Esketamine

Medically reviewed by Drugs.com. Last updated on May 14, 2019.

• Overview
• Side Effects
• Dosage
• Professional
• Interactions
• Pregnancy
• More

Pronunciation

(es KET a meen)

Index Terms

• Esketamine Hydrochloride
• Spravato

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Therapy Pack, Nasal, as hydrochloride:

Spravato (56 MG Dose): 28 mg/device (dose pack of 2) (1 ea) [contains edetate disodium]

Spravato (84 MG Dose): 28 mg/device (dose pack of 3) (1 ea) [contains edetate disodium]

Brand Names: U.S.

• Spravato (56 MG Dose)
• Spravato (84 MG Dose)

Pharmacologic Category

• N-Methyl-D-Aspartate (NMDA) Receptor Antagonist

Pharmacology

Esketamine (S-enantiomer of racemic ketamine) is a nonselective, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. The mechanism by which it exerts its antidepressant effect is unknown. The major circulating metabolite noresketamine demonstrated activity at the same receptor with less affinity.

Distribution

V_d: 709 L

Metabolism

Primarily metabolized to the active metabolite noresketamine via cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4 and to a lesser extent CYP2C9 and CYP2C19. Noresketamine is metabolized via CYP-dependent pathways and certain subsequent metabolites undergo glucuronidation.

Excretion

Urine (<1% as unchanged drug)

Time to Peak

Plasma: 20 to 40 minutes

Half-Life Elimination

Esketamine: 7 to 12 hours; Noresketamine (active metabolite): ~8 hours

Protein Binding

~43% to 45%

Special Populations: Hepatic Function Impairment

Mean esketamine AUC and t_1/2 values were higher in patients with moderate hepatic impairment.

Special Populations: Elderly

Mean esketamine C_max and AUC values were higher in elderly patients compared with younger adult patients.

Use: Labeled Indications

Depression, treatment-resistant: Treatment of treatment-resistant depression (TRD) in adults, in conjunction with an oral antidepressant

Limitations of use: Not approved as an anesthetic agent. The safety and effectiveness of esketamine as an anesthetic agent have not been established.

Contraindications

Hypersensitivity to esketamine, ketamine, or any component of the formulation; aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation; history of intracerebral hemorrhage

Dosing: Adult

Depression, treatment-resistant: Note: Administer in conjunction with an oral antidepressant. Must be administered under the direct supervision of a health care provider with patients monitored for adverse effects for at least 2 hours following administration.

Intranasal:

Induction: 56 mg twice weekly; may increase dose (after first dose) based on response and tolerability up to 84 mg twice weekly. After 4 weeks, evaluate for evidence of therapeutic benefit to determine need for continued treatment.

Maintenance: Beginning on week 5, using the previously established dose (56 or 84 mg) decrease the dosing frequency to once weekly. At week 9 and onward, adjust the dosing frequency to the least frequent interval to maintain remission/response; continue once weekly or decrease to every 2 weeks.

Missed treatment sessions or worsening of symptoms: Consider returning to patient's previous dosing schedule (eg, every 2 weeks to once weekly or weekly to twice weekly).

Dosing: Geriatric

Refer to adult dosing.

Administration

Intranasal: To reduce risk of nausea and vomiting, avoid food for at least 2 hours before administration and avoid drinking liquids at least 30 minutes prior to administration. If patient requires a nasal corticosteroid or nasal decongestant on a dosing day, administer at least 1 hour prior to administration of esketamine. Do not prime the device prior to use to avoid medication loss. Each nasal spray device contains 2 sprays (1 spray for each nostril) and delivers a total of 28 mg; spray once into each nostril per device. Use 2 devices for 56 mg dose or 3 devices for 84 mg dose, with a 5-minute rest between use of each device to allow for absorption. Gently blow nose to clear nostrils before the first device only. Dispose of used devices according to procedure for a schedule III drug and according to federal, state, and local regulations.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: Esketamine may enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CNS Stimulants: Esketamine may enhance the hypertensive effect of CNS Stimulants. Monitor therapy

Corticosteroids (Nasal): May diminish the therapeutic effect of Esketamine. Management: Patients who require a nasal corticosteroid on an esketamine dosing day should administer the nasal corticosteroid at least 1 hour before esketamine. Consider therapy modification

Decongestants (Nasally Administered): May diminish the therapeutic effect of Esketamine. Management: Patients who require a nasal decongestant on an esketamine dosing day should administer the nasal decongestant at least 1 hour before esketamine. Consider therapy modification

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Memantine: NMDA Receptor Antagonists may enhance the adverse/toxic effect of Memantine. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Monoamine Oxidase Inhibitors: Esketamine may enhance the hypertensive effect of Monoamine Oxidase Inhibitors. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Solriamfetol: Esketamine may enhance the hypertensive effect of Solriamfetol. Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Increased systolic blood pressure (3% to 17%), increased diastolic blood pressure (4% to 14%)

Central nervous system: Depersonalization (≤75%), derealization (≤75%), dissociative reaction (41% to 75%), sedated state (23% to 61%), dizziness (29%), vertigo (23%), headache (20%), hypoesthesia (18%), anxiety (13%), lethargy (11%)

Gastrointestinal: Nausea (27% to 32%), dysgeusia (19%), vomiting (6% to 12%)

1% to 10%:

Cardiovascular: Increased blood pressure (10%), tachycardia (2%)

Central nervous system: Insomnia (8%), intoxicated feeling (5%), dysarthria (4%), euphoria (4%), feeling abnormal (3%), mental deficiency (3%)

Dermatologic: Hyperhidrosis (4%)

Gastrointestinal: Diarrhea (7%), xerostomia (5%), constipation (3%), severe nausea (3%), severe vomiting (3%)

Genitourinary: Pollakiuria (3%)

Neuromuscular & skeletal: Tremor (3%)

Respiratory: Nasal discomfort (7%), throat irritation (7%), oropharyngeal pain (3%)

Frequency not defined:

Central nervous system: Cognitive dysfunction, drug abuse

Genitourinary: Cystitis, dysuria, nocturia, urinary urgency

<1%, postmarketing, and/or case reports: Loss of consciousness

Warnings/Precautions

Concerns related to adverse effects:

• Abuse and misuse: [US Boxed Warning]: Esketamine has the potential to be abused and misused. Consider the risks and benefits of prescribing esketamine prior to use in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse including drug-seeking behavior, while on therapy. Individuals with a history of drug abuse or dependence are at greater risk; use careful consideration prior to treatment and monitor for signs of abuse or dependence.

• CNS depression: [US Boxed Warning]: Patients are at risk for sedation after administration of esketamine. Because of the risks of sedation, 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 health care setting. CNS depression may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving) until the next day after a restful sleep. Manufacturer labeling recommends patients arrange transportation home following treatment. No adverse effects of esketamine nasal spray on cognitive functioning were observed in a one-year open-label safety study; long-term cognitive and memory impairment have been reported with repeated ketamine misuse or abuse. Closely monitor sedation with concomitant CNS depressants.

• Dissociation: [US Boxed Warning]: Patients are at risk for dissociative or perceptual changes after administration of esketamine. Because of the risks of dissociation, 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 health care setting. Given its potential to induce dissociative or perceptual changes (including distortion of time, space, and illusions), derealization and depersonalization, assess patients with psychosis carefully before esketamine administration; treatment should only be initiated if benefit outweighs risk.

• Blood pressure: Increases in systolic and/or diastolic blood pressure (BP) (occurring ~40 minutes after administration and lasting ~4 hours) have been observed at all recommended doses. Substantial BP increases may occur after any dose even if smaller effects were observed with previous administrations. Esketamine is contraindicated in patients for whom an increase in BP or intracranial pressure poses a serious risk (eg, aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage). Carefully assess patients with other cardiovascular and cerebrovascular conditions prior to esketamine use to determine whether the potential benefits outweigh the risks. Assess BP prior to administration; if elevated (>140/90 mm Hg) consider the benefits and risks of delaying therapy. Measure BP ~40 minutes post-dose and subsequently as clinically indicated for at least 2 hours after administration of last dose or until values decline. Refer patients experiencing symptoms of a hypertensive crisis (eg, chest pain, shortness of breath) or hypertensive encephalopathy (eg, sudden severe headache, visual disturbance, seizures, diminished consciousness or focal neurological deficits) immediately for emergency care. Closely monitor blood pressure with concomitant use of esketamine with psychostimulants or monoamine oxidase inhibitors. In patients with a history of hypertensive encephalopathy, more intensive monitoring, including more frequent BP and symptom assessment is warranted because these patients are at increased risk for developing encephalopathy with even small increases in BP.

• Suicidal thoughts and behaviors: [US Boxed Warning]: Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor all patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with health care provider. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Esketamine is not approved in pediatric patients.

• Ulcerative or interstitial cystitis: Cases of ulcerative or interstitial cystitis have been reported in individuals with long-term off-label use or misuse/abuse of ketamine. In clinical trials there was a higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in esketamine-treated patients; however, no cases of esketamine-related interstitial cystitis were observed in patients treated for up to a year. Monitor for urinary tract and bladder symptoms during the course of treatment and refer to an appropriate health care provider as clinically indicated.

Disease-related concerns:

• Hepatic impairment: Patients with moderate hepatic impairment may need to be monitored for adverse reactions for a longer period of time. Esketamine is not recommended in patients with severe hepatic impairment.

Concurrent drug therapy issues:

• Drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• REMS program: [US Boxed Warning]: Because of the risks of serious adverse outcomes resulting from sedation, dissociation, and abuse and misuse, esketamine is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS. Under the esketamine REMS program, only certified health care settings and pharmacies may administer and dispense esketamine. Esketamine may only be administered to patients who are enrolled in the program and under the direct observation of a health care provider (during administration) with monitoring for at least 2 hours following the last dose. Call 855-382-6022 or visit www.spravatorems.com for further information.

Monitoring Parameters

Monitor all patients for adverse effects in a health care setting for at least 2 hours following administration of the last dose.

Blood pressure (prior to dose; repeat ~40 minutes post-dose, and then as clinically indicated for at least 2 hours post-dose); suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased)

Prior to administration, assess patient risk for abuse or misuse, psychosis, and cardiovascular and cerebrovascular conditions.

Closely monitor all patients for clinical worsening of depression and emergence of suicidal thoughts and behaviors, especially during the initial few months of therapy and at times of dosage changes; assess for evidence of therapeutic benefit at the end of the induction phase to determine need for continued treatment; closely monitor patients for signs/symptoms of abuse and misuse during therapy; monitor for sedation with use of concomitant CNS depressants; monitor for urinary tract or bladder symptoms during the course of treatment.

Pregnancy Considerations

Based on animal data, use of medications that block N-methyl-D-aspartate (NMDA) receptors and/or potentiate gamma-aminobutyric acid (GABA) activity, may affect brain development.

The ACOG recommends treatment of depression during pregnancy should be individualized and incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. For women who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (ACOG 2008; APA 2010; Yonkers 2009)

Based on adverse events observed in animal reproduction studies, the manufacturer recommends females of reproductive potential consider pregnancy planning and prevention during esketamine therapy.

Pregnant females exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Females 18 to 45 years of age or their health care providers may contact the registry by calling 1-844-405-6185 or online at https://womensmentalhealth.org/clinical-and-researchprograms/ pregnancyregistry/antidepressants/. Enrollment should be done as early in pregnancy as possible.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience drunk feeling, sluggishness, nausea, vomiting, change in taste, or numbness or tingling feeling. Have patient report immediately to prescriber fatigue, dizziness, passing out, anxiety, narcolepsy, hallucinations, signs of depression (thoughts of suicide, anxiety, emotional instability, or confusion), panic attacks, irritability, mood changes, behavioral changes, severe headache, vision changes, chest pain, shortness of breath, seizures, confusion, memory impairment, polyuria, or painful urination (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Related questions

• Is Spravato (esketamine) a controlled substance?

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