SUMMARY  

• The phase 3 clinical program for SPRAVATO nasal spray in treatment-resistant depression (TRD) excluded patients with a history of significant pulmonary insufficiency/condition or an arterial blood oxygen saturation of <93% at screening or on day 1 prior to randomization or the first intranasal treatment session.^1-5
• The phase 3 clinical program for SPRAVATO in patients with major depressive disorder and active suicidal ideation with intent excluded patients with clinically significant pulmonary disease.^6,7
• There were no cases of respiratory depression reported in clinical trials of SPRAVATO.^8,9
• Two patients in the phase 3 TRD studies experienced transient, clinically significant decreases in respiratory rate; both were in the long-term, open-label safety study (SUSTAIN-2).^5,8
  • A 43-year-old male with no recorded history of compromised respiratory function was reported to have symptoms of drug-induced delirium on day 127. At the time of the event, he had been receiving SPRAVATO 56 mg weekly and venlafaxine XR 150 mg daily. Thirty-five minutes after administration of the SPRAVATO dose on day 127, the patient’s breathing became faster followed by 30 seconds of apnea, which did not require cardiopulmonary resuscitation. The patient also exhibited stupor and unconsciousness before becoming alert after 10 minutes. The patient discontinued the study. Concomitant medications recorded at about the time of the event included dimenhydrinate and clonazepam. At no time point was the oxygen saturation <93%.⁸ As a note, a serious adverse event of delirium was reported on day 127, which resolved 18 days after discontinuation, but the underlying cause of the delirium was unknown; however, there was ongoing use of naltrexone for prevention of alcohol cravings that suggested that alcohol abuse could not be excluded.^8,10
  • A 53-year-old female, assigned to SPRAVATO 56 mg plus sertraline, with no recorded history of compromised respiratory function, was reported to have 3 treatment-emergent adverse events of decreased respiratory rate on 3 separate dosing days.⁸ On days 4, 8, and 15 of the study, pre-dose respiratory rates were 10, 13, and 16 breaths/minute, respectively, which decreased at 40 minutes post-dose to 8, 8, and 7 breaths/minute, respectively.^8,11 The events were mild and resolved spontaneously at the 1-hour time point. Pulse oximetry was within the normal range during the study. Concomitant medications recorded at about the time of the event included alprazolam, zolpidem, midazolam, lorazepam, and diphenhydramine.⁸
• Events of oxygen saturation levels <93% for 2 or more consecutive assessments within the same visit were reported only in isolated cases. These cases were not associated with clinical symptoms of compromised respiratory function and resolved spontaneously in the postdose period and prior to discharge. In all subjects, vital signs remained within the normal range.^8,9

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.¹²
• In postmarketing experience, respiratory depression was observed with the use of SPRAVATO. In addition, there were rare reports of respiratory arrest.¹²
• SPRAVATO may cause sedation or loss of consciousness. In some cases, patients may display diminished or less apparent breathing.¹²
• 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.¹²

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 16 April 2024.