SUMMARY

• SPRAVATO nasal spray contains esketamine (ESK) hydrochloride, which is the (S)-enantiomer of ketamine. ESK is a Schedule III controlled substance under the United States’ Controlled Substances Act.¹
• Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of SPRAVATO. Careful consideration is advised prior to treatment of individuals with a history of substance use disorder, including alcohol. Monitoring for signs of abuse or dependence is recommended.²
• Patients with a history of moderate or severe substance or alcohol use disorder were excluded from clinical studies of SPRAVATO. Similarly, a history (lifetime) of ketamine, PCP, LSD, or MDMA related use disorder was exclusionary.^3-9
• In a study of abuse potential conducted in recreational polydrug users (n=34), single doses of SPRAVATO nasal spray (84 mg and 112 mg) and the positive control drug, intravenous ketamine (0.5 mg/kg infused over 40 minutes), produced significantly greater scores than placebo (PBO) on subjective ratings of “drug liking at the moment” and on other measures of subjective drug effects.¹⁰
• Across phase 3 studies, SPRAVATO was administered under direct supervision at the clinical trial site and devices for each patient were inventoried and accounted for throughout. There were no confirmed cases of drug diversion.^10-12
• A post hoc analysis of Physician Withdrawal Checklist (PWC-20) results from a long-term phase 3 study (SUSTAIN-2)⁶ suggests that SPRAVATO is unlikely to be associated with a withdrawal syndrome. In addition, the analysis found 6 positive urine drug screens without an underlying cause among 802 patients and no reports of drug-seeking behavior.¹³
• In a post hoc subgroup analysis of a retrospective real-world study in 26 patients with treatment-resistant depression (TRD) and comorbid substance use disorder (SUD), no cases of abuse or misuse of SPRAVATO were reported.¹⁴
• In an analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) and the European EudraVigilance (EV) database through 2 June 2021, adverse events reported with SPRAVATO that were suggestive of abuse potential were identified and were consistent with the characteristics of abuse and misuse in the SPRAVATO label.¹⁵
• A 34-year-old woman was reported to have experienced a high level of craving for SPRAVATO when treatment was initiated for the management of treatment-resistant depression.¹⁶

product labeling

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 Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS.¹⁷

For additional information or questions about the REMS, call 1-855-382-6022 or visit www.SPRAVATOrems.com.

clinical Trial data

Phase 1 Study

A phase 1, single-center, single-dose, double-blind, double-dummy, PBO-controlled, randomized crossover study was conducted to evaluate the abuse potential of SPRAVATO nasal spray compared to IV ketamine in nondependent, recreational users of perception-altering drugs.¹⁰

Study Design/Methods

Subjects included in the study had at least 10 total lifetime occasions of drug use and liked the drugs’ effects, reported having used racemic ketamine at least once in their lifetime, and had used a perception-altering drug within 3 months prior to screening. Eligible subjects were enrolled in the treatment phase and assigned to 1 of 4 treatment groups (84 mg SPRAVATO and IV PBO, 112 mg SPRAVATO and IV PBO, 0.5 mg/kg IV ketamine and PBO nasal spray, and IV PBO and PBO nasal spray).

Results

Of the 41 subjects who participated in the treatment phase, 34 subjects completed treatment. The study showed that single doses of SPRAVATO nasal spray (84 mg and 112 mg) and IV ketamine (0.5 mg/kg infused over 40 minutes) produced significantly greater scores compared to PBO on subjective ratings of “drug liking at the moment” and “take drug again” scores. The 112 mg dose of SPRAVATO was associated with significantly higher scores for “hallucinating,” “floating,” “detached,” and “spaced out” than the 84 mg dose of SPRAVATO and the intravenous ketamine dose.

Post Hoc Analyses

Aluisio et al (2019)¹³ conducted a post hoc analysis of results from patients enrolled in a long-term (up to 1 year of exposure), phase 3 study (SUSTAIN-2)⁶ to investigate potential withdrawal symptoms using the PWC-20 (total score range, 0-60; higher results indicative of higher severity). Mean PWC-20 total scores (n=307) were stable across treatment endpoint (7.2) and weeks 1 (7.5), 2 (7.4), and 4 (7.2) after treatment discontinuation, which suggests a lack of a distinct withdrawal syndrome. There were 6 positive urine drug screens without an underlying cause among 802 patients (equivalent to 410 patient years) and no reports of drug-seeking behavior during the study. Adverse events possibly related to SPRAVATO during the follow-up phase were reported in 2.5% of patients (9/357). Serious adverse events reported during the follow-up phase included depression (n=5), suicide attempt (n=1), hepatobiliary disorders (n=1), and neoplasm malignant (n=1).

Chiappini et al (2023)¹⁴ conducted a post hoc subgroup analysis of an observational, retrospective study (REAL-ESK)in 26 patients with TRD and comorbid SUD from Italian mental health facilities.¹⁸ After 3 months of treatment with SPRAVATO, response and remission were reported in 50% (13/26) and 30.8% (8/26) of patients, respectively. The most frequently reported side effects were dissociative symptoms (38%), sedation (26%), increased blood pressure (11%), hypomanic symptoms (11%), psychomotor agitation (4%), and anxiety (4%). No cases of abuse or misuse of SPRAVATO were reported.

Postmarketing Data

External Pharmacovigilance Databases

Baudot et al (2021)¹⁵ performed a multidimensional study that included an analysis of adverse events reported with SPRAVATO through 2 June 2021 in the FAERS and EV databases. The authors included adverse event terms suggestive of abuse referenced by Romach et al.¹⁹ Of the 2,141 cases reported to the FAERS, 687 (32.1%) cases reported 996 events that may reflect abuse potential. Of the 311 cases reported through the EV database, 116 (37.3%) cases reported 178 events potentially reflective of abuse. Adverse events considered potentially reflective of abuse included dissociation (FAERS, 404; EV, 56), sedation (FAERS, 319; EV, 32), euphoric mood (FAERS, 24; EV, 5), hallucination (FAERS, 22; EV, 8), feeling drunk (FAERS, 21; EV, 8), and derealization (FAERS, 5; EV, 3). Others included withdrawal syndrome or drug withdrawal syndrome (FAERS, 10 reports; EV, 1); overdose (FAERS, 8; EV, 0); substance abuse or drug abuse (FAERS, 7; EV, 0); dependence or drug dependence (FAERS, 5; EV, 0); drug tolerance increased or drug tolerance (FAERS, 2; EV, 0); intentional product misuse or intentional product use issue (FAERS, 3; EV, 1); and drug diversion (FAERS, 1; EV, 0). Note that these lists are not exhaustive. Web forum discussions (N=38) on SPRAVATO were also analyzed with themes related to its subjective psychoactive effects, usage compared to other drugs or combining with other illicit drugs, and tolerance.

The authors noted limitations with analyzing pharmacovigilance data mining databases, such as FAERS and EV.¹⁵ According to an article that was published in response to a previous analysis of SPRAVATO adverse events reported in the FAERS, limitations of the FAERS include: duplicate, incomplete case details, and/or unverified AEs, which make causality difficult to prove; most AE reports are voluntary and unsolicited (which generally leads to under-reporting of AEs for most drugs) and, therefore, AE rates cannot be determined.²⁰ In addition, expected AEs such as dissociation and sedation are solicited and reported via the REMS at every outpatient SPRAVATO treatment session in the US triggering multiple reports in FAERS.

Case Reports

A 34-year-old woman initiated SPRAVATO nasal spray for the management of treatment-resistant depression (MADRS=48) and generalized anxiety disorder.¹⁶ A visual analogue scale for craving (VASc; 0-100, 100=extreme craving) was administered before each treatment session then monthly during maintenance, and during the observational follow-up phase for up to 3 months after SPRAVATO discontinuation. Though the MADRS score was improving over the first 3 months, her craving started soon after SPRAVATO initiation with a VASc=100 over the first month and then decreased to a VASc=80 during the second month. The patient experienced increased anxiety, irritability, nervousness, tension, insomnia, and a subjective need to shorten the interval between SPRAVATO treatment sessions. The craving worsened again when the SPRAVATO dosing frequency was decreased to every other week in month 3. Bupropion was added to her regimen to alleviate the craving. After 6 months on SPRAVATO + duloxetine + bupropion, the depression remitted (MADRS=10) and the craving subsided significantly (VASc=10). The authors stated that the patient maintained stable clinical remission with bupropion alone over the 3-month follow-up period.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 12 April 2024. Search results incorporated are limited to SPRAVATO nasal spray and no other formulations of esketamine or ketamine.