In this Pharmacy Times interview, Gerard Sanacora, M.D., Ph.D, discusses the long-term real-world safety data of intranasal esketamine (Spravato), which has been used in clinical practice since its FDA approval in 2019 for treatment-resistant depression and major depressive disorder with suicidal ideation. Drawing on nearly 1.5 million treatment administrations across more than 58,000 patients, Sanacora explains that the adverse events observed—including sedation, blood pressure changes, and dissociation—were consistent with prior clinical trial data, with no unexpected safety concerns emerging. For pharmacists, these findings reinforce the importance of REMS monitoring, accurate documentation, and counseling patients on what to expect during administration, ultimately supporting safe and effective use of Spravato in outpatient settings.
Pharmacy Times: Could you provide some background on SPRAVATO and walk through the goals of this long-term safety study, particularly why it was important to examine real-world data from the REMS program and Global Medical Safety database?
Gerard Sanacora, M.D., Ph.D.: Sure, Spravato is actually intranasal S-ketamine delivered through a nasal spray. Ketamine has been developed over the past 2 decades—actually about 25 years now—originally in the racemic version. Early studies suggested efficacy, but there was very limited data regarding long-term efficacy and safety.
Intranasal esketamine was studied in a large portfolio of phase 2 and phase 3 studies that determined sufficient efficacy and safety for FDA approval in 2019 and then a secondary indication. The initial approval was for treatment-resistant major depressive disorder, and then a secondary approval was granted for major depressive disorder with suicidal ideation. We had good evidence of its efficacy and relatively good evidence of safety, but there was still the outstanding question of how safe this was going to be in real-world studies outside the rigors of clinical trial facilities or laboratories.
When the FDA granted approval, it did so alongside a required Risk Evaluation and Mitigation Strategy (REMS). This required patients to be registered, sites to be registered, and pharmacies to be registered and followed. It also required patients, when treated, to be under the observation of a health care professional in a health care facility for at least 2 hours. So, there was very strict guidance on how this was to be delivered. It also mandated that data be collected on adverse events of special interest and serious adverse events over time.
This paper is really motivated by wanting to know what the real-world safety data looks like now, over nearly 5 years of data.
Pharmacy Times: Can you walk us through the methodology—how the patient monitoring forms and GMS reports were used together to create such a robust safety analysis?
Sanacora: With the mandate of the Risk Evaluation and Mitigation Strategy (REMS), we were able to collect data on every outpatient treatment that was provided using Spravato since it was initiated. These REMS forms are filled out for every single dose that is administered by providers. As a result, we had evidence from nearly 1.5 million treatment administrations.
This allowed us to collect very important data on some of the main potential adverse events of interest, such as dissociation, changes in heart rate, and sedation, and to determine where we could expect these effects to occur. In total, we have data on nearly 1.5 million different doses across about 58,000 patients, and that is just from the REMS forms completed by clinicians.
In addition to this, we also had data from the Global Medical Safety database, which includes adverse events reported in the REMS. Beyond that, it captures information from clinical trials, post-marketing surveillance studies, spontaneous reports, literature reviews, regulatory authority submissions, patient medical records, and even reports on social media. Altogether, it represents a robust collection of potential adverse events
Pharmacy Times: With data covering 58,000 patients and nearly 1.5 million treatment sessions, what stood out to you most regarding the long-term safety of SPRAVATO?
Sanacora: There are a few major lessons we took from this. The major finding was that there were no big surprises. In terms of the relative percentage of people experiencing sedation, changes in blood pressure, or dissociation, the rates were about what we expected based on the previous clinical trials. We did not see any large differences.
We do see some concerns regarding blood pressure, sedation, and dissociation that we need to attend to, but we understand what those are. We can be fairly comfortable with the levels observed, and we can also be confident that the way we have been addressing these issues has been effective.
We also learned a little bit about how to collect REMS data, and it is an imperfect process. We found that some things are either not collected in the REMS or are collected in ways that may not be as accurate as we would like. However, the addition of the Global Medical Safety database really provides a secondary backup, creating a much fuller and more robust dataset.