Esketamine

Uses

Esketamine is a NMDA receptor antagonist used for treatment-resistant depression.

This drug is indicated in conjunction with an oral antidepressant for the treatment of treatment-resistant depression (TRD) in adults .

Note: Esketamine is not approved as an anesthetic agent. The safety and effectiveness of esketamine as an anesthetic agent have not been established to this date .

Esketamine is also used to associated treatment for these conditions: Pain, Treatment Resistant Depression (TRD), Intubations

How Esketamine works

Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The exact mechanism by which esketamine acts as an antidepressant is unknown. The primary circulating metabolite of esketamine (noresketamine) shows activity at the same receptor with a weaker affinity .

Toxicity

Ketamine hydrochloride LD50: 447 mg/kg, Rat (oral)

Neurotoxicity

In a one-dose neuronal toxicity study with esketamine intranasal administration to adult female rats, no finding of neuronal vacuolation in the brain occurred with doses up to the equivalent of the maximum recommended human dose of 84 mg/day. In a second single dose neurotoxicity study performed with intranasal esketamine administration in adult female rats, no observation of neuronal necrosis up to a dose equivalent to the maximum recommended human dose was made. Neuronal vacuolation was not evaluated in this study . The relevance of these findings in humans is unknown at this time .

A note on dependence and tolerance

Reports of physical dependence have been made following prolonged use of ketamine. Withdrawal signs and symptoms after abrupt discontinuation or significant dosage reduction of a drug is a common manifestation of drug dependence. There were no withdrawal symptoms observed up to 4 weeks in subjects after stopping esketamine treatment. Withdrawal symptoms have been observed after the discontinuation of frequently used (more than weekly) high doses of ketamine for a longer duration. These symptoms of withdrawal have a higher chance of occurring if esketamine was similarly abused .

Symptoms of withdrawal reported to be associated with daily intake of high ketamine doses include craving, fatigue, poor appetite, and anxiety. Therefore, monitor esketamine-treated patients for symptoms and signs of physical dependence upon the discontinuation of the drug. Tolerance has been reported with prolonged use of ketamine. Tolerance is characterized by a decreased response to a drug following repeated doses (i.e., a higher dose of a drug is required to produce the same effect that was previously achieved at a lower dose). Comparable tolerance would be expected to occur with long-term use of esketamine .

Use in pregnancy

This drug may cause fetal harm, based on the findings of animal studies. Pregnancy planning and prevention in females of reproductive potential should occur before the initiation of esketamine treatment . There is a pregnancy registry for women who exposed to esketamine during pregnancy. The goal of the registry is to gather data about the health of women and infants exposed to esketamine.

Use in lactation

Esketamine is present in human milk. No safety data on the effects of esketamine on the breastfed infant or on milk production are available. Studies in young animals report neurotoxicity. Due to the risk of neurotoxicity, advise patients that breastfeeding is not recommended during treatment with this drug .

Food Interaction

• Avoid alcohol. Ingesting alcohol may increase the sedative effects of esketamine.
• Take separate from meals. Avoid eating for at least 2 hours, and drinking for at least 30 minutes before taking esketamine.

[Moderate] ADJUST DOSING INTERVAL: Nausea and vomiting may occur following intranasal administration of esketamine.

In clinical studies, nausea and vomiting were reported in approximately 25% and 10% of esketamine-treated patients, respectively.

MANAGEMENT: To help prevent nausea and vomiting, patients should be advised not to eat for at least 2 hours before intranasal administration of esketamine and not to drink liquids for at least 30 minutes prior to administration.

Esketamine Alcohol interaction

[Moderate] GENERALLY AVOID:

Alcohol may potentiate some of the pharmacologic effects of central nervous system (CNS)-active agents.

Use in combination may result in additive CNS depression and/or impairment of judgment, thinking, and psychomotor skills.

Patients receiving CNS-active agents should be advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled against driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Esketamine Hypertension interaction

[Major] Esketamine causes an increase in systolic and

The increase peaks approximately 40 minutes after administration of esketamine, and lasts for about 4 hours.

Blood pressure should be monitored prior and after administration.

If baseline blood pressure is elevated before administering (e.g., >140 mmHg systolic, >90 mmHg diastolic), consider the risks of short term increases in blood pressure and benefit of treatment in patients with treatment- resistant depression (TRD).

Do not administer esketamine if an increase in blood pressure or intracranial pressure poses a serious risk.

Esketamine is contraindicated in patients with aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels), arteriovenous malformations, or a history of intracerebral hemorrhage.

Esketamine Drug Interaction

Major: amphetamine / dextroamphetamine, methylphenidate, lisdexamfetamineModerate: lorazepam, diphenhydramine, lamotrigine, brexpiprazole, quetiapine, alprazolamUnknown: loratadine, duloxetine, omega-3 polyunsaturated fatty acids, escitalopram, paroxetine, desvenlafaxine, fluoxetine, vortioxetine, cholecalciferol, bupropion, sertraline

Esketamine Disease Interaction

Major: high blood pressure, psychosis, substance abuseModerate: hepatic impairment

Volume of Distribution

The average steady-state volume of distribution of esketamine administered by the intravenous route is 709 L .

Elimination Route

Due to the fact that this drug is administered via nasal spray, absorption is rapid. The mean absolute bioavailability is approximately 48% after esketamine nasal spray administration. The time to achieve peak esketamine plasma concentration is 20 to 40 minutes after the last nasal spray of esketamine. Inter-subject variability of esketamine ranges from 27% to 66% for Cmax (maximum concentration) and 18% to 45% for AUC (area under the curve). The intra-subject variability of esketamine is about 15% for Cmax and 10% for AUC .

Half Life

The mean terminal half-life (t1/2) ranges from 7 to 12 hours .

Clearance

The average clearance of esketamine is approximately 89 L/hour following intravenous administration .

Elimination of the major esketamine metabolite, noresketamine, from plasma is slower than esketamine. The decrease of noresketamine plasma concentrations occurs in a biphasic fashion, with a more rapid decline for the first 4 hours post-administration, and an average terminal t1/2 of approximately 8 hours .

Elimination Route

Less than 1% of a dose of nasal esketamine is measured as unchanged drug, excreted in the urine. Following intravenous (IV) or oral (PO) administration, esketamine-derived metabolites were mainly recovered in urine (≥ 78% of a radiolabeled dose), and a smaller percentage was measured in the feces (≤ 2% of a radiolabeled dose) .

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