Data as of November 2022. Source: IQVIA projected data and Janssen data on file.
TRD=treatment-resistant depression in adults (for patients with MDD who have had an inadequate response to 2 or more oral ADs).
TRD Study 1 (Short-term)
AD=antidepressant.
LS=least squares.
MADRS=Montgomery-Åsberg Depression Rating Scale.
TRD Study 1 (Short-term) study design2,3
Evaluated in a randomized, placebo-controlled, double-blind, short-term (4-week) study in adults with TRD; all patients in the trial received a new oral AD. Primary endpoint was change from baseline in the MADRS total score at 4 weeks.2,3
Demonstrated superior improvement in depression symptoms at Week 4 for adults with TRD2,3
Other Secondary Descriptive Endpoints
Flexible Dosing
Oral Antidepressant
Demographics and Baseline Characteristics
SSRI=selective serotonin reuptake inhibitor.
SNRI=serotonin and norepinephrine reuptake inhibitor.
Key secondary efficacy results3,4
– The difference was not statistically significant
*Response was defined as ≥ 50% improvement in MADRS total score by Day 2 that continued through to the end of the double-blind treatment phase, with 1 excursion allowed.
Given the lack of statistical significance on the first secondary endpoint, analyses of the other 2 key secondary endpoints could not be formally evaluated.†
†The 3 key secondary endpoints were analyzed sequentially and were considered significant at the 2-sided, 0.05 level only if the individual and previous endpoints in the hierarchy, including the primary endpoint, were significant.
AD=antidepressant.
MADRS=Montgomery-Åsberg Depression Rating Scale.
PHQ-9=Patient Health Questionnaire-9 (used specifically for depression).
SDS=Sheehan Disability Scale.
Secondary descriptive endpoints:
TRD Study 1 (Short-term)
SPRAVATO® plus oral antidepressant offers your patients a consistent safety profile with a minimal risk for sexual dysfunction compared to placebo + oral antidepressant2,5
TRD=treatment-resistant depression in adults (for patients with MDD who have had an inadequate response to 2 or more oral ADs).
*The following terms were combined:
Dissociation includes: delusional perception; depersonalization/derealization disorder; derealization; diplopia; dissociation; dysesthesia; feeling cold; feeling hot; feeling of body temperature change; hallucination; hallucination, auditory; hallucination, visual; hyperacusis; illusion; ocular discomfort; oral dysesthesia; paresthesia; paresthesia oral; pharyngeal paresthesia; photophobia; time perception altered; tinnitus; vision blurred; visual impairment
Dizziness includes: dizziness; dizziness exertional; dizziness postural; procedural dizziness
Sedation includes: altered state of consciousness; hypersomnia; sedation; somnolence
Vertigo includes: vertigo; vertigo positional
Hypoesthesia includes: hypoesthesia; hypoesthesia oral, hypoesthesia teeth, pharyngeal hypoesthesia
Anxiety includes: agitation; anticipatory anxiety; anxiety; fear; feeling jittery; irritability; nervousness; panic attack; tension
Lethargy includes: fatigue; lethargy
Blood pressure increased includes: blood pressure diastolic increased; blood pressure increased; blood pressure systolic increased; hypertension
Headache includes: headache; sinus headache
Dysgeusia includes: dysgeusia; hypogeusia
Nasal discomfort includes: nasal crusting; nasal discomfort; nasal dryness; nasal pruritus
Dysarthria includes: dysarthria; slow speech; speech disorder
Tachycardia includes: extrasystoles; heart rate increased; tachycardia
AD=antidepressant.
TEAEs=treatment-emergent adverse effects.
Across all Phase 3 studies, adverse reactions leading to SPRAVATO® discontinuation in more than 2 patients included anxiety (1.2%), depression (0.9%), blood pressure increased (0.6%), dizziness (0.6%), suicidal ideation (0.5%), dissociation (0.4%), nausea (0.4%), vomiting (0.4%), headache (0.3%), muscular weakness (0.3%), vertigo (0.2%), hypertension (0.2%), panic attack (0.2%), and sedation (0.2%).2
For additional information, please see full Prescribing Information, including Boxed WARNINGS.
*Two short-term TRD studies in adults <65 years.
†An ongoing study of which the proportion of patients with greater duration of exposure (ie, ≥36 months) is expected to increase with time and does not currently reflect discontinuations related to adverse reactions.
OP/M=optimization/maintenance.
SPRAVATO® is administered at certified treatment centers.
Contraindications
SPRAVATO® is contraindicated in patients with:
Sedation
In clinical trials, 48% to 61% of SPRAVATO®-treated patients developed sedation and 0.3% to 0.4% of SPRAVATO®-treated patients experienced loss of consciousness.*
Because of the possibility of delayed or prolonged sedation, patients must be monitored by a healthcare provider 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.
Closely monitor for sedation with concomitant use of SPRAVATO® with CNS depressants (e.g., benzodiazepines, opioids, alcohol).
*Based on the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scale.
Dissociation
What is dissociation?†
Dissociation includes the most common psychological effects of SPRAVATO®, which have been dissociative/perceptual changes (including distortion of time and space, and illusions), derealization, and depersonalization. Patients may describe these symptoms as feeling disconnected from themselves, their thoughts and feelings, space and time.
Dissociation was reported in 2 ways in the clinical studies: through adverse event reports, and by using the Clinician-Administered Dissociative States Scale (CADSS).
In clinical trials, dissociation was reported as transient and occurred on the day of dosing.
Given its dissociative effects, carefully assess patients with psychosis before administering SPRAVATO®; treatment should be initiated only if the benefit outweighs the risk.
Because of the risks of dissociation, patients must be monitored by a healthcare provider 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.
†Based on the CADSS.
Abuse and Misuse
REMS
SPRAVATO® Risk Evaluation and Mitigation Strategy (REMS): SPRAVATO® is available only through a restricted program called the SPRAVATO® REMS because of the risks of serious adverse outcomes from sedation, dissociation, and abuse and misuse.
Important requirements of the SPRAVATO® REMS include the following:
Further information, including a list of certified pharmacies, is available at www.SPRAVATOrems.com or 1-855-382-6022.
Suicidal Thoughts and Behaviors in Young Adults
In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included adult and pediatric patients, the incidence of suicidal thoughts and behaviors in patients age 24 years and younger was greater than in placebo-treated patients. SPRAVATO® is not approved in pediatric (<18 years of age) patients.
There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.
Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing SPRAVATO® and/or the concomitant oral antidepressant, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
Blood Pressure
SPRAVATO® causes increases in systolic and/or diastolic blood pressure (BP), which peak at approximately 40 minutes after administration and last approximately 4 hours.
Approximately 8%-19% of SPRAVATO®-treated patients experienced an increase of more than 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A substantial increase in blood pressure could occur after any dose administered even if smaller blood pressure effects were observed with previous administrations. SPRAVATO® is contraindicated in patients for whom an increase in BP or intracranial pressure poses a serious risk (eg, aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage). Before prescribing SPRAVATO®, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of SPRAVATO® outweigh its risk.
Assess BP prior to administration of SPRAVATO®. In patients whose BP is elevated prior to SPRAVATO® administration (as a general guide: >140/90 mmHg), a decision to delay SPRAVATO® therapy should take into account the balance of benefit and risk in individual patients.
BP should be monitored for at least 2 hours after SPRAVATO® administration. Measure blood pressure around 40 minutes post-dose and subsequently as clinically warranted until values decline. If BP remains high, promptly seek assistance from practitioners experienced in BP management. Refer patients experiencing symptoms of a hypertensive crisis (eg, chest pain, shortness of breath) or hypertensive encephalopathy (eg, sudden severe headache, visual disturbances, seizures, diminished consciousness, or focal neurological deficits) immediately for emergency care.
Closely monitor blood pressure with concomitant use of SPRAVATO® with psychostimulants or monoamine oxidase inhibitors (MAOIs).
In patients with a history of hypertensive encephalopathy, more intensive monitoring, including more frequent blood pressure and symptom assessment, is warranted because these patients are at increased risk for developing encephalopathy with even small increases in blood pressure.
Cognitive Impairment
In a study in healthy volunteers, a single dose of SPRAVATO® caused cognitive performance decline 40 minutes post-dose. Cognitive performance and mental effort were comparable between SPRAVATO® and placebo at 2 hours post-dose. Sleepiness was comparable after 4 hours post-dose.
Long-term cognitive and memory impairment have been reported with repeated off-label ketamine misuse or abuse.
No adverse effects of SPRAVATO® nasal spray on cognitive functioning were observed in a 1-year open-label safety study; however, the long-term cognitive effects of SPRAVATO® have not been evaluated beyond 1 year.
Impaired Ability to Drive and Operate Heavy Machinery
Before SPRAVATO® administration, instruct patients not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery, until the next day following a restful sleep. Patients will need to arrange transportation home following treatment with SPRAVATO®.
Ulcerative or Interstitial Cystitis
Cases of ulcerative or interstitial cystitis have been reported in individuals with long‑term off-label use or misuse/abuse of ketamine. In clinical studies with SPRAVATO® nasal spray, there was a higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in SPRAVATO®-treated patients than in placebo-treated patients. No cases of esketamine‑related interstitial cystitis were observed in any of the studies, which involved treatment for up to a year.
Monitor for urinary tract and bladder symptoms during the course of treatment with SPRAVATO® and refer to an appropriate healthcare provider as clinically warranted.
Use in Specific Populations
Pregnancy: SPRAVATO® is not recommended during pregnancy. SPRAVATO® may cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to an infant exposed to SPRAVATO® in utero. There are risks to the mother associated with untreated depression in pregnancy. If a woman becomes pregnant while being treated with SPRAVATO®, treatment with SPRAVATO® should be discontinued and the patient should be counseled about the potential risk to the fetus.
Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including SPRAVATO®, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1‑844‑405‑6185 or online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.
Lactation: SPRAVATO® is present in human milk. Because of the potential for neurotoxicity, advise patients that breastfeeding is not recommended during treatment with SPRAVATO®.
Females and Males of Reproductive Potential: SPRAVATO® may cause embryo-fetal harm when administered to a pregnant woman. Consider pregnancy planning and prevention for females of reproductive potential during treatment with SPRAVATO®.
Pediatric Use: The safety and effectiveness of SPRAVATO® in pediatric patients have not been established.
Geriatric Use: Of the total number of patients in Phase 3 clinical studies exposed to SPRAVATO®, 12% were 65 years of age and older, and 2% were 75 years of age and older. No overall differences in the safety profile were observed between patients 65 years of age and older and patients younger than 65 years of age.
The mean esketamine Cmax and AUC values were higher in elderly patients compared with younger adult patients.
The efficacy of SPRAVATO® for the treatment of TRD in geriatric patients was evaluated in a 4-week, randomized, double-blind study comparing flexibly-dosed intranasal SPRAVATO® plus a newly initiated oral antidepressant compared to intranasal placebo plus a newly initiated oral antidepressant in patients ≥65 years of age. 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).
Hepatic Impairment: SPRAVATO®-treated patients with moderate hepatic impairment may need to be monitored for adverse reactions for a longer period of time. SPRAVATO® has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use in this population is not recommended.
Drug Interactions
CNS depressants: closely monitor for sedation with concomitant use of SPRAVATO® with CNS depressants, including benzodiazepines, opioids, and alcohol.
Psychostimulants and monoamine oxidase inhibitors (MAOIs): closely monitor blood pressure with concomitant use of SPRAVATO® with psychostimulants (including amphetamines, methylphenidate, modafinil, and armodafinil) and MAOIs.
For additional information, please see full Prescribing Information.
Data on File. RF-247473. Janssen Pharmaceuticals, Inc.
SPRAVATO® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. July 2020.
Popova V, Daly E, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438. doi:10.1176/appi.ajp.2019.19020172
Popova V, Daly E, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6)(Suppl.). https://ajp.psychiatryonline.org/doi/suppl/10.1176/appi.ajp.2019.19020172/suppl_file/appi.ajp.2019.19020172.ds001.pdf
Data on File. RF-210003. Janssen Pharmaceuticals, Inc.
Data on File. RF-240359. Janssen Pharmaceuticals, Inc.
Zaki N, Fu DJ, Daly E, et al. Long-term safety of esketamine nasal spray in adults with treatment-resistant depression: a subgroup analysis of the ongoing SUSTAIN-3 study. Poster presented at: Neuroscience Education Institute (NEI) Congress; November 4-7, 2021; Colorado Springs, CO.
During the combined Induction (IND) and Optimization/Maintenance (OP/M) phases, 93.5% of patients experienced ≥1 TEAEs2
IND Phase=56 mg or 84 mg—twice weekly.
OP/M Phase=56 mg or 84 mg—flexibly dosed.*
*Based on CGI-S and tolerability.
Most TEAEs (96.7%) occurred and resolved on same day of dosing2
The majority of dissociation (93.2%), blood pressure increase (86.1%), and sedation (87.4%) resolved in less than 2 hours3
Additional 4-year safety results2
TRD=treatment-resistant depression in adults (for patients with MDD who have had an inadequate response to 2 or more oral ADs).
In an ongoing, long-term, open-label safety study, MADRS scores were consistent through interim analysis at 4 years2,4
4-year safety trial was composed of 2 phases: a 4-week IND phase and a variable OP/M phase.2,4
BL=baseline.
LOCF=last observation carried forward.
MADRS=Montgomery-Åsberg Depression Rating Scale.
PHQ-9=Patient Health Questionnaire-9 (used specifically for depression).
In an open-label, long-term safety study, SPRAVATO®-treated patients showed consistent PHQ-9 scores over 4 years4
Mean change from baseline in the PHQ-9 total scores (LOCF) showed an improvement over the 4-week IND phase.
This improvement appeared to be maintained with flexibly dosed SPRAVATO® over the OP/M phase.
BL=baseline.
LOCF=last observation carried forward.
PHQ-9=Patient Health Questionnaire-9 (used specifically for depression).
TRD long-term safety extension study2
The following data is drawn from an ongoing, Phase 3, open-label, long-term safety extension study in adults with treatment-resistant depression (TRD).
Limitations:
Study Design2
A subgroup analysis was conducted on a cohort of 1006 patients who met criteria consistent with the on-label population.
Primary Endpoint: Number of participants with treatment-emergent adverse effects (TEAEs)
IND Phase=56 mg or 84 mg - twice weekly.
OP/M Phase=56 mg or 84 mg - flexibly dosed.*
*Based on CGI-S and tolerability.
CGI-S=Clinical Global Impressions-Severity scale.
AD=antidepressant.
*Relapse was defined as a MADRS total score of ≥22 for 2 consecutive weeks and/or hospitalization for worsening depression, or any other clinically relevant event determined per clinical judgment to be suggestive of a relapse of depressive illness.
AD=antidepressant.
MADRS=Montgomery-Åsberg Depression Rating Scale.
TRD Study 2 (Long-term) study design5,6
Evaluated in a long-term, randomized, double-blind, parallel-group, variable duration study in adults who were known remitters and responders. Primary endpoint was time to relapse in patients in stable remission.5,6
Significantly delayed time to relapse in a long-term maintenance trial in adults with TRD with stable remission5,6
Enrollment
Demographics and Baseline Characteristics
SPRAVATO® is administered at certified treatment centers.
Data on File. RF-247473. Janssen Pharmaceuticals, Inc.
Zaki N, Fu DJ, Daly E, et al. Long-term safety of esketamine nasal spray in adults with treatment-resistant depression: a subgroup analysis of the ongoing SUSTAIN-3 study. Poster presented at: Neuroscience Education Institute (NEI) Congress; November 4-7, 2021; Colorado Springs, CO.
Data on File. RF-201855. Janssen Pharmaceuticals, Inc.
Zaki N, Fu DJ, Daly E, et al. Long-term efficacy of esketamine nasal spray in adults with treatment-resistant depression: a subgroup analysis of the ongoing SUSTAIN-3 study. Poster presented at: Neuroscience Education Institute (NEI) Congress; November 4-7, 2021; Colorado Springs, CO.
SPRAVATO® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. July 2020.
Daly E, Trivedi M, Janik A, et al. Efficacy of esketamine nasal spray plus an oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903. doi:10.1001/jamapsychiatry.2019.1189
The following data is drawn from an ongoing, Phase 3, open-label, long-term safety extension study in adults with treatment-resistant depression (TRD).
Limitations:
TRD long-term safety extension study2
Study Design2
A subgroup analysis was conducted on a cohort of 1006 patients who met criteria consistent with the on-label population.
MADRS=Montgomery-Åsberg Depression Rating Scale.
Primary endpoint: Number of participants with treatment-emergent adverse effects (TEAEs)
IND Phase=56 mg or 84 mg—twice weekly.
OP/M Phase=56 mg or 84 mg—flexibly dosed.*
*Based on CGI-S and tolerability.
CGI-S=Clinical Global Impressions-Severity scale.
AD=antidepressant.
