Esketamine kalceks

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESKETAMINE KALCEKS (ESKETAMINE KALCEKS)

Composition:

Active substance: esketamine hydrochloride;

1 ml of solution (1 ampoule) contains esketamine hydrochloride 5.77 mg (equivalent to 5 mg of esketamine);

5 ml of solution (1 ampoule) contains esketamine hydrochloride 28.85 mg (equivalent to 25 mg of esketamine);

1 ml of solution (1 ampoule) contains esketamine hydrochloride 28.85 mg (equivalent to 25 mg of esketamine);

2 ml of solution (1 ampoule) contains esketamine hydrochloride 57.7 mg (equivalent to 50 mg of esketamine);

10 ml of solution (1 ampoule) contains esketamine hydrochloride 288.5 mg (equivalent to 250 mg of esketamine);

Excipients: sodium chloride, hydrochloric acid concentrated, water for injections.

Pharmaceutical form. Solution for injection and infusion.

Main physicochemical properties: clear, colourless solution.

Pharmacotherapeutic group. Anaesthetics. Agents for general anaesthesia.

ATC code N01AX14.

Pharmacological Properties

Pharmacodynamics

Esketamine is a chiral derivative of cyclohexanone that exerts analgesic and, with increasing doses, anesthetic effects. Esketamine produces so-called dissociative anesthesia. By interfering with associative pathways in the brain, esketamine induces a cataleptic state resembling unconsciousness and amnesia.

The components of racemic ketamine include esketamine and (R)-ketamine. Analgesic action is achieved primarily by esketamine blocking the N-methyl-D-aspartate (NMDA) receptors for aspartate. The potency ratio of analgesic anesthesia between the R- and S-isomers is approximately 1:3.

Esketamine exerts pronounced local anesthetic effects on the spinal cord and peripheral nerves. Esketamine does not cause respiratory or circulatory depression; it only slightly interferes with protective reflexes. During anesthesia with esketamine, muscle tone is maintained or even enhanced, and protective reflexes are generally preserved. The seizure threshold is not lowered. With spontaneous respiration, an increase in intracranial pressure may occur, which can be avoided by adequate pulmonary ventilation.

Due to its sympathomimetic effect, esketamine increases arterial blood pressure and heart rate, leading to increased myocardial oxygen consumption and coronary blood flow. Esketamine exerts negative inotropic and antiarrhythmic effects on the heart. Peripheral resistance changes only slightly due to opposing effects.

After administration of esketamine, moderate hyperventilation may be observed, but this does not significantly affect blood gas exchange.

Esketamine exerts a bronchodilatory effect, making it suitable for use in patients with asthma and during mechanical ventilation in patients with status asthmaticus.

Pharmacokinetics

Differences in the pharmacokinetics of esketamine and racemic (±) ketamine are absent or very minor. Therefore, reference can be made to the pharmacokinetic data of racemic ketamine (hereinafter referred to as ketamine). The pharmacokinetics of ketamine are linear.

Absorption

Ketamine is rapidly absorbed after intramuscular administration, with a bioavailability of 90%.

Distribution

Plasma protein binding is approximately 50%. Ketamine has high lipid solubility.

Ketamine rapidly distributes into highly perfused tissues (e.g., heart, lungs, and brain), followed by muscle and peripheral tissues, and subsequently into adipose tissue. In humans, after an intravenous bolus dose of 2.5 mg/kg, the distribution phase of ketamine lasts approximately 45 minutes, with a half-life of 10 to 15 minutes, which corresponds to the duration of the anesthetic effect (approximately 20 minutes). Plasma concentration of esketamine is approximately 2.6 µg/mL at 1 minute and 0.9 µg/mL at 5 minutes after an intravenous bolus dose of 1 mg/kg esketamine. Peak plasma concentration of esketamine is approximately 0.14 µg/mL at 25 minutes after an intramuscular dose of 0.5 mg/kg esketamine.

Biotransformation

Ketamine is metabolized in the liver by demethylation (via the cytochrome P450 system) to the significantly less potent primary metabolite norketamine and other inactive metabolites. The enzyme CYP3A4 is the primary enzyme responsible for N-demethylation of ketamine to norketamine in human liver microsomes; interactions with CYP2B6 and CYP2C9 enzymes are secondary. Metabolism is rapid and largely complete, with a metabolic clearance ranging from 1200 to 1500 mL/min.

Elimination

The terminal half-life of ketamine ranges from 79 minutes (after continuous infusion) to 186 minutes (after low-dose intravenous administration). Approximately 98% of ketamine and its metabolites are excreted via the kidneys and 2% via feces, with only a negligible amount excreted unchanged. About 95% of the administered dose is eliminated within the first 24 hours.

Clinical characteristics.

Indications.

• Induction and maintenance of general anesthesia as the sole anesthetic agent or in combination with another anesthetic;
• anesthesia and analgesia in emergency medicine;
• supplementation to regional or local anesthesia.

Contraindications.

• Patients for whom an increase in arterial or intracranial pressure poses a serious risk.
• As the sole anesthetizing agent in patients with evident ischemic cardiac disorders.
• Eclampsia and pre-eclampsia.
• In combination with xanthine derivatives and ergometrine.
• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Concomitant administration is contraindicated:

The seizure threshold may be lowered when used in combination with xanthine derivatives (e.g., aminophylline, theophylline); therefore, such combinations should be avoided. The medicinal product should not be used in combination with ergometrine.

Concomitant administration with caution:

Sympathomimetics (direct or indirect-acting), thyroid hormones, and vasopressin may lead to increased arterial pressure and heart rate, which should be taken into account when administering esketamine concomitantly.

When used in combination with sedative medicinal products, benzodiazepines, or antipsychotics, adverse effects are reduced, but the duration of action of esketamine is prolonged.

Barbiturates and opioids administered concurrently with esketamine may prolong the recovery phase.

Diazepam is known to increase the elimination half-life of racemic ketamine and prolong its pharmacodynamic effect. Therefore, dose adjustment may also be required for esketamine.

The anesthetic effect of halogenated hydrocarbons (e.g., halothane, isoflurane, desflurane, sevoflurane) is enhanced by the administration of esketamine; therefore, lower doses of halogenated hydrocarbons may be required.

The effect of non-depolarizing (e.g., pancuronium) and depolarizing (e.g., suxamethonium) muscle relaxants may be prolonged due to the use of esketamine.

The risk of cardiac arrhythmia after adrenaline administration may be increased when esketamine and halogenated hydrocarbons are administered simultaneously.

An increase in arterial pressure is observed when esketamine and vasopressin are used concomitantly.

Medicinal products that inhibit CYP3A4 enzyme activity generally reduce hepatic clearance, leading to increased plasma concentrations of CYP3A4 substrate drugs such as esketamine. When esketamine is used concomitantly with agents that inhibit CYP3A4, a reduction in the dose of esketamine may be required to achieve the desired clinical effect.

Medicinal products that induce CYP3A4 enzyme activity generally increase hepatic clearance, leading to decreased plasma concentrations of CYP3A4 substrate drugs such as esketamine. When esketamine is used concomitantly with agents that induce CYP3A4, an increase in the dose of esketamine may be required to achieve the desired clinical effect.

Special precautions for use.

Es ketamine should be used with caution in the following situations:

• Hypovolemia, dehydration, or heart disease, particularly ischemic heart disease (e.g., congestive heart failure, myocardial ischemia, and myocardial infarction), due to a significant increase in myocardial oxygen consumption;
• Decompensated heart failure and untreated hypertension;
• Unstable angina or myocardial infarction within the past 6 months;
• Mild to moderate hypertension and tachyarrhythmia;
• Increased intracranial pressure and injury or disease of the central nervous system, as elevation of cerebrospinal fluid pressure has been reported in association with ketamine anesthesia;
• Pulmonary or upper respiratory infection (esketamine sensitizes the pharyngeal reflex, potentially causing laryngospasm);
• In patients with elevated intraocular pressure (e.g., with glaucoma), penetrating eye injury, or during eye examination or surgery where intraocular pressure must not increase;
• Acute intermittent porphyria (due to the potential to provoke a porphyric reaction);
• Patients under chronic or acute alcohol influence;
• Patients who have or have had serious psychiatric disorders;
• Poorly controlled hyperthyroidism;
• Situations requiring a relaxed uterine myometrium (e.g., threatened uterine rupture, umbilical cord prolapse).

Es ketamine is metabolized in the liver, and hepatic clearance is required for termination of clinical effects. Abnormal liver function tests have been reported with esketamine use, particularly with prolonged administration (>3 days) or drug abuse. Prolonged duration of action may occur in patients with cirrhosis or other forms of hepatic impairment. In such patients, dose reduction should be considered.

When high doses are administered or rapid intravenous injection is performed, respiratory depression may occur.

Since aspiration and respiratory depression cannot be completely ruled out, intubation and ventilation equipment must be readily available.

Continuous cardiac monitoring during surgery is necessary for patients with hypertensive disease or cardiac decompensation.

If esketamine is administered to patients in shock, principles of shock therapy (volume replacement, oxygenation) must be taken into account. Particular caution is required in severe shock states when arterial pressure is difficult to measure or is absent.

Since the need for additional anesthetics or muscle relaxants cannot always be predicted, patients should fast for 4–6 hours before surgery to prevent aspiration. Since pharyngeal reflexes usually remain intact, mechanical stimulation of the pharynx should be avoided unless muscle relaxants are used with appropriate care.

Increased salivation should be prophylactically treated with atropine.

In diagnostic and therapeutic procedures involving the upper airways, hyperreflexia and laryngospasm are possible, especially in children. Therefore, muscle relaxants and controlled ventilation may be required during procedures on the pharynx, larynx, and bronchi.

For surgical procedures that may involve visceral pain, muscle relaxation and additional analgesia are indicated (controlled ventilation and administration of nitrous oxide/oxygen).

After outpatient anesthesia, patients should be accompanied home, and patients should not consume alcohol for the next 24 hours.

Prolonged use

Cases of cystitis, including hemorrhagic cystitis, have been reported in patients using racemic ketamine for prolonged periods (from one month to several years). Similar effects may also occur after abuse of esketamine (see section "Special precautions for use" ("Abuse and dependence")). Hepatotoxicity has also been reported in patients with prolonged use of the drug (>3 days).

Abuse and dependence

Reports indicate that racemic ketamine has been used as a recreational drug. These reports describe various symptoms, including flashbacks, hallucinations, dysphoria, anxiety, insomnia, or disorientation. Cases of cystitis, including hemorrhagic cystitis, and hepatotoxicity have also been documented. Therefore, such effects cannot be excluded during esketamine use.

In individuals with a history of substance abuse or addiction, dependence and tolerance to esketamine may develop. Therefore, esketamine should be prescribed with caution.

The risk of psychiatric reactions occurring during recovery from anesthesia (see section "Adverse reactions") may be significantly reduced by concomitant administration of a benzodiazepine.

This medicinal product contains less than 1 mmol of sodium (23 mg) per milliliter, i.e., essentially "sodium-free"*.

*One 2-mL ampoule contains 2.36 mg of sodium.
One 5-mL ampoule contains 15.75 mg of sodium.
One 10-mL ampoule contains 11.8 mg of sodium.

Use during pregnancy or breastfeeding.

Pregnancy

There are no confirmed data on the use of esketamine in pregnant women. Animal studies have demonstrated reproductive toxicity. The use of esketamine should be limited during pregnancy and administered only after careful assessment if the potential benefit to the mother outweighs the possible risk to the fetus.

Es ketamine crosses the placental barrier and may cause respiratory depression in the newborn if administered during labor.

Breastfeeding

Es ketamine is excreted in breast milk, but effects on the infant are unlikely when the drug is used at therapeutic doses.

Fertility

There are no data on the effect of esketamine on human fertility.

Ability to affect reaction speed when driving or operating machinery.

Treatment with esketamine may impair reaction time. This should be taken into account in situations requiring special alertness, such as driving or operating machinery.

The patient should not drive or operate machinery for at least 24 hours after anesthesia with esketamine.

Method of Administration and Dosage

Esketamine should be administered as a slow intravenous (i.v.) or intramuscular (i.m.) injection. If necessary, the injection may be repeated or administered as an infusion.

For hospital or pre-hospital emergency use only. Esketamine must be administered only under the supervision of an anesthesia specialist. Life-support equipment must also be available.

Wherever possible, standard fasting guidelines should be followed when administering esketamine, generally 4 to 6 hours prior to anesthesia.

Although esketamine has only a minimal effect on protective reflexes of the pharynx and airways, the possibility of aspiration of fluids or solids cannot be completely excluded. High doses or excessively rapid intravenous administration may cause respiratory depression.

Increased salivation may occur with the use of esketamine, which can be prevented by administering atropine or another anticholinergic agent.

Adults

For induction of general anesthesia, administer 0.5–1 mg/kg esketamine intravenously or 2–4 mg/kg intramuscularly.

For maintenance of general anesthesia, half of the initial dose should be administered as needed, usually every 10–15 minutes.

Esketamine may also be administered as a continuous infusion at a rate of 0.5 to 3 mg/kg/hour.

Dosage reduction is required in patients with multiple injuries or poor general condition. For example, the dose should be reduced in patients who have experienced shock; as a guideline, approximately half the usual dose should be administered.

For analgesic supplementation to regional and local anesthesia, administer 0.125–0.25 mg esketamine/kg/hour as an intravenous infusion.

For analgesia in emergency medicine, administer 0.25–0.5 mg esketamine/kg intramuscularly or 0.125–0.25 mg/kg as a slow intravenous injection.

As with other general anesthetics, individual response to esketamine varies depending on dose, route of administration, patient age, and concomitant use of other medications; therefore, dosage recommendations cannot be absolutely definitive. The dose should be titrated according to the patient's needs.

Hepatic Impairment

In patients with a history of hepatic impairment, dosage reduction should be considered in those with cirrhosis or other liver dysfunction (see section "Special Warnings and Precautions for Use").

Pediatric Population

The dosing of esketamine in pediatric patients of different ages has not been sufficiently studied. Based on limited data, no significant difference in dosing is expected between pediatric patients and adults.

In pediatric surgery and emergency medicine, esketamine is primarily used as a monotherapy; in other cases, combination with sedative agents is recommended.

How to open the ampoule:

1. Turn the ampoule with the colored dot facing toward you. Gently tap the top of the ampoule with your finger to allow the solution to flow down to the lower part of the ampoule (Fig. 1).

2. Open the ampoule with both hands: hold the lower part of the ampoule in one hand and press the top part in the direction away from the colored dot with the other hand (Fig. 2).

Fig. 1 Fig. 2

Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should not be used if discolored, cloudy, or if particulate matter is present.

For single use only. The medicinal product should be used immediately after opening the ampoule. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Esketamine Calceks may be mixed with:

• Sodium chloride 9 mg/ml (0.9%) solution for injection;
• 50 mg/ml (5%) glucose solution for injection.

After dilution to 1 mg/ml and 2 mg/ml with the above-mentioned solutions, Esketamine Calceks is chemically and physically stable in contact with PVC and EVA infusion bags, PVC and polyethylene tubing, and polypropylene and polycarbonate syringes.

Children

The dosing of esketamine in pediatric patients of different ages has not been sufficiently studied. Based on limited information, no significant difference in dosing is expected compared to adults.

In pediatric surgery and emergency medicine, esketamine is primarily used as monotherapy; in other indications, combination with sedative agents is recommended.

Overdose

Clinical symptoms of overdose include seizures, cardiac arrhythmia, and respiratory arrest.

Respiratory depression should be treated with assisted or controlled ventilation until adequate spontaneous respiration is achieved.

Convulsions should be treated with intravenous diazepam. If treatment with diazepam does not produce an adequate response, administration of phenytoin or thiopental is recommended.

To date, no specific antidote is known.

Adverse reactions.

Unwanted adverse reactions depend on the dose and rate of injection and are spontaneously reversible. Adverse reactions related to the central nervous system (CNS) and psychiatric effects are more common when esketamine is administered as the sole analgesic agent.

The adverse reactions listed below are categorized according to the following frequency classification:

Very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from available data).

1 When ketamine is used as the sole analgesic, dose-dependent reactions may occur in the recovery phase in 30% of patients.

2 These reactions can be significantly reduced by administering a benzodiazepine.

3 Prolonged use (>3 days) or drug abuse.

Shelf life.

2 years.

Shelf life after dilution

After dilution, the solution should not be stored in the refrigerator.

Chemical and physical stability after dilution has been demonstrated for 48 hours at 25 °C.

From a microbiological standpoint, diluted solutions should be used immediately, unless the method of dilution precludes microbiological contamination.

Do not use after the expiry date stated on the packaging.

Storage conditions.

No special storage conditions required.

Do not freeze.

Keep out of reach of children.

Incompatibility.

Ketamine is chemically incompatible with barbiturates, diazepam, and doxapram due to precipitate formation. These should not be administered using the same syringe and needle.

This medicinal product should not be mixed with other medicinal products, except as specified in the section "Method of administration and dosage."

Packaging.

5 ml (for 5 mg/ml concentration), 2 ml and 10 ml (for 25 mg/ml concentration) in a vial made of colorless glass of hydrolytic class I with scoring rings and a break point.

5 vials in a blister pack made of polyvinyl chloride film.

1 or 2 blister packs together with the medical instructions for use in a cardboard carton with a first-opening control in the form of a self-adhesive sticker on each opening part of the carton.

Prescription status.

Prescription only.

Manufacturer.

Manufacturer responsible for batch release:

JSC "Kalceks".

Manufacturer's address and place of business.

71E Krustpils Street, Riga, LV-1057, Latvia.

Marketing Authorization Holder.

JSC "Kalceks".

Address of the Marketing Authorization Holder.

53 Krustpils Street, Riga, LV-1057, Latvia.