Esketamine


Generic Medicine Info
Indications and Dosage
Intramuscular, Intravenous
Induction and maintenance of general anaesthesia
Adult: Alone or in combination with another anaesthetic: Induction: Initially, 0.5-1 mg/kg via slow IV inj or 2-4 mg/kg via IM inj. Maintenance: Half of the initial dose every 10-15 minutes as necessary. Alternatively, 0.5-3 mg/kg/hour via continuous IV infusion. In patients with multiple injuries and those with poor general condition (e.g. shock): Dose reduction (approx half of the usual dose) is required. All doses must be titrated according to individual requirements.

Intramuscular, Intravenous
Analgesia in emergency medicine
Adult: 0.125-0.25 mg/kg via slow IV inj or 0.25-0.5 mg/kg via IM inj, may be adjusted according to individual requirements.

Intravenous
Analgesic supplementation of regional and local anaesthesia
Adult: 0.125-0.25 mg/kg/hour via infusion. Dose must be titrated according to individual requirements.

Nasal
Major depressive disorder with acute suicidal thoughts or behaviour
Adult: In combination with oral antidepressant: Each nasal spray device delivers 2 sprays (1 spray per nostril) containing a total of 28 mg esketamine: Initially, 84 mg twice weekly for 4 weeks, may be decreased to 56 mg twice weekly according to patient tolerability. Evaluate therapeutic benefit after 4 weeks to determine the need for continuation of treatment. Missed treatment session(s): If there are no signs of worsening of symptoms, continue current dosing schedule.

Nasal
Treatment-resistant major depressive disorder
Adult: In combination with oral antidepressant (e.g. SSRI, serotonin and norepinephrine reuptake inhibitor [SNRI]): Each nasal spray device delivers 2 sprays (1 spray per nostril) containing a total of 28 mg esketamine: Induction phase (weeks 1-4): Initially, 56 mg on day 1, followed by 56 mg or 84 mg twice weekly. Maintenance phase: Weeks 5-8: 56 mg or 84 mg once weekly. Week 9 onwards: 56 mg or 84 mg every 1-2 weeks, dosing frequency must be individualised to the lowest frequency to maintain response. Assess the need for continued treatment at the end of the induction phase and periodically, thereafter. Observe a 5-minute rest between use of each device. Recommended treatment duration is at least 6 months once depressive symptoms improve. Missed treatment session(s): 1 or 2 sessions: Next session must be scheduled when the next session was scheduled to occur based on current treatment frequency; >2 sessions: Dose or frequency adjustment may be appropriate based on clinical judgement.
Elderly: ≥65 years In combination with oral antidepressant (e.g. SSRI, SNRI): Each nasal spray device delivers 2 sprays (1 spray per nostril) containing a total of 28 mg esketamine: Induction phase (weeks 1-4): Initially, 28 mg on day 1, followed by 28 mg, 56 mg or 84 mg twice weekly. Maintenance phase: Weeks 5-8: 28 mg, 56 mg or 84 mg once weekly. Week 9 onwards: 28 mg, 56 mg or 84 mg every 1-2 weeks; dosing frequency must be individualised to the lowest frequency to maintain response. All dose changes must be in 28 mg increments. Assess the need for continued treatment at the end of the induction phase and periodically, thereafter. Observe a 5-minute rest between use of each device. Recommended treatment duration is at least 6 months once depressive symptoms improve. Missed treatment session(s): 1 or 2 sessions: Next session must be scheduled when the next session was scheduled to occur based on current treatment frequency; >2 sessions: Dose or frequency adjustment may be appropriate based on clinical judgement.
Special Patient Group
Nasal:
Treatment-resistant major depressive disorder:
In patients of Japanese ancestry, in combination with oral antidepressant (e.g. SSRI, SNRI): Induction phase (weeks 1-4): Initially, 28 mg on day 1, followed by 28 mg, 56 mg or 84 mg twice weekly. Maintenance phase: Weeks 5-8: 28 mg, 56 mg or 84 mg once weekly. Week 9 onwards: 28 mg, 56 mg or 84 mg every 1-2 weeks, dosing frequency must be individualised to the lowest frequency to maintain response. All dose changes must be in 28 mg increments. Assess the need for continued treatment at the end of the induction phase and periodically, thereafter. Observe a 5-minute rest between use of each device. Recommended treatment duration is at least 6 months once depressive symptoms improve.
Hepatic Impairment
IV/IM:
Dose reduction may be required.

Nasal:
Severe (Child-Pugh class C): Not recommended.
Reconstitution
Solution for inj: May be diluted in dextrose 5% or 0.9% NaCl solution.
Incompatibility
Solution for inj: May form precipitate with barbiturates, diazepam and doxapram.
Contraindications
Patient with condition in which an increased blood or intracranial pressure poses a serious risk (e.g. aneurysmal vascular disease, history of intracerebral haemorrhage, arteriovenous malformation, recent [within 6 weeks] CV event including MI). IV/IM: Eclampsia and pre-eclampsia; ischaemic cardiac disorders (when used as sole anaesthetic agent); concomitant use with xanthine derivatives and ergometrine.
Special Precautions
Patient with existing or history of psychosis or severe psychiatric disturbances; history of substance abuse or dependence (including alcohol), unstable hypertension, inadequately treated hyperthyroidism, condition related to increased intracranial pressure (e.g. hypertensive encephalopathy, intrathecal therapy with ventricular shunts), CV disease (e.g. decompensated heart failure, unstable angina pectoris, uncontrolled brady- or tachyarrhythmia). IV/IM: Patient under chronic or acute influence of alcohol; undergoing eye examination or eye surgery (in which intraocular pressure must not increase); with condition needing a relaxed uterus myometrium (e.g. prolapsed umbilical cord, uterus rupture), multiple injuries or poor general condition. Nasal: Patient with existing or history of mania or bipolar disorder; history of suicide-related events or exhibiting significant degree of suicidal ideation, other cerebrovascular diseases, significant or unstable respiratory condition (e.g. sleep apnoea with morbid obesity, significant pulmonary insufficiency); Japanese ancestry. Hepatic impairment. Elderly. Pregnancy and lactation. Esketamine nasal spray is not recommended in patient with severe hepatic impairment.
Adverse Reactions
Significant: Respiratory depression (high IV doses or rapid IV inj), abnormal LFT, increased salivation, CNS depression (e.g. sedation), dissociation or perceptual changes (including depersonalisation, derealisation, distortion of time, space and illusions), short-term cognitive impairment, increased blood pressure (transient), lower urinary tract symptoms (e.g. pollakiuria, dysuria, micturition urgency, nocturia, cystitis).
Cardiac disorders: Tachycardia.
Ear and labyrinth disorders: Hyperacusis, tinnitus, vertigo.
Eye disorders: Blurred vision.
Gastrointestinal disorders: Nausea, vomiting, dysgeusia, dry mouth, hypoaesthesia oral, throat irritation.
General disorders and administration site conditions: Lethargy, feeling abnormal, feeling drunk, feeling of body temperature change (nasal).
Hepatobiliary disorders: Drug-induced liver injury (IV/IM).
Investigations: Increased heart rate, oxygen consumption (IV/IM).
Nervous system disorders: Dizziness, tremor, paraesthesia, hypoaesthesia; tonic and clonic movements, nystagmus (IV/IM); headache (nasal).
Psychiatric disorders: Anxiety, hallucination, irritability, mental impairment, dysarthria, panic attack; recovery reactions (e.g. nightmares, motor restlessness) [IV/IM]; euphoric mood (nasal).
Respiratory, thoracic and mediastinal disorders: Increased vascular resistance in pulmonary circulation, increased mucus secretion, laryngospasm (IV/IM); nasal discomfort, nasal dryness including nasal crusting, nasal pruritus.
Skin and subcutaneous tissue disorders: Morbilliform rash, exanthema (IV/IM); hyperhidrosis (nasal).
Vascular disorders: Rarely, hypotension (IV/IM).
Patient Counseling Information
This drug may cause somnolence, drowsiness, dizziness, or reduced alertness, if affected, do not drive or operate machinery until the next day after a restful sleep.
Monitoring Parameters
For treatment of depression: Monitor for adverse reactions for at least 2 hours after each treatment session. Obtain blood pressure prior to and after dose administration (approx 40 minutes post-dose then as necessary for at least 2 hours post-dose). Evaluate patient risk for abuse or misuse, psychosis, CV and cerebrovascular conditions before initiation of therapy. Monitor for signs and symptoms of abuse and misuse; urinary tract or bladder symptoms during treatment. Observe for clinical worsening, suicidality, or unusual changes in behaviour (particularly during the initial months of therapy and dose changes).
Overdosage
IV/IM: Symptoms: Convulsions, cardiac arrhythmia, respiratory arrest. Management: In case of respiratory arrest, treatment with assisted or controlled ventilation must be provided until sufficient spontaneous respiration is achieved. May give IV diazepam to treat convulsions, or if response is inadequate, may give phenytoin or thiopental.
Drug Interactions
May prolong effect with hypnotics or neuroleptics. May prolong the recovery phase with barbiturates and opiates. Anaesthetic effect of halogenated hydrocarbons (e.g. halothane, isoflurane, desflurane, sevoflurane) may be potentiated by IV/IM esketamine. May prolong the effect of depolarising (e.g. suxamethonium) and non-depolarising (e.g. pancuronium) muscle relaxants. Risk of cardiac arrhythmia of epinephrine may be increased with concurrent use of esketamine and halogenated hydrocarbons. Increased plasma concentration with CYP3A4 inhibitors (e.g. clarithromycin). Decreased plasma concentration with CYP3A4 inducers (e.g. rifampicin). May increase sedation with CNS depressants (e.g. benzodiazepines, opioids). May increase blood pressure with psychostimulants (e.g. amphetamines, methylphenidate, modafinil), thyroid hormones, vasopressin, MAOIs (e.g. tranylcypromine, selegiline, phenelzine). Reduced plasma concentration of oral midazolam.
Potentially Fatal: May decrease the convulsion threshold with concomitant use of xanthine derivatives (e.g. aminophylline, theophylline). Concomitant use of IV/IM esketamine with ergometrine may increase the risk of elevated blood pressure.
Food Interaction
May increase sedation with alcohol.
Action
Description: Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the inotropic glutamate receptor N-methyl-D-aspartate (NMDA) receptor. Although its exact mechanism for the treatment of depression is unknown, it is expected to exert its effect by blocking the NMDA receptors which transiently increases the release of glutamate, resulting to increased stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and neurotrophic signalling thus restoring the synaptic function of the brain regions responsible in the mood and emotional regulation. Additionally, it has anaesthetic effect (at increasing doses) and analgesic property; it causes cataleptic like state with loss of consciousness and amnesia by interrupting the brain’s association pathways.
Pharmacokinetics:
Absorption: Rapidly absorbed from the nasal mucosa (intranasal). Bioavailability: Approx 90% (IM); approx 48% (nasal). Time to peak plasma concentration: 20-40 minutes (nasal).
Distribution: Rapidly distributed into highly perfused tissues (e.g. brain, lungs, heart), followed by peripheral tissues, muscle, and fat after IV/IM administration. Crosses the placenta and enters breast milk. Volume of distribution: 709 L (IV). Plasma protein binding: Approx 50% (IV/IM); approx 43-45% (nasal).
Metabolism: Extensively metabolised in the liver via N-demethylation mainly by CYP2B6 and CYP3A4, and to lesser extent by CYP2C9 and CYP2C19, into the active metabolite, noresketamine. Noresketamine is further metabolised by CYP-dependent pathways and certain subsequent metabolites undergo metabolism via glucuronidation.
Excretion: IV: Mainly via urine (approx 78% as metabolites, <1% as unchanged drug); faeces (approx 2% as metabolites). Terminal elimination half-life: IV: Approx 79 minutes (continuous infusion), 186 minutes (low dose IV inj). Nasal: 7-12 hours (as esketamine); approx 8 hours (as noresketamine).
Chemical Structure

Chemical Structure Image
Esketamine_01

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 182137, Esketamine. https://pubchem.ncbi.nlm.nih.gov/compound/Esketamine. Accessed Jan. 26, 2021.

Storage
Nasal spray: Store between 15-30°C. Solution for inj: Diluted solutions in dextrose 5% or 0.9% NaCl may be stored at 25°C for 48 hours. Do not freeze. Refer to detailed product guideline for specific storage conditions.
References
Anon. Esketamine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 20/11/2020.

Buckingham R (ed). Esketamine Hydrochloride. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 20/11/2020.

Janssen-Cilag (New Zealand) Ltd. Spravato Nasal Spray data sheet 19 December 2019. Medsafe. http://www.medsafe.govt.nz/. Accessed 20/11/2020.

Joint Formulary Committee. Esketamine. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 20/11/2020.

Spravato 28 mg Nasal Spray, Solution (Janssen-Cilag International NV). European Medicines Agency [online]. Accessed 04/12/2020.

Spravato Solution (Janssen Pharmaceuticals Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 20/11/2020.

Vesierra 25 mg/mL Solution for Injection/Infusion (Pfizer Limited). MHRA. https://products.mhra.gov.uk/. Accessed 03/12/2020.

Disclaimer: This information is independently developed by MIMS based on Esketamine from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2021 MIMS. All rights reserved. Powered by MIMS.com
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