SPRAVATO® SPRAVATO® (esketamine) nasal spray, CIII (esketamine) nasal spray, CIII Brief Summary Suicidal Thoughts and Behaviors in Adolescents and Young Adults ® BEFORE PRESCRIBING SPRAVATO , PLEASE SEE FULL PRESCRIBING INFORMATION, INCLUDING In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant BOXED WARNING. classes) that included approximately 77,000 adult patients and 4,500 pediatric patients (SPRAVATO is WARNING: SEDATION; DISSOCIATION; ABUSE AND MISUSE; and not approved in pediatric patients), the incidence of suicidal thoughts and behaviors in patients age SUICIDAL THOUGHTS AND BEHAVIORS 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 Sedation young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts • Patients are at risk for sedation after administration of SPRAVATO [see Warnings and Precautions]. and behaviors across the different indications, with the highest incidence in patients with major Dissociation depressive disorder (MDD). The drug-placebo differences in the number of cases of suicidal thoughts • Patients are at risk for dissociative or perceptual changes after administration of SPRAVATO [see and behaviors per 1000 patients treated are provided in Table 1. Warnings and Precautions]. Because of the risks of sedation and dissociation, patients must be monitored for at least 2 hours Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the at each treatment session, followed by an assessment to determine when the patient is considered Pooled Placebo-Controlled Trials of Antidepressants in Pediatric* and Adult Patients clinically stable and ready to leave the healthcare setting [see Warnings and Precautions]. Age Range (Years) Drug-Placebo Difference in Number of Patients with Abuse and Misuse Suicidal Thoughts or Behaviors per 1000 Patients Treated • SPRAVATO has the potential to be abused and misused. Consider the risks and benefits of Increases Compared to Placebo prescribing SPRAVATO prior to use in patients at higher risk of abuse. Monitor patients for <18 14 additional patients signs and symptoms of abuse and misuse [see Warnings and Precautions]. 18-24 5 additional patients Because of the risks of serious adverse outcomes resulting from sedation, dissociation, and abuse Decreases Compared to Placebo 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]. 25-64 1 fewer patient Suicidal Thoughts and Behaviors ≥65 6 fewer patients Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult * SPRAVATO is not approved in pediatric patients. 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 It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young use in pediatric patients [see Warnings and Precautions]. 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. INDICATIONS AND USAGE Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts SPRAVATO® is indicated, in conjunction with an oral antidepressant, for the treatment of: and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. • Treatment-resistant depression (TRD) in adults Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the • Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing or behavior SPRAVATO and/or the concomitant oral antidepressant, in patients whose depression is persistently Limitations of Use: worse, or who are experiencing emergent suicidal thoughts or behaviors. • The effectiveness of SPRAVATO in preventing suicide or in reducing suicidal ideation or behavior Increase in Blood Pressure has not been demonstrated [see Clinical Studies (14.2) in Full Prescribing Information]. Use of SPRAVATO causes increases in systolic and/or diastolic blood pressure (BP) at all recommended SPRAVATO does not preclude the need for hospitalization if clinically warranted, even if patients doses. Increases in BP peak approximately 40 minutes after SPRAVATO administration and last experience improvement after an initial dose of SPRAVATO. approximately 4 hours [see Adverse Reactions]. • SPRAVATO is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO as Approximately 8% to 19% of SPRAVATO-treated patients and 1% to 4% of placebo-treated patients an anesthetic agent have not been established. experienced an increase of greater than or equal to 40 mmHg in systolic BP and/or 25 mmHg in diastolic CONTRAINDICATIONS BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A SPRAVATO is contraindicated in patients with: 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 • Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral for whom an increase in BP or intracranial pressure poses a serious risk (e.g., aneurysmal vascular arterial vessels) or arteriovenous malformation [see Warnings and Precautions] disease, arteriovenous malformation, history of intracerebral hemorrhage) [see Contraindications]. • History of intracerebral hemorrhage [see Warnings and Precautions] Before prescribing SPRAVATO, patients with other cardiovascular and cerebrovascular conditions • Hypersensitivity to esketamine, ketamine, or any of the excipients. should be carefully assessed to determine whether the potential benefits of SPRAVATO outweigh its risks. WARNINGS AND PRECAUTIONS Assess BP prior to administration of SPRAVATO. In patients whose BP is elevated prior to SPRAVATO Sedation administration (as a general guide: >140/90 mmHg) a decision to delay SPRAVATO therapy should take In clinical trials, 48% to 61% of SPRAVATO-treated patients developed sedation based on the Modified into account the balance of benefit and risk in individual patients. Observer’s Assessment of Alertness/Sedation scale (MOAA/S) [see Adverse Reactions], and 0.3% to BP should be monitored for at least 2 hours after SPRAVATO administration [see Dosage and 0.4% of SPRAVATO-treated patients experienced loss of consciousness (MOAA/S score of 0). Administration (2.1, 2.4) in Full Prescribing Information]. Measure blood pressure around 40 minutes Because of the possibility of delayed or prolonged sedation, patients must be monitored by a healthcare post-dose and subsequently as clinically warranted until values decline. If BP remains high, promptly provider for at least 2 hours at each treatment session, followed by an assessment to determine when seek assistance from practitioners experienced in BP management. Refer patients experiencing the patient is considered clinically stable and ready to leave the healthcare setting [see Dosage and symptoms of a hypertensive crisis (e.g., chest pain, shortness of breath) or hypertensive encephalopathy Administration (2.4) in Full Prescribing Information]. (e.g., sudden severe headache, visual disturbances, seizures, diminished consciousness or focal neurological deficits) immediately for emergency care. Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants [see Drug Interaction]. Closely monitor blood pressure with concomitant use of SPRAVATO with psychostimulants or monoamine oxidase inhibitors (MAOIs) [see Drug Interactions]. SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions]. In patients with history of hypertensive encephalopathy, more intensive monitoring, including more Dissociation frequent blood pressure and symptom assessment, is warranted because these patients are at The most common psychological effects of SPRAVATO were dissociative or perceptual changes (including increased risk for developing encephalopathy with even small increases in blood pressure. distortion of time, space and illusions), derealization and depersonalization (61% to 84% of SPRAVATO- Cognitive Impairment treated patients developed dissociative or perceptual changes based on the Clinician-Administered Dissociative States Scale) [see Adverse Reactions]. Given its potential to induce dissociative effects, Short-Term Cognitive Impairment carefully assess patients with psychosis before administering SPRAVATO; treatment should be initiated In a study in healthy volunteers, a single dose of SPRAVATO caused cognitive performance decline only if the benefit outweighs the risk. 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.