Esketamine (Monograph)

Brand name: Spravato
Drug class: Antidepressants, Miscellaneous
- NMDA Receptor Antagonists
- N-Methyl-d-aspartate Receptor Antagonists
Chemical name: (2S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one
Molecular formula: C₁₃H₁₆ClNOC₁₃H₁₆ClNO•HCl
CAS number: 33643-46-8

Medically reviewed by Drugs.com on Oct 25, 2023. Written by ASHP.

Introduction

Antidepressant; N-methyl-d-aspartate (NMDA) receptor antagonist and S-enantiomer of racemic ketamine.

Uses for Esketamine

Treatment-resistant Depression

Used intranasally for treatment (in combination with an oral antidepressant) of treatment-resistant depression. Although there are various definitions of treatment-resistant depression, the condition is often defined as the failure of ≥2 trials of first-line antidepressants given in an adequate dosage for an adequate duration of therapy.

Intranasal esketamine substantially improved depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) within 24 hours of administration in a short-term clinical trial and prolonged time to relapse in a longer-term maintenance trial.

Other Uses

Esketamine is the S-enantiomer of racemic ketamine, which is an anesthetic agent. However, esketamine is not labeled for use as an anesthetic agent^{† [off-label]}; efficacy and safety not established.

Esketamine Dosage and Administration

General

Assessment of BP

• Because esketamine nasal spray can increase SBP and/or DBP, monitor BP prior to intranasal administration, approximately 40 minutes after administration (which corresponds to peak plasma concentrations), and as clinically indicated thereafter until BP values decline.

• If baseline BP is elevated (i.e., SBP >140 mm Hg or DBP >90 mm Hg), consider risks of short-term BP increases and benefit of esketamine treatment. Do not administer in patients in whom an increase in BP or intracranial pressure would constitute a serious hazard.

• If BP is decreasing and patient appears clinically stable for ≥2 hours, may discharge patient at the end of the post-dose monitoring period; if not, continue patient monitoring. (See Contraindications under Cautions and also see Increases in BP under Cautions.)

Pretreatment Oral Intake

• Nausea and vomiting may occur following intranasal administration; advise patients to avoid eating food for ≥2 hours and to avoid drinking liquids for ≥30 minutes prior to administration.

Posttreatment Activities

• Prior to administration, advise patients not to engage in potentially hazardous activities (e.g., driving a motor vehicle, operating machinery) until the next day after a restful sleep. (See Impaired Ability to Drive or Operate Machinery under Cautions and also see Advice to Patients.)

Concomitant Intranasal Therapy

• If use of an intranasal corticosteroid or intranasal decongestant is required on the same day as intranasal esketamine, administer ≥1 hour prior to esketamine.

Monitoring for Suicidality

• Monitor for possible worsening of depression or emergency of suicidality, especially at the beginning of therapy or during periods of dosage adjustments. (See Suicidality under Cautions.)

Post-administration Observation

• During and following administration of esketamine nasal spray at each treatment session, observe patient (i.e., for sedation, dissociation, and increased BP). Continue observation for ≥2 hours until the patient can safely leave the healthcare setting. (See Cautions.)

Restricted Distribution Program

• Only available through the Spravato REMS program. Healthcare settings and pharmacies must be certified with the program before they can supervise patient self-administration of esketamine nasal spray and dispense the drug; patients must be enrolled in the program to receive treatment.

• Esketamine nasal spray must be administered under the direct observation of a healthcare provider in a healthcare setting certified with the Spravato REMS program.

• Further information available at [Web] or at 855-382-6022.

Administration

Intranasal Administration

Intended for patient self-administration under the direct supervision of a healthcare provider. A treatment session consists of intranasal administration of esketamine and post-administration observation under supervision.

Instruct patients on use of the nasal spray device and advise them to read the patient instructions for use provided by the manufacturer.

Device Preparation

Esketamine nasal solution is commercially available in kits containing either 2 (56-mg dose kit) or 3 (84-mg dose kit) stoppered glass vials within a nasal spray device. Each device delivers 14 mg of esketamine per spray and delivers 2 sprays (1 spray per nostril) per device. Therefore, a 56-mg dose requires 2 devices, and an 84-mg dose requires 3 devices.

An indicator on the device displays one green light for each spray remaining in the device. Prior to administration, a healthcare provider should confirm the number of nasal spray devices required for the dose and check that each device indicator displays 2 green dots prior to use.

To prevent loss of the drug, do not prime esketamine nasal spray devices before use.

Administration Procedure

Before the initial spray from the first device at each treatment session, blow the nose to clear the nasal passages. During administration, patients should recline their head to about 45 degrees to help keep the solution inside the nose.

Insert the tip of the device straight into one nostril; the nose rest should touch the skin between the nostrils. While holding the other nostril closed, concurrently inspire through the nose while pushing on the plunger to activate the spray. Following actuation of the spray, sniff gently to keep the solution in the nose. Repeat this procedure for the other nostril. If liquid drips out of the nostril, dab the nose with a tissue.

Repeat procedure for each device until the full dose has been administered. Following administration of each device (i.e., 2 sprays), patients should rest in a comfortable position (preferably semi-reclined) for 5 minutes.

Following use, the healthcare provider should check each device to ensure that both sprays have been delivered; if a green dot appears in the device indicator, the patient should spray again into the second nostril.

Properly dispose of used devices in accordance with the facility's procedures and federal, state, and local regulations for controlled substance disposal. (See Abuse and Misuse under Cautions.)

Dosage

Available as esketamine hydrochloride; dosage expressed in terms of esketamine.

Adults

Treatment-resistant Depression

Intranasal

Administer in combination with an oral antidepressant.

Induction phase: Initially, 56 mg on day 1 followed by 56 or 84 mg (adjust dosage based on efficacy and tolerability) administered twice weekly during weeks 1–4.

Maintenance phase: 56 or 84 mg once weekly during weeks 5–8, then 56 or 84 mg administered every 2 weeks or once weekly during week 9 and afterward. Individualize dosing frequency to the least frequent dosing interval that maintains remission or response.

Assess clinical benefit at the end of the induction phase (i.e., week 4) to determine need for continued therapy.

In short- and long-term efficacy trials, approximately one-third of patients received 56-mg doses and two-thirds received 84-mg doses of the drug.

If a treatment session is missed and worsening of depression occurs, may increase dosing frequency back to patient's previous dosing schedule (i.e., every 2 weeks to once weekly, once weekly to twice weekly) based on clinical judgment.

Special Populations

Hepatic Impairment

Mild hepatic impairment: No specific dosage recommendations.

Moderate hepatic impairment: No specific dosage adjustment recommended; may require prolonged monitoring for adverse effects.

Severe hepatic impairment: Use not recommended. (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations. (See Geriatric Use under Cautions.)

Cautions for Esketamine

Contraindications

• Patients in whom an increase in BP or intracranial pressure poses a serious risk such as patients with aneurysmal vascular disease (including that affecting the thoracic and abdominal aorta and intracranial and peripheral arterial vessels) or arteriovenous malformation. (See Increases in BP under Cautions.)

• History of intracerebral hemorrhage.

• Hypersensitivity to esketamine, ketamine, or any excipient in the formulation.

Warnings/Precautions

Warnings

Sedation

Commonly causes dose-related sedation and, rarely, loss of consciousness.

Because of possible delayed or prolonged sedation, a healthcare provider must monitor patients for ≥2 hours at each treatment session, then assess patients to determine if they are clinically stable and ready to leave the healthcare setting. (See Post-administration Observation under Dosage and Administration.)

Closely monitor patients receiving CNS depressants concurrently. (See Specific Drugs under Interactions.)

Dissociation

Esketamine may cause dissociative effects (e.g., derealization, depersonalization) and perceptual changes (e.g., distortion of time and space, illusions); these adverse effects appear to be dose related. In clinical trials, dissociation was transient and occurred on the day of treatment.

Because of the risk of dissociative effects, carefully assess patients with psychosis prior to treatment; initiate therapy only if the benefit outweighs the risks.

A healthcare provider must monitor patients for dissociative effects for ≥2 hours at each treatment session, then assess patients to determine if they are clinically stable and ready to leave the healthcare setting. (See Post-administration Observation under Dosage and Administration.)

Abuse and Misuse

Potential for abuse or misuse; abuse potential appears to be similar to that of IV ketamine (also a schedule III [C-III] drug). Esketamine produces a variety of symptoms, including anxiety, dysphoria, disorientation, insomnia, flashbacks, hallucinations, and feelings of floating, detachment, and being “spaced out”.

Physical dependence reported with prolonged ketamine use and withdrawal symptoms reported following discontinuance of frequently used large doses of ketamine given over prolonged periods. Although withdrawal symptoms have not been observed after cessation of esketamine therapy, such symptoms are likely to occur if esketamine is similarly abused. Tolerance reported with prolonged use of ketamine; similar tolerance would be expected with prolonged use of esketamine.

Assess patient's risk for abuse or misuse prior to prescribing esketamine, and monitor all patients receiving the drug for the development of these behaviors or conditions, including drug-seeking behavior, during therapy. Individuals with a history of drug abuse or dependence may be at increased risk for abuse and misuse of esketamine. Careful consideration is advised prior to esketamine use in individuals with a history of substance use disorder, including alcohol. Monitor patients for signs and symptoms of physical dependence following discontinuance of therapy.

Handle esketamine nasal spray devices with adequate security and accountability, and ensure disposal is in accordance with the facility's procedures and federal, state, and local regulations for C-III drug products.

Suicidality

Possible worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality). (See Boxed Warning.) Increased risk of suicidality in pediatric patients and young adults (18–24 years of age) in short-term, placebo-controlled studies receiving antidepressants for major depressive disorder and other indications. Risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo. It is not known whether the risk of suicidality in children, adolescents, and young adults extends to longer-term use (i.e., >4 months) of antidepressants; however, substantial evidence indicates that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidality. (See Pediatric Use under Cautions.)

Monitor all patients being treated with antidepressants for any indication for clinical worsening and emergence of suicidality, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. Advise family members and caregivers of patients being treated with antidepressants to monitor patients for changes in behavior and to alert the clinician if such changes occur.

Consider changing the therapeutic regimen, including possible discontinuance of esketamine and/or the concomitant oral antidepressant, in patients whose depression is persistently worse or who are experiencing emergent suicidality.

Esketamine is not labeled for use in pediatric patients. (See Pediatric Use under Cautions.)

Other Warnings and Precautions

Increases in BP

Increases in SBP and/or DBP can occur at all recommended doses. Substantial increases in BP could occur after any dose even if smaller BP effects were observed with previous doses. BP increases peak approximately 40 minutes after intranasal administration and last for approximately 4 hours.

Assess BP prior to each treatment session, approximately 40 minutes after administration of the dose, and as clinically warranted for ≥2 hours following administration until values decline. If baseline BP is elevated (i.e., SBP ≥140 mm Hg or DBP ≥90 mm Hg) prior to administration, consider potential benefit and risk of esketamine when deciding whether to delay therapy or administer the drug.

If BP is decreasing following esketamine administration and the patient appears clinically stable for ≥2 hours, may discharge patient from the healthcare setting; otherwise, continue monitoring. If BP remains elevated, promptly consult clinicians experienced in BP management. If patients experiences symptoms of hypertensive crisis (e.g., chest pain, shortness of breath) or hypertensive encephalopathy (e.g., sudden severe headache, visual disturbances, seizures, diminished consciousness, focal neurologic deficits), immediately refer for emergency care.

Patients with a history of hypertensive encephalopathy are at increased risk for developing encephalopathy with even small BP increases; monitor such patients more intensively, including more frequent BP monitoring and symptom assessment.

Contraindicated in patients in whom an increase in BP or intracranial pressure would constitute a serious hazard (e.g., aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage). Carefully assess patients with other cardiovascular or cerebrovascular conditions to determine whether the potential benefits of esketamine treatment outweigh the risks.

Closely monitor BP if esketamine is used concomitantly with psychostimulants or monoamine oxidase (MAO) inhibitors. (See Specific Drugs under Interactions.)

Cognitive Impairment

May cause short-term impairment in attention, judgment, thinking, reaction speed, and motor skills.

In a clinical study, a greater decline in cognitive function was observed and greater mental effort was required to complete cognitive tests compared with placebo at 40 minutes post-dose; however, cognitive performance and mental effort were comparable to placebo groups at 2 hours post-dose. Esketamine also was associated with increased sleepiness at 40 minutes and 2 hours post-dose, but was comparable to placebo by 4 hours post-dose. (See Sedation under Cautions.)

Esketamine did not adversely affect cognitive function in a 1-year, open-label study; long-term cognitive effects beyond 1 year not evaluated.

Impaired Ability to Drive or Operate Machinery

May impair the ability to drive a motor vehicle or operate machinery. Following treatment, patients should not engage in potentially hazardous activities requiring full mental alertness and motor coordination, such as driving or operating machinery, until the next day after a restful sleep. Patients should also arrange transportation home following each esketamine treatment session. (See Advice to Patients.)

Ulcerative or Interstitial Cystitis

Ulcerative or interstitial cystitis reported with long-term, off-label use or misuse/abuse of ketamine. In clinical studies, lower urinary tract symptoms (e.g., pollakiuria, dysuria, urgency, nocturia, cystitis) reported more frequently in patients receiving intranasal esketamine compared with placebo. However, interstitial cystitis not reported in any studies, including those of up to 1 year's duration.

Monitor patients for urinary tract and bladder symptoms (e.g., dysuria, urinary frequency or urgency, nocturia) during therapy. If such symptoms occur, refer patient to an appropriate healthcare provider for evaluation as clinically warranted.

Embryofetal Toxicity

Based on ketamine data in animals, esketamine may cause fetal harm if administered to pregnant women. Clinical relevance in humans treated with intranasal esketamine at the recommended dosage not known.

Repeated or prolonged use of drugs that block NMDA receptors, including ketamine and esketamine, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus. (See Pediatric Use under Cautions.)

Not recommended for use during pregnancy. Women of reproductive potential should consider pregnancy planning and contraception during therapy. If patient becomes pregnant while receiving the drug, discontinue therapy and apprise of potential fetal hazard. (See Advice to Patients.)

Specific Populations

Pregnancy

Insufficient experience in pregnant women; may cause fetal harm. Not recommended for use during pregnancy. (See Embryofetal Toxicity under Cautions.)

National Pregnancy Registry for Antidepressants: 844-405-6185 or [Web].

Consult joint APA and ACOG guidelines (at [Web]) for additional information on management of depression in women prior to conception and during pregnancy, including treatment algorithms.

Lactation

Distributed into milk in humans. Effects on the nursing infant or milk production not known. Potential for neurotoxicity in nursing infants; breast-feeding during therapy not recommended. (See Embryofetal Toxicity under Cautions.)

Pediatric Use

Safety and efficacy not established in pediatric patients.

Increased risk of suicidality in children and adolescents receiving antidepressants for major depressive disorder and other indications. (See Suicidality under Cautions.)

Repeated or prolonged use of drugs that block NMDA receptors, including ketamine and esketamine, in children ≤3 years of age may adversely affect neurodevelopment. In animals, use of drugs that block NMDA receptors leads to neuronal and oligodendrocyte cell loss and alterations in synaptic morphology and neurogenesis in the developing brain. Clinical relevance of these findings to humans treated with intranasal esketamine at the recommended dosage is not known.

Geriatric Use

No overall differences in safety profile observed between geriatric patients ≥65 years of age and younger adults in phase 3 trials. (See Absorption: Special Populations, under Pharmacokinetics.)

In a 4-week clinical trial in patients ≥65 years of age with treatment-resistant depression, intranasal esketamine in conjunction with a newly initiated oral antidepressant reduced the MADRS total score compared with intranasal placebo plus an oral antidepressant; however, the difference was not statistically significant.

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Slightly increased peak plasma concentrations and exposure; these changes not considered clinically important.

Moderate hepatic impairment (Child-Pugh class B): Increased systemic exposure and prolonged half-life. Monitoring for possible adverse effects may be needed for a longer period of time. (See Hepatic Impairment under Dosage and Administration.)

Severe hepatic impairment (Child-Pugh class C): Not studied; use not recommended.

Renal Impairment

Slightly increased systemic exposure in individuals with renal impairment; not considered clinically important. (See Absorption: Special Populations, under Pharmacokinetics.)

Not studied in individuals requiring dialysis to date.

Common Adverse Effects

Dissociation (e.g., derealization, depersonalization) and perceptual changes (e.g., distortion of time and space, illusions), dizziness, nausea, sedation, vertigo, headache, dysgeusia, hypoesthesia, anxiety, lethargy, increased BP, vomiting, insomnia, diarrhea, nasal discomfort, throat irritation, dry mouth, feeling drunk, dysarthria, euphoric mood, hyperhidrosis, constipation, abnormal feeling, mental impairment, tremor, pollakiuria, oropharyngeal pain, tachycardia.

Drug Interactions

Principally metabolized by CYP2B6 and CYP3A4 and, to a lesser extent, by CYP2C9 and CYP2C19. Major active metabolite noresketamine also metabolized via CYP-mediated pathways.

Esketamine modestly induces CYP2B6 and CYP3A4 and noresketamine weakly and reversibly inhibits CYP3A4 in vitro.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP2B6 or CYP3A4: Clinically important pharmacokinetic interactions unlikely; dosage adjustment of esketamine not necessary.

Substrates of CYP2B6 or CYP3A: Clinically important pharmacokinetic interactions unlikely.

Specific Drugs

Esketamine Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following intranasal administration; peak concentrations attained in 20–40 minutes following the last nasal spray of a treatment session.

Absolute bioavailability: Approximately 48% following intranasal administration.

Exposure increases with dose at intranasal dosages of 28–84 mg; peak concentrations and AUC increase in a less than dose-proportional manner between 28 mg and 56 or 84 mg and in a nearly dose-proportional manner between 56 and 84 mg.

Interpatient variation in peak plasma concentrations and exposure: 27–66 and 18–45%, respectively.

Intrapatient variation in peak plasma concentrations and exposure: Approximately 15 and 10%, respectively.

Accumulation not observed during twice-weekly administration.

Onset

Increases in BP peak approximately 40 minutes following intranasal administration.

Duration

Increases in BP last approximately 4 hours following intranasal administration.

Special Populations

Geriatric patients: Increased peak plasma concentrations and AUC.

Mild hepatic impairment (Child-Pugh class A): Slightly increased peak plasma concentrations and exposure; not considered clinically important.

Moderate hepatic impairment (Child-Pugh class B): Peak plasma concentrations and exposure increased by approximately 8% and 103%, respectively, compared with individuals with normal hepatic function.

Mild to severe renal impairment (Cl_cr 5–77 mL/minute; not requiring dialysis): Slightly increased systemic exposure; not considered clinically important.

Distribution

Extent

Crosses the blood-brain barrier; brain-to-plasma ratio of noresketamine (the principal active metabolite of esketamine) is 4–6 times lower than that of esketamine.

Plasma Protein Binding

Approximately 43–45%.

Elimination

Metabolism

Metabolized principally by CYP2B6 and CYP3A4 and, to a lesser extent, by CYP2C9 and CYP2C19 to its principal active metabolite noresketamine.

Noresketamine also metabolized via CYP-mediated pathways and certain metabolites undergo glucuronidation.

Elimination Route

Excreted in urine (≥78%) and feces (≤2%) as metabolites.

<1% excreted unchanged in urine.

Half-life

Following intranasal administration, plasma esketamine and noresketamine concentrations decline in a biphasic manner, with a rapid initial phase (2–4 or 4 hours for esketamine or noresketamine, respectively) and a longer elimination phase (mean terminal half-life of 7–12 or 8 hours for esketamine or noresketamine, respectively).

Special Populations

Moderate hepatic impairment (Child-Pugh class B): Increased half-life of esketamine (18.7 hours).

Stability

Storage

Intranasal

Solution

20–25°C (may be exposed to 15–30°C).

Actions

• Esketamine is the S-enantiomer of racemic ketamine, a derivative of phencyclidine (PCP). The drug is a nonselective, noncompetitive antagonist of the NMDA receptor (an inotropic glutamate receptor). Esketamine has a higher affinity for the NMDA receptor than the R-enantiomer of racemic ketamine.

• Precise mechanism of antidepressant activity not fully established. Thought to preferentially block NMDA receptors on inhibitory γ-aminobutyric acid (GABA)-ergic interneurons and transiently enhance the activity of glutamatergic neurons, leading to improved synaptic connectivity.

• Esketamine's mechanism of antidepressant activity is thought to be similar to that of ketamine and is not thought to directly involve serotonin, norepinephrine, or dopamine reuptake, nor is it believed to directly involve µ opioid receptor stimulation.

Advice to Patients

• Importance of advising patients to read the manufacturer's medication guide and instructions for use.

• Esketamine nasal spray is only available through the Spravato REMS program. Importance of informing patients that they must be enrolled in the REMS program prior to drug administration. Importance of also informing patients that esketamine treatment must be administered under the direct supervision of a healthcare provider and that patients must be monitored by a healthcare provider for ≥2 hours following intranasal administration of the drug.

• Risk of sedation, dissociative symptoms, disturbances in perception, dizziness, vertigo, and/or anxiety. Importance of advising patients to notify a healthcare provider immediately if they feel like they cannot stay awake or feel like they may lose consciousness. Importance of informing patients that they will be monitored by a healthcare provider until these potential adverse effects resolve.

• Importance of advising patients that esketamine is a federally controlled substance because of its potential for abuse, misuse, and dependence.

• Risk of suicidal thoughts and behaviors (suicidality); importance of patients and caregivers being alert to emergence of suicidality, especially early during therapy or during periods of dosage adjustments. (See Suicidality under Cautions.)

• Risk of BP increases. Importance of informing patients that they may require observation by a healthcare provider until the BP elevation resolves. Importance of advising patients to notify a healthcare provider immediately if they experience chest pain, shortness of breath, sudden severe headache, changes in vision, or seizures after administration.

• Nausea and vomiting may occur in some patients. Importance of advising patients not to eat for ≥2 hours before administering esketamine nasal spray and to avoid drinking liquids for ≥30 minutes before administering the drug.

• Importance of informing patients that esketamine may impair their ability to drive or operate machinery. Following a treatment session, importance of advising patients not to drive, operate machinery, or engage in potentially hazardous activities requiring full mental alertness and motor coordination until the next day after a restful sleep. Advise patients that they will need someone to drive them home after each treatment session.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; importance of advising women to avoid breast-feeding during esketamine therapy. Importance of informing patients about the potential fetal risk and informing women who become pregnant while taking esketamine about the existence of the national pregnancy registry for antidepressants. (See Pregnancy under Cautions.)

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription, OTC, and recreational drugs and dietary or herbal supplements, as well as any concomitant or past illnesses (e.g., cardiovascular or cerebrovascular disease, hepatic disease, psychosis, substance abuse or dependence).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule III (C-III) drug.

Distribution of esketamine is restricted. (See Restricted Distribution Program under Dosage and Administration.)

Reload page with references included

Frequently asked questions

• Is Spravato (esketamine) a controlled substance?

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