VERKET INJECTION (Each ml contains Esketamine Hydrochloride 50mg)

Indications

• Peri-operative analgesia
• Management of treatment-resistant depression
• Dissociative anaesthesia

Dosage

Adults: For intravenous administration: Initial dose of 0.5–1 mg/kg, followed by maintenance doses of 0.25–0.5 mg/kg every 10–15 minutes, adjusted according to response. For intramuscular injection: Initial dose of 2–4 mg/kg, followed by maintenance doses of 1–2 mg/kg every 10–15 minutes, adjusted according to response. For continuous intravenous infusion: 0.5–3 mg/kg/hour, adjusted according to response.

Mechanism of action

Esketamine blocks NMDA receptors, interrupting excitatory neurotransmission associated with pain and mood regulation. It also influences neural pathways that govern emotional behavior, contributing to its antidepressant effects. The primary metabolite, noresketamine, retains some activity at NMDA receptors, albeit with reduced affinity.

Pharmacodynamics

As a central nervous system depressant, esketamine induces sedation, dizziness, and lethargy, alongside dissociative and antidepressant effects. Acute use may impair cognitive functions such as attention and motor skills. Studies indicate that at therapeutic doses, esketamine does not significantly prolong QTc intervals, though it may lead to increased heart rate and blood pressure.

Pharmacokinetics

Esketamine is rapidly absorbed and distributed throughout the body, with its effects beginning shortly after administration. It undergoes extensive metabolism, primarily through the liver, and its metabolites are excreted via urine. The pharmacokinetic profile supports both intravenous and intranasal routes of administration, with specific dosing adjustments based on individual response.

Adverse effects

• Sedation
• Dizziness
• Lethargy
• Impaired attention
• Impaired judgment
• Impaired thinking
• Impaired reaction speed
• Impaired motor skills
• Increased heart rate
• Elevated blood pressure

Interactions

• Severe: esketamine + ergotamine (increases risk of elevated blood pressure)
• Moderate: esketamine + cobicistat (increases exposure)
• Moderate: esketamine + idelalisib (increases exposure)
• Moderate: esketamine + mitotane (decreases exposure)
• Moderate: esketamine + clarithromycin (increases exposure)
• Moderate: esketamine + rifampicin (decreases exposure)

Precautions

• Monitor blood pressure regularly
• Assess for potential CNS depression
• Use caution in patients with a history of cardiovascular disease
• Avoid use in patients with uncontrolled hypertension

Pregnancy

The safety of esketamine during pregnancy has not been established; use only if the benefits outweigh the risks.

Breast-feeding

It is not known whether esketamine is excreted in human milk; caution should be exercised when administering to nursing women.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Intravenous injection
• Intramuscular injection
• Nasal spray

Mechanism of action

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.

Pharmacodynamics

**General effects** Esketamine is considered a central nervous system (CNS) depressant agent. It may cause sedation, dizziness, and lethargy, among other symptoms. This drug has dissociative and antidepressant properties. Acutely, esketamine may impair attention, judgment, thinking, reaction speed, and motor skills. Two placebo-controlled studies were performed to evaluate the effects of ketamine on the ability to drive. The effects of esketamine 84 mg were comparable to placebo at 6 hours and 18 hours post-ingestion. **Effects on cardiac electrophysiology** The effect of esketamine (84 mg nasal spray and 0.8 mg/kg esketamine intravenously infused over 40 minutes) on the QTc interval was studied in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy volunteers. A marked increase in heart rate (higher than 10 bpm) was measured in subjects receiving intranasal and intravenous esketamine. Summative evidence from both nonclinical and clinical data suggests a lack of clinically relevant QTc prolongation at the normal therapeutic dose of esketamine. **Effects on blood pressure** Eskestamine causes increases in systolic and/or diastolic blood pressure at all therapeutic doses. Peak blood pressure elevation after esketamine administration occurs about 40 minutes after administration and lasts approximately 4 hours. **Cognitive effects** In a study of healthy volunteers, one dose of this agent caused decline in cognitive performance 40 minutes after administration. Compared to subjects ingesting a placebo, esketamine-treated subjects required a higher level of effort to complete assigned cognitive tests at 40 minutes after administration. Cognitive performance and mental effort were found to be similar between esketamine and placebo at 2 hours after administration. Reports of long-term memory or cognitive impairment have been made following repeated ketamine misuse or abuse. No adverse effects of esketamine nasal spray on cognitive function were seen in a one-year open-label safety study. The long-term cognitive effects of esketamine have not been studied for more than a 1 year period, therefore, the risk of cognitive decline with long-term use is not yet confirmed.