Safety and tolerability
Overall consistent safety across indications1
Adverse reactions in ≥2% of patients treated with SPRAVATO® plus oral AD in the short-term TRD studies*
Adverse Reactions in ≥2% of patients with MDSI treated with SPRAVATO® plus oral AD*
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.
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?
Healthcare setting certification
All healthcare settings must be certified in the REMS in order to receive, dispense, and/or treat patients with SPRAVATO®.
All pharmacies must be certified in the REMS in order to receive and dispense SPRAVATO®.
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 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 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.
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
• 0.3% to 0.4% of SPRAVATO®-treated patients experienced loss of consciousness across indications‡
• 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 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
• 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
• Given its dissociative effects, carefully assess patients with psychosis before administering SPRAVATO®; treatment should be initiated only if the benefit outweighs the risk
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
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.
1. SPRAVATO® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. July 2020.