• Induction and maintenance of general anesthesia , as the only anesthetic agent or in combination with another anesthetic agent
• Anesthesia and pain relief ( analgesia ) in emergency medicine
• Complement to regional or local anesthesia .

Patients in whom an increase in blood pressure or intracranial pressure poses a serious risk.

As the only anesthetic agent in patients with manifest ischemic heart disease.

Eclampsia and preeclampsia .

In combination with xanthine derivatives and ergometrine.

Hypersensitivity to the active substance or to any excipient listed in section Contents.

See also section Interactions Interactions with other medicines and other interactions .

Dosage

Only for hospital use or pre-hospital emergency care. Esketamine should only be administered by or under the direction of a specialist in anesthesiology. Equipment to ensure vital functions should be available.

When using esketamine, if possible, customary guidelines for fasting should be followed, i.e. 4–6 hours before anesthesia .

Although esketamine has only a small effect on the protective reflexes in the pharynx and airways, the risk of aspiration of liquid or solid material cannot be completely excluded. 

High doses or too rapid intravenous administration can lead to respiratory depression .

Esketamine should be used with caution in the following situations:

• decompensated heart failure and untreated hypertension
• unstable angina pectoris
• increased intracranial pressure and damage or disease of the central nervous system , as an increase in cerebrospinal pressure has been described in association with ketamine as an anesthetic
• in connection with eye examination or eye surgery when the intraocular pressure should not be raised
• patients with chronic or acute alcoholism
• patients who have or have had serious mental disorders
• inadequately treated hyperthyroidism
• situations that require a relaxed uterine muscle (e.g. in case of threatened uterine rupture or umbilical cord prolapse)

Esketamine is metabolized in the liver and hepatic clearance is required for the clinical effects to subside. Abnormal liver function values ​​associated with the use of esketamine have been reported, particularly with long-term use (> 3 days) or abuse. 

Prolonged duration of effect may occur in patients with cirrhosis or other types of liver impairment. Dose reduction should be considered in these patients.

In the case of high doses or rapid intravenous injection , respiratory depression may occur.

Because aspiration cannot be completely excluded and because of the risk of respiratory depression , equipment for intubation and ventilation must be available.

Increased salivation should be treated prophylactically with atropine.

During diagnostic and therapeutic interventions in the upper respiratory tract, hyperreflexia and laryngospasm may occur, especially in children.

 For this reason, the administration of muscle relaxants and controlled ventilation may be necessary in procedures involving the pharynx, larynx and trachea.

In surgical procedures where visceral pain may occur, muscle relaxation and additional analgesia (controlled ventilation and administration of nitrous oxide/oxygen) are justified.

After outpatient anesthesia , the patient should be escorted home, and the patient should refrain from alcohol for the next 24 hours.

Long-term use

Cases of cystitis , including hemorrhagic cystitis , acute kidney injury, hydronephrosis, and ureteric disease have been reported with long-term use (one month to several years) of racemic ketamine, particularly when ketamine has been abused. 

Similar effects can also occur after abuse of esketamine. Hepatotoxicity has also been reported in patients with long-term use (> 3 days).

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Abuse of racemic ketamine has been reported. Racemic ketamine is reported to cause a range of symptoms, including flashbacks, hallucinations, dysphoria , anxiety, insomnia, and disorientation. Side effects have also been reported: see “Long-term use”. Similar effects resulting from esketamine use cannot therefore be excluded.

Esketamine dependence and tolerance may develop in people who have previously abused or been dependent on drugs. Therefore, caution should be exercised when prescribing and administering esketamine.

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The risk of psychological reactions upon awakening after anesthesia (see also section Adverse effects ) can be greatly reduced by simultaneous administration of a benzodiazepine .

Concomitant administration that is contraindicated:

The seizure threshold can be lowered in combination with xanthine derivatives (for example aminophylline and theophylline) and therefore these combinations should be avoided.

The medicine should not be used together with ergometry.

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Sympathomimetics (direct or indirect acting), thyroid hormones and vasopressin can raise blood pressure et and increase pulse en, which should be taken into account when co- administering with esketamine.

Side effects are reduced in combination with hypnotics , benzodiazepines or neuroleptics , but the effect of esketamine is prolonged.

Barbiturates and opiates given at the same time as esketamine may prolong the recovery period after anesthesia.

Diazepam increases the half-life of racemic ketamine and prolongs its pharmacodynamic effects. Therefore, dose adjustments may also be required for esketamine.

Administration of esketamine may enhance the anesthetic effect of halogenated hydrocarbons (for example halothane, isoflurane, desflurane and sevoflurane) and therefore the dosage of one of these may need to be reduced.

Use of esketamine may prolong the effect of non-depolarizing (for example, pancurone) and depolarizing (for example, suxamethone) muscle relaxants.

The risk of arrhythmia after the administration of epinephrine may increase with the simultaneous administration of esketamine and halogenated hydrocarbons.

Elevated blood pressure has been observed with the simultaneous administration of esketamine and vasopressin .

Drugs that inhibit CYP3A4 activity usually reduce hepatic clearance , leading to increased plasma concentrations of CYP3A4 substrate drugs, such as esketamine.

 When esketamine is co- administered with drugs that inhibit the CYP3A4 enzyme , a reduced dosage of esketamine may be required to obtain the desired clinical result.

Drugs that induce CYP3A4 activity usually increase hepatic clearance , leading to decreased plasma

concentrations of CYP3A4 substrate drugs, such as esketamine. When esketamine is co- administered with

drugs that induce CYP3A4 enzyme , increased dosage of esketamine may be required to obtain the desired clinical result.

Category C.

Pregnancy

There are insufficient data on the use of esketamine in pregnant women.  Animal studies have shown reproductive toxicity (see section Preclinical data).

 Use of esketamine should be limited during pregnancy and not administered until it has been judged that the potential benefit to the mother outweighs the possible risk to the child.

Esketamine crosses the placental barrier and can lead to respiratory depression in the newborn if given during labor.

Group II.

Esketamine is excreted in breast milk, but at therapeutic doses the risk of affecting the baby is unlikely.

There are no data on the effects of esketamine on fertility .

Treatment with esketamine may decrease responsiveness. This should be taken into account in situations where increased attention is required, e.g. when driving.

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

Side effects normally depend on the dose and the injection speed and are usually spontaneously reversible . Side effects affecting the central and peripheral nervous system occur more often if esketamine is given as the only anesthetic agent.

Mechanism of action

Esketamine is a chiral cyclohexanone derivative with analgesic and, at higher doses , anesthetic effect. Esketamine forms a so-called dissociative anesthetic agent. By disrupting the association pathways in the brain, esketamine induces a catalepsy-like state that brings about unconsciousness and amnesia .

Pharmacodynamic effect

The ketamine racemate components include esketamine and (R)-ketamine. The analgesic effect is primarily due to the blockade of the N-methyl-D-aspartate (NMDA) receptors by esketamine. The anesthetic/analgesic potency between the R and S isomers is approximately 1:3.

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Esketamine has a significant local anesthetic effect on the spinal cord and peripheral nerves.

Esketamine does not cause respiratory or circulatory depression and has only a marginal effect on the protective reflexes: When using esketamine as an anesthetic drug, muscle tone is maintained or increased , and the protective reflexes are not normally impaired. 

The seizure threshold is not lowered. During spontaneous breathing, there is an increase in intracranial pressure, which can be avoided with the help of adequate ventilation of the lungs.

As a result of a sympathomimetic effect, esketamine causes increased blood pressure and increased heart rate , which leads to an increase in the heart’s oxygen consumption and blood flow in the coronary vessels. 

Esketamine has a negative inotropic and antiarrhythmic effect on the heart. The peripheral resistance hardly changes due to opposing effects.

After administration of esketamine, moderate hyperventilation may be observed. However, this has no significant effect on blood gases.

Esketamine has a bronchodilating effect that makes the preparation suitable for asthmatic patients and for assisted ventilation of patients with status asthmaticus .

There are no or only small differences in the pharmacokinetic properties of esketamine and racemic (±)-ketamine. 

However, parallels can be drawn to the pharmacokinetics of racemic ketamine (called ketamine below). The pharmacokinetics of ketamine are linear.

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Ketamine is rapidly absorbed after intramuscular administration and is approximately 90% bioavailable.

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The degree of binding to plasma protein is around 50%. Lipid solubility is high.

Ketamine is rapidly distributed to tissues with high perfusion (eg, heart, lungs, and brain), followed by muscle and peripheral tissues , and then fat.

 At 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 is associated with the duration of the analgesic effect (approximately 20 minutes), in humans. 

Plasma concentrations of esketamine are approximately 2.6 µg/ml at 1 minute and 0.9 µg/ml at 5 minutes following an intravenous bolus dose of esketamine of 1 mg/kg. Maximum plasma concentration of esketamine is approximately 0.14 µg/ml at 25 minutes after an intramuscular dose of esketamine of 0.5 mg/kg.

Metabolism

Ketamine is metabolized in the liver by demethylation (via the cytochrome P450 system) to the significantly less potent main metabolite norketamine and other inactive metabolites . 

The enzyme CYP3A4 is the major enzyme responsible for N-demethylation of ketamine to norketamine in human liver microsomes, with minor contributions from CYP2B6 and CYP2C9. Metabolism one is rapid and almost complete; metabolic clearance is 1,200 to 1,500 mL/min.

Elimination

The terminal elimination half-life of ketamine is between 79 minutes (after continuous infusion ) and 186 minutes (after low-dose intravenous administration ).

 Ketamine and its metabolites are 98% eliminated via the kidneys and 2% via the faeces, and only a small part is eliminated in unchanged form. Overall, about 95% is eliminated in the first 24 hours.

Preclinical data on esketamine regarding genotoxicity did not show any particular risks for humans.

Published studies in animals (including primates) at doses resulting in mild to moderate anesthesia show that the use of anesthetics during the period of rapid brain growth or synaptogenesis results in cell loss in the developing brain that may be associated with long-term cognitive deficits. The clinical significance of these nonclinical findings is unknown.