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
• Clinical studies of SPRAVATO found a higher rate of urinary tract symptoms (including cystitis) in SPRAVATO-treated patients vs placebo (PBO).^1,5
  • There were no cases of SPRAVATO-related interstitial cystitis observed in any of the studies, which included treatment for up to 6.5 years.^2,3,6
• The most commonly observed adverse reactions in adult patients (incidence ≥5% in SPRAVATO plus oral AD group and twice that of oral AD plus PBO group):
  • Being treated for treatment-resistant depression (TRD): dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, feeling drunk, and headache.^7-9
  • Being treated for major depressive disorder (MDD) with acute suicidal ideation or behavior: dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo.^10,11
• 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.¹²
• 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.⁶
• Post hoc analysis of pooled data from SUSTAIN-1 and SUSTAIN-2 studies^3,13 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.¹⁴ However, the overall recurrence of these AEs diminished over the 12-month treatment period.
• Postmarketing safety data from the REMS and SPRAVATO global medical safety database from March 5, 2019, to January 5, 2023, identified sedation and dissociation as the most commonly reported AEs; the majority of sedation and dissociation reports were nonserious and resolved within the postdose monitoring period.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 serious adverse events (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 (BPICSS) 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)¹² 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)⁶ conducted a phase 3, open-label study to evaluate the longterm (up to 6.5 years) safety and efficacy of flexibly-dosed esketamine 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,^3,7,8,19-21 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 blood pressure (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)¹⁴ conducted a post hoc analysis of pooled data from SUSTAIN-1 and SUSTAIN-2 trials^3,13 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

4-year REMS Data

Safety data of interest were gathered from REMS patient monitoring forms completed by certified US healthcare settings and pharmacies from 3/5/19 to 1/5/2023.²² Results from this analysis showed that in 34,110 patients who had received at least 1 SPRAVATO treatment session, 21,956 (64.4%) reported sedation, 22,953 (67.3%) reported dissociation, and 4,120 (12.1%) reported increased BP (defined as either an increase of ≥20 mmHg before administration to ≥180 mmHg [systolic] after administration and/or ≥15 mmHg before administration to ≥105 mmHg [diastolic] after administration, or if values before administration were missing, ≥180 mmHg [systolic] and/or ≥105 mmHg [diastolic] were used). In the 815,172 treatment sessions, sedation, dissociation, and increased BP were reported in 36.6%, 42.3%, and 1.0% of treatment sessions. The majority of sedation and dissociation reports were nonserious and resolved within the postdose monitoring period. There were 1580 SAEs with increased BP, dizziness, nausea, and vomiting being the most frequently (≥5%) reported; 4.9% of events were non-evaluable, in that key information was missing (e.g., lack of information regarding onset of event relative to drug exposure, key patient characteristics, medical and medication history) and a meaningful medical assessment could not be made.

In a separate search of the SPRAVATO global medical safety database, which included AEs reported from the REMS, there were 440,369 cases from the REMS reporting a total of 658,360 AEs within the same time frame. Among those cases, 2,437 (0.4%) were reported as serious. There were 147 cases reporting 160 fatal events. 136 of 147 cases reported only 1 fatal event which included 67 deaths not otherwise specified, 45 completed suicide, 3 overdose, 2 COVID-19 infection, 2 road traffic accidents, and 1 death each due aortic aneurysm, arteriosclerosis, Candida infection, cerebrovascular accident, diabetes mellitus, drug abuse, electrolyte imbalance, failure to thrive, hepatic cirrhosis, intestinal obstruction, intestinal perforation, multimorbidity, myocardial infarction, neoplasm malignant, post procedural complication, pulmonary embolism, and sepsis. 11 remaining fatal cases which reported more than 1 fatal event: cardiac disorder, sepsis, and COVID-19; cardiovascular disorder, multiple organ dysfunction syndrome, and cerebrovascular accident; toxicity to various agents and accidental overdose; hip fracture and gall; hallucination auditory and completed suicide; pneumonia and multiple organ dysfunction syndrome; toxicity to various agents and completed suicide; suspected suicide and alcohol use; overdose and brain injury; organ failure and COVID-19; and substance abuse and accidental overdose. The majority of deaths were assessed by Global Medical Safety as not related to SPRAVATO treatment.²²

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.²³ At the first treatment session, 65.2% of patients were aged between 18 and 49 years and 61.1% were female.²³ 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.²³ 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.²³

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.²³

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%).²³

FAERS

An analysis was conducted using the Food and Drug Administration Adverse Event Reporting System (FAERS) to identify relevant safety signals for SPRAVATO.²⁴ A case/non-case study design was utilized in which cases were defined by reports about SPRAVATO, while non-cases were represented by AEs recorded for all other drugs in FAERS over the first year of SPRAVATO approval. If the proportion of AEs of interest was greater in cases versus non-cases, then this was considered a disproportionality signal. AEs were classified into 4 categories, according to their predictability: expected AEs with a detected signal, expected AEs without a signal, diseaserelated AEs, or unexpected AEs.

There was a total of 2274 SPRAVATO-related AEs in 962 patients with 389 SAEs, including 22 deaths. The most frequently reported AEs (≥5%) were dissociation (n=212, 9.32%), sedation (n=173, 7.6%), and drug ineffective (n=119, 5.23%). The top 3 AEs in the expected AEs with signal category based on reporting odds ratio (listed in descending order) were dissociation (n=212), sedation (n=173), and feeling drunk (n=20); in the expected AEs without a signal category were vertigo (n=5), vision blurred (n=8), and tremor (n=9); in the disease-related AEs category were self-injurious ideation (n=5), suicidal ideation (n=64), and depression (n=65); and in the unexpected AEs category were dissociative disorder (n=4), autoscopy (n=6), and drug monitoring procedure not performed (n=4). The frequency of SAEs was higher in patients receiving SPRAVATO 84 mg compared to patients receiving SPRAVATO 56 mg. Females were also more likely to suffer from SPRAVATO-related SAEs compared to males. A sensitivity analysis using venlafaxine as a comparator for disease-related AEs identified the following signals: self-injurious ideation, suicidal ideation, emotional disorder, depression, crying, and depressed mood.²⁴

Limitations of the FAERS include: the database contains duplicate, incomplete, and/or unverified AEs, making causality difficult to prove; AE reports are voluntary and unsolicited (which generally leads to under-reporting of AEs for most drugs) and, therefore, AE rates cannot be determined; FAERS does not include information on the patient’s baseline suicidality and illness severity (which are important risk factors for suicide-related AEs).²⁵ Other considerations include: the increasing AE trends for SPRAVATO over the first year are expected due to the low initial SPRAVATO usage following approval, partly due to REMS requirements for certifying treatment centers; expected AEs such as dissociation and sedation are solicited and reported via the REMS at every SPRAVATO treatment session triggering multiple reports in FAERS; use of venlafaxine as a control for sensitivity analyses may not be appropriate since the TRD population indicated for SPRAVATO likely possess a significantly greater burden of disease.

Another analysis conducted using the FAERS database for 5061 SPRAVATO-related AEs from the first quarter of 2019 to the first quarter of 2023 reported that apart from the AEs mentioned in its labeling, this study identified additional potential signals, including flashback, tachyphylaxis, and autoscopy.²⁶

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 14 April 2024.