SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Esketiv 5 mg/ml, solution for injection Esketiv 25 mg/ml, solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Esketiv 5 mg/ml, solution for injection Each ml solution for injection contains esketamine hydrochloride equivalent to 5 mg esketamine. 1 ampoule of 5 ml contains esketamine hydrochloride equivalent to 25 mg esketamine. 1 ampoule of 20 ml contains esketamine hydrochloride equivalent to 100 mg esketamine.

Esketiv 25 mg/ml, solution for injection Each ml solution for injection contains esketamine hydrochloride equivalent to 25 mg esketamine. 1 ampoule of 10 ml contains esketamine hydrochloride equivalent to 250 mg esketamine.

Excipients with known effect: sodium. For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

The solution is clear and colourless.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Esketiv is indicated in children and in adults

Esketiv is an anaestetic and is used: - for the induction and maintenance of general anaesthesia and as a supplement to other anaesthetics ,

- in short-term diagnostic procedures and small surgical procedures that do not require muscle relaxation

4.2 Posology and method of administration

Esketiv should only be administered by or under supervision of medically qualified anaesthetists or emergency physicians. Equipment to ensure the vital functions should be available. Premedication: Atropine or glycopyrrolate should be given preoperatively to inhibit mucus secretion. Benzodiazepine derivate such as midazolam, as premedication (intravenous or rectal), can be given to supress the initial hyperkinetic circulation and reduce the frequency of anxiety during awakening.

Posology

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The individual dose response to Esketiv may vary depending on the dose, route of administration, co- medication and age of the patient. The dose should be individually adjusted based on its clinical effect. The recommended dose Esketiv in combination with other anesthetic agents is usually the same as the advice below. The use of another anesthetic agent can possibly induce a dose reduction of Esketiv.

Anaesthesia: Intravenous administration For the induction of anesthesia 0.5 – 1.0 mg esketamine / kilogram body weight should be used. Intravenous administration should be performed slowly for 60 seconds. When needed, half of the dose can be used for maintenance in general every 10 to 15 minutes.

Intramuscular administration 3,3 – 6,5 mg esketamine / kilogram body weight should be used. When needed, half of the dose can be used for maintenance in general every 10 to 15 minutes.

In case of multiple injuries (polytrauma) and in patients in poor general condition dose reduction is required.

Hepatic impairment When insufficient liver function has been described, a dose reduction should be considered in patients diagnosed with cirrhosis or other liver impairments (see section 4.4)

Paediatric population The dose for subgroups of the paediatric population of different ages has not been investigated sufficiently. On the basis of the limited available data it is unlikely that the dose regimens differ significantly between adults and children/adolescents.

Method of administration For intravenous injection or infusion as solution for injection or solution of infusion. For intramuscular injection as solution for injection. For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Esketiv is contra-indicated in persons: - in whom an elevation of blood pressure or intracranial pressure would constitute a serious hazard (see section 4.8) - with high blood pressure and proteinuria (pre-eclampsia) and convulsions (eclampsia) due to pregnancy - as a sole anaesthetic agent in patients with manifest ischaemic cardiac diseases - when combined with xanthine derivatives, e.g. aminophylline, theophylline (see section 4.5) - when combined with ergometrine (see section 4.5)

4.4 Special warnings and precautions for use

Esketiv should be used with caution in patients with:

- hypovolemia, dehydration or heart disease especially coronary artery disease (e.g. congestive heart failure, myocardial ischemia and myocardial infarction), because of the substantial increase in myocardial oxygen consumption. - in patients with unstable angina pectoris or myocardial infarction in the last 6 months,

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- mild to moderate hypertension and tachyarrhythmias. - chronic or acute alcohol intoxication. - neurotic traits or psychiatric history ( e.g. schizophrenia and acute psychosis).(see section 4.8) - acute intermittent porphyria (because of the possibility of triggering a porphyric reaction). - hyperthyroidism or patients receiving thyroid replacement (increased risk of hypertension and tachycardia). - pulmonary or upper respiratory infection (esketamine sensitises the gag reflex, potentially causing laryngospasm). - situations in which the myometrium of the uterus should be calm (e.g. threatening uterus rupture, prolapsed umbilical cord). - in patients with cardiac insufficiency - in patients with increased intracranial pressure except under appropriate ventilation, and injuries or diseases of the central nervous system, since an increase in cerebrospinal fluid pressure has been reported during esketamine use - in patients with increased intraocular pressure (e.g. glaucoma), penetrating eye injury, and examinations or surgery of the eye, where increased intraocular pressure is undesirable - cerebrovascular accident or cerebral trauma. - if hypertension is poorly adjusted or not treated (arterial hypertension - systolic / diastolic blood pressure above 180/100 mmHg at rest)

High and quick intravenous dosing can cause respiratory depression. Although pharyngeal and laryngeal reflexes usually remain active, aspiration (liquid or solid material entering the airway) cannot be ruled out completely. Therefore, and because of a potential respiratory depression with high doses or after rapid intravenous injection, the equipment and facilities necessary for intubation and ventilation of the patient must be available. Prophylactic atropine should be given to prevent increased secretion of saliva with esketamine.

The induction of the anaesthesia is accompanied by occasional tachycardia, elevation of the blood pressure and cardiac output, which return to baseline within 15 minutes after the injection. The median peak rise of the blood pressure in clinical studies has ranged from 20 to 25 percent of the initial values. Depending on the condition of the patient, this elevation of the blood pressure may be considered an adverse reaction or a beneficial effect of esketamine.

If esketamine is used on an outpatient basis, the patient should be accompanied home and should not drink alcohol for the next 24 hours.

Esketamine is metabolised in the liver and hepatic clearance is required for termination of the clinical effects. Abnormal liver function tests in connection with esketamine have been reported, especially in patients after prolonged use (> 3 days) or in abuse. A prolonged duration of action may occur in patients with cirrhosis or other types of liver impairment. Dose reduction should be considered in these patients (see section 4.2).

In case of insufficient ventilation there is a regular increase in intracranial pressure, intraocular pressure and muscle tone. In rare cases, the skin may turn red. In a few cases hypersensitivity reactions (anaphylaxis). Patients in shock can have an extra lower blood pressure.

In diagnostic and therapeutic interventions of the upper respiratory tract hyperreflexia and laryngospasm may occur, especially in children. Interventions in pharynx, larynx and bronchial tree will possibly require muscle relaxation with artificial respiration. ln surgical procedures involving visceral pain pathways, esketamine should be supplemented with a muscle relaxant, additional analgesia, controlled ventilation and the administration of nitrous oxide/oxygen.

The effect of non-depolarizing (for example pancuronium) and depolarizing (for example

3 suxamethonium) muscle relaxants may be prolonged due to the use of esketamine

Continuous monitoring of cardiac function during surgery is required in patients with hypertension or cardiac decompensation.

The risk of psychiatric reactions during the recovery period can be significantly reduced by additional administration of benzodiazepines (see sections 4.8 and 4.2).

If esketamine is used in the shock patient the principles of shock therapy (volume substitution, oxygen supply) must be considered. special caution is required in severe states of shock where blood pressure can be hardly measured or not at all.

As the need for additional anaesthetics or muscle relaxants cannot always be predicted it is recommended that the patient fasts for 4-6 hours prior to surgery to prevent aspiration. Because pharyngeal reflexes usually remains active, mechanical stimulation of the pharynx should be avoided unless muscle relaxants with proper attention are used.

Abuse and dependence The abuse of racemic ketamine has been reported. These reports suggest that racemic ketamine produces a variety of symptoms including (but not limited to) flashbacks, hallucinations, dysphoria, anxiety, insomnia, or disorientation. Moreover, cases of cystitis including haemorrhagic cystitis and cases of hepatotoxicity have also been reported. Therefore, similar effects cannot be excluded following therapeutic use of esketamine. Dependence and tolerance may develop, particularly in individuals with an existing or a history of drug abuse or dependence. Therefore the use of esketamine should be closely supervised, and it should be prescribed and administered with special caution.

Long-term use Cases of cystitis including haemorrhagic cystitis have been reported in patients given racemic ketamine on a long-term basis (one month up to several years). Comparable effects may also occur with the abuse of esketamine. Hepatotoxicity has also been reported in patients with extended use (longer than 3 days).

This medicinal product contains sodium This medicinal product contains 3.2 mg (0.14 mmol) sodium per ml Esketiv 5 mg/ml solution for injection, or 1,2 mg (0.05 mmol) sodium per ml Esketiv 25 mg/ml, solution for injection. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Esketamine may increase the effect of co-administered opioids causing increased CNS- and/or respiratory depression.

Contra-indication with simultaneously administration Xanthine derivatives Since there is clinical and experimental evidence of lowered seizure threshold at the combination of theophylline and esketamine combination with theophylline should be avoided. Unpredictable extensor-type seizures have been reported with concurrent administration of these agents. precaution with simultaneously administration

Uterotonics Esketamine may not be used in combination with ergometrine

Neuromuscular blockers

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Esketamine may potentiate and prolong the effect of neuromuscular blocking agents (e g suxametonium and atracurium) causing prolonged muscle relaxation and/or respiratory depression.

Hypnotics, benzodiazepines, neuroleptics. Premedication with diazepam prolongs the half-life of esketamine with enhanced efficacy as a result. The combination may require dose adjustment.

Vasopressin At concurrent administration of esketamine and vasopressin synergetic increase in the blood pressure been observed.

Halogenated hydrocarbons Anesthetic effect of halogenated hydrocarbons (e.g. isoflurane) is enhanced in combination with esketamine. Lower doses of these halogenated hydrocarbons may be needed. In case of simultaneously administration of esketamine and halogenated hydrocarbons can cause cardiac arrhythmia after administering adrenaline.

Barbiturates, narcotics, inhalation anaesthetics, alcohol, muscular relaxants Prolonged recovery time may occur if barbiturates, narcotics and inhalation anaesthetics are used concurrently with esketamine. Concurrent use of esketamine (especially in high doses or when rapidly administered) with halogenated anaesthetics can increase the risk of developing bradycardia, hypotension or decreased cardiac output. Concurrent administration of esketamine and other sedatives (e.g. ethanol, phenothiazines, sedating H1-blockers or muscle relaxants) can potentiate CNS depression and/or increase risk of respiratory depression. Reduced doses of esketamine may be required with concurrent administration of other anxiolytics, sedatives and hypnotics.

Sympathomimetics, Thyroid hormones, vasopressin Patients taking Sympathomimetics (with direct or indirect effects) thyroid hormones and vasopressin have an increased risk of developing hypertension and tachycardia when given esketamine.

Antihypertensive agentsncomitant use of antihypertensive agents and esketamine increase the risk of developing hypotension.

Medicinal products that inhibit the enzyme activity of CYP3A4 usually decrease hepatic clearance which may cause increased plasma concentrations of CYP3A4 substrates such as esketamine. A dose reduction of esketamine may be required in case of concomitant administration with CYP3A4 inhibitors (e g itraconazole, fluconazole, clarithromycin, erythromycin, verapamil, diltiazem).

Medicinal products that induce the enzyme activity of CYP3A4 usually increase hepatic clearance which may cause decreased plasma concentrations of CYP3A4 substrates such as esketamine. A dose increase of esketamine may be required in case of concomitant administration with CYP3A4 inducers (e.g. phenytoin, carbamazepine, St John´s Wort).

Paediatric population Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy There are no adequate data from the use of esketamine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Use of esketamine should be restricted during pregnancy and only administered after consideration if the potential benefits for the mother outweighs the possible hazard for the child.

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Esketamine crosses the placental barrier and may cause respiratory depression in the neonate if used during delivery.

Lactation Esketamine is excreted into breast milk, but an effect on the child seems unlikely when using therapeutic doses.

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

4.7 Effects on ability to drive and use machines

After treatment with esketamine the ability to react may be impaired. This should be considered when alertness is required, e.g. when driving a car. Patients should not drive motor vehicles or operate machinery at least 24 hours after administration with esketamine.

4.8 Undesirable effects

The adverse reactions are mostly related to dose and rate of injection and are reversible. CNS adverse events are more common if Esketiv is given as a single anaesthetic.

The following adverse reactions have been observed and reported in treatment with esketamine. Frequency description: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to<1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (frequency cannot be estimated from available data).

MedDRA Common Uncommon Rare Not known system organ class (1/100, <1/10) (1/1 000, (1/10 000, (frequency cannot database <1/100) <1/1 000) be estimated from available data) Immune system anaphylactic disorders reaction Psychiatric disorders abnormal dreams, hallucination, nightmare, dysphoria, anxiety, dizziness, disorientation restlessness Nervous system nystagmus, tonic disorders clonic movements Eye disorders blurred vision diplopia, increased intraocular pressure Cardiac disorders increased blood bradycardia, pressure, arrhythmia increased heart rate, temporary tachycardia Vascular disorders hypotension

Respiratory, thoracic Increased vascular and mediastinal resistance in the disorders pulmonary circulation and increased mucus

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MedDRA Common Uncommon Rare Not known system organ class (1/100, <1/10) (1/1 000, (1/10 000, (frequency cannot database <1/100) <1/1 000) be estimated from available data) secretion. Increased oxygen consumption, laryngospasm and temporary respiratory depression. (The risk of respiratory depression usually depends on the dose and rate) Gastrointestinal nausea, vomiting, disorders salivary hypersecration Hepatobilary abnormal liver disorders function test drug induced liver damage* Skin and erythema, rash subcutaneous tissue mobilliform, disorders exanthem

General disorders injection site pain, and administration injection site rash site conditions

* After prolonged use (>3 days) or drug abuse

When esketamine is used as the sole anaesthetic, up to 30% of patients may have dose-dependent responses in the recovery phase. Awakening from the anaesthesia is often accompanied by vivid dreams, with or without psychomotor activity, which can be manifested in nightmares or hallucinations, confusion, emergence delirium (often with dissociative or floating sensation) and irrational behaviour. The incidence of these reactions is reduced by combination of Esketiv and a benzodiazepine derivate. Transient respiratory depression due to CNS disorders can be seen at intravenous induction and is dependent on dose and rate of injection.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*.

4.9 Overdose

Clinical signs of overdose are convulsions, cardiac arrest and respiratory depression.

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

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Convulsion should be treated with intravenous diazepam. If this treatment does not give the desired result intravenous administration of phenytoin or thiopental is recommended.

No specific antidote is available.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: general anaesthetic, ATC code: N01AX14

Esketamine is a fast-acting anaesthetic and analgesic. It causes dissociative anaesthesia. The analgesic effect occurs at doses lower than those required for the dissociative anaesthesia and lasts longer. These pharmacological effects are attributed to the blockade of the N-methyl-D-aspartate (NMDA) receptors by esketamine.

The ketamine-racemate consists of the enantiomers esketamine ((S)-ketamine) and (R)-ketamine. The analgesic anaesthetic effect between the (R) - and (S) -isomer is in a ratio of 1: 4. The efficacy of (S)- ketamine compared to the racemic ketamine is 1.5:1.

During anaesthesia with esketamine, signs of suppression of the bio-electrical cerebral cortex activity, especially in the frontal areas, as well as activation of the subcortical structures may be observed on the EEG. Because the muscle tone stays enforced, or has increased, the protective reflexes are in general not reduced. The seizure threshold is lowered. During spontaneous breathing the cerebrospinal fluid pressure can be increased, which can be prevented by adequate mechanical ventilation.

Due to the sympathomimetic effect caused by esketamine, the blood pressure and heart rate increase, resulting in an increase of the cardiac oxygen consumption as well as the coronary circulation. The vascular resistance is hardly influenced by the opposing (reflex) mechanisms.

After administration of esketamine a moderate hyperventilation was observed without any significant change in the blood gas levels. Esketamine has a bronchial musculature relaxing effect.

5.2 Pharmacokinetic properties

Absorption Esketamine is rapidly absorbed following intramuscular administration.The bioavailability following intramuscular administration is 93 %. Ketamine can be detected in plasma after 4 min, and plasma concentrations peak within 5–30 min after injection with a t max of 22 min. Cmax 243 ng/ml following a dose of 0.5 mg/kg

After intravenous infusion of 40 mg/h/70 kg, the Tmax is 110 min, CMax is 305 ng/ml with an AUC of 142 ng*h/ml.

Distribution The binding to plasma proteins is about 10-30%. Esketamine has a biphasic plasma profile with a distribution phase lasting for 45 minutes and with distribution half-life of 10-15 minutes, which clinically corresponds to the anaesthetic effect. For a standardized 70-kg person a central volume of distribution of 38.7 L/70 kg is observed and peripheral volume of distribution of 102 L/70 kg.

Biotransformation Metabolism of esketamine occurs mainly in the liver. Esketamine is N-demethylated and hydroxylated in the cyclohexane ring. CYP2B6 is the primary enzymes responsible for N-demethylation of esketamine to norketamine. Norketamine is further demethylated to dehydronorketamine via

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CYP2B6. Norketamine has been demonstrated to have 1/3 of the potency of esketamine. CYP3A5 and CYP2A6 are involved in the hydroxylation of esketamine. The N-demethylated and hydroxylated metabolites are further conjugated via UGT and excreted in urine.

Excretion Excretion was measured after intravenous administration. The elimination half-life for esketamine is approximately 2.5 hours and for norketamine about 4 hours. Clearance is between 60-147 Liter/h/70 kg. Esketamine and its metabolites are excreted primarily after glucurodination via the kidneys in the urine.

Paediatric population In 20 children (age 1-7 years) it was found that after intravenous administration (bolus dose 2 mg/kg over 10 seconds) Cmax is 1860 ± 883 ng/ml. It seems that more norketamine metabolites are found in children. In a second study (4 children, ages 5-9 year) it was found that there were no significant differences in concentrations between children and adults in the interval up to 3h after intravenous injection of 2 mg/kg. However, concentrations at 5h were smaller in children after the i.v. injection of ketamine and the difference was significant.. Apparent volumes of distribution after i.v. injection were similar in the children and adults. Although the half-life was shorter (100 vs. 153 min.) and the plasma clearance greater (16.8 vs. 12.6 ml/min/kg) in children than in adults. Also, at 5 min after i.m. ketamine injection (6 mg/mk) to 5 children (4-9 years) than in adults after both i.v. and i.m. administration. These differences were significant for up to 1 h after i.v. injection and i.m. injection.

5.3 Preclinical safety data

Published studies in animals (including primates) at doses resulting in light to moderate anaesthesia demonstrate that the use of anaesthetic agents during the period of rapid brain growth or synaptogenesis results in cell loss in the developing brain that can be associated with prolonged cognitive deficiencies. The clinical significance of these nonclinical findings is not known.

In studies with single and repeated intravenous administration symptoms of toxicity were due to exaggerated pharmacodynamic effects of esketamine.

In vitro and in vivo studies on genotoxicity revealed no evidence of genotoxic potential. Long-term studies on carcinogenicity were not carried out.

In studies on reproductive toxicity, an increased postnatal mortality up to day 4 post-partum was found in a peri/postnatal study in rats in all dose groups, which is probably attributable to an insufficient brood care by the mother animals.

Other reproduction parameters were not affected in any dose group. Similarly, there was no influence on the parents of the F1 generation and their reproductive behaviour. There were no indications of teratogenic properties.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride Hydrochloric acid (for pH adjustment) Water for injections

6.2 Incompatibilities

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Esketiv is chemically incompatible with barbiturates and diazepam because of formation of precipitate. Therefore, these should not be mixed in the same syringe or infusion fluid.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

24 months.

Chemical and physical in-use stability has been demonstrated for 48 hours at 25°C. from a microbiological point of view, unless the method of opening/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Store in the original package to protect from light. Do not freeze

6.5 Nature and contents of container

Esketiv 5 mg/ml, solution for injection - 5 ml (25 mg) in an ampoule (glass type I), packed in a carton of 5, 10, 20, 30, 50, 100 - 20 ml (100 mg) in an ampoule (glass type I), packed in a carton of 5, 10, 20, 30, 50, 100

Esketiv 25 mg/ml, solution for injection - 10 ml (250 mg) in an ampoule (glass type I), packed in a carton of 5, 10, 20, 30, 50, 100

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

For single use only.

Esketiv can be diluted with 50 mg/ml (5%) glucose solution and 9 mg/ml (0.9%) sodium chloride.

To obtain a solution of 0.5 mg/kg esketamine, 10 ml of Esketiv 25mg/ml should be added to 500 mL 5% dextrose or 0.9% NaCl solution. When prepared under aseptically conditions, this solution can be used for 24 hours maximum, when stored below 25°C. When solution is not prepared under aseptically conditions, this can be used tor 24 hours maximum when stored between 2-8°C, or for 12 hours when stored below 25°C. Dilution of Esketiv 5 mg/ml is not recommended.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Parenteral products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit. The solution should not be used if discoloured or cloudy or if particulate matter is observed

7. MARKETING AUTHORISATION HOLDER

Eurocept International BV

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Trapgans 5 1244 RL Ankeveen The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<[To be completed nationally]>

10. DATE OF REVISION OF THE TEXT

22-5-2018

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