Esketamine Hydrochloride

FDA Drug Information • Also known as: Spravato

Brand Names: Spravato
Dosage Form: POWDER
Product Type: BULK INGREDIENT

⚠ Boxed Warning (Black Box)

WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. 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 prescribing SPRAVATO prior to using in patients at higher risk of abuse. Monitor patients 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 ) Sedation Patients are at risk for sedation after administration of SPRAVATO [see Warnings and Precautions (5.1) ]. Dissociation Patients are at risk for dissociative or perceptual changes after administration of SPRAVATO [see Warnings and Precautions (5.2) ]. Respiratory Depression Respiratory depression has been observed in postmarketing experience [see Warnings and Precautions (5.3) ] . Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored 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 [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Abuse and Misuse SPRAVATO has the potential to be abused and misused. Consider the risks and benefits of prescribing SPRAVATO prior to use in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse [see Warnings and Precautions (5.4) ] . Because of the risks of serious adverse outcomes resulting from sedation, dissociation, respiratory depression, abuse and misuse, SPRAVATO is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS [see Warnings and Precautions (5.5) ] . Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. SPRAVATO is not approved for use in pediatric patients [see Warnings and Precautions (5.6) ] .

Description

11 DESCRIPTION SPRAVATO ® contains esketamine hydrochloride, a non-competitive N -methyl- D -aspartate (NMDA) receptor antagonist. Esketamine is the S-enantiomer of racemic ketamine. The chemical name is (S) -2-(o-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride. Its molecular formula is C 13 H 16 ClNO.HCl and its molecular weight is 274.2. The structural formula is: Esketamine hydrochloride is a white or almost white crystalline powder that is freely soluble in water and in methanol, and soluble in ethanol. SPRAVATO nasal spray is intended for nasal administration. Esketamine hydrochloride is contained as a solution in a stoppered glass vial within the nasal spray device. Each device delivers two sprays with a total of 32.3 mg of esketamine hydrochloride (equivalent to 28 mg of esketamine) in 0.2 mL of a clear, colorless aqueous solution with a pH of 4.5. The inactive ingredients are citric acid monohydrate, edetate disodium, sodium hydroxide, and water for injection. Chemical Structure

What Is Esketamine Hydrochloride Used For?

1 INDICATIONS AND USAGE SPRAVATO is indicated for the treatment of: Treatment-resistant depression (TRD) in adults as monotherapy or in conjunction with an oral antidepressant Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior in conjunction with an oral antidepressant SPRAVATO is a non-competitive N -methyl D -aspartate (NMDA) receptor antagonist indicated for the treatment of: Treatment-resistant depression (TRD) in adults, as monotherapy or in conjunction with an oral antidepressant. ( 1 ) Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior in conjunction with an oral antidepressant. ( 1 ) 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. ( 1 ) SPRAVATO is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO as an anesthetic agent have not been established. ( 1 ) Limitations of Use The effectiveness of SPRAVATO in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated [see Clinical Studies (14.2) ] . 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.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Administer SPRAVATO intranasally under the supervision of a healthcare provider. ( 2.1 ) Assess blood pressure prior to and after administration. ( 2.1 ) TRD: Evidence of therapeutic benefit should be evaluated at the end of the 4-week induction phase to determine need for continued treatment. ( 2.2 ) Depressive symptoms in MDD with acute suicidal ideation or behavior : Evidence of therapeutic benefit should be evaluated after 4 weeks to determine need for continued treatment. Treatment beyond 4 weeks has not been systematically evaluated. ( 2.3 ) See Full Prescribing Information for recommended dosage. ( 2.2 , 2.3 ) See Full Prescribing Information for important administration instructions. ( 2.4 ) 2.1 Important Considerations Prior to Initiating and During Therapy SPRAVATO must be administered under the direct supervision of a healthcare provider. A treatment session consists of nasal administration of SPRAVATO and post-administration observation under supervision. Respiratory Status Assessment During Treatment Monitor patients for changes in respiratory status for at least 2 hours (including pulse oximetry) at each treatment session [see Warnings and Precautions (5.3) ] . Blood Pressure Assessment Before and After Treatment Assess blood pressure prior to dosing with SPRAVATO [see Warnings and Precautions (5.7) ] . If baseline blood pressure is elevated (e.g., >140 mmHg systolic, >90 mmHg diastolic), consider the risks of short term increases in blood pressure and benefit of SPRAVATO treatment [see Warnings and Precautions (5.7) ]. Do not administer SPRAVATO if an increase in blood pressure or intracranial pressure poses a serious risk [see Contraindications (4) ] . After dosing with SPRAVATO, reassess blood pressure at approximately 40 minutes (which corresponds with the C max ) and subsequently as clinically warranted. If blood pressure is decreasing and the patient appears clinically stable for at least two hours, the patient may be discharged at the end of the post-dose monitoring period; if not, continue to monitor [see Warnings and Precautions (5.7) ]. Food and Liquid Intake Recommendations Prior to Administration Because some patients may experience nausea and vomiting after administration of SPRAVATO [see Adverse Reactions (6.1) ], advise patients to avoid food for at least 2 hours before administration and to avoid drinking liquids at least 30 minutes prior to administration. Nasal Corticosteroid or Nasal Decongestant Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should administer these medications at least 1 hour before SPRAVATO [see Clinical Pharmacology (12.3) ]. 2.2 Treatment-Resistant Depression The recommended dosage of SPRAVATO for the treatment of TRD in adults as monotherapy or in conjunction with an oral antidepressant is shown in Table 1. Dosage adjustments should be made based on efficacy and tolerability. Evidence of therapeutic benefit should be evaluated at...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Sedation [see Warnings and Precautions (5.1) ] Dissociation [see Warnings and Precautions (5.2) ] Respiratory Depression [see Warnings and Precautions (5.3) ] Increase in Blood Pressure [see Warnings and Precautions (5.7) ] Cognitive Impairment [see Warnings and Precautions (5.8) ] Impaired Ability to Drive and Operate Machinery [see Warnings and Precautions (5.9) ] Ulcerative or Interstitial Cystitis [see Warnings and Precautions (5.10) ] Embryo-fetal Toxicity [see Warnings and Precautions (5.11) ] The most commonly observed adverse reactions (incidence ≥5% and at least twice that of placebo): TRD: dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, feeling drunk, and headache. ( 6 ) 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. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Treatment-Resistant Depression In Conjunction with an Oral Antidepressant SPRAVATO was evaluated for safety in 1709 adults diagnosed with treatment-resistant depression (TRD) [see Clinical Studies (14.1) ] from five Phase 3 studies (3 short-term and 2 long-term studies) and one Phase 2 dose-ranging study. Of all SPRAVATO-treated patients in the completed Phase 3 studies, 479 (30%) received at least 6 months of treatment, and 178 (11%) received at least 12 months of treatment. Adverse Reactions Leading to Discontinuation of Treatment In short-term studies in adults <65 years old (Study 1 pooled with another 4-week study), the proportion of patients who discontinued treatment because of an adverse reaction was 4.6% in patients who received SPRAVATO plus oral AD compared to 1.4% for patients who received placebo nasal spray plus oral AD. For adults ≥65 years old, the proportions were 5.6% and 3.1%, respectively. In Study 2, a long-term maintenance study, the discontinuation rates because of an adverse reaction were similar for patients receiving SPRAVATO plus oral AD and placebo nasal spray plus oral AD in the maintenance phase, at 2.6% and 2.1%, respectively. Across all Phase 3 studies, adverse reactions leading to SPRAVATO discontinuation in more than 2 patients were (in order of frequency): 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%). Most Common Adverse Reactions The most commonly observed adverse reactions in patients treated with SPRAVATO plus oral AD (incidence ≥5% and at least twice that of placebo nasal spray plus oral AD) were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk. Table 3 shows the incidence of adverse reactions that occurred in patients treated with SPRAVATO plus oral AD at any dose and greater than patients treated with placebo nasal spray plus oral AD. Table 3: Adverse Reactions Occurring in ≥2% of Adult TRD Patients Treated with SPRAVATO + Oral AD at Any Dose and at a Greater Rate than Patients Treated with Placebo Nasal Spray + Oral AD SPRAVATO + Oral AD (N=346) Placebo + Oral AD (N=222) Cardiac disorders Tachycardia The following terms were combined:...

Drug Interactions

7 DRUG INTERACTIONS 7.1 Central Nervous System Depressants Concomitant use with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation [see Warnings and Precautions (5.1) ] . Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants. 7.2 Psychostimulants Concomitant use with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) may increase blood pressure [see Warnings and Precautions (5.7) ] . Closely monitor blood pressure with concomitant use of SPRAVATO with psychostimulants. 7.3 Monoamine Oxidase Inhibitors (MAOIs) Concomitant use with monoamine oxidase inhibitors (MAOIs) may increase blood pressure [see Warnings and Precautions (5.7) ] . Closely monitor blood pressure with concomitant use of SPRAVATO with MAOIs.

Contraindications

4 CONTRAINDICATIONS SPRAVATO is contraindicated in patients with: Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation [see Warnings and Precautions (5.7) ] History of intracerebral hemorrhage [see Warnings and Precautions (5.7) ] Hypersensitivity to esketamine, ketamine, or any of the excipients. Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation. ( 4 ) Intracerebral hemorrhage. ( 4 ) Hypersensitivity to esketamine, ketamine, or any of the excipients. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy 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/ . Risk Summary SPRAVATO is not recommended during pregnancy. There are insufficient data on SPRAVATO use in pregnant women to draw conclusions about any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on published findings from pregnant animals treated with ketamine, the racemic mixture of arketamine and esketamine, SPRAVATO may cause fetal harm when administered to pregnant women (see Data ) . 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 (see Clinical Considerations ). If a woman becomes pregnant while being treated with SPRAVATO, treatment with esketamine should be discontinued and the patient should be counseled about the potential risk to the fetus. Published studies in pregnant primates demonstrate that the administration of drugs that block N -methyl- D -aspartate (NMDA) receptors during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans [see Use in Specific Populations (8.2) ] . In an embryo-fetal reproduction study in rabbits, skeletal malformations were noted at maternally toxic doses when ketamine was intranasally administered with a No Observed Adverse Effect Level (NOAEL) at estimated esketamine exposures 0.3 times the exposures at the maximum recommended human dose (MRHD) of...

Overdosage

10 OVERDOSAGE Management of Overdosage There is no specific antidote for esketamine overdose. In the case of overdose, the possibility of multiple drug involvement should be considered. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222 or www.poison.org).

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING SPRAVATO ® nasal spray is available as an aqueous solution of esketamine hydrochloride in a stoppered glass vial within a nasal spray device. Each nasal spray device delivers two sprays containing a total of 28 mg of esketamine (supplied as 32.3 mg of esketamine hydrochloride). SPRAVATO is available in the following presentations: 56 mg Dose Kit: Unit-dose carton containing two 28 mg nasal spray devices (56 mg total dose) (NDC 50458-028-02). 84 mg Dose Kit: Unit-dose carton containing three 28 mg nasal spray devices (84 mg total dose) (NDC 50458-028-03). Within each kit, each 28 mg device is individually packaged in a sealed blister (NDC 50458-028-00). Storage Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] . Disposal SPRAVATO nasal spray devices must be handled with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.