Real-World Safety Profile of Esketamine Nasal Spray: An Analysis of the Risk Evaluation and Mitigation Strategy Program Approximately 5 Years After Approval in the United States

Purpose: To examine real-world incidence of adverse events of special interest (AESIs), specifically, actively solicited events of sedation, dissociation, and increased blood pressure (BP), and serious adverse events (SAEs) associated with esketamine nasal spray (ESK).

Methods: The analysis used ESK Risk Evaluation and Mitigation Strategy (REMS) patient monitoring form data collected over the first 58 months following product approval in the United States (March 5, 2019–January 5, 2024). Safety data were assessed by sex, age, and treatment phase (induction, treatment sessions 1-8; early maintenance, sessions 9-12; late maintenance, sessions ≥13).

Results: A total of 58,483 patients completed 1,486,213 treatment sessions. Most patients were female (61.1%), and median age was 42 years. Of those initiating ESK, 75.1% of patients received ≥9 treatment sessions, and 60.3% received ≥13 sessions. Sedation, dissociation, and increased BP were reported in 34.7%, 41.0%, and 0.9% of sessions, respectively, with SAEs reported in < 0.1% of sessions. While incidence of sedation and dissociation were similar regardless of sex or age, the incidence of increased BP trended higher in males (1.1%) compared with females (0.8%), and with increasing age (0.5%, < 25 years; 0.9%, 25-55 years; 1.1%, >55 years). Incidence of AESIs and SAEs decreased throughout the induction phase and remained relatively stable in the maintenance phase.

Conclusion: These findings were consistent with the known safety profile of ESK, with no new safety signals identified in this dataset. Rates of sedation, dissociation, increased BP, and SAEs decreased over the course of treatment. The frequency of SAEs was low.