SUMMARY

• SPRAVATO nasal spray is contraindicated in patients for whom an increase in blood pressure (BP) or intracranial pressure poses a serious risk (e.g., aneurysmal vascular disease, arteriovenous malformation, and history of intracerebral hemorrhage).¹
• Concomitant use with psychostimulants and monoamine oxidase inhibitors may increase BP.¹
• During phase 3 studies, a formal screening for aneurysmal vascular disease was not conducted. Presence of aneurysmal disease was determined by the site investigator based on the patient’s medical history and assessment at screening.²
• SPRAVATO causes increases in systolic BP (SBP) and/or diastolic BP (DBP) at all recommended dosages. Increases in BP peak at approximately 40 minutes after SPRAVATO administration and last approximately 4 hours.¹
  • While the mechanism by which SPRAVATO nasal spray or ketamine increases BP is not fully known, the literature suggests that ketamine blocks the reuptake of catecholamines and stimulates alpha- and beta-adrenergic receptors.^3-6
• During phase 3 trials in treatment-resistant depression (TRD), investigators were instructed to withhold ESK dosing if predose SBP was >140 mmHg (>150 mmHg for those >65 years of age) or DBP was >90 mmHg. Those with elevated BPs were referred to a specialist or general practitioner for evaluation and potential treatment.⁷
• BP should be monitored after ESK administration. Measure BP around 40 minutes post dose and subsequently as clinically warranted until values decline.⁸ If BP remains high, promptly seek assistance from practitioners experienced in BP management.⁹
• In phase 2/3 trials for TRD, increased BP was reported as an adverse event (AE) in 12.8% of SPRAVATO-treated patients and abnormal heart rate was reported in 3.0% of all SPRAVATO-treated patients. Most AEs had an onset shortly after dosing and resolved 1.5 hours post-dose while patients were still in the clinic.⁷
• A post hoc analysis of 2 long-term studies (SUSTAIN -1 and -2) in TRD found that patients who experienced an increase in BP during the first week of treatment with SPRAVATO were more likely to have recurrence during subsequent weeks.¹⁰
• A post hoc analysis of SUSTAIN-2 comparing the efficacy and safety of SPRAVATO nasal spray in younger (18-64 years) vs older (≥65 years) patients with TRD reported incidence of increased BP during induction (IND) (6.9% [43/624] vs 6.5% [10/155]) and optimization/maintenance (OP/MA) phases (7.1% [34/477] vs 9.5% [12/126]).¹¹
• Discontinuations of SPRAVATO treatment due to increased BP and tachycardia were reported at rates <2% across all completed studies in TRD.⁷
  • Across 5 phase 3 studies, 13 patients on SPRAVATO+oral AD discontinued study medication due to AEs related to increased BP.
• In the TRD clinical studies, unless clinically indicated, it was recommended that transient increases in BP not be treated, as the BP typically returns to predose values within 2 hours following SPRAVATO administration.^12,13See Management of High Blood Pressure.
• Clinical data indicate a lack of clinically relevant QTc prolongation at therapeutic and supratherapeutic doses of SPRAVATO.⁷ See Effects on Cardiac Electrophysiology and QT/QTc Interval.
• Real-world studies reported rates of increased BP between 10.0% to 14.0%.^14,15 
• In an analysis of postmarketing safety data from the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) data from 5 March 2019 to 5 January 2024, increased BP was reported in 11.7% (6,818/58,483) of patients and in 0.9% (13,510/1,486,213) of treatment sessions.¹⁶ 
• In an analysis of postmarketing safety data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the second quarter of 2023, 211 cases of increased BP and 237 cases of hypertension were reported.^17,18 
• Hypotension has been reported as a postmarketing adverse reaction.¹⁹ 

CLINICAL studies

AEs Related to Increased BP Across Clinical Studies

Across 5 phase 3^9,20-23 and 1 phase 2²⁴ studies in TRD, AEs related to increased BP (DBP increased, BP increased, SBP increased, hypertension, hypertensive crisis, hypertensive heart disease) were reported in 12.8% of all SPRAVATO-treated patients (in double-blind [DB] trials: 11.6% vs. 3.9% in SPRAVATO+oral AD and oral AD+placebo [PBO], respectively; odds ratio [OR] 3.2 [95% confidence interval [CI]: 1.9-5.8]), of which 98% of CV events were mild or moderate. Approximately 94% of the events resolved/were resolving.⁷

A phase 3 study in patients with major depressive disorder and active suicidal ideation with intent (MDSI) reported BP increases in 16% (19/113) of patients treated with 84 mg SPRAVATO+standard of care (SOC) and 5.4% (6/112) of those treated with PBO+SOC.²⁵

In a 4-week, randomized, DB, active-controlled, multicenter study in China and the US that evaluated the efficacy and safety of flexibly dosed (56 or 84 mg) SPRAVATO+oral AD (n=126) vs PBO+oral AD (n=126) in patients with TRD, treatment-emergent adverse events (TEAEs) related to increased BP were reported in 30.2% (38/126) of the patients in the SPRAVATO+oral AD group and 10.3% (13/126) in the PBO+oral AD group. Discontinuation due to increased BP was reported in 1 patient (0.8%) in the SPRAVATO+oral AD group and none in the PBO+oral AD group.²⁶

In SUSTAIN-3, a phase 3, open-label extension study, that evaluated the long-term (up to 6.5 years) safety and efficacy of flexibly-dosed SPRAVATO+oral AD in patients with TRD (N=1148), TEAEs related to increased BP were reported in 19.9% of patients, and discontinuation due to increased BP was reported in 0.5% of patients. Most events (≥95%) occurred and resolved on the same day of dosing, and an incidence of hypertensive emergency was reported in 1 (0.1%) patient.²⁷

AEs Related to Heart Rate Across TRD Clinical Studies

Across 5 phase 3^9,20-23 and 1 phase 2²⁴ studies in TRD, AEs related to abnormal heart rate (extrasystoles, heart rate increased, palpitations, sinus tachycardia, and tachycardia) were reported in 3.0% of all SPRAVATO-treated patients (in DB trials: 1.6% vs. 0.8% in SPRAVATO+oral AD and oral AD+PBO, respectively; OR 1.9 [0.5, 8.6]), of which ~97% of CV events were mild or moderate. Approximately 88% of the events resolved/were resolving.⁷

Discontinuations of SPRAVATO treatment due to increased BP and tachycardia were reported at rates below 2% across the 5 phase 3^9,20-23 studies and 1 phase 2²⁴ study in TRD.⁷

Cardiovascular AEs of Clinical Interest in Phase 2/3 TRD Studies

Cardiovascular AEs of clinical interest (angina pectoris, cardiac failure acute, chest discomfort, chest pain, hypertensive heart disease) were reported in 1.3% of all SPRAVATO-treated patients (in DB trials: 0.5% vs. 0.4% in SPRAVATO+oral AD and oral AD+PBO, respectively; OR 1.3 [95% CI: 0.1-15.4]), of which ~74% of the events were mild to moderate. All events resolved/were resolving.⁷

Changes in BP Across Clinical Studies

SPRAVATO can cause increases in SBP and/or DBP which peak at approximately 40 minutes after drug administration and generally last approximately 4 hours.¹

Based on 3 short-term studies^9,22,23 in TRD, the mean PBO-adjusted increases in SBP and DBP over time were about 7 to 9 mmHg in SBP and 4 to 6 mmHg in DBP at 40 minutes post-dose and 2 to 5 mmHg in SBP and 1 to 3 mmHg in DBP at 1.5 hours post-dose in patients receiving ESK.²⁸ Elevations in BP can be higher or longer in individual patients.

Across 3 short-term studies in TRD^9,22,23, approximately 8% to 17% of SPRAVATO-treated patients and 1% to 3% of PBO-treated patients experienced an increase of more than 40 mmHg in SBP and/or 25 mmHg in DBP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A substantial increase in BP could occur after any dose administered even if smaller BP effects were observed with previous administrations.⁷ See BP Increases in DB Randomized-Controlled, Short-Term Studies of SPRAVATO+Oral AD Compared to Oral AD+PBO in TRD

Similar BP changes were observed in phase 3 clinical trials for patients with MDSI who were treated with ESK+SOC.^13,25

In the phase 3 fixed-dose TRD study²², differences in the maximum mean changes in BP between the 56 mg and 84 mg doses of SPRAVATO were small and not suggestive of a dose response (SBP: 14.3 and 15.0 mmHg, respectively; DBP: 8.9 and 9.4 mmHg, respectively).⁷

Across completed studies of SPRAVATO in TRD, markedly abnormal elevations in BP (SBP ≥180 mmHg and/or DBP ≥110 mmHg) occurred at a higher rate in patients with a history of hypertension vs without a history of hypertension.⁷

• 5.5%-7.6% of patients aged 18-64 with a history of hypertension vs 4.1%-4.3% of patients without had markedly abnormal elevations in BP.
• 14.6% of elderly patients with a history of hypertension vs 6.5% of patients without had markedly abnormal elevations in BP.

Post Hoc Analysis of Vital Sign Measurement and BP Reporting

Fua et al (2019)²⁹ conducted a post hoc analysis of an open-label, flexibly-dosed study (SUSTAIN-2)²¹ that evaluated the long-term safety of SPRAVATO+oral AD in patients with TRD. Patients received treatment twice a week for the first 4 weeks (IND), weekly for the next 4 weeks, and then once every 2 weeks or weekly thereafter (up to 48-week OP/MA phase). The objective was to examine the relationship between spontaneously reported AEs and events identified by vital sign data for safety evaluation in SUSTAIN-2.

In the IND phase (N=779), acute hypertension (SBP ≥180 mmHg or DBP ≥110 mmHg) was reported in 18 patients (2.3%), and discontinuation due to increased BP or hypertension occurred in 6 patients (0.8%) (4 of the 6 patients met criteria for acute hypertension). In the OP/MA phase (N=603), acute hypertension was reported in 18 patients (3.0%), and discontinuation due to increased BP or hypertension occurred in 3 patients (0.5%) (1 of the 3 patients met criteria for acute hypertension).

TEAEs of angina pectoris, coronary artery disease, ventricular arrhythmia, and arrhythmia were reported in 3 patients with a prior history of hypertension. All 3 discontinued the study and recovered.

A 60-year-old male patient died from acute cardiac and respiratory failure 5 days after receiving SPRAVATO 56 mg (study day 113). The patient had normal BP during the study but had a history of hypertension, obesity and right lower limb vein surgery. His death was considered by investigators to be doubtfully related to SPRAVATO.

Williamson et al (2022)¹⁰ conducted a post hoc analysis of pooled data from 2 long-term TRD studies^20,21 to evaluate whether the incidence of increased BP during weeks 1 and 4 of treatment predicted the recurrence of this AE as a spontaneously reported AE with long-term treatment.¹⁰ Results showed that if BP increase was not reported in week 1, ≤4% of patients experienced this AE during subsequent weeks (see Table: Rates of Increased Blood Pressure Recurrence According to the Frequency of Increased Blood Pressure Occurrence in Week 1). Compared with week 1, the occurrence of BP in week 4 was more closely associated with later recurrence.

Fua et al (2020)³⁰ performed a post hoc analysis of patients with MDSI (pooled data from the ASPIRE I and ASPIRE II trials), which found 15% of patients (34/227) who had received SPRAVATO+SOC and 4.9% of patients (11/225) who had received PBO+SOC experienced clinician-reported hypertension. Among the SPRAVATO+SOC group, clinician-reported severe hypertension, defined as distress that caused significant impairment in function and prevented normal daily activities, occurred in 5 patients (2.2%). Further, 9 SPRAVATO+SOC patients (4%) vs. 5 PBO+SOC patients (2.2%) experienced acute hypertension, defined as a BP of ≥180/110 mmHg. Two patients in the SPRAVATO+SOC group and 1 in the PBO+SOC group discontinued treatment due to hypertension. All severe hypertensive TEAEs resolved on the same day of dosing. No cases of severe (non-HTN) cardiovascular TEAEs were reported on the day that the dose was given.

Ochs-Ross et al (2022)¹¹ performed a post hoc analysis of the long-term (1-year), open-label, multicenter, phase 3 SUSTAIN-2 study to compare the efficacy and safety of SPRAVATO nasal spray in younger (18-64 years) vs older (≥65 years) patients with TRD. For results, See Table: Summary of BP-Related Changes in the IND and OP/MA Phases.

McIntyre et al (2024)³¹ conducted a secondary safety and tolerability analysis of the ESCAPE-TRD³² study, a 32-week, randomized, phase 3b study that evaluated the efficacy and safety of SPRAVATO vs quetiapine extended-release (QUE-XR) in the treatment of patients with TRD.³¹ Serious TEAEs of acute coronary syndrome and atrial fibrillation were reported in 1 patient each (0.3%) from the 334 patients in the SPRAVATO group and in none of the 336 patients in the QUE-XR group.³³ Abnormal BP was reported in a small percentage of patients (see Table: Treatment-Emergent Abnormally Low/High Blood Pressure).

Treatment-emergent acute hypertension was reported in 2.1% of patients in the SPRAVATO group and in none of the patients in the QUE-XR group. Hypertension was not associated with study discontinuation in any of the groups.³¹

EffectS ON cardiac electrophysiology and QT/QTc interval

Across all completed phase 2 and 3 TRD studies, there was no clinically relevant effect on ECG parameters observed.⁷

The effect of SPRAVATO (84 mg nasal spray and 0.8 mg/kg SPRAVATO intravenously infused over 40 minutes) on the QTc interval was evaluated in a randomized, DB, PBO-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy subjects. The mean difference from PBO for the change in baseline-corrected QTcF over a 30-hour post-dose interval fell below the accepted threshold of 10 ms for both SPRAVATO nasal spray and IV (nasal spray: -2.02 ms to 2.16 ms; IV: -3.51 ms to 4.89 ms). These results suggest that therapeutic and supratherapeutic doses of SPRAVATO do not prolong the QTcF interval.⁷

Real-World Retrospective Studies

POSTMARKETING SAFETY DATA

REMS Database

Safety data of interest were gathered from REMS patient enrollment and monitoring forms completed by certified US healthcare settings and pharmacies from 5 March 2019, to 5 January 2024. Of the 58,483 patients who received at least 1 SPRAVATO treatment session, 44,908 patients (76.8%) reported ≥1 AE of special interest. Increased BP (defined as a BP increase at 40 min after administration of ≥20 mmHg or a value ≥180 mmHg for systolic, or ≥15 mmHg or a value of ≥105 mmHg for diastolic, compared with values prior to administration) was reported in 6,818 patients (11.7%) and in 13,510/1,486,213 (0.9%) treatment sessions.¹⁶ 

The rate of increased BP dropped from 1.6% during the first session to below 1% by the end of the induction phase. An increased proportion of males vs females (13.4% vs 10.6%) experienced increased BP. Increased BP was also more common in patients aged 25-55 years and those aged >55 years (11.7% and 12.9%, respectively) vs patients aged <25 years (6.8%). Of the 2096 AEs reported to be serious (i.e., led to death, disability or permanent damage, hospitalization, a life-threatening event, or any event that may jeopardize the patient or require intervention to prevent the above outcomes), 6.8% were due to increased BP.¹⁶

FDA Adverse Event Reporting System (FAERS)

An analysis was conducted using the FAERS database (first quarter of 2004 to second quarter of 2023) to evaluate gender-based differences in adverse drug events (ADEs) of esketamine and ketamine.¹⁷ For increased BP, there were 211 cases (reporting odds ratio [ROR], 6.89). For hypertension, there were 237 cases (ROR, 6.21). Note that ROR >1 represents a safety signal. Men were more likely than women to report hypertension as an ADE.¹⁸  

The authors noted that confounding factors that may have affected results include age, gender, concomitant treatments, underlying conditions, and lifestyle. In addition, there may have been duplicate reports and inaccurate or incomplete data (e.g., medical history).^17,35 Although most reports were from the US, not all were reported within the US. The analysis was not limited to esketamine nasal spray and could have included other formulations of esketamine.¹⁷

Management of High BP

In the TRD clinical studies, unless clinically indicated, it was recommended that transient increases in BP not be treated, as the BP typically returns to predose values within 2 hours following SPRAVATO administration. The effect of any treatment may result in hypotension.¹²

Across 6 completed TRD studies, 2.2% (2/93) events in the SPRAVATO+oral AD group and 0% (0/2) events in the oral AD+PBO group in the DB short-term studies and 2.4% (8/330) events in patients who received SPRAVATO in the long-term open-label study had increased BP that required rescue medication. New antihypertensive medications initiated in DB short-term studies in SPRAVATO-treated patients without a history of hypertension (2.1%; n=6/280) included amlodipine, captopril, losartan, metoprolol, propranolol, hydrochlorothiazide, and prazosin.⁷

In a post hoc analysis of patients with MDSI (pooled data from the ASPIRE I and ASPIRE II trials; see details from Fua et al [2020]), 3 patients from the SPRAVATO+SOC group received a single dose of captopril in response to a hypertensive AE.³⁰

Hauser et al (2024)³⁶ conducted a retrospective observational study in 37 patients with TRD to evaluate the effect of music on AEs (including increased BP) during treatment with intranasal racemic ketamine (n=31) or SPRAVATO (n=6). Multivariate comparisons between the music-listening and non-music-listening treatment sessions found significantly lower maximum systolic BP in the music-listening group (music-listening group, 138 mmHg; non-music-listening group, 140 mmHg; P=0.017).

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 14 March 2025.

This response excludes studies in which <50 patients received SPRAVATO.