Safety

Safety and tolerability

Actor portrayal.

Overall consistent safety across indications1

Adverse reactions in ≥2% of patients treated with SPRAVATO® plus oral AD in the short-term TRD studies*

TRD Safety Chart

Adverse reactions in ≥2% of patients treated with SPRAVATO® plus oral AD in the short-term TRD studies*

MDSI Safety Chart

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.

*At any dose and at a greater rate than patients receiving placebo nasal spray and an oral antidepressant.

Based on the CADSS.

SPRAVATO® REMS1

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 www.SPRAVATOrems.com or call 1-855-382-6022 (8AM to 8PM ET).

The REMS updates summarized above will take effect by mid-September 2020.

For additional information, please see full Prescribing Information.

 

Safety 
information1

Actor portrayal.

SEDATION
sedation

Sedation was reported in 2 ways in the clinical studies: through adverse event reports and by using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) Scale.

Based on the MOAA/S Scale, 48% to 61% of patients treated with SPRAVATO® developed sedation across indications

consciousness

0.3% to 0.4% of SPRAVATO®-treated patients experienced loss of consciousness across indications

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

Based on the MOAA/S Scale.

DISSOCIATION
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

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

Dissociation1:

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

The severity of these symptoms tended to diminish over time with repeated treatments

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

DEPENDENCE
depedence

Physical dependence has been reported with prolonged off-label use of ketamine. In Study 1, there were no withdrawal symptoms captured up to 4 weeks after cessation of SPRAVATO® treatment. Monitor SPRAVATO®-treated patients for symptoms and signs of physical dependence upon discontinuation of the drug

EFFECT ON DRIVING
driving

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

Patients will require transportation from the treatment center after administration

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 to any of the excipients

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 for blood pressure with concomitant use of SPRAVATO® with psychostimulants (including amphetamines, methylphenidate, modafinil, and armodafinil) and MAOIs

BLOOD PRESSURE
blood-pressure

SPRAVATO® causes increases in systolic blood pressure (SBP) and/or diastolic blood pressure (DBP), which peak at approximately 40 minutes after administration and last approximately 4 hours:

40 minutes post dose, mean placebo-adjusted increases in SBP=7 to 9 mmHg and DBP=4 to 6 mmHg

If blood pressure is decreasing and the patient appears clinically stable for at least 2 hours, the patient may be discharged at the end of the post-dose monitoring period

Assess blood pressure prior to, and approximately 40 minutes after dosing with SPRAVATO® and subsequently as clinically warranted until values decline

Do not administer SPRAVATO® if an increase in blood pressure or intracranial pressure poses a serious risk

Before prescribing SPRAVATO®, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of SPRAVATO® outweigh its risks

PREGNANCY & LACTATION
pregnancy

SPRAVATO® is not recommended for women who are pregnant or may become pregnant, or in women who are breastfeeding. Women who become pregnant should stop taking SPRAVATO® and the patient should be counseled about the potential risk to the fetus

SPRAVATO® was not assessed in pregnant women. SPRAVATO® may cause fetal harm when administered to pregnant women

COGNITION
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

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 one-year open-label safety study; however, the long-term cognitive effects of SPRAVATO® have not been evaluated beyond one year

Discontinuation rates due to adverse events were <7% across short- and long-term clinical trials1

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%).1

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.

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Reference:

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