esketamine intranasal (Rx)

Brand and Other Names:Spravato
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Dosing & Uses


Dosage Forms & Strengths

solution, intranasal: Schedule III

  • 28mg/device; each nasal spray device delivers 2 sprays that total 28mg
  • Available as a 56mg kit (two 28-mg nasal spray devices) or an 84mg kit (three 28-mg nasal spray devices)

Treatment Resistant Depression

Indicated in conjunction with an oral antidepressant for treatment-resistant depression (TRD)

Adjust dose based on efficacy and tolerability

At the end of the induction phase, evaluate evidence of therapeutic benefit to determine need for continued treatment

Induction phase

  • Weeks 1-4
    • Administer twice per week
    • Day 1 starting dose: 56 mg
    • Subsequent doses: 56 mg or 84 mg

Maintenance phase

  • Weeks 5-8
    • Administer once weekly
    • 56 mg or 84 mg
  • Week 9 and after
    • Administer q2Week or once weekly; individualize dosing frequency to the least frequent dosing to maintain remission/response
    • 56 mg or 84 mg

Dosage Modifications

Hepatic impairment

  • Moderate (Child-Pugh class B): Higher AUC and half-life observed compared with normal hepatic function; may need to be monitored for longer period after dose administration
  • Severe (Child-Pugh class C): Not studied, and therefore not recommended

Renal impairment

  • Renal dialysis: No clinical experience

Dosing Considerations

Limitation of use: Not approved as an anesthetic agent; safety and effectiveness not established

Must be administered under direct supervision of a healthcare provider during entire treatment session (ie, nasal administration and postadministration direct observation)

Blood pressure monitoring

  • Assess blood pressure before administration
  • If baseline blood pressure is elevated (eg, >140 mm Hg systolic, >90 mm Hg diastolic), consider the risks of short-term increases in blood pressure and benefit of treatment
  • Do not administer if increased blood pressure or intracranial pressure poses serious risk
  • After dosing, reassess blood pressure at ~40 minutes (corresponds with peak plasma concentration) and subsequently as clinically warranted
  • If blood pressure is decreasing and patient appears clinically stable for at least 2 hr, may discharge patient at the end of the postdose monitoring period; if not, continue to monitor

Food and liquid ingestion

  • Some patients may experience nausea and vomiting after administration
  • Because of this, advise patients to avoid food for at least 2 hr before administration and to avoid drinking liquids at least 30 minutes before

Nasal corticosteroids or decongestants

  • Administer nasal corticosteroid or decongestant at least 1 hr before esketamine

Safety and efficacy not established

In clinical trials, 14% of patients were aged 65 yr or older; no overall differences in safety profile were observed

See adult dosing



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            Adverse Effects


            Dissociation (41%)

            Dizziness (29%)

            Nausea (28%)

            Vertigo (23%)

            Sedation (23%)

            Headache (20%)

            Dysgeusia (19%)

            Hypoesthesia (18%)

            Anxiety (13%)

            Lethargy (11%)


            • Aged <65 yr, 84 mg (61%)
            • Aged <65 yr, 56 mg (50%)
            • Aged ≥65 yr, 28-84 mg (49%)

            Dissociation or perceptual changes

            • Aged ≥65 yr, 28-84 mg (75%)
            • Aged <65 yr, 84 mg (69%)
            • Aged <65 yr, 56 mg (61%)

            Blood pressure

            • Aged <65 yr
              • Systolic BP ≥180 mm Hg (3%)
              • Systolic BP ≥40 mm Hg increase (8%)
              • Diastolic BP ≥110 mm Hg (4%)
              • Diastolic BP ≥25 mm Hg increase (13%)
            • Aged ≥65 yr
              • Systolic BP ≥180 mm Hg (3%)
              • Systolic BP ≥40 mm Hg increase (17%)
              • Diastolic BP ≥25 mm Hg increase (14%)

            Nausea and vomiting

            • 56 mg
              • Nausea (27%)
              • Vomiting (6%)
            • 84 mg
              • Nausea (32%)
              • Nausea, severe (3%)
              • Vomiting (12%)
              • Vomiting, severe (3%)


            Increased blood pressure (10%)

            Vomiting (9%)

            Insomnia (8%)

            Diarrhea (7%)

            Nasal discomfort (7%)

            Throat irritation (7%)

            Dry mouth (5%)

            Feeling drunk (5%)

            Dysarthria (4%)

            Euphoric mood (4%)

            Hyperhidrosis (4%)

            Constipation (3%)

            Feeling abnormal (3%)

            Mental impairment (3%)

            Tremor (3%)

            Pollakiuria (3%)

            Oropharyngeal pain (3%)

            Tachycardia (2%)



            Black Box Warnings

            Sedation and dissociation

            • Risk for sedation and dissociation after administration
            • Because of these risks, monitor for at least 2 hr at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting

            Abuse and misuse

            • Potential for drug abuse and misuse
            • Consider risks and benefits of prescribing esketamine in patients at higher risk of abuse
            • Monitor for signs and symptoms of abuse and misuse

            Suicidal thoughts and behaviors

            • Antidepressants increased the risk of suicidal thoughts and behavior in children and young adults 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 in pediatric patients


            • Owing to serious adverse outcomes resulting from sedation, dissociation, abuse, and misuse, esketamine is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS)
            • Pharmacies must be certified and only dispense esketamine to healthcare settings that are certified
            • More information is available at or 1-855-382-6022


            Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation

            History of intracerebral hemorrhage

            Hypersensitivity to esketamine, ketamine, or any excipients


            Available only through a restricted access program (REMS)

            Sedation is likely to occur

            The most common psychological effects are dissociative or perceptual changes (including distortion of time, space, and illusions), derealization, and depersonalization; carefully assess patients with psychosis before administering to determine if benefit outweighs risk

            Because of risk of sedation, dissociation, and increased blood pressure, patients must be monitored for at least 2 hr after each treatment session; carefully assess to determine if the patient is clinically stable and ready to leave the healthcare setting

            Esketamine is a schedule III controlled substance and may be subject to abuse and diversion; assess risk for each patient before prescribing

            Pooled analyses of placebo-controlled trials of antidepressant drugs have shown an increased risk for suicidality in patients aged ≤24 yr; monitor all patients receiving antidepressants, especially during the initial phase of treatment, for clinical worsening and emergence of suicidal thoughts and behaviors

            Ulcerative or interstitial cystitis reported with long-term, off-label use or misuse/abuse of ketamine; esketamine intranasal showed a higher rate of lower urinary tract symptoms compared with placebo; however, no cases of interstitial cystitis observed

            May cause fetal harm when administered to pregnant women

            Cognitive impairment

            • Short-term
              • After single dose in healthy volunteers, esketamine caused cognitive performance decline 40 minutes postdose compared with placebo
              • Cognitive performance, mental effort, and sleepiness were comparable at 2 hr postdose
            • Long-term
              • Long-term cognitive and memory impairment reported with repeated ketamine misuse or abuse
              • No adverse effects were observed esketamine intranasal on cognitive functioning in a 1-year open-label safety study
              • Long-term cognitive effects have not been evaluated beyond 1 yr

            Drug interaction overview

            • No clinically significant interactions were observed when esketamine intranasal was coadministered with CYP inducers, CYP3A inhibitors, CYP2B6 inhibitors, or substrates of CYP3A or CYP2B6
            • Coadministration with other CNS depressants may cause additive risk for sedation
            • Coadministration with psychostimulants or MAOIs may add to risk of increased blood pressure



            Not recommended during pregnancy

            Based on published findings from pregnant animals treated with ketamine (racemic mixture of arketamine and esketamine), may cause fetal harm when administered to pregnant women

            Antidepressant registry: Healthcare providers are encouraged to register patients exposed to antidepressants during pregnancy at 1-844-405-6185 or

            Animal data

            • N-methyl-D-aspartate (NMDA) receptors blockers administered during the period of peak brain development in pregnant primates increased neuronal apoptosis in the developing brain of the offspring
            • Embryo-fetal reproduction studies in rabbits showed skeletal malformations at maternally toxic doses when ketamine was intranasally administered with a No Observed Adverse Effect Level (NOAEL) at estimated esketamine exposures 0.3 times the exposures at the maximum recommended human dose (MRHD) of 84 mg/day
            • Additionally, intranasal administration of esketamine to pregnant rats during pregnancy and lactation at exposures that were similar to those at the MRHD resulted in a delay in sensorimotor development in pups during the preweaning period and a decrease in motor activity in the postweaning period

            Clinical considerations

            • A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy
            • The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants
            • Consider the risk of untreated depression when discontinuing or changing treatment with antidepressants during pregnancy and postpartum


            • Based on published animal reproduction studies, esketamine may cause embryo-fetal harm when administered to a pregnant woman
            • However, it is not clear how these animal findings relate to females of reproductive potential treated with the recommended clinical dose
            • Consider pregnancy planning and prevention for females of reproductive potential during treatment


            Esketamine is present in human milk; there are no data on the effects on the breastfed infant or on milk production

            Published studies in juvenile animals report neurotoxicity; because of the potential for neurotoxicity, advise patients that breastfeeding is not recommended during treatment

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.



            Mechanism of Action

            Esketamine, the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (NMDA is an ionotropic glutamate receptor)

            The mechanism by which esketamine exerts its antidepressant effect is unknown


            Bioavailability: 48%

            Peak plasma time: 20-40 minutes after last nasal spray of treatment session


            Vd (IV): 709 L

            Protein bound: 43-45%


            Primarily metabolized to noresketamine by CYP2B and 3A4, and to a lesser extent by CYP2C9/2C19

            Noresketamine is metabolized by CYP-dependent pathways, and certain subsequent metabolites undergo glucuronidation

            Noresketamine demonstrated activity at the NMDA receptor with less affinity


            Half-life: 7-12 hr; 8 hr (noresketamine)

            Clearance (IV): 89 L/hr


            • Urine: <1% unchanged; ≥78% metabolites
            • Feces: ≤2% metabolites


            Intranasal Administration

            For nasal use only

            To prevent loss of medication, do not prime the device before use

            Use 2 devices (for 56-mg dose) or 3 devices (for 84-mg dose), with a 5-minute rest between use of each device

            See prescribing information for detailed pictures and diagrams

            Patient preparation

            • Measure blood pressure before dose; if elevated, a decision to delay therapy should take into account benefit and risk to patient
            • Instruct patient to blow nose before first device only
            • Have patient hold device and recline head to 45° to keep medication inside nose
            • See prescribing information for detailed pictures regarding administration technique
            • Food and liquid ingestion
              • Food: Do not eat for at least 2 hr before administration
              • Liquids: Do not drink liquids for at least 30 min before administration

            Postadministration observation

            • During and after administration at each treatment session, observe patient for at least 2 hr until the patient is safe to leave
            • Measure blood pressure 40 minutes postdose and subsequently as clinically warranted 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 disturbances, seizures, diminished consciousness, or focal neurological deficits) immediately for emergency care
            • Closely monitor blood pressure with concomitant use of psychostimulants or MAOIs
            • Patients with history of hypertensive encephalopathy require more intensive and frequent blood pressure monitoring
            • Before administration, instruct patients not to engage in potentially hazardous activities (eg, driving a motor vehicle, operating machinery) until the next day after a restful sleep
            • Missed treatment sessions
              • Consider returning to previous dosing schedule (ie, q2Weeks to once weekly or weekly to twice weekly) if treatment sessions are missed and there is worsening of depression symptoms


            Store at 20-25°C (68-77°F); excursion permitted from 15-30°C (59-86°F)

            Security and disposal

            • Nasal spray devices must be handled with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations




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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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