SUMMARY  

• Careful consideration is advised prior to treatment with SPRAVATO in individuals with a history of substance use disorder, including alcohol, due to greater risk for abuse and misuse of SPRAVATO. Monitoring for signs of abuse or dependence is recommended.¹
• 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.^2,3
• Closely monitor all antidepressant (AD)-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. SPRAVATO is not approved in pediatric patients.^2,4
• SPRAVATO is contraindicated in patients with aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage, and hypersensitivity to SPRAVATO, ketamine, or to any of the excipients.²
• SPRAVATO causes increases in systolic and/or diastolic blood pressure (BP) at all recommended dosages. BP increases peaked at approximately 40 minutes after SPRAVATO administration and lasted approximately 4 hours. BP assessment should be conducted before SPRAVATO administration.²
• 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
• The most commonly observed adverse reactions in adult patients (incidence ≥5% in SPRAVATO plus oral AD group and twice that of oral AD plus placebo group):
  • Being treated for treatment-resistant depression (TRD): dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, BP increased, vomiting, feeling drunk, and headache.^5-7
  • Being treated for major depressive disorder (MDD) with acute suicidal ideation or behavior: dissociation, dizziness, sedation, BP increased, hypoesthesia, vomiting, euphoric mood, and vertigo.^8,9
• SUSTAIN-2, a long-term (up to 1 year), open-label, phase 3 study, was conducted to evaluate the safety and tolerability of SPRAVATO plus oral AD in patients with TRD.³
  • Primary endpoint: Treatment-emergent adverse events (TEAEs) occurred in 723 (90.1%) patients, of which 55 (6.9%) were considered serious. The majority of TEAEs were mild or moderate in intensity, occurred on dosing days, and usually resolved the same day.
  • TEAEs that resulted in SPRAVATO discontinuation occurred in 76 (9.5%) patients.
  • In a post hoc analysis of younger (18-64 years) vs older (≥65 years) patients with TRD, TEAEs were reported in 86.1% vs 74.8% in the induction (IND) phase and 86.8% vs 81.0% in the optimization/maintenance (OP/M) phase; serious TEAEs were reported in 2.2% vs 1.9% in the IND phase and 6.7% vs 4.8% in the OP/M phase.¹⁰
• Safety results from SUSTAIN-3, a long-term, open-label safety study (up to ~6.5 years from study initiation), were consistent with the above 1-year study.¹¹
• Post hoc analysis of pooled data from SUSTAIN-1 and SUSTAIN-2 studies^3,12 showed that adverse events (AEs) of dizziness, dissociation, increased BP, nausea, vertigo, and sedation were more likely to recur later in treatment if the AE was experienced once or twice during the first week of treatment.¹³ However, the overall recurrence of these AEs diminished over the 12-month treatment period.
• Postmarketing safety data from the Risk Evaluation and Mitigation Strategy (REMS) and SPRAVATO global medical safety database from March 5, 2019, to January 5, 2024, identified sedation, dissociation, and increased BP as adverse event of special interest (AESI) associated with reports of serious adverse events (SAEs) during the overall evaluation period.¹⁴ 
• In an analysis of postmarketing safety data (first quarter of 2004 to second quarter of 2023) from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, the top 5 SPRAVATO-related AEs with the highest signal were dissociation, dissociative disorder, sedation, flashback, and morbid thoughts.¹⁵ 
• A separate analysis of the database identified postmarketing cases of respiratory depression (including rare cases of respiratory arrest).¹⁶ 

product labeling

• Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored for at least 2 hours (including using 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.¹⁷
• 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 REMS.¹⁷
  • For additional information or questions about the REMS program, call 18553826022 or visit www.SPRAVATOrems.com.¹⁷
• Monitoring for urinary tract and bladder symptoms during SPRAVATO treatment and referral to an appropriate healthcare provider as clinically warranted is recommended.¹⁷

CLINICAL DATA

SUSTAIN-2 Trial

Wajs et al (2020)³ conducted an open-label, multicenter, phase 3 study to evaluate the long-term (up to 1 year of exposure) safety, tolerability and efficacy of SPRAVATO (28, 56, or 84 mg) plus a newly initiated oral AD in patients with TRD.

Study Design/Methods

• The long-term safety study consisted of up to 4 phases: a screening phase (4 weeks) for direct-entry patients only, an open-label IND phase (4 weeks) for direct-entry patients and transferred-entry nonresponder patients, an open-label OP/M phase (48 weeks) for all responders from the open-label IND phase of the current study and the transferred-entry responders, and a follow-up phase (4 weeks) for all patients. See Figure: Study Design and Patient Disposition During IND and OP/M Phases.
• In the open-label IND phase, patients self-administered flexibly-dosed SPRAVATO under supervision twice weekly for 4 weeks. Patients who were <65 years old started with 56 mg and subsequent doses of SPRAVATO 56 or 84 mg; patients who were ≥65 years old started with 28 mg and subsequent doses of 28, 56, or 84 mg dose.
• Direct-entry patients were assigned to receive SPRAVATO with 1 of 4 selected ADs (duloxetine, escitalopram, sertraline, or venlafaxine XR) on day 1 and continued through the duration of the study. Transfer-entry patients continued their same AD from the acute trial through the duration of this study.
• During the OP/M phase, responders from the IND phase were administered SPRAVATO once-weekly at the same dose. Transfer-entry responder patients were initiated at 28 mg at week 5 and were allowed to titrate up to 56 mg or 84 mg through week 8. SPRAVATO treatment sessions were reduced from twice weekly to weekly for the first 4 weeks of this phase, and then individualized to either once weekly or once every other week based on the severity of depressive symptoms.
• Per protocol, SPRAVATO was not recommended in patients <65 years with a BP >140/90 mmHg or in patients ≥65 years with a BP >150/90 mmHg. SPRAVATO was discontinued in patients <65 years when BP was ≥200/120 mmHg or in patients ≥65 years with BP ≥190/110 mmHg.

Results

Baseline Characteristics

• For all enrolled patients at baseline of the IND phase (n=802), the mean age was 52.2 years, 62.6% were female, 85.5% were White and 58% had no response to 2 prior ADs. Approximately 27% had a history of suicidal ideation in the past 6 months.
• Enrolled patients at IND baseline (n=801) received the following AD: duloxetine (31.3%), escitalopram (29.6%), sertraline (19.6%), and venlafaxine XR (19.5%).
• Patient disposition can be found in Figure: Patient Disposition During IND and OP/M Phase.

Extent of Exposure

Median exposure to SPRAVATO was 22.9 weeks.

Safety

• Overall, 90.1% of patients in the IND and OP/M phases experienced ≥1 TEAE. Most were primarily mild or moderate in intensity, occurred on dosing days, and resolved on the same day. TEAEs experienced by ≥10% of patients within the combined phases group are found in Table: Treatment-Emergent Adverse Events.
• Of the 55 SAEs reported, 5 were considered SPRAVATO-related by the investigator, including anxiety and delusion (both in 1 patient), delirium (n=1), suicidal ideation (n=1), and suicidal attempt (n=1). There were 2 deaths, one of which was considered by investigators to be doubtfully related to SPRAVATO, in which a 60-year-old man died due to acute cardiac and respiratory failure. The other was a suicide-related death in a 55-year-old woman, which was not considered by investigators to be related to SPRAVATO.

• Within the combined IND and OP/M phases, 76 patients (9.5%) had TEAEs that led to the discontinuation of SPRAVATO, and 33 patients (4.1%) had TEAEs that led to discontinuation with oral ADs. TEAEs leading to discontinuation of SPRAVATO in ≥2 patients within the combined phases can be found in Table: Most Common TEAEs Leading to Discontinuation of SPRAVATO Nasal Spray in ≥2 Patients.

• There were no reported cases of interstitial or ulcerative cystitis. TEAEs related to renal and urinary system disorders were reported in 136 (17.0%) patients. Urinary tract infections (UTIs) were reported in 8.1% of patients. Most cases of urinary symptoms were mild to moderate and resolved within 2 weeks. A total of 14 patients had multiple episodes of bladder pain/interstitial cystitis symptom score (BPIC-SS) scores >18 (6 patients had UTI/cystitis, 2 had dysuria and pollakiuria, 1 had a history of benign prostate hyperplasia, 3 showed signs of UTI on urinalysis, and 2 had no AEs/laboratory changes).
• Nasal tolerability was considered acceptable (≥99% of patients had a normal nasal examination). Based on a nasal symptom questionnaire, patients reported moderate to severe symptoms including taste disturbance (IND, 10.2%; OP/M, 11.0%), postnasal drip (IND, 9.9%; OP/M, 11.0%), and stuffy nose (IND, 5.9%; OP/M, 9.1%).
• BP increases were reported 40 minutes postdose and generally returned to near baseline values by 1.5 hours. Thirty-three patients (4.1%) experienced systolic BP ≥180 mmHg or diastolic BP ≥110 mmHg. Four patients were withdrawn from the study due to increased BP.

Post hoc Analysis of SUSTAIN-2 Based on Age

Ochs-Ross et al (2022)¹⁰ conducted a post hoc analysis of SUSTAIN-2 comparing the efficacy and safety of SPRAVATO between younger (18-64 years; IND, n=624; OP/M, n=477) and older (≥65 years; IND, n=155; OP/M, n=126) patients with TRD. In younger vs older patients, TEAEs were reported in 86.1% vs 74.8% in the IND phase and 86.8% vs 81.0% in the OP/M phase. The most common TEAEs (≥10%) were dizziness (IND: 30.8% vs 23.2%; OP/M: 22.0% vs 23.8%), dissociation (IND: 24.0% vs 20.6%; OP/M: 19.3% vs 16.7%), nausea (IND: 22.9% vs 9.0%; OP/M: 15.3% vs 8.7%), headache (IND: 20.2% vs 7.1%; OP/M: 21.2% vs 10.3%), somnolence (IND: 12.3% vs 11.0%; OP/M: 13.8% vs 15.1%), and hypoesthesia (IND: 11.5% vs 4.5%; OP/M: 7.1% vs 4.8%). Serious TEAEs were reported in 2.2% vs 1.9% in the IND phase and 6.7% vs 4.8% in the OP/M phase. In younger vs older patients, SPRAVATO was discontinued owing to TEAEs in 7.5% vs 3.9% in the IND phase and 3.8% vs 4.0% in the OP/M phase.

SUSTAIN-3 Trial

Zaki et al (2023)¹¹ conducted a phase 3, open-label study to evaluate the long-term (up to 6.5 years) safety and efficacy of flexibly-dosed SPRAVATO with an oral AD in adult patients with TRD.

Study Design/Methods

• Based on the patient’s status at the end of one of the previous parent studies,^3,5,6,19-21 patients were enrolled in either one of 2 phases: an open-label IND phase (4 weeks) or an open-label OP/M phase (variable duration).
• In the open-label IND phase, patients received flexible doses of SPRAVATO (28, 56, and 84 mg) twice weekly for 4 weeks; and during the OP/M phase, patients received SPRAVATO 28, 56, and 84 mg either weekly, every other week or every 4 weeks, based on severity of depression. SPRAVATO 28 mg was the optional starting dose only for patients ≥65 years.

Results

Baseline Characteristics

• Of the 1148 patients enrolled at baseline of both phases, the mean age was 49.6 years, 66.6% of participants were female, 86.8% of individuals were White and 23.6% of participants had pre-existing hypertension.
• Of the 1148 patients enrolled, 458 patients were enrolled into the IND phase, 38 of whom discontinued and 420 continued to the OP/M phase. An additional 690 patients were directly enrolled into the OP/M phase. Of the 1110 patients participating in the OP/M phase of the study, 430 patients (38.7%) discontinued the study (see Table: Patient Disposition in the OP/M Phase).

Duration of Exposure

The mean (SD) exposure to SPRAVATO was 42.9 (24.22) months; total exposure was 3777 cumulative patient-years.

Adverse Events

• Common AEs can be found in Table: Most Frequently (≥10%) Reported Adverse Events.

• Dissociation was reported in 25.5% of patients, with very few patients (0.6%) requiring medication treatment. Over 99% of cases occurred and resolved in the same dosing day across study phases. Five patients (0.4%) discontinued due to dissociation. No SAEs of dissociation were reported.
• Increased BP was reported in 19.9% of patients. Most events (≥95%) occurred and resolved on the same day of dosing. An incidence of hypertensive emergency was reported in 1 (0.1%) patient, and 6 (0.5%) patients discontinued due to increased BP.
• UTIs were reported in 15.8% of patients; no cases of interstitial/ulcerative cystitis were reported. Other AEs (≥1%) related to renal disorder included dysuria (3.0%), cystitis (2.4%), pollakiuria (2.4%), nephrolithiasis (1.7%), micturition urgency (1.5%), urinary incontinence (1.5%), and hematuria (1.3%).
• Treatment discontinuation due to ≥1 AEs was reported in 6.3% patients. The most common AEs leading to discontinuation were increased BP (0.5%) and dissociation (0.4%).

Serious Adverse Events

• Overall, SAEs occurred in 18.8% of patients. SAEs related to depression and suicidality were reported in 2.0% and 2.4% of patients, respectively. Other SAEs (>2 patients) included cholelithiasis (0.9%); COVID-19 (0.8%); pneumonia (0.6%); nephrolithiasis (0.5%); anxiety (0.4%); atrial fibrillation (0.4%); and myocardial infarction, back pain, cellulitis, UTI, intentional overdose, lower limb fracture, headache, cholecystitis, intervertebral disc protrusion, and osteoarthritis (0.3% each). Most of the SAEs (98.5%) were considered doubtfully related or unrelated to SPRAVATO by the investigators.
• Death was reported in 9 patients (COVID-19 [n=3], pneumonia (n=2), suicide, myocardial infarction, multiple injuries, unknown [n=1 each]); none were considered by investigators to be related to SPRAVATO.

Cognition

• Mean performance on all tests (Cogstate [computerized cognitive test battery] and Hopkins Verbal Learning Test-Revised [HVLT-R]), including attention (simple and choice reaction time [RT]), visual and verbal learning and memory, and executive function, remained stable for the total population and for patients aged <65 years, without changes over time.
• In patients aged ≥65 years, performance on the tests of higher cognitive function remained stable or slightly improved; small increase in simple and choice RT occurred during the OP/M phase.

Post hoc Analysis of Tolerability Trends During Postdose Monitoring

Williamson et al (2022)¹³ conducted a post hoc analysis of pooled data from SUSTAIN-1 and SUSTAIN-2 trials^3,12 to characterize recurrence of AEs for SPRAVATO based on AEs that occurred during the early and later courses of treatment. Incidence, frequency, and severity of the most common AEs (i.e., dizziness, dissociation, nausea, vertigo, increased BP, and sedation) were evaluated.

Dizziness (20.6%), dissociation (16.7%), nausea (14.0%), vertigo (12.1%), increased BP (4.3%), and sedation (3.8%) were the most common AEs during the first week of treatment and decreased with ongoing treatment over a 12-month period. Recurrence rates of AEs (based on clinician-reported AEs and standard measures of dissociation, sedation, and increased BP) that were more frequent during the first week were higher later in the treatment course. Therefore, AEs that occurred twice during week 1 were more likely to recur than AEs that occurred once during week 1, which in turn, were more likely to recur than AEs that had no occurrence during week 1. Recurrence rates after week 4 appeared more like the rates seen in week 4 vs. those seen in week 1. Most AEs were mild or moderate in severity with no correlation found between initial and future severity due to a low number of patients with moderate or severe AEs.

POSTMARKETING SAFETY DATA

REMS Database

5-Year REMS Data

Safety data of interest were gathered from REMS patient enrollment and monitoring forms completed by certified US healthcare settings and pharmacies from March 5, 2019, to January 5, 2024. Of the 58,483 patients who received at least 1 SPRAVATO treatment session, 44,908 (76.8%) reported ≥1 AESI. Sedation, dissociation, and increased BP (defined as a BP increase at 40 min after administration of ≥20 mmHg or a value of ≥180 mmHg for systolic BP or a BP increase of ≥15 mmHg or a value of ≥105 mmHg for diastolic BP, compared to values prior to administration) were reported by 61.9%, 65.7%, and 11.7% patients, respectively. Among 1,486,213 treatment sessions, sedation, dissociation, and increased BP were reported in 515,367 (34.7%), 608,746 (41.0%), and 13,510 (0.9%) treatment sessions, respectively.¹⁴ 

Sedation and dissociation rates decreased during the induction phase (sessions 1-8) and remained consistent in the early (sessions 9-12) and late (sessions ≥13) maintenance phases. The rate of increased BP dropped from 1.6% during the first session to below 1% by the end of the induction phase. The percentage of patients experiencing ≥1 AESI was similar between males (76.9%) and females (76.8%). Increased BP was more common in patients aged 25-55 years and those aged >55 years (11.7% and 12.9%, respectively) vs patients aged <25 years (6.8%).¹⁴ 

An SAE was defined as any event that led to hospitalization, disability or permanent damage, death, a life-threatening condition or any event that could jeopardize the patient or require intervention to prevent the aforementioned outcomes. SAEs were reported by 1.6% of patients and in <0.1% of treatment sessions. Of the 2096 SAEs reported, vomiting (7.5%), increased BP (6.8%), and nausea (6.7%) were the most frequent (≥5%); 4.1% of events were unevaluable. The occurrence rate of SAEs was similar for males (1.5%) and females (1.6%); younger patients experienced a slightly lower rate as compared with patients from other age groups: <25 years, 1.1%; 25-55 years, 1.5%; and >55 years, 1.9%.¹⁴ 

AESIs reported as SAEs during the overall evaluation period (per the REMS patient monitoring form) are illustrated in Table: Summary of AESIs Associated With Reports of SAEs.¹⁴

Based on the REMS patient monitoring form, <0.1% of patients reported SAEs that were life-threatening, resulted in death, caused disability or permanent damage; 0.3% resulted in hospitalization; 0.5% were not specified; and 0.8% were considered important medical events.¹⁴ 

5-year REMS Data (A Focus on the First 12 Treatment Sessions)

The 5-year REMS database analysis (March 5, 2019 to January 5, 2024) included 58,483 patients who had ≥1 SPRAVATO treatment sessions.²² At the first treatment session, 65.2% of patients were aged between 18 and 49 years and 61.1% were female.²² A more in-depth analysis of the first 12 treatment sessions found that the cumulative rates of SPRAVATO TEAEs of interest in sessions 1-8, which included 58,471 patients, were 55.8% for sedation, 61.2% for dissociation, and 6.2% for increased BP.²² In sessions 9-12, which included 43,908 patients, the rates of TEAEs were 46.2% for sedation, 51.2% for dissociation, and 2.8% for increased BP.²²

The decrease in the rate of TEAEs of interest from sessions 1-8 to sessions 9-12 across both dose levels is depicted in Table: TEAEs of Interest by Dose Level and Treatment Session.

SAEs (as determined by the reporter) during the overall evaluation period are illustrated in Table: Summary of AEs of Interest Associated With Reports of SAEs by Treatment Session.

The most common SAEs (≥0.1%) in the first 12 treatment sessions were dissociation, dizziness, hypertension, nausea, vomiting and increased BP.²²

Based on the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice (ICP-CGP) criteria, ≤0.4% of patients across all treatment phases reported SAEs resulting in hospitalization (sessions 1-8 and 9-12, 0.1%), death (sessions 1-8, <0.1%), a life-threatening event (sessions 1-8 and 9-12, <0.1%), or an important medical event (sessions 1-8, 0.4%; sessions 9-12, 0.1%).²²

Food and Drug Administration Adverse Event Reporting System

Liu et al (2024),¹⁵ using data from the FAERS database, conducted an analysis of 14,606 SPRAVATO-related AEs reported in 6887 patients between the first quarter of 2019 and the fourth quarter of 2023. Among the top 50 preferred terms (PTs), psychiatric disorder events (70%), general disorders and administration site condition events (10%), and nervous system disorder events (8%) were the major AEs. At the PT level, the 5 most frequently reported SPRAVATO-related AEs were dissociation, suicidal ideation, sedation, drug ineffectiveness, and nausea. PTs with a high signal intensity were dissociation (cases, 1093; reporting odds ratio [ROR], 2257.80; proportional reporting ratio [PRR], 1899.64; and empirical Bayesian geometric mean [EBGM], 876.86), dissociative disorder (cases, 57; ROR, 510.92; PRR, 506.70; and EBGM, 386.60), sedation (cases, 688; ROR, 172.68; PRR, 155.53; and EBGM, 142.05), flashback (cases, 9; ROR, 127.48; PRR, 127.31; and EBGM, 118.14), and morbid thoughts (cases, 17; ROR, 107.45; PRR, 107.19; and EBGM, 100.63). The study reported that apart from the AEs mentioned in its labeling, it identified additional potential signals, including impaired hand-eye coordination, feelings of worthlessness, agoraphobia, feeling of guilt, inappropriate affect, and increased therapeutic response in top 50 PTs.

Limitations of the FAERS database include the inability to infer causality, barriers to reporting, limitations in the quality of information received, and the inability to calculate the incidence rates of the events.²³ Although most reports were from the US, not all were reported within the US.¹⁵

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 19 March 2025.