Version July 2025
Patients are at risk for sedation after administration of esketamine.
Patients are at risk for dissociative or perceptual changes after administration of esketamine.
Respiratory depression has been observed in postmarketing experience.
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 health care setting.
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.
Because of the risks of serious adverse outcomes resulting from sedation, dissociation, respiratory depression, and abuse and misuse, esketamine is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS.
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. Esketamine is not approved for use in pediatric patients.
Dosage guidance:
Safety: 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.
Clinical considerations: In those who respond to short-term esketamine treatment (eg, 1 to 4 weeks), some experts recommend transitioning to maintenance treatment with antidepressants and/or psychotherapy instead of prolonged esketamine treatment (Ref).
Depression, treatment resistant: Intranasal:
Note: May be used as monotherapy or in conjunction with an oral antidepressant.
Induction: 56 or 84 mg twice weekly; adjust dose based on response and tolerability. 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, continue effective dose (56 or 84 mg) once weekly or decrease to every 2 weeks.
Major depressive disorder (unipolar), with suicidality: Intranasal:
Note: Use in conjunction with an oral antidepressant.
Initial: 84 mg twice weekly for 4 weeks; may reduce dosage to 56 mg twice weekly based on tolerability. After 4 weeks, evaluate for evidence of therapeutic benefit to determine need for continued treatment; use beyond 4 weeks has not been evaluated.
Missed treatment sessions:
Treatment-resistant depression:
Missed treatment sessions and no worsening of symptoms: Continue current dosing schedule.
Missed treatment sessions during maintenance treatment and worsening of symptoms: Consider returning to patient's previous dosing schedule (eg, every 2 weeks to once weekly or weekly to twice weekly).
Major depressive disorder (unipolar) with suicidality:
Missed treatment sessions and no worsening of symptoms: Continue current dosing schedule.
There are no dosage adjustments provided in the manufacturer labeling (has not been studied).
Mild to moderate impairment (Child-Pugh classes A and B): There are no dosage adjustments provided in the manufacturer labeling (has not been studied); patients with moderate impairment may need to be monitored for adverse effects for a longer period of time.
Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).
Consider use of lower initial doses (28 to 84 mg twice weekly for 4 weeks); refer to adult dosing (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Gastrointestinal: Nausea (25%)
Nervous system: Dissociative reaction (28%; including depersonalization, derealization), dizziness (22%), headache (19%)
1% to 10%:
Cardiovascular: Increased blood pressure (5%; including hypertension)
Gastrointestinal: Vomiting (7%)
Nervous system: Anxiety (10%), disturbance in attention (2%), hypoesthesia (4%), insomnia (5%), intoxicated feeling (7%), lethargy (7%), sedated state (6%), vertigo (3%)
Respiratory: Throat irritation (4%)
Frequency not defined: Nervous system: Drug abuse
Postmarketing:
Cardiovascular: Bradycardia, hypotension
Nervous system: Akathisia (Gastaldon 2021), ataxia (Gastaldon 2021), crying (Gastaldon 2021), depression (Gastaldon 2021), mania (Gastaldon 2021), panic attack (Gastaldon 2021), paranoid ideation (Gastaldon 2021), talkativeness (logorrhea) (Gastaldon 2021)
Respiratory: Respiratory depression
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.
Canadian labeling: Additional contraindications (not in US labeling): Recent (within 6 weeks) major cardiovascular event (such as myocardial infarction or cerebrovascular accident).
Major psychiatric warnings:
• Suicidal thinking/behavior: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years of age. Closely monitor 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 postpartum 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. Use caution in high-risk patients during initiation of therapy.
- The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors, such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression or psychosis occur.
Concerns related to adverse effects:
• Abuse and misuse: 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.
• Blood pressure: Increases in systolic and/or diastolic 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.
• CNS depression: 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.
• Cognitive impairment: Short-term cognitive impairment (eg, greater effort to complete cognitive test) was seen at 40 minutes after administration; cognition returned to being similar to placebo at 2 hours and sleepiness at 4 hours after administration. Long-term cognitive and memory impairment has been reported with repeated ketamine misuse or abuse; long-term studies on the effect of cognitive functioning remained stable.
• Dissociation: 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.
• 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.
Other warnings/precautions:
• Appropriate use: Use of esketamine does not preclude the need for hospitalization if clinically needed, even if improvement is seen after initial dose. Additionally, esketamine treats depressive symptoms; the safety and effectiveness of esketamine in the prevention of suicide or reducing suicidal ideation or behavior has not been established.
• REMS program: 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 1-855-382-6022 or visit www.spravatorems.com for further information.
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 (edta) disodium]
Spravato (84 MG Dose): 28 mg/device (dose pack of 3) (1 ea) [contains edetate (edta) disodium]
No
Soln Therapy Pack (Spravato (56 MG Dose) Nasal)
28MG/DEVICE% (per each): $500.52
Soln Therapy Pack (Spravato (84 MG Dose) Nasal)
28MG/DEVICE% (per each): $500.52
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Therapy Pack, Nasal:
Spravato: 28 mg (1 ea) [contains edetate (edta) disodium]
C-III
In Canada, Spravato is only available through the JANSSEN JOURNEY Program. Patients, pharmacists, and physicians must all be enrolled in the program prior to prescribing and dispensing. More information can be obtained by contacting the JANSSEN JOURNEY Program at 1-833-257-7191 or at https://www.janssenjourney.ca/en/.
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; device indicator will show 2 green dots indicating ready for use (get a new device if dots are not present). 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. Instruct patient to recline head about 45 degrees. Instruct patient to close opposite nostril and breathe in through the nose while pushing plunger all way up the nose until it stops. Instruct patient to sniff gently after spraying into the nose. Dab any excess liquid with a tissue; do not blow nose. Dispose of used devices according to procedure for a schedule III drug and according to federal, state, and local regulations.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s016lbl.pdf#page=47, must be dispensed with this medication.
Depression, treatment-resistant: Treatment of treatment-resistant depression in adults, as monotherapy or in conjunction with an oral antidepressant.
Major depressive disorder (unipolar) with suicidality: Treatment of depressive symptoms in adults with major depressive disorder with suicidal ideation or behavior, 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. Additionally, esketamine treats depressive symptoms; effectiveness of esketamine in preventing suicide or decreasing suicidal ideation has not been shown.
Spravato may be confused with Steglatro
Substrate of CYP2B6 (Major with inhibitors), CYP2B6 (Minor with inducers), CYP2C19 (Minor), CYP2C9 (Minor), CYP3A4 (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Androgens: Hypertension-Associated Agents may increase hypertensive effects of Androgens. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification
Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects 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. Risk D: Consider Therapy Modification
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
CNS Depressants: Esketamine (Nasal) may increase CNS depressant effects of CNS Depressants. Risk C: Monitor
CNS Stimulants: Esketamine (Nasal) may increase hypertensive effects of CNS Stimulants. Risk C: Monitor
Corticosteroids (Nasal): May decrease therapeutic effects of Esketamine (Nasal). Management: Patients who require a nasal corticosteroid on an esketamine dosing day should administer the nasal corticosteroid at least 1 hour before esketamine. Risk D: Consider Therapy Modification
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Decongestants (Nasally Administered): May decrease therapeutic effects of Esketamine (Nasal). Management: Patients who require a nasal decongestant on an esketamine dosing day should administer the nasal decongestant at least 1 hour before esketamine. Risk D: Consider Therapy Modification
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Memantine: NMDA Receptor Antagonists may increase adverse/toxic effects of Memantine. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
MiFEPRIStone: May increase serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Monoamine Oxidase Inhibitors: Esketamine (Nasal) may increase hypertensive effects of Monoamine Oxidase Inhibitors. Risk C: Monitor
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification
OxyCODONE: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Solriamfetol: May increase hypertensive effects of Hypertension-Associated Agents. Risk C: Monitor
Suvorexant: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Thiotepa: May increase serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor
Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
Evaluate pregnancy status prior to initiating treatment in patients who could become pregnant. Treatment should not be withheld, but pharmacologic management may vary based on reproductive status, severity of illness, and history of antidepressant response (ACOG 2023; WFSBP [Dodd 2018]). Patients effectively treated may continue their current medication when planning a pregnancy unless contraindications exist (BAP [McAllister-Williams 2017]). Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]).
Based on adverse events observed in animal reproduction studies, the manufacturer recommends patients who could become pregnant consider pregnancy planning and prevention during esketamine therapy.
Esketamine crosses the placenta (Xu 2023).
Data related to nasal use of esketamine during pregnancy are limited (Jiang 2023). Based on animal data, use of medications that block N-methyl-D-aspartate receptors and/or potentiate gamma-aminobutyric acid activity, may affect brain development.
Perioperative and postoperative administration of IV esketamine have been evaluated for analgesia and prevention of postpartum depression following cesarean delivery (Li 2024; Ma 2024). Subanesthetic doses of esketamine used for postoperative pain were not found to affect neonatal respirations when administered during cesarean delivery (Li 2024; Xu 2023).
Untreated and undertreated mental health conditions are associated with adverse pregnancy outcomes. Untreated or undertreated depression is associated with preterm birth, low birth weight, preeclampsia, postpartum depression, and impaired infant attachment (associated with long-term developmental effects). Discontinuing effective medications during pregnancy increases the risk of relapse. Management should be made as part of a shared decision-making process (ACOG 2023). Patients effectively treated for depression prepregnancy may use the same medication during pregnancy unless contraindications exist (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]). Treatment should not be withheld or discontinued based only on pregnancy status. When medications are used, the lowest effective dose of a single agent is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Monthly monitoring for symptom improvement with a validated screening tool during pregnancy is recommended. Manage side effects as needed (ACOG 2023).
Data collection to monitor pregnancy and infant outcomes following exposure to antidepressant medications is ongoing. Pregnant patients ≤45 years of age with a history of psychiatric illness are encouraged to enroll in the National Pregnancy Registry for Antidepressants (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/antidepressants).
Esketamine is present in breast milk
Patients effectively treated for depression during pregnancy may continue their medication postpartum unless contraindications to breastfeeding exist. The presence and concentration of the drug in breast milk, efficacy of maternal treatment, and infant age should be considered when initiating a medication for the first time postpartum (ABM [Sriraman 2015]; BAP [McAllister-Williams 2017]).
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. Infants may be most vulnerable during the first several months of life and possibly until ~3 years of age. Due to the potential for neurotoxicity in a breastfeeding infant, breastfeeding is not recommended by the manufacturer.
Monitor all patients for adverse effects in a health care setting for at least 2 hours following administration of the last dose.
Monitor patients for changes in respiratory status for at least 2 hours (including pulse oximetry) at each treatment session.
BP (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.
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: Vd: 709 L
Protein binding: ~43% to 45%
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.
Bioavailability: ~48%
Half-life elimination: Esketamine: 7 to 12 hours; Noresketamine (active metabolite): ~8 hours
Time to peak, plasma: 20 to 40 minutes
Excretion: Urine (<1% as unchanged drug)
Hepatic function impairment: Mean esketamine AUC and t1/2 values were higher in patients with moderate hepatic impairment.
Older adult: Mean esketamine Cmax and AUC values were higher in elderly patients compared with younger adult patients.
