Indications:
- Treatment-resistant depression (TRD) in adults.
- Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.
Limitations of Use:
- The effectiveness of SPRAVATO® in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use of SPRAVATO® does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO®.
- SPRAVATO® is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO® as an anesthetic agent have not been established.
Important Safety Information
- Risk for sedation, dissociation, and respiratory depression after administration. Monitor patients for at least two hours after administration (5.1, 5.2, 5.3).
- Potential for abuse and misuse. Consider the risks and benefits of using SPRAVATO® prior to use in patients at higher risk of abuse. Monitor for signs and symptoms of abuse and misuse (5.4).
- SPRAVATO® is only available through a restricted program called the SPRAVATO® REMS (5.5).
- Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. SPRAVATO® is not approved for use in pediatric patients (5.6).
Contraindications
- 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.
Warnings and precautions
SPRAVATO® may cause sedation or loss of consciousness. In some cases, patients may display diminished or less apparent breathing. 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).
The most common psychological effects of SPRAVATO® were dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization (61% to 84% of SPRAVATO®-treated patients developed dissociative or perceptual changes). Given its potential to induce 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.
In postmarketing experience, respiratory depression was observed with the use of SPRAVATO®. In addition, there were rare reports of respiratory arrest.
Because of the risks of respiratory depression, patients must be monitored for changes in respiratory status by a healthcare provider for at least 2 hours (including pulse oximetry) at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.
- 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 (e.g., 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.
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.
SPRAVATO® causes increases in systolic and/or diastolic blood pressure (BP) at all recommended doses. Increases in BP peak approximately 40 minutes after SPRAVATO® administration and last approximately 4 hours.
Approximately 8% to 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 (e.g., 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 (e.g., chest pain, shortness of breath) or hypertensive encephalopathy (e.g., 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 (e.g., amphetamines, methylphenidate, modafinil, armodafinil) 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.
Short-Term Cognitive Impairment: In a study in healthy volunteers, a single dose of SPRAVATO® caused cognitive performance decline 40 minutes post-dose. Compared to placebo-treated subjects, SPRAVATO®-treated subjects required a greater effort to complete the cognitive tests at 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 Impairment: Long-term cognitive and memory impairment have been reported with repeated 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.
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.
Pregnancy, Embryo-fetal toxicity, and lactation
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. Advise women of reproductive potential to consider pregnancy planning and prevention.
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.
Select use in specific populations
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.
Adverse reactions
The most common adverse reactions with SPRAVATO® plus oral antidepressant (incidence ≥5% and at least twice that of placebo nasal spray plus oral antidepressant) were:
TRD: dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk.
Treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior: dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo.
Please see full Prescribing Information, including Boxed WARNINGS, and Medication Guide for SPRAVATO®.
