b'Important Safety Information (continued)Cognitive Impairment Females and Males of Reproductive Potential: SPRAVATO Short-Term Cognitive Impairment: In a study in healthymay cause embryo-fetal harm when administered to a pregnant volunteers, a single dose of SPRAVATO caused cognitivewoman. Consider pregnancy planning and prevention for females performance decline 40 minutes post-dose. SPRAVATO-treatedof reproductive potential during treatment with SPRAVATO.subjects required a greater effort to complete the cognitive testsPediatric Use: The safety and effectiveness of SPRAVATO in at 40 minutes post-dose. Cognitive performance and mentalpediatric patients have not been established.effort were comparable between SPRAVATO and placebo atGeriatric Use: Of the total number of patients in Phase 3 clinical 2 hours post-dose. Sleepiness was comparable after 4 hours post- studies exposed to SPRAVATO, 12% were 65 years of age dose. and older, and 2% were 75 years of age and older. No overall Long-Term Cognitive Impairment: Long-term cognitive anddifferences in the safety profile were observed between patients memory impairment have been reported with repeated ketamine65 years of age and older and patients younger than 65 years of age.misuse or abuse. No adverse effects of SPRAVATO nasal sprayThe mean esketamine C maxand AUC values were higher in elderly on cognitive functioning were observed in a one-year open- patients compared with younger adult patients.label safety study; however, the long-term cognitive effects ofThe efficacy of SPRAVATO for the treatment of TRD in geriatric SPRAVATO have not been evaluated beyond one year. patients was evaluated in a 4-week, randomized, double-blind Impaired Ability to Drive and Operate Machinery: Beforestudy comparing flexibly-dosed intranasal SPRAVATO plus SPRAVATO administration, instruct patients not to engagea newly initiated oral antidepressant compared to intranasal in potentially hazardous activities requiring complete mentalplacebo plus a newly initiated oral antidepressant in patients alertness and motor coordination, such as driving a motor 65 years of age. At the end of four weeks, there was no vehicle or operating machinery, until the next day following astatistically significant difference between groups on the primary restful sleep. Patients will need to arrange transportation homeefficacy endpoint of change from baseline to Week 4 on thefollowing treatment with SPRAVATO. Montgomery-sberg Depression Rating Scale (MADRS).Ulcerative or Interstitial Cystitis: Cases of ulcerative orHepatic Impairment: SPRAVATO-treated patients with interstitial cystitis have been reported in individuals withmoderate hepatic impairment may need to be monitored for long-term off-label use or misuse/abuse of ketamine. In clinicaladverse reactions for a longer period of time.studies with SPRAVATO nasal spray, there was a higher rate ofSPRAVATO has not been studied in patients with severe hepatic lower urinary tract symptoms (pollakiuria, dysuria, micturitionimpairment (Child-Pugh class C). Use in this population is not urgency, nocturia, and cystitis) in SPRAVATO-treated patientsrecommended.than in placebo-treated patients. No cases of esketamine-relatedDRUG ABUSE AND DEPENDENCEinterstitial cystitis were observed in any of the studies, whichControlled Substance: SPRAVATO contains esketamine involved treatment for up to a year. hydrochloride, the (S)-enantiomer of ketamine and a Schedule III Monitor for urinary tract and bladder symptoms during thecontrolled substance under the Controlled Substances Act.course of treatment with SPRAVATO and refer to an appropriate healthcare provider as clinically warranted. Abuse: Individuals with a history of drug abuse or dependence Embryo-fetal Toxicity: SPRAVATO may cause fetal harm whenmay be at greater risk for abuse and misuse of SPRAVATO.administered to pregnant women. Advise pregnant women of theAbuse is the intentional, non-therapeutic use of a drug, even potential risk to an infant exposed to SPRAVATO in utero. Advise womenonce, for its psychological or physiological effects. Misuse is the of reproductive potential to consider pregnancy planning and prevention. intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider DRUG INTERACTIONS or for whom it was not prescribed. Careful consideration is CNS depressants (e.g., benzodiazepines, opioids, alcohol):advised prior to use of individuals with a history of substance use Concomitant use may increase sedation. Closely monitor fordisorder, including alcohol. sedation with concomitant use of CNS depressants.SPRAVATO may produce a variety of symptoms including Psychostimulants (e.g., amphetamines, methylphenidate,anxiety, dysphoria, disorientation, insomnia, flashback, modafinil, armodafinil): Concomitant use may increase bloodhallucinations, and feelings of floating, detachment, and to be pressure. Closely monitor blood pressure with concomitant usespaced out. Monitoring for signs of abuse and misuseof psychostimulants. is recommended.Monoamine oxidase inhibitors (MAOIs): Concomitant use may increase blood pressure. Closely monitor blood pressure withADVERSE REACTIONSconcomitant use of MAOIs. The most common adverse reactions with SPRAVATO plus oral USE IN SPECIFIC POPULATIONSantidepressant (incidence 5% and at least twice that of placebo Pregnancy:SPRAVATO is not recommended during pregnancy.nasal spray plus oral antidepressant) were:SPRAVATO may cause fetal harm when administered to pregnantTRD: dissociation, dizziness, nausea, sedation, vertigo, women. Advise pregnant women of the potential risk to an infanthypoesthesia, anxiety, lethargy, blood pressure increased, exposed to SPRAVATO in utero. There are risks to the mothervomiting, and feeling drunk. associated with untreated depression in pregnancy. If a womanTreatment of depressive symptoms in adults with MDD with acute becomes pregnant while being treated with SPRAVATO, treatmentsuicidal ideation or behavior: dissociation, dizziness, sedation, with SPRAVATO should be discontinued and the patient should beblood pressure increased, hypoesthesia, vomiting, euphoric counseled about the potential risk to the fetus. mood, and vertigo.Pregnancy Exposure Registry: There is a pregnancy exposure registryPlease see additional Important Safety Information and Brief that monitors pregnancy outcomes in women exposed toSummary of full Prescribing Information, including Boxed antidepressants, including SPRAVATO, during pregnancy.WARNINGS, on following and prior pages.Healthcare providers are encouraged to register patients bycp-170362v1contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.Lactation: SPRAVATO is present in human milk. Because of the potential for neurotoxicity, advise patients that breastfeeding is not recommended during treatment with SPRAVATO.Janssen Pharmaceuticals, Inc. 2020November 2020cp-193335v1 1641587-CHAESK_Journal AD_Mech AP1_Rv8.indd 3 11/24/20 10:38 AM'