tinnitus; vision blurred; visual impairment <content styleCode="bold">Dizziness includes:</content> dizziness; dizziness exertional; dizziness postural; procedural dizziness <content styleCode="bold">Dysarthria includes:</content> dysarthria; slow speech; speech disorder <content styleCode="bold">Dysgeusia includes:</content> dysgeusia; hypogeusia <content styleCode="bold">Headache includes:</content> headache; sinus headache <content styleCode="bold">Hypoesthesia includes:</content> hypoesthesia; hypoesthesia oral, hypoesthesia teeth, pharyngeal hypoesthesia <content styleCode="bold">Lethargy includes:</content> fatigue; lethargy <content styleCode="bold">Nasal discomfort includes:</content> nasal crusting; nasal discomfort; nasal dryness; nasal pruritus <content styleCode="bold">Sedation includes:</content> altered state of consciousness; hypersomnia; sedation; somnolence <content styleCode="bold">Tachycardia includes:</content> extrasystoles; heart rate increased; tachycardia <content styleCode="bold">Vertigo includes:</content> vertigo; vertigo positional</footnote></td><td styleCode="Rrule">6 (2%)</td><td styleCode="Rrule">1 (0.5%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Ear and labyrinth disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vertigo <footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">78 (23%)</td><td styleCode="Rrule">6 (3%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">98 (28%)</td><td styleCode="Rrule">19 (9%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">32 (9%)</td><td styleCode="Rrule">4 (2%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">23 (7%)</td><td styleCode="Rrule">13 (6%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dry mouth</td><td styleCode="Rrule">19 (5%)</td><td styleCode="Rrule">7 (3%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">11 (3%)</td><td styleCode="Rrule">3 (1%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Feeling drunk</td><td styleCode="Rrule">19 (5%)</td><td styleCode="Rrule">1 (0.5%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Feeling abnormal</td><td styleCode="Rrule">12 (3%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Investigations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Blood pressure increased <footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">36 (10%)</td><td styleCode="Rrule">6 (3%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness <footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">101 (29%)</td><td styleCode="Rrule">17 (8%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Sedation <footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">79 (23%)</td><td styleCode="Rrule">21 (9%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache <footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">70 (20%)</td><td styleCode="Rrule">38 (17%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dysgeusia <footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">66 (19%)</td><td styleCode="Rrule">30 (14%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypoesthesia <footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">63 (18%)</td><td styleCode="Rrule">5 (2%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Lethargy <footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">37 (11%)</td><td styleCode="Rrule">12 (5%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dysarthria <footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">15 (4%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Tremor</td><td styleCode="Rrule">12 (3%)</td><td styleCode="Rrule">2 (1%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Mental impairment</td><td styleCode="Rrule">11 (3%)</td><td styleCode="Rrule">2 (1%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dissociation <footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">142 (41%)</td><td styleCode="Rrule">21 (9%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anxiety <footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">45 (13%)</td><td styleCode="Rrule">14 (6%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Insomnia</td><td styleCode="Rrule">29 (8%)</td><td styleCode="Rrule">16 (7%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Euphoric mood</td><td styleCode="Rrule">15 (4%)</td><td styleCode="Rrule">2 (1%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Renal and urinary disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pollakiuria</td><td styleCode="Rrule">11 (3%)</td><td styleCode="Rrule">1 (0.5%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nasal discomfort <footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">23 (7%)</td><td styleCode="Rrule">11 (5%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Throat irritation</td><td styleCode="Rrule">23 (7%)</td><td styleCode="Rrule">9 (4%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Oropharyngeal pain</td><td styleCode="Rrule">9 (3%)</td><td styleCode="Rrule">5 (2%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td></tr><tr><td styleCode="Lrule Rrule"> Hyperhidrosis</td><td styleCode="Rrule">14 (4%)</td><td styleCode="Rrule">5 (2%)</td></tr></tbody></table>

<table width="85%"><caption>Table 4: Adverse Reactions Occurring in &#x2265;2% of Adult TRD Patients Treated with SPRAVATO and at a Greater Rate than Patients Treated with Placebo Nasal Spray</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">SPRAVATO 56mg + 84mg (N=226) </th><th styleCode="Rrule">Placebo (N=250) </th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Ear and labyrinth disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vertigo</td><td styleCode="Rrule">6 (3%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">56 (25%)</td><td styleCode="Rrule">21 (8%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">15 (7%)</td><td styleCode="Rrule">1 (&lt;1%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Feeling drunk</td><td styleCode="Rrule">16 (7%)</td><td styleCode="Rrule">2 (&lt;1%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Investigations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Blood pressure increased <footnote ID="Tb4ft">The following terms were combined: <content styleCode="bold">Anxiety:</content> anxiety, agitation, fear, feeling jittery, irritability, panic attack <content styleCode="bold">Blood pressure increased:</content> blood pressure increased, hypertension <content styleCode="bold">Dissociation:</content> depersonalization/derealization disorder, derealization, diplopia, dissociation, feeling hot, paresthesia, paresthesia oral, pharyngeal paresthesia, photophobia, tinnitus, vision blurred <content styleCode="bold">Dizziness:</content> dizziness, dizziness postural <content styleCode="bold">Hypoesthesia:</content> hypoesthesia, hypoesthesia oral, pharyngeal hypoesthesia <content styleCode="bold">Lethargy:</content> fatigue, lethargy <content styleCode="bold">Sedation:</content> sedation, somnolence</footnote></td><td styleCode="Rrule">11 (5%)</td><td styleCode="Rrule">4 (2%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Disturbance in attention</td><td styleCode="Rrule">5(2%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness <footnoteRef IDREF="Tb4ft"/></td><td styleCode="Rrule">50 (22%)</td><td styleCode="Rrule">18 (7%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Sedation <footnoteRef IDREF="Tb4ft"/></td><td styleCode="Rrule">13 (6%)</td><td styleCode="Rrule">4 (2%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">43 (19%)</td><td styleCode="Rrule">22 (9%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dysgeusia</td><td styleCode="Rrule">10 (4%)</td><td styleCode="Rrule">9 (4%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypoesthesia <footnoteRef IDREF="Tb4ft"/></td><td styleCode="Rrule">10 (4%)</td><td styleCode="Rrule">1 (&lt;1%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Lethargy <footnoteRef IDREF="Tb4ft"/></td><td styleCode="Rrule">16 (7%)</td><td styleCode="Rrule">12 (5%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dissociation <footnoteRef IDREF="Tb4ft"/></td><td styleCode="Rrule">63 (28%)</td><td styleCode="Rrule">11 (4%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anxiety <footnoteRef IDREF="Tb4ft"/></td><td styleCode="Rrule">22 (10%)</td><td styleCode="Rrule">8 (3%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Insomnia</td><td styleCode="Rrule">11 (5%)</td><td styleCode="Rrule">9 (4%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, thoracic, and mediastinal disorders</content></td></tr><tr><td styleCode="Lrule Rrule"> Throat irritation</td><td styleCode="Rrule">8 (4%)</td><td styleCode="Rrule">2 (1%)</td></tr></tbody></table>

<table width="85%"><caption>Table 5: Adverse Reactions Occurring in &#x2265;2% of Adult Patients with MDD and Acute Suicidal Ideation or Behavior Treated with SPRAVATO + Oral AD and at a Greater Rate than Patients Treated with Placebo Nasal Spray + Oral AD</caption><col width="60%" align="left" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule" valign="bottom">SPRAVATO + Oral AD (N=227) </th><th styleCode="Rrule" valign="bottom">Placebo + Oral AD (N=225) </th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Cardiac disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Tachycardia <footnote ID="t4f1">The following terms were combined: <content styleCode="bold">Anxiety includes:</content> agitation; anxiety; anxiety disorder; fear; irritability; nervousness; panic attack; psychomotor hyperactivity; tension <content styleCode="bold">Blood pressure increased includes:</content> blood pressure diastolic increased; blood pressure increased; blood pressure systolic increased; hypertension <content styleCode="bold">Dissociation includes:</content> depersonalization/derealization disorder; derealization; diplopia; dissociation; dysesthesia; feeling cold; feeling hot; hallucination; hallucination, auditory; hallucination, visual; hallucinations, mixed; hyperacusis; paresthesia; paresthesia oral; pharyngeal paresthesia; photophobia; time perception altered; tinnitus; vision blurred <content styleCode="bold">Dizziness includes:</content> dizziness; dizziness exertional; dizziness postural <content styleCode="bold">Dysgeusia includes:</content> dysgeusia; hypogeusia <content styleCode="bold">Hyperhidrosis includes:</content> cold sweat; hyperhidrosis <content styleCode="bold">Hypoesthesia includes:</content> hypoesthesia; hypoesthesia oral; intranasal hypoesthesia; pharyngeal hypoesthesia <content styleCode="bold">Lethargy includes:</content> fatigue; lethargy; psychomotor retardation <content styleCode="bold">Pollakiuria includes:</content> micturition urgency; pollakiuria <content styleCode="bold">Sedation includes:</content> sedation; somnolence; stupor <content styleCode="bold">Tachycardia includes:</content> heart rate increased; sinus tachycardia; tachycardia</footnote></td><td styleCode="Rrule">8 (4%)</td><td styleCode="Rrule">2 (1%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Ear and labyrinth disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vertigo</td><td styleCode="Rrule">14 (6%)</td><td styleCode="Rrule">1 (0.4%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">61 (27%)</td><td styleCode="Rrule">31 (14%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">26 (11%)</td><td styleCode="Rrule">12 (5%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">22 (10%)</td><td styleCode="Rrule">14 (6%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dry mouth</td><td styleCode="Rrule">8 (4%)</td><td styleCode="Rrule">6 (3%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Toothache</td><td styleCode="Rrule">5 (2%)</td><td styleCode="Rrule">2 (1%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Feeling drunk</td><td styleCode="Rrule">8 (4%)</td><td styleCode="Rrule">1 (0.4%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Feeling of relaxation</td><td styleCode="Rrule">5 (2%)</td><td styleCode="Rrule">3 (1%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Investigations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Blood pressure increased <footnoteRef IDREF="t4f1"/></td><td styleCode="Rrule">34 (15%)</td><td styleCode="Rrule">14 (6%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Myalgia</td><td styleCode="Rrule">5 (2%)</td><td styleCode="Rrule">1 (0.4%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness <footnoteRef IDREF="t4f1"/></td><td styleCode="Rrule">103 (45%)</td><td styleCode="Rrule">34 (15%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Sedation <footnoteRef IDREF="t4f1"/></td><td styleCode="Rrule">66 (29%)</td><td styleCode="Rrule">27 (12%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dysgeusia <footnoteRef IDREF="t4f1"/></td><td styleCode="Rrule">46 (20%)</td><td styleCode="Rrule">29 (13%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypoesthesia <footnoteRef IDREF="t4f1"/></td><td styleCode="Rrule">30 (13%)</td><td styleCode="Rrule">4 (2%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Lethargy <footnoteRef IDREF="t4f1"/></td><td styleCode="Rrule">10 (4%)</td><td styleCode="Rrule">4 (2%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Confusional state</td><td styleCode="Rrule">5 (2%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dissociation <footnoteRef IDREF="t4f1"/></td><td styleCode="Rrule">108 (48%)</td><td styleCode="Rrule">30 (13%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anxiety <footnoteRef IDREF="t4f1"/></td><td styleCode="Rrule">34 (15%)</td><td styleCode="Rrule">20 (9%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Euphoric mood</td><td styleCode="Rrule">17 (7%)</td><td styleCode="Rrule">1 (0.4%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Intentional self-injury</td><td styleCode="Rrule">7 (3%)</td><td styleCode="Rrule">3 (1%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dysphoria</td><td styleCode="Rrule">5 (2%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Renal and urinary disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pollakiuria <footnoteRef IDREF="t4f1"/></td><td styleCode="Rrule">5 (2%)</td><td styleCode="Rrule">2 (1%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Oropharyngeal pain</td><td styleCode="Rrule">10 (4%)</td><td styleCode="Rrule">3 (1%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Throat irritation</td><td styleCode="Rrule">9 (4%)</td><td styleCode="Rrule">5 (2%)</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td></tr><tr><td styleCode="Lrule Rrule"> Hyperhidrosis <footnoteRef IDREF="t4f1"/></td><td styleCode="Rrule">11 (5%)</td><td styleCode="Rrule">5 (2%)</td></tr></tbody></table>