SUMMARY  

• No adverse events (AEs) of respiratory depression were reported in SPRAVATO Phase 3 clinical trials.
• In a post hoc analysis of a phase 3b, open-label, head-to-head study, the safety and tolerability of SPRAVATO+oral antidepressant (AD) was evaluated in comparison to quetiapine extended-release (QUE-XR)+oral AD in adults with treatment-resistant depression (TRD).¹
  • Abnormally low respiratory rate (<10 breaths/min) occurred in 3% and 0.3% of patients in the SPRAVATO group and QUE-XR group, respectively. No clinically significant decreases were reported as treatment-emergent adverse events (TEAEs) and no discontinuations occurred due to abnormal respiratory rates.¹
• An evaluation of the Janssen Global Medical Safety database for SPRAVATO, identified 96 cases from postmarketing reports of adverse events (AEs) under the Standardized Medical Dictionary for Regulatory Activity (MedDRA) Query (SMQ) of “acute central respiratory depression (broad)”.²
  • Of the 96 cases, 50 involved patients who had clinical symptoms on the day of administration, and either had respiratory rates and/or oxygen saturation levels below threshold (≤10 breaths per minute and/or oxygen saturation ≤93%; n=11), or cases that did not report one or either value (n=39).
  • Of the 50 cases, 32 involved patients who required medical intervention, including emergency medical service/emergency room visit/hospitalization (12), oxygen (9), medication (4), tactile or verbal stimulation (4), CPR and/or rescue breathing (2), and not specified (1).
  • The majority of these 50 cases were reported in patients using concomitant CNS depressants and/or in patients with comorbidities such as anxiety/panic disorder/PTSD, obesity, cardiovascular disease, and respiratory conditions.
  • Eight of the 50 cases were assessed to have a stronger association with SPRAVATO use. In most of these cases, symptoms were reported within the 2-hour monitoring period and were transient in nature, usually resolving with minor supportive measures, such as verbal or tactile stimulation, or the administration of supplemental oxygen. There does not appear to be a dose-response relationship in these cases.
• Forty of the 96 global cases of respiratory depression were reported from the US SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) program (based on data collected from 868,446 treatment sessions from March 2019 to February 2023).^2,3 These cases did not meet the criteria of having a strong association with SPRAVATO use.
• Two cases of respiratory arrest were reported in the US. Rescue breathing was administered in one case, and the patient was discharged after an observation period of 150 minutes. In the other case, the patient was reported to have stopped breathing, and the nursing assistant had to sit her up to help her breathe again. A case of cardiorespiratory arrest was reported for a patient where cardiopulmonary resuscitation was performed; the patient was taken to the emergency department and was discharged the same day.²
• The mechanism of respiratory depression with SPRAVATO is not clear. A preclinical study in mu-opioid knock-out mice administered esketamine intraperitoneally with doses up to 200 mg/kg saw dose-dependent respiratory depression. At the 200 mg/kg dose, a reduction in the hypercapnic ventilatory response was observed. More prominent respiratory depression and antinociception effects were observed in wild-type mice compared with the knock-out mice. Translation of these results to humans requires further study.^2,4 

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.⁵
• In postmarketing experience, respiratory depression was observed with the use of SPRAVATO. In addition, there were rare reports of respiratory arrest.⁵
• SPRAVATO may cause sedation or loss of consciousness. In some cases, patients may display diminished or less apparent breathing.⁵
• Because of the risks of respiratory depression, patients must be monitored by a healthcare provider including pulse oximetry for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.⁵

NOTE:

• Changes to the SPRAVATO REMS are forthcoming and will be communicated from the REMS administrator prior to implementation. Please proceed with the current SPRAVATO REMS requirements. For outpatient treatment centers, please complete the Patient Monitoring Form after each treatment session and submit this form to the REMS within 7 days.
• While pulse oximetry is required, no additional equipment or supplies, such as crash carts or oxygen, are required to become a certified treatment center. However, supplementary oxygen therapy was used as an intervention for respiratory depression in some cases.

RESPIRATORY DEPRESSION

Phase 3 Clinical Trials

No AEs of respiratory depression were reported in SPRAVATO Phase 3 clinical trials. Less than 3% of participants (out of 2009) had oxygen saturation levels <93% for 2 or more consecutive assessments during dosing sessions with all other vitals remaining within normal range.³ All but one case resolved without intervention within 2 hours of SPRAVATO administration and prior to discharge. Supplementary oxygen was administered to one participant. The non-serious AE was potentially related to a prior respiratory tract infection; no additional occurrences were observed during their continued participation in the study.

Post-hoc Analysis of ESCAPE-TRD

McIntyre et al (2024)¹ conducted a secondary analysis of key safety and tolerability findings from an open-label, head-to-head study evaluating the effectiveness and safety of SPRAVATO+oral AD (n=334) compared to QUE-XR+oral AD (n=336) in adults with TRD.⁶ Vital signs, including respiratory rate, were collected as part of the safety analysis in patients who received ≥1 dose of study treatment. Ten (3.0%) patients in the SPRAVATO group and 1 (0.3%) patient in the QUE-XR group experienced an abnormally low respiratory rate (<10 breaths/min). Six (1.8%) patients in the SPRAVATO group and 1 (0.3%) patient in the QUE-XR group experienced an abnormally high respiratory rate (>24 breaths/min). No clinically significant decreases were reported as TEAEs and no discontinuations occurred due to abnormal respiratory rates.¹

Real World Data Analysis

A search of 5 databases (IQVIA PharMetrics Plus, Optum SES, IBM MarketScan CCAE, Optum EHR, and IQVIA Ambulatory EMR) identified 8505 patients treated with SPRAVATO who received 115,534 doses.³ The incidence of hypoxemia (a proxy for respiratory depression) occurring the day of SPRAVATO administration ranged from 0 to 2.32 per 1000 persons and 0 to 0.37 per 1000 administrations. Another analysis of the incidence rates of hypoxemia occurring the first 28 days after SPRAVATO initiation in patients with TRD (0 to 4.23 per 100 person-years of time-at-risk) found the rates to be within the range of TRD patients during the first 28 days after switching to their third SSRI or SNRI (0.4 to 6.65 per 100 person-years of time-at-risk).

Postmarketing Reports from Janssen Global Medical Safety Database

An evaluation of the Global Medical Safety database for SPRAVATO (from March 2019 through February 2023), identified 96 cases from postmarketing reports of adverse events under the Standardized Medical Dictionary for Regulatory Activity (MedDRA) Query (SMQ) of “acute central respiratory depression (broad)”.²

Of the 96 cases, 30 were unspecified in terms of latency to event onset (missing either event onset date or earliest therapy start date), 8 cases included AEs that occurred at least 1 day after SPRAVATO administration, and 58 cases included AEs that occurred on the day of administration. In 8 of the 58 cases, patients had a respiratory rate ≥10 breaths per minute and/or an oxygen saturation ≥93%. The remaining 50 cases involved patients who had clinical symptoms on the day of administration, and either had respiratory rates and/or oxygen saturation levels below these thresholds (n=11), or cases that did not report one or either values (n=39).² The subsequent analyses focus on this cohort of 50 patients as well as a subset of 8 patients in which causality was thought to be likely.

Patient Characteristics

Of the 50 cases, 31 (62%) occurred in females; 10 occurred in patients 18 to 35 years of age, 13 in those 36 to 50 years, and 17 in those 51 to 64 years of age. Thirty-six cases (72%) were reported in patients using concomitant medications that could have contributed to respiratory depression, with the most frequently reported being benzodiazepines (n=18), antidepressants (16), hypnotics (4), antipsychotics (4), and anticonvulsants (4). Many also had comorbidities that could have predisposed or contributed to these adverse events, such as anxiety/panic disorder/PTSD (n=23), obesity (8), cardiovascular disease (4), respiratory conditions (i.e., asthma [2], COPD [1]) and unhealthy lifestyle (4).²

Adverse Event Details

There was a total of 51 adverse events in the 50 cases. The most common adverse events included dyspnea (n=24), oxygen saturation decreased (8), respiratory rate decreased (3), hypopnea, hypoxia, respiratory depression, respiratory distress, respiratory arrest, and oxygen saturation abnormal (2 each). In half these cases, symptoms were co-reported with sedation and/or dissociation. Thirty-five (70%) events were reported to be serious. For 43/50 patients, the time of event onset occurred within the 2-hour post dose monitoring period with the remainder of cases (7) occurring within the same dosing day. The last dose prior to the adverse event was 84 mg in 21 patients, 56 mg in 17 patients, and 28 mg in 1 patient (the dose was unknown in 11 cases).² 

Intervention and Resolution Details

Of the 50 cases, 15 were reversible and resolved within the 2-hour observation period. In 32 (64%) cases, patients required medical intervention, including emergency medical service/emergency room visit/hospitalization (12), oxygen (9), medication (4), tactile or verbal stimulation (4), CPR and/or rescue breathing (2), and not specified (1). Two cases were considered life-threatening (1 due to respiratory arrest and 1 due to cardiorespiratory arrest). No cases were fatal.² 

Fifteen events resolved within 2 hours post dose, 11 resolved in >2 hours, and 1 case resolved within an unspecified time. Three events were reported as “resolving” while 2 events were reported as “not resolved”. No information on resolution was available for the remaining 19 cases.²

Cases Assessed to be Likely Associated with SPRAVATO

Fifty cases involved patients who had clinical symptoms on the day of administration and reported a respiratory rate <10 breaths per minute and/or oxygen saturation <93% (11) or lacked information on oxygen saturation and/or respiratory rate values (39).² Of those, 8 were assessed as having a stronger association with the use of SPRAVATO by meeting the case definition of having 3 of the following 4 criteria:  1) temporal relationship (latency to onset ≤2h after administration); 2) standalone respiratory symptoms; 3) respiratory rate values (<10 breaths per minute) and/or oxygen saturation (<93%) outside of normal range; and 4) positive rechallenge.^2,7 In most cases, symptoms were reported within the 2-hour monitoring period and were transient in nature, usually resolving with minor supportive measures, such as verbal or tactile stimulation or the administration of supplemental oxygen.³ Please refer to Table: Cases Assessed to be Likely Associated with SPRAVATO for case details. Please note that these are postmarketing reports and inherent limitations include missing details.        

An in-depth review of US REMS Cases

Forty of the 96 global cases were from the US SPRAVATO REMS program (based on data collected from 868,446 treatment sessions from March 2019 to February 2023).^2,10 These 40 cases were reported in 37 patients who experienced 41 AEs, the majority of which were dyspnea (23), hypopnea (5 [4 of these cases occurred in the same patient]), cardiac arrest (2), and oxygen saturation decreased (2). Of the 40 cases, 22 occurred in patients who received SPRAVATO 84 mg, 15 occurred in those who received 56 mg, 1 occurred in a patient who received 28 mg, and 2 cases did not report a dose. Most respiratory-related AE cases (31) occurred less than 2 hours after receiving a dose of SPRAVATO; 1 occurred the same day, 2 occurred after the day of dosing, and 6 cases did not report a latency period.

In most cases, patients were taking concomitant medications and had concurrent medical conditions. The most common medications were benzodiazepine (15), antidepressants including SSRIs (21), hypnotics (5), antipsychotics (2), and anticonvulsants (2). The most common concurrent conditions reported were anxiety (14), obesity (9), PTSD (6), thyroid disease (6), panic disorder (3), alcohol use disorder (2), substance abuse (2), and hypertension (2).¹⁰

Twenty-three of the 40 cases resolved, 11 of which resolved within the 2-hour monitoring period, 5 took up to 180 minutes to resolve, and 7 cases reported that the patient was transported to the ER with no resolution time. An additional 3 cases were reported as “not resolved”, 2 cases were reported as fatal, and 1 resolved within ≤2 hours “with sequelae”. Twelve cases did not report a resolution. The most common interventions reported included stimulation (tactile or verbal), oxygen supplementation, or referral to emergency service for further assessment.¹⁰ 

The 2 fatalities occurred in patients with cardiac arrest. In both cases, the healthcare provider who reported the events considered the causality to be unrelated to SPRAVATO. One case occurred in a “47 or 48-year-old” female and the other in a 20-year-old male. No information was provided as to the cause of the cardiac arrest or the time of when the event occurred in relation to treatment, and autopsy results were not provided. Based on the reports, the Company assessed the cases as being unrelated to SPRAVATO.¹⁰

Case Summaries of Respiratory and Cardiopulmonary Arrest

Respiratory arrest was reported in a patient with a history of polysubstance abuse and kidney transplant (due to end-stage renal disease). She was reported to be unresponsive and “was not breathing” during one of her treatment sessions, and only became alert after being given rescue breathing. She was discharged after an observation period of 150 minutes.² 

Another case of respiratory arrest was reported in a patient who was described to have “paralysis” and “stopped breathing” along with visual hallucination and autoscopy. The patient resumed breathing normally after being seated upright by a nurse.² 

Cardiorespiratory arrest was reported in a third patient with a history of syncope, very low blood pressure, hypothyroidism, and who had used a cardiac loop recorder. Concomitant medications reported included lithium, clonazepam, eszopiclone, trazodone, and bupropion. Cardiopulmonary resuscitation was performed, which resulted in reinitiation of their pulse and respiration. The patient was taken to the emergency department and was discharged on the same day.² 

Postmarketing Databases

An evaluation of respiratory depression adverse events for all routes of administration of esketamine (using MEDRA SMQ: acute central respiratory depression [broad]) reported in the FDA Adverse Event Reporting System found hypopnea to have met the threshold for disproportionality, and asphyxia, oxygen saturation decreased, respiratory depression, and apnea to have met the disproportionality threshold in the EudraVigilance safety database.² 

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 18 September 2024.