Safety

Safety and tolerability of SPRAVATO® (esketamine)

Actor portrayal.

TRD=treatment-resistant depression in adults.

MDSI=depressive symptoms in adults with MDD with acute suicidal ideation or behavior.

AE=adverse event.

TEAE=treatment-emergent adverse effect.

SPRAVATO® offers your patients a consistent safety profile with a minimal risk for weight gain and sexual dysfunction compared to placebo1-3

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Sexual dysfunction was not observed in SPRAVATO® trials at a rate greater than 2%

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No notable difference in mean body weight change compared to placebo plus oral AD from baseline in the short-term Phase 2 and 3 studies

TRD short-term most common adverse event percentage data table

*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.

At the 4-year analysis of the ongoing SUSTAIN-3 trial there were no new safety signals observed1,2

During the combined Induction (IND) and Optimization/Maintenance (OP/M) phases, 93.5% of patients experienced ≥1 TEAEs1

Treatment adverse event dosing icon

Most TEAEs (96.7%) occurred and resolved on same day of dosing1

Less than or equal to 2 hours icon

The majority of dissociation (93.2%), blood pressure increase (86.1%), and sedation (87.4%) resolved in less than 2 hours2

TRD long-term treatment-emergent adverse effect percentage data table

Additional 4-year safety results1

  • Three patients (0.7%) in the IND phase (N=436) and 139 patients (14.3%) in the OP/M phase (N=971) experienced ≥1 serious AE
  • Three deaths occurred: 1 in the IND phase and 2 in the OP/M phase (COVID-19, accidental polytrauma, suicide); none were related to ESK
  • A total of 60 (6.0%) patients experienced 1 or more TEAEs potentially related to suicidality (suicidal ideation, n=44; suicide attempt, n=11; suicidal behavior, n=3; complete suicide, n=1; depression suicidal, n=1)

SPRAVATO® (esketamine) showed overall consistent safety across indications1

Rates of AEs in MDSI clinical trials

MDSI Safety Table

*The following terms were combined:

Dissociation includes: depersonalization/derealization disorder; derealization; diplopia; dissociation; dysesthesia; feeling cold; feeling hot; hallucination; hallucination, auditory; hallucination, visual; hallucinations, mixed; hyperacusis; paresthesia; paresthesia oral; pharyngeal paresthesia; photophobia; time perception altered; tinnitus; vision blurred

Dizziness includes: dizziness; dizziness exertional; dizziness postural

Sedation includes: sedation; somnolence; stupor

Blood pressure increased includes: blood pressure diastolic increased; blood pressure increased; blood pressure systolic increased; hypertension

Hypoesthesia includes: hypoesthesia; hypoesthesia oral; intranasal hypoesthesia; pharyngeal hypoesthesia

Hyperhidrosis includes: cold sweat; hyperhidrosis

Dysgeusia includes: dysgeusia; hypogeusia

Anxiety includes: agitation; anxiety; anxiety disorder; fear; irritability; nervousness; panic attack; psychomotor hyperactivity; tension

Lethargy includes: fatigue; lethargy; psychomotor retardation

Tachycardia includes: heart rate increased; sinus tachycardia; tachycardia

Pollakiuria includes: micturition urgency; pollakiuria

AD=antidepressant.

What is Dissociation?*

Patients may describe these symptoms as feeling disconnected from themselves, their thoughts and feelings, space and time. The most common psychological effects of SPRAVATO® have been dissociative/perceptual changes (including distortion of time and space, and illusions), derealization, and depersonalization.

*Based on the CADSS.
CADSS=Clinician-Administered Dissociative States Scale.

SPRAVATO® REMS13

REMS goals

A Risk Evaluation and Mitigation Strategy (REMS) is a strategy to manage known or potential risks associated with a drug and is required by the U.S. Food and Drug Administration (FDA) to ensure that the benefits of the drug outweigh its risks

SPRAVATO® is available only through a restricted distribution program called the SPRAVATO® REMS because of the risks of serious adverse outcomes resulting from sedation and dissociation caused by SPRAVATO® administration, and abuse and misuse of SPRAVATO®. SPRAVATO® is intended for use only in a certified healthcare setting.

SPRAVATO® is intended for patient administration under the direct observation of a healthcare provider, and patients are required to be monitored by a healthcare provider for at least 2 hours. SPRAVATO® must never be dispensed directly to a patient for home use.

What are the REMS requirements?


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Healthcare setting certification

All healthcare settings must be certified in the REMS in order to receive, dispense, and/or treat patients with SPRAVATO®.

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Pharmacy certification

All pharmacies must be certified in the REMS in order to receive and dispense SPRAVATO®.

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Patient enrollment

Patients in an outpatient setting must be enrolled in the REMS with their prescriber in order to receive SPRAVATO® treatment.

Healthcare Settings Type*

All REMS-certified Inpatient and Outpatient Healthcare Settings must have a healthcare provider counsel patients on the safety risk of SPRAVATO® and monitor patients post-dose.

inpatient-healthcare

Inpatient healthcare settings

 Covers inpatient units, inpatient pharmacy, and emergency departments

 Before prescribing SPRAVATO® treatment, complete and submit the inpatient healthcare setting enrollment form

 Before starting SPRAVATO® treatment, inpatient settings are not required to enroll the patient in the SPRAVATO® REMS

 During SPRAVATO® treatment, inpatient settings do not require the patient monitoring form. Report all suspected adverse events to the SPRAVATO® REMS

outpatient-healthcare

Outpatient healthcare settings

 Covers outpatient medical offices and clinics

 Before prescribing SPRAVATO® treatment, complete and submit the outpatient healthcare setting enrollment form

 Before starting SPRAVATO® treatment, enroll the patient by completing and submitting the patient enrollment form to the SPRAVATO® REMS

 During SPRAVATO® treatment, submit the patient monitoring form and report all suspected adverse events to the SPRAVATO® REMS

*To get started, find more information on how to certify as a healthcare setting and/or pharmacy, and to view all REMS requirements and attestations by type of REMS stakeholder visit SPRAVATOrems.com or call 1-855-382-6022 (Monday – Friday, 8 AM to 8 PM ET).

For additional information, please see full Prescribing Information.

 

Safety 
considerations13

Actor portrayal.

CONTRAINDICATIONS
contraindications

SPRAVATO® is contraindicated in patients with:

  • Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation
  • History of intracerebral hemorrhage
  • Hypersensitivity to esketamine, ketamine, or any of the excipients
SEDATION
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.*

prolonged sedation

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.

consciousness

Closely monitor for sedation with concomitant use of SPRAVATO® with CNS depressants.

*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.

sedation

Dissociation was reported in 2 ways in the clinical studies: through adverse event reports, and by using the Clinician-Administered Dissociative States Scale (CADSS).

  • Based on the CADSS, 61% to 84% of patients treated with SPRAVATO® developed dissociative or perceptual changes across indications
dissociation

In clinical trials, dissociation was reported as transient and occurred on the day of dosing.

prolonged sedation

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.

dissociation

Given its dissociative effects, carefully assess patients with psychosis before administering SPRAVATO®; treatment should be initiated only if the benefit outweighs the risk.

Based on the CADSS.

ABUSE AND MISUSE
abuse-misuse

SPRAVATO® is a Schedule III controlled substance and may be subject to abuse and diversion. Assess each patient's risk for abuse or misuse prior to prescribing SPRAVATO® and monitor all patients receiving SPRAVATO® for the development of these behaviors or conditions, including drug-seeking behavior, while on therapy.

abuse-misuse

Individuals with a history of drug abuse or dependence are at greater risk; therefore, use careful consideration prior to treatment of individuals with a history of substance use disorder. Monitoring for signs of abuse is recommended.

REMS
SPRAVATO® 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:

  • Healthcare settings must be certified in the program and ensure that SPRAVATO® is:
    • Only dispensed and administered in healthcare settings
    • Patients treated in outpatient settings (eg, medical offices and clinics) must be enrolled in the program
    • Administered by patients under the direct observation of a healthcare provider and that patients are monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO®
  • Pharmacies must be certified in the REMS and must only dispense SPRAVATO® to healthcare settings that are certified in the program

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
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 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
cognition

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
driving

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
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.

DRUG INTERACTIONS
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.

USE IN SPECIFIC POPULATIONS
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.

For additional information, please see full Prescribing Information.

You can have the confidence that SPRAVATO® demonstrated low discontinuation rates:

Discontinuation rates
Discontinuation rates
Discontinuation Rates

For patients with TRD, adverse events leading to SPRAVATO® discontinuation in >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%).13

For patients with MDSI, adverse reactions leading to SPRAVATO® discontinuation in >1 patient included dissociation-related events (2.6%), blood pressure increased (0.9%), dizziness-related events (0.9%), nausea (0.9%), and sedation-related events (0.9%).

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.

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References:

1. SPRAVATO® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. July 2020.

2. Data on File. RF-210003. Janssen Pharmaceuticals, Inc.

3. Data on File. RF-210004. Janssen Pharmaceuticals, Inc.

4. 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.

1. 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.

2. Data on File. RF-201855. Janssen Pharmaceuticals, Inc.

3. SPRAVATO® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. July 2020.

1. SPRAVATO® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. July 2020.

2. 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.