SUMMARY  

• SPRAVATO is intended for administration by the patient under the direct supervision of a healthcare professional, using 2 devices (for a 56 mg dose) or 3 devices (for an 84 mg dose), with a 5-minute rest between use of each device to allow medication to be absorbed.¹
• The nasal spray device delivers a total of 28 mg of SPRAVATO. To prevent loss of medication, do not prime the device before use.¹
• Please refer to local labeling for instructions on appropriate administration and use of the nasal spray device.
• Blood Pressure Assessment Pre-dose: Blood pressure should be assessed prior to dosing SPRAVATO. In patients whose BP is elevated prior to administration (as a general guide: >140/90 mmHg), a decision to delay SPRAVATO therapy should account for the balance of benefit and risk for the individual based on clinical judgment. SPRAVATO is contraindicated in patients for whom an increase in BP or intracranial pressure poses a serious risk.¹ See Administration Instructions and Considerations.
• In studies in patients with major depressive disorder (MDD) with active suicidal ideation and intent (ASPIRE-I and ASPIRE-II), SPRAVATO was administered in conjunction with standard of care (SOC).^2,3
  • SOC included initial psychiatric hospitalization and newly initiated or optimized oral AD(s), consisting of AD monotherapy or AD plus augmentation therapy (second AD, atypical antipsychotic, or a mood stabilizer).
• Dosing:
  • Treatment-Resistant Depression (TRD) Studies – The recommended dose of SPRAVATO during the first 4 weeks is 56 mg or 84 mg twice per week in adults. Dosage adjustments should be made based on efficacy and tolerability.⁴See Figure: Recommended Dosage for SPRAVATO Nasal Spray in Adults with TRD.
  • ASPIRE-I and ASPIRE-II Studies – SPRAVATO was studied at 84 mg twice weekly for 4 weeks.^2,3 After Day 1, a single dose reduction to 56 mg was permitted for intolerance and continued thereafter. See SPRAVATO Dosing and ASPIRE-I and ASPIRE-II.
• Post-dose Observation/Monitoring: SPRAVATO causes increases in systolic and/or diastolic blood pressure (BP) at all recommended doses. Increases in BP peak approximately 40 minutes after the start of SPRAVATO administration (i.e., from the time first spray of first device) and last approximately 4 hours. Measure BP around 40 minutes post dose and subsequently as clinically warranted until values decline.¹
  • Before SPRAVATO administration, instruct patients not to engage in potentially hazardous activities, such as driving a motor vehicle or operating machinery, until the next day after a restful sleep.¹
  • SPRAVATO can cause other adverse effects, including sedation, dissociation, and respiratory depression so patients should be monitored by a healthcare professional until they are clinically stable to leave.¹
• Dose Distribution in TRD Studies: In a short-term, randomized, flexible-dose study in adults <65 years (TRANSFORM-2), 66.7% received SPRAVATO 84 mg as the final dose.⁵ In the long-term randomized withdrawal study (SUSTAIN-1),⁶ of the patients randomized to SPRAVATO, 39.5% received the 56 mg dose and 60.5% received the 84 mg dose.⁷ See CLINICAL STUDIES.
• Dose Frequency in TRD Studies: Dosing frequency in the phase 3 program was twice weekly during the 4 week induction phase, decreasing to weekly or every other week with longer term treatment based on efficacy (in SUSTAIN-1 and SUSTAIN-2).^5,6,8-10 See CLINICAL STUDIES.

PRODUCT LABELING

Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored for at least 2 hours (including pulse oximetry for respiratory depression) at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.¹¹

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.¹¹

Dosing in Patients with TRD

SPRAVATO should be self-administered by the patient as monotherapy or in conjunction with an oral AD.  A treatment session consists of nasal administration of SPRAVATO and post-administration observation under the supervision of a healthcare provider.¹¹See Figure: Recommended Dosage for SPRAVATO Nasal Spray in Adults with TRD.

Dosing in Patients with MDD and Active Suicidal Ideation with Intent

Administer SPRAVATO in conjunction with an oral AD.

The recommended dosage of SPRAVATO for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior is 84 mg twice per week for 4 weeks. Dosage may be reduced to 56 mg twice per week based on tolerability. After 4 weeks of treatment with SPRAVATO, evidence of therapeutic benefit should be evaluated to determine need for continued treatment.¹¹ The use of SPRAVATO, in conjunction with an oral antidepressant, beyond 4 weeks has not been systematically evaluated in this patient population. The intent was to provide rapid antidepressant efficacy during the interval needed for additional comprehensive therapeutic measures to be put in place and to reach full effect.

Administration Instructions and Considerations

Do not administer SPRAVATO if an increase in BP or intracranial pressure poses a serious risk.¹

If baseline BP is elevated (e.g., >140 mmHg systolic, >90 mmHg diastolic), a decision to delay SPRAVATO therapy should take into account the balance of benefit and risk in individual patients.¹

The nasal spray device delivers a total of 28 mg of SPRAVATO in 2 sprays (one spray per nostril). To prevent loss of medication, the device should not be primed before use. SPRAVATO nasal spray is intended for administration by the patient under the supervision of a healthcare professional, using 2 devices (for a 56 mg dose) or 3 devices (for an 84 mg dose), with a 5-minute rest between use of each device to allow medication to be absorbed.¹

Since some patients may experience nausea and vomiting after administration of SPRAVATO, patients should be advised to avoid food for at least 2 hours before administration and not to drink liquids at least 30 minutes prior to administration.¹

Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should administer these medications at least 1 hour before SPRAVATO.¹

Post-administration observation  

Due to the risk of post-administration adverse effects, including sedation, dissociation, respiratory depression, increased blood pressure, and cognitive/motor impairment, a healthcare provider should observe the patient during each treatment session until the patient is safe to leave.^12,13 Before SPRAVATO administration, instruct patients not to engage in potentially hazardous activities, such as driving a motor vehicle or operating machinery, until the next day after a restful sleep.¹

USE IN Elderly (65 years of age and older)

In a phase 3, randomized, double-blind, multicenter study⁸ in elderly patients (≥65 years) with TRD, SPRAVATO was initiated at 28 mg twice-weekly and could be titrated to 56 mg or 84 mg administered twiceweekly. At the endpoint, the percentage of patients receiving SPRAVATO 28 mg, 56 mg, and 84 mg at day 25 were 9.7%, 25.8%, and 64.5%, respectively.¹⁴ At the end of four weeks, there was no statistically significant difference between groups on the primary efficacy endpoint of change from baseline to Week 4 on the Montgomery-Åsberg Depression Rating Scale (MADRS).⁸

Hepatic impairment

The mean ESK AUC and t_1/2 values were higher in patients with moderate hepatic impairment compared to those with normal hepatic function. SPRAVATO-treated patients with moderate hepatic impairment may need to be monitored for adverse reactions for a longer period of time.¹

SPRAVATO has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use in this population is not recommended.¹

CLINICAL STUDIES

Treatment-Resistant Depression

Rationale for Initiating a New Antidepressant Concomitantly With SPRAVATO

In the phase 3 program in TRD, SPRAVATO was studied in patients who had nonresponse (i.e., ≤25% improvement since initiation) to 2 or more ADs of adequate dose and duration in the current depressive episode. ^5,6,8-10 This is in contrast to studies evaluating adjunctive therapy in patients who have experienced a partial response (>25% to <50% improvement) to their current AD therapy.

This design is aligned with the recommendations of the European Medicines Agency who issued a guideline on clinical investigation of medicinal products in the treatment of depression, stating that patients with TRD and nonresponse to AD therapy are not eligible for augmentation therapy and should be switched to an alternative AD treatment.¹⁵

Dosing Schedule in Phase 3 Studies

During the 4-week induction period of SPRAVATO phase 3 studies, SPRAVATO was dosed twice weekly.^5,6,8-10 Dosing on consecutive days was not studied during the SPRAVATO phase 3 studies and investigators were advised not to dose on consecutive days.¹⁶ However, the time to reach maximum ESK plasma concentration is 20 to 40 minutes after the last nasal spray of a treatment session and the mean terminal half-life (t_1/2) of ESK is relatively short (7 to 12 hours), therefore although not optimal, the pharmacokinetic profile of the product suggests that there are no significant concerns with consecutive day dosing, if needed.

In the longer-term studies,^6,10 during weeks 5-8, treatment sessions were weekly. From week 9 onward, SPRAVATO was administered either weekly or every other week depending on the MADRS score (re-evaluated every 4 weeks) with the goal to maintain the patient on the lowest dosing frequency to maintain response/remission.

SPRAVATO Dose Distribution and Dosing Frequency in TRANSFORM-2

Of 99 patients from the short-term, randomized, flexible-dose trial, 32% (n=32) of the patients received SPRAVATO 56 mg and 67% (n=66) received SPRAVATO 84 mg as the final dose (all patients dosed twice weekly for 4 weeks).⁵

SPRAVATO Dose Distribution and Dosing Frequency in SUSTAIN-1 STUDY (Maintenance Phase)

Of patients randomized to SPRAVATO, 39.5% received the 56 mg dose and 60.5% received the 84 mg dose.⁷

Of patients who were stable remitters, 68.9% (62/90) received every-other-week dosing for the majority of time during the maintenance phase while 23.3% (21/90) received weekly dosing.^6,17

Of patients who were stable responders, 33.9% (21/62) received every-other-week-dosing while 54.8% (34/62) received weekly dosing the majority of time during the maintenance phase.^6,17

SPRAVATO Dose Distribution and Dosing Frequency in SUSTAIN-2 STUDY

Of 603 patients in the optimization/maintenance phase (weeks 5-52), 24% were dosed weekly, 38.1% were dosed every-other-week, and 37.8% had dosing schedules changed back and forth from weekly to every other week more than once. The final SPRAVATO dose was 56 mg in 45.6%, 84 mg in 50.2%, and 28 mg in 4% of patients.¹⁰

ASPIRE-I and ASPIRE-II

Dosing in ASPIRE-I and ASPIRE-II STUDIES (in Patients with MDD and Active Suicidal ideation and Intent)

Patients randomized to SPRAVATO received 84 mg twice weekly for 4 weeks plus SOC (monotherapy or AD plus augmentation therapy [second AD, atypical antipsychotic, or a mood stabilizer]). The SPRAVATO dose could have been reduced at any time after the first dose to 56 mg to improve tolerability. During the double-blind treatment phase of ASPIRE-I and ASPIRE-II, 24/113 (21.2%) and 21/114 (18.4%) patients treated with SPRAVATO plus SOC received less than 84 mg of SPRAVATO on at least 1 dosing day, respectively.^18,19

Dosing Rationale in ASPIRE-I and ASPIRE-II STUDIES

In both studies, no further dose adjustment was allowed during the double-blind treatment phase. Unlike the SPRAVATO clinical studies in patients with TRD, where a titration in dose was implemented to improve tolerability, 84 mg was used as the starting dose in order to optimize treatment response given that patients were presenting with active suicidal ideation and intent. SPRAVATO was administered for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) to provide rapid antidepressant efficacy during the interval needed for additional comprehensive therapeutic measures to be put in place and to reach full effect. The starting dose of SPRAVATO in these studies was 84 mg, without a dose titration, in order to optimize treatment response early on given that patients were presenting with active suicidal ideation and intent.^20,21

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 14 May 2024.