b'Important Safety Information (continued)CONTRAINDICATIONS Suicidal Thoughts and Behaviors in Adolescents and Young SPRAVATO is contraindicated in patients with: Adults: In pooled analyses of placebo-controlled trials ofAneurysmal vascular disease (including thoracic and antidepressant drugs (SSRIs and other antidepressant classes) abdominal aorta, intracranial and peripheral arterial vessels)that included adult and pediatric patients, the incidence of or arteriovenous malformation. suicidal thoughts and behaviors in patients age 24 years andHistory of intracerebral hemorrhage. younger was greater than in placebo-treated patients. SPRAVATOHypersensitivity to esketamine, ketamine, or any of the is not approved in pediatric (18 years of age) patients.excipients. There was considerable variation in risk of suicidal thoughts WARNINGS AND PRECAUTIONS and behaviors among drugs, but there was an increased risk Sedation: In clinical trials, 48% to 61% of SPRAVATO-treatedidentified in young patients for most drugs studied. patients developed sedation and 0.3% to 0.4% of SPRAVATO- Monitor all antidepressant-treated patients for clinical worsening treated patients experienced loss of consciousness.and emergence of suicidal thoughts and behaviors, especially Because of the possibility of delayed or prolonged sedation,during the initial few months of drug therapy and at times patients must be monitored by a healthcare provider for at leastof dosage changes. Counsel family members or caregivers 2 hours at each treatment session, followed by an assessment toof patients to monitor for changes in behavior and to alert determine when the patient is considered clinically stable andthe healthcare provider. Consider changing the therapeutic ready to leave the healthcare setting. regimen, including possibly discontinuing SPRAVATO and/or the Closely monitor for sedation with concomitant use of SPRAVATOconcomitant oral antidepressant, in patients whose depression with CNS depressants [see Drug Interaction (7.1)].is persistently worse, or who are experiencing emergent suicidal SPRAVATO is available only through a restricted program underthoughts or behaviors.a REMS. Increase in Blood Pressure: SPRAVATO causes increases in Dissociation: The most common psychological effects ofsystolic and/or diastolic blood pressure (BP) at all recommended SPRAVATO were dissociative or perceptual changes (includingdoses. Increases in BP peak approximately 40 minutes after distortion of time, space and illusions), derealization andSPRAVATO administration and last approximately 4 hours.depersonalization (61% to 84% of SPRAVATO-treated patientsApproximately 8% to 19% of SPRAVATO-treated patients developed dissociative or perceptual changes). Given itsexperienced an increase of more than 40 mmHg in systolic potential to induce dissociative effects, carefully assess patientsBP and/or 25 mmHg in diastolic BP in the first 1.5 hours with psychosis before administering SPRAVATO; treatmentafter administration at least once during the first 4 weeks of should be initiated only if the benefit outweighs the risk. treatment. A substantial increase in blood pressure could occur Because of the risks of dissociation, patients must be monitoredafter any dose administered even if smaller blood pressure by a healthcare provider for at least 2 hours at each treatmenteffects were observed with previous administrations. SPRAVATO session, followed by an assessment to determine when theis contraindicated in patients for whom an increase in BP or patient is considered clinically stable and ready to leave theintracranial pressure poses a serious risk (e.g., aneurysmal healthcare setting. vascular disease, arteriovenous malformation, history of SPRAVATO is available only through a restricted program underintracerebral hemorrhage). Before prescribing SPRAVATO, a REMS. patients with other cardiovascular and cerebrovascular Abuse and Misuse: SPRAVATO contains esketamine, a Scheduleconditions should be carefully assessed to determine whether III controlled substance (CIII), and may be subject to abuse andthe potential benefits of SPRAVATO outweigh its risk.diversion. Assess each patients risk for abuse or misuse priorAssess BP prior to administration of SPRAVATO. In patients to prescribing and monitor all patients for the developmentwhose BP is elevated prior to SPRAVATO administration (as a of these behaviors or conditions, including drug-seekinggeneral guide: 140/90 mmHg), a decision to delay SPRAVATO behavior, while on therapy. Individuals with a history of drugtherapy should take into account the balance of benefit and risk abuse or dependence are at greater risk; therefore, use carefulin individual patients.consideration prior to treatment of individuals with a historyBP should be monitored for at least 2 hours after SPRAVATO of substance use disorder and monitor for signs of abuse oradministration. Measure blood pressure around 40 minutes dependence. post-dose and subsequently as clinically warranted until values SPRAVATO is available only through a restricted program underdecline. If BP remains high, promptly seek assistance from a REMS. practitioners experienced in BP management. Refer patients SPRAVATO Risk Evaluation and Mitigation Strategy (REMS):experiencing symptoms of a hypertensive crisis (e.g., chest SPRAVATO is available only through a restricted program calledpain, shortness of breath) or hypertensive encephalopathy the SPRAVATO REMS because of the risks of serious adverse(e.g., sudden severe headache, visual disturbances, seizures, outcomes from sedation, dissociation, and abuse and misuse. diminished consciousness, or focal neurological deficits) Important requirements of the SPRAVATO REMS include theimmediately for emergency care.following: Closely monitor blood pressure with concomitant use ofHealthcare settings must be certified in the program and SPRAVATO with psychostimulants or monoamine oxidase ensure that SPRAVATO is: inhibitors (MAOIs) [see Drug Interactions (7.2, 7.3)]. Only dispensed and administered in healthcare settings. In patients with history of hypertensive encephalopathy, morePatients treated in outpatient settings (e.g., medical offices intensive monitoring, including more frequent blood pressure and clinics) must be enrolled in the program. and symptom assessment, is warranted because these patientsAdministered by patients under the direct observation of are at increased risk for developing encephalopathy with even a healthcare provider and that patients are monitored by a small increases in blood pressure. healthcare provider for at least 2 hours after administration of Please see additional Important Safety Information and Brief SPRAVATO. Summary of full Prescribing Information, including BoxedPharmacies must be certified in the REMS and must only WARNINGS, on following and prior pages.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 1-855-382-6022.1641587-CHAESK_Journal AD_Mech AP1_Rv8.indd 2 11/24/20 10:38 AM'