mg (61%) Blood pressure Aged <65 yr Diastolic BP ≥25 mm Hg increase (13%) Aged ≥65 yr ​Systolic BP ≥40 mm Hg increase (17%) Diastolic BP ≥25 mm Hg increase (14%) Nausea and vomiting 56 mg Nausea (27%) 84 mg Nausea (32%) Vomiting (12%) >10% (MDD) Dissociation (48%) Dizziness (45%) Sedation (29%) Nausea (27%) Dysgeusia (20%) Increased blood pressure (15%) Anxiety (15%) Hypoesthesia (13%) Vomiting (11%) 1-10% (TRD) 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%) Blood pressure Aged <65 yr Systolic BP ≥40 mm Hg increase (8%) Diastolic BP ≥110 mm Hg (4%) Systolic BP ≥180 mm Hg (3%) Aged ≥65 yr Systolic BP ≥180 mm Hg (3%) Nausea and vomiting 56 mg Vomiting (6%) 84 mg Nausea, severe (3%) Vomiting, severe (3%) 1-10% (MDD) Constipation (10%) Euphoric mood (7%) Vertigo (6%) Hyperhidrosis (5%) Tachycardia (4%) Dry mouth (4%) Lethargy (4%) Oropharyngeal pain (4%) Throat irritation (4%) Intentional self-injury (3%) Toothache (2%) Felling of relaxation (2%) Myalgia (2%) Confusion (2%) Dysphoria (2%) Pollakiuria (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 REMS 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) Patients treated in outpatient settings (e.g. medical offices and clinics) must be enrolled in the program Pharmacies must be certified and only dispense esketamine to healthcare settings that are certified More information is available at www.spravatorems.com or 1-855-382-6022 Healthcare setting must be certified Only dispensed and administered in healthcare settings Patients treated in outpatient settings must be enrolled in the program Administered by patients under the direct observation of a healthcare provider and monitored by a healthcare provider for at least 2 hr after administration Contraindications 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 Cautions Available only through a restricted access program (REMS) Sedation is likely to occur Dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization reported 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 Pregnancy 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 https://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants/ 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 Contraception 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 Lactation 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 treatmentPregnancy 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 Absorption Bioavailability: 48% Peak plasma time: 20-40 minutes after last nasal spray of treatment session Distribution Vd (IV): 709 L Protein bound: 43-45% Metabolism 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 Elimination Half-life: 7-12 hr; 8 hr (noresketamine) Clearance (IV): 89 L/hr Excretion 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 Treatment session(s) missed resulting in worsening symptoms: Consider returning to previous dosing schedule Treatment session(s) missed with no worsening symptoms: Continue current dosing schedule Storage 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 BRAND FORM. UNIT PRICE PILL IMAGE Spravato nasal- 56 mg (28 mg x 2) liquidSpravato nasal- 28 mg liquidSpravato nasal- 84 mg (28 mg x 3) liquidCopyright © 2010 First DataBank, Inc.A Patient Handout is not currently available for this monograph.Print FormularyPatient DiscountsAdding plans allows you to compare formulary status to other drugs in the same class.To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.Create Your List of PlansAdding plans allows you to:View the formulary and any restrictions for each plan.Manage and view all your plans together – even plans in different states.Compare formulary status to other drugs in the same class.Access your plan list on any device – mobile or desktop. The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information. View explanations for tiers and restrictions 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. QL Quantity Limits Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered. ST Step Therapy Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription. OR Other Restrictions Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with