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
• 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.
• Patients with certain cardiovascular conditions were excluded from phase 3 studies.^9,13-18 See Cardiovascular-Related Exclusion Criteria from SPRAVATO Phase 3 Studies.
• Concomitant use with psychostimulants and monoamine oxidase inhibitors may increase BP.¹
• A real-world study in patients with TRD reported transitory hypertension in 10.3% of patients treated with SPRAVATO.¹⁹
• In postmarketing safety data from the Risk Evaluation and Mitigation Strategy (REMS) program, from 5 March 2019 to 5 January 2023 increased BP was reported in 12.1% (4,120/34,110) of patients and 1.0% (8,147/815,172) of treatment sessions.²⁰ In an analysis of postmarketing safety data (March 2019 to first quarter 2020) from the Food and Drug Administration Adverse Event Reporting System (FAERS), increased BP was reported (62 cases) as an expected AE with a detected signal.²¹

CLINICAL studies

AEs Related to Increased BP Across Clinical Studies

Across 5 phase 3^9,14-17 and 1 phase 2²² 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.¹⁸

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.²³

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.²⁴

Real-world Study (REAL-ESK)

An observational, retrospective, multicentric study analyzing data from 116 patients with TRD reported transitory hypertension in 10.3% of patients treated with SPRAVATO.¹⁹

AEs Related to Heart Rate Across TRD Clinical Studies

Across 5 phase 3^9,14-17 and 1 phase 2²² 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 3^9,14-17 studies and 1 phase 2²² 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 SPRAVATOtreated 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^9,16,17 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.²⁵ Elevations in BP can be higher or longer in individual patients.

Across 3 short-term studies in TRD^9,16,17, 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.^13,18

In the phase 3 fixed-dose TRD study¹⁶, 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)²⁶ conducted a post hoc analysis of an open-label, flexibly-dosed study (SUSTAIN-2)¹⁵ 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 longterm TRD studies^14,15 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)²⁷ 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, clinicianreported 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), openlabel, 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.

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

Cardiovascular-Related Exclusion Criteria in SPRAVATO Phase 3 Studies

TRD^7,12

• Cerebrovascular disease with a medical history of stroke or transient ischemic attack
• Active aneurysmal vascular disease (including intracranial, thoracic or abdominal aorta, or peripheral arterial vessels)
• Coronary artery disease with MI, unstable angina or revascularization procedure (e.g., coronary angioplasty or bypass graft surgery), within 12 months before the start of the screening phase
  • Patients who have had a revascularization performed ˃12 months prior to screening and were clinically stable and symptom free, per investigator’s clinical judgment, were included.
• Hemodynamically significant valvular heart disease such as mitral regurgitation, aortic stenosis, or aortic regurgitation
• NYHA Class III-IV heart failure of any etiology
• Medical history of uncontrolled hypertension despite diet, exercise, or antihypertensive medications defined as:
  • Supine SBP (SBP) >140 mmHg or DBP (DBP) >90 mmHg during screening/prospective observational phase in patients <65 years old
  • Supine SBP >150 mmHg or DBP >90 mmHg during screening/prospective observational phase in patients ≥65 years old
• Patients could have current antihypertensive medication(s) adjusted during the screening/prospective observational phase and be re-evaluated to assess BP control
  • The patient had to be on a stable regimen for at least 2 weeks before day 1 of SPRAVATO treatment.
• Patients with a current or past history of significant pulmonary insufficiency/condition or with an arterial blood oxygen saturation of <93%
• Patients with clinically significant ECG abnormalities
  • On day 1 (predose), a QT interval corrected according to Fridericia's formula (QTcF): ≥450 msec based on the site-evaluated ECG; if the QTcF is prolonged on the initial ECG, the average QTcF of 3 ECGs, recorded 4 minutes apart, must not be ≥450 msec.
    • Note: this was prior to conduct of the thorough QT study which indicated that concurrent use of SPRAVATO did not have a significant effect on QT interval
  • Evidence of 2nd and 3rd degree AV block, complete left bundle branch block, or complete right bundle branch block
  • Features of new ischemia
  • Arrhythmia (except premature atrial contractions and premature ventricular contractions)
• Patients with a history of additional risk factors for Torsades des Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)

Major Depressive Disorder and Active Suicidal Ideation and Intent^13,18

• Clinically significant cardiac disease, which included unstable coronary artery disease, congestive heart failure, tachyarrhythmias, and recent myocardial infarction
• Uncontrolled hypertension or history of hypertensive crisis
  • This includes conditions in which elevated BP could pose a serious risk, including unstable heart failure, severe cardiovascular disease, recent cerebral injury, increased intracranial pressure, intracranial mass lesion, intracranial bleeding or acute stroke, untreated glaucoma, perforating eye injury

POSTMARKETING SAFETY DATA

REMS Database

REMS patient monitoring forms completed by certified US healthcare settings and pharmacies from 5 March 2019 to 5 January 2023 identified 34,110 patients who received at least 1 SPRAVATO treatment session and a total of 815,172 treatment sessions. Increased BP was reported in 4,120 (12.1%) patients and 8,147 (1.0%) treatment sessions.²⁰ Increased BP was defined either as an increase of ≥20 mmHg before administration to ≥180 mmHg (systolic) after administration and/or ≥15 mmHg before administration to ≥105 mmHg (diastolic) after administration; if values before administration were missing, values of ≥180 mmHg (systolic) and/or ≥105 mmHg (diastolic) were used. Of the 1,580 serious AEs, 102 (6.5%) were related to increased BP and 63 (4.0%) were related to hypertension.

In a separate search of the SPRAVATO global medical safety database, which included AEs reported from the REMS, 2,437 AEs (out of 658,360) were reported to be serious, of which 192 involved increased BP and hypertension.²⁰

FDA Adverse Event Reporting System (FAERS)

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.²¹ A case/non-case study design was utilized in which cases were defined by reports about SPRAVATO, while non-cases were represented by AEs recorded for all other drugs in FAERS over the first year of SPRAVATO approval (March 2019 to first quarter 2020). If the proportion of AEs of interest was greater in cases versus non-cases, then this was considered a disproportionality signal. AEs were classified into four categories, according to their predictability: expected AEs with a detected signal, expected AEs without a signal, disease-related AEs, or unexpected AEs.

Increased BP was reported as an expected AE with a detected signal with 62 reports, a reporting odds ratio (ROR) of 10.13 (95% CI: 7.87-13.05), and a Bayesian information component (IC) of 3.2 (95% CI: 2.78-3.5). The authors noted that the results must be interpreted with caution, partly due to the FAERS database having limitations, including the inability to infer causality, barriers to reporting, limitations in the quality of information received, and the inability to calculate an incidence rate due to a lack of a denominator.²¹ Other considerations included: the increasing AE trends for SPRAVATO over the first year were expected due to the low initial SPRAVATO usage following approval, partly due to REMS requirements for certified treatment centers; in addition, expected AEs such as BP are solicited and reported via the REMS at every outpatient SPRAVATO treatment session triggering multiple reports in FAERS.²⁸

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.²⁷

Hauser et al (2024)²⁹ conducted a retrospective observational study in 37 patients with TRD to evaluate the effect of music on adverse events (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 12 April 2024.