Limitations of Use:

• The effectiveness of SPRAVATO in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated [see Clinical Studies (14.2)] . Use of SPRAVATO does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO.
• SPRAVATO is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO as an anesthetic agent have not been established.

2.1 Important Considerations Prior to Initiating and During Therapy

SPRAVATO must be administered under the direct supervision of a healthcare provider. A treatment session consists of nasal administration of SPRAVATO and post-administration observation under supervision.

2.2 Treatment-Resistant Depression

Administer SPRAVATO in conjunction with an oral antidepressant (AD).

The recommended dosage of SPRAVATO for the treatment of TRD in adults is shown in Table 1. Dosage adjustments should be made based on efficacy and tolerability. Evidence of therapeutic benefit should be evaluated at the end of the induction phase to determine need for continued treatment.

2.3 Depressive Symptoms in Patients with Major Depressive Disorder with Acute Suicidal Ideation or Behavior

Administer SPRAVATO in conjunction with an oral antidepressant (AD).

The recommended dosage of SPRAVATO for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior is 84 mg twice per week for 4 weeks. Dosage may be reduced to 56 mg twice per week based on tolerability. After 4 weeks of treatment with SPRAVATO, evidence of therapeutic benefit should be evaluated to determine need for continued treatment. The use of SPRAVATO, in conjunction with an oral antidepressant, beyond 4 weeks has not been systematically evaluated in the treatment of depressive symptoms in patients with MDD with acute suicidal ideation or behavior.

2.4 Administration Instructions

SPRAVATO is for nasal use only. The nasal spray device delivers a total of 28 mg of esketamine. To prevent loss of medication, do not prime the device before use. Use 2 devices (for a 56 mg dose) or 3 devices (for an 84 mg dose), with a 5-minute rest between use of each device. Follow these administration instructions and read the Instructions for Use before administration:

2.5 Post-Administration Observation

During and after SPRAVATO administration at each treatment session, observe the patient for at least 2 hours until the patient is safe to leave [see Warnings and Precautions (5.1, 5.2, 5.6, 5.8)] . Before SPRAVATO administration, instruct patients not to engage in potentially hazardous activities, such as driving a motor vehicle or operating machinery, until the next day after a restful sleep.

2.6 Missed Treatment Session(s)

If a patient misses treatment session(s), provided there is no worsening of their depressive symptoms, the patient should continue the current dosing schedule.

For patients who miss treatment session(s) during maintenance treatment and have worsening of depression symptoms, per clinical judgement, consider returning to the previous dosing schedule (e.g., if doses missed during weekly dosing, revert to twice weekly dosing).

5.1 Sedation

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 (2.4)] .

Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants [see Drug Interaction (7.1)] .

SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.4)] .

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 (2.4)] .

SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.4)] .

5.3 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 (5.4)] .

5.4 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, and abuse and misuse [see Boxed Warning and Warnings and Precautions (5.1, 5.2, 5.3)].

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 (2.4)].

• 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.

5.5 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.

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.

5.6 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 8% 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, 2.4)] . 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.

5.7 Cognitive Impairment

5.8 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.

5.9 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.

5.10 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)].

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.

7.1 Central Nervous System Depressants

Concomitant use with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation [see Warnings and Precautions (5.1)] . Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants.

7.2 Psychostimulants

Concomitant use with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) may increase blood pressure [see Warnings and Precautions (5.6)] . Closely monitor blood pressure with concomitant use of SPRAVATO with psychostimulants.

7.3 Monoamine Oxidase Inhibitors (MAOIs)

Concomitant use with monoamine oxidase inhibitors (MAOIs) may increase blood pressure [see Warnings and Precautions (5.6)] . Closely monitor blood pressure with concomitant use of SPRAVATO with MAOIs.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of SPRAVATO in pediatric patients have not been established. Clinical studies of SPRAVATO in pediatric patients have not been conducted.

8.5 Geriatric Use

Of the total number of patients in Phase 3 clinical studies exposed to SPRAVATO, (N=1601), 194 (12%) were 65 years of age and older, and 25 (2%) were 75 years of age and older. No overall differences in the safety profile were observed between patients 65 years of age and older and patients younger than 65 years of age.

The mean esketamine C max and AUC values were higher in elderly patients compared with younger adult patients [see Clinical Pharmacology (12.3)] .

The efficacy of SPRAVATO for the treatment of TRD in geriatric patients was evaluated in a 4-week, randomized, double-blind study comparing flexibly-dosed intranasal SPRAVATO plus a newly initiated oral antidepressant compared to intranasal placebo plus a newly initiated oral antidepressant in patients ≥ 65 years of age. SPRAVATO was initiated at 28 mg twice weekly and could be titrated to 56 mg or 84 mg administered twice-weekly. At the end of four weeks, there was no statistically significant difference between groups on the primary efficacy endpoint of change from baseline to Week 4 on the Montgomery-Åsberg Depression Rating Scale (MADRS).

8.6 Hepatic Impairment

The mean esketamine AUC and t 1/2 values were higher in patients with moderate hepatic impairment compared to those with normal hepatic function [see Clinical Pharmacology (12.3)] . SPRAVATO-treated patients with moderate hepatic impairment may need to be monitored for adverse reactions for a longer period of time.

SPRAVATO has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use in this population is not recommended [see Clinical Pharmacology (12.3)].

9.1 Controlled Substance

SPRAVATO contains esketamine hydrochloride, the (S)-enantiomer of ketamine and a Schedule III controlled substance under the Controlled Substances Act.

9.2 Abuse

Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of SPRAVATO. Abuse is the intentional, non-therapeutic use of a drug, even once, for its psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Careful consideration is advised prior to use of individuals with a history of substance use disorder, including alcohol.

SPRAVATO may produce a variety of symptoms including anxiety, dysphoria, disorientation, insomnia, flashback, hallucinations, and feelings of floating, detachment and to be "spaced out". Monitoring for signs of abuse and misuse is recommended.

9.3 Dependence

Physical dependence has been reported with prolonged use of ketamine. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dosage reduction of a drug. There were no withdrawal symptoms captured up to 4 weeks after cessation of esketamine treatment. Withdrawal symptoms have been reported after the discontinuation of frequently used (more than weekly) large doses of ketamine for long periods of time. Such withdrawal symptoms are likely to occur if esketamine were similarly abused. Reported symptoms of withdrawal associated with daily intake of large doses of ketamine include craving, fatigue, poor appetite, and anxiety. Therefore, monitor SPRAVATO-treated patients for symptoms and signs of physical dependence upon the discontinuation of the drug.

Tolerance has been reported with prolonged use of ketamine. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Similar tolerance would be expected with prolonged use of esketamine.

Management of Overdosage

There is no specific antidote for esketamine overdose. In the case of overdose, the possibility of multiple drug involvement should be considered. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222 or www.poison.org).

12.1 Mechanism of Action

Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl- D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The mechanism by which esketamine exerts its antidepressant effect is unknown. The major circulating metabolite of esketamine (noresketamine) demonstrated activity at the same receptor with less affinity.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Esketamine exposure increases with dose from 28 mg to 84 mg. The increase in C max and AUC values was less than dose-proportional between 28 mg and 56 mg or 84 mg, but it was nearly dose proportional between 56 mg and 84 mg. No accumulation of esketamine in plasma was observed following twice a week administration.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14.1 Treatment-Resistant Depression

14.2 Depressive Symptoms in Patients with Major Depressive Disorder with Acute Suicidal Ideation or Behavior

SPRAVATO was evaluated in two identical Phase 3 short-term (4-week) randomized, double-blind, multicenter, placebo-controlled studies, Study 3 (NCT03039192) and Study 4 (NCT03097133), in adults with moderate-to-severe MDD (MADRS total score >28) who had active suicidal ideation and intent. In these studies, patients received treatment with SPRAVATO 84 mg or placebo nasal spray twice-weekly for 4 weeks. After the first dose, a one-time dose reduction to SPRAVATO 56 mg was allowed for patients unable to tolerate the 84 mg dose. All patients received comprehensive standard of care treatment, including an initial inpatient psychiatric hospitalization and a newly initiated or optimized oral antidepressant (AD) (AD monotherapy or AD plus augmentation therapy) as determined by the investigator. After completion of the 4-week treatment period with SPRAVATO/placebo, study follow-up continued through Day 90.

The baseline demographic and disease characteristics of patients in Study 3 and Study 4 were similar between the SPRAVATO plus standard of care or placebo nasal spray plus standard of care treatment groups. The median patient age was 40 years (range 18 to 64 years), 61% were female; 73% Caucasian and 6% Black; and 63% of patients had at least one prior suicide attempt. Prior to entering the study, 92% of the patients were receiving antidepressant therapy. During the study, as part of standard of care treatment, 40% of patients received AD monotherapy, 54% of patients received AD plus augmentation therapy, and 6% received both AD monotherapy/AD plus augmentation therapy.

The primary efficacy measure was the change from baseline in the MADRS total score at 24 hours after first dose (Day 2). In Study 3 and Study 4, SPRAVATO plus standard of care demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus standard of care (see Table 10).

The secondary efficacy measure was the change in Clinical Global Impression of Suicidal Severity - Revised (CGI-SS-r) score at 24 hours after first dose (Day 2). The CGI-SS-r is a one-item, clinician-rated assessment used to rate the current severity of a patient's suicidal ideation and behavior. Scores on the CGI-SS-r range from 0 to 6, with higher scores indicating more severe suicidal ideation and behavior. In Study 3 and Study 4, SPRAVATO plus standard of care did not demonstrate superiority compared to placebo nasal spray plus standard of care in improving CGI-SS-r.

14.3 Special Safety Studies

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Disposal

SPRAVATO nasal spray devices must be handled with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations.

Sedation and Dissociation

Inform patients that SPRAVATO has potential to cause sedation, dissociative symptoms, perception disturbances, dizziness, vertigo, and anxiety. Advise patients that they will need to be observed by a healthcare provider until these effects resolve [see Boxed Warning, Warnings and Precautions (5.1, 5.2)] .

Potential for Abuse, Misuse, and Dependence

Advise patients that SPRAVATO is a federally controlled substance because it can be abused or lead to dependence [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9)].

SPRAVATO Risk Evaluation and Mitigation Strategy (REMS)

SPRAVATO is available only through a restricted program called the SPRAVATO REMS [see Warnings and Precautions (5.4)] . Inform the patient of the following notable requirements:

• Patients treated in outpatient healthcare settings (e.g. medical offices and clinics) must be enrolled in the SPRAVATO REMS Program prior to administration.
• SPRAVATO must be administered under the direct observation of a healthcare provider.
• Patients must be monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO .

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted [see Boxed Warning and Warnings and Precautions (5.5)] .

Increases in Blood Pressure

Advise patients that SPRAVATO can cause increases in blood pressure. Inform patients that after treatment sessions they should be advised that they may need to be observed by a healthcare provider until these effects resolve [see Warnings and Precautions (5.6)] .

Impaired Ability to Drive and Operate Machinery

Caution patients that SPRAVATO may impair their ability to drive or operate machinery. 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 after a restful sleep. Advise patients that they will need someone to drive them home after each treatment session [see Warnings and Precautions (5.8)] .

Pregnancy

Advise pregnant women and women of reproductive potential of the potential risk to a fetus. Advise patients to notify their healthcare provider if they are pregnant or intend to become pregnant during treatment with SPRAVATO. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SPRAVATO during pregnancy. [See Use in Specific Populations (8.1)] .

Lactation

Advise women not to breastfeed during treatment with SPRAVATO [see Use in Specific Populations (8.2)] .