Safety

Safety and Tolerability

Demonstrated safety profile1

ADVERSE REACTIONS IN ≥2% OF PATIENTS TREATED WITH SPRAVATO™ PLUS ORAL AD IN THE SHORT-TERM STUDIES*
Adverse reaction n (% of population)     Adverse Reaction n (% of population)
  SPRAVATO™
(N=346)
Placebo
(N=222)
  SPRAVATO™
(N=346)
Placebo
(N=222)
Dissociation 142 (41%) 21 (9%) Nasal discomfort 23 (7%) 11 (5%)
Dizziness 101 (29%) 17 (8%) Throat irritation 23 (7%) 9 (4%)
Nausea 98 (28%) 19 (9%) Feeling drunk 19 (5%) 1 (0.5%)
Sedation 79 (23%) 21 (9%) Dry mouth 19 (5%) 7 (3%)
Vertigo 78 (23%) 6 (3%) Hyperhidrosis 14 (4%) 5 (2%)
Headache 70 (20%) 38 (17%) Euphoric mood 15 (4%) 2 (1%)
Dysgeusia 66 (19%) 30 (14%) Dysarthria 15 (4%) 0 (0%)
Hypoesthesia 63 (18%) 5 (2%) Tremor 12 (3%) 2 (1%)
Anxiety 45 (13%) 14 (6%) Oropharyngeal pain 9 (3%) 5 (2%)
Lethargy 37 (11%) 12 (5%) Mental impairment 11 (3%) 2 (1%)
Blood pressure increased 36 (10%) 6 (3%) Constipation 11 (3%) 3 (1%)
Vomiting 32 (9%) 4 (2%) Pollakiuria 11 (3%) 1 (0.5%)
Insomnia 29 (8%) 16 (7%) Feeling abnormal 12 (3%) 0 (0%)
Diarrhea 23 (7%) 13 (6%) Tachycardia 6 (2%) 1 (0.5%)

Discontinuation rates due to adverse reactions were <5% across short- and long-term clinical studies1

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

Safety information1

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 Scale (MOAA/s).

Adverse events of sedation were reported in approximately 23% of patients treated with SPRAVATO™ at any dose (N=346)

Based on the MOAA/s, 49% to 61% of patients treated with SPRAVATO™ developed sedation

0.3% of patients treated with SPRAVATO™ experienced loss of consciousness

Because of the possibility of delayed or prolonged sedation, patients must be monitored by a healthcare professional for at least 2 hours following 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

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

Adverse events of dissociation were reported in approximately 41% of patients treated with SPRAVATO™ at any dose (N=346)

Based on the CADSS, 61% to 75% of patients treated with SPRAVATO™ developed dissociative or perceptual changes

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

Because of the risks of dissociation, patients must be monitored by a healthcare professional 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 potential dissociative effects, carefully assess patients with psychosis before administering SPRAVATO™; treatment should be initiated only if the benefit outweighs the risk

WHAT IS DISSOCIATION?

The most common psychological effects of SPRAVATO™ 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.

Based on the CADSS.

ABUSE AND 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

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

Physical dependence has been reported with prolonged off-label use of ketamine. 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

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

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

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

SPRAVATO™ caused 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

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

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

SPRAVATO™ REMS goals

Discontinuation rates due to adverse reactions were <5% across short- and long-term clinical trials

§Based on data from Study 2 maintenance phase.

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%).1

For additional information, please see full Prescribing Information, including Boxed WARNINGS.

References

1.SPRAVATO™ [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. March 2019.