Esketamine Sintetica 25 mg/ml solution for injection/infusion

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Esketamine
Available from:
Sintetica Ireland Limited
ATC code:
N01AX14
INN (International Name):
Esketamine
Dosage:
25 milligram(s)/millilitre
Pharmaceutical form:
Solution for injection/infusion
Therapeutic area:
esketamine
Authorization status:
Marketed
Authorization number:
PA22903/004/002
Authorization date:
2020-10-02

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Package leaflet: Information for the user

Esketamine Sintetica 5 mg/ml solution for injection/infusion

Esketamine Sintetica 25 mg/ml solution for injection/infusion

esketamine

Read all of this leaflet carefully before you are given this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or nurse.

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet

What Esketamine Sintetica is and what it is used for

What you need to know before you are given Esketamine Sintetica

How to use Esketamine Sintetica

Possible side effects

How to store Esketamine Sintetica

Contents of the pack and other information

1.

What Esketamine Sintetica and what it is used for

Esketamine Sintetica belongs to one of a group of medicines called general anaesthetics, which is used

to put you to sleep during an operation.

Esketamine Sintetica is used:

- to initiate and perform general anaesthesia, as the only anaesthetic or possibly in combination with

sleeping pills (hypnotics),

- to supplement regional anaesthesia (local anaesthesia),

- for anaesthesia and pain relief (analgesia) in emergency situations,

- for pain control in artificial respiration (intubation).

2.

What you need to know before you are given Esketamine Sintetica

Esketamine Sintetica must not be used:

if you are allergic to esketamine or any of the other ingredients of this medicine (listed in

section 6),

if high blood pressure or increased pressure in the brain is a serious risk for you,

if you have poorly controlled or untreated high blood pressure,

if you have a condition called eclampsia or pre-eclampsia (which is a complication of pregnancy

that causes high blood pressure),

if you have an overactive thyroid (insufficiently treated hyperthyroidism),

in situations during childbirth which require relaxed uterus muscle, (e.g. threat of a uterus

rupture, prolapsed umbilical cord),

if you suffer from an existing heart disease with reduced blood flow and get esketamine as the

only remedy for anaesthesia.

in combination with xanthine derivatives (e.g. aminophylline or theophylline) (the convulsion

threshold may become lower),

in combination with ergometrine (used during or after childbirth and to inhibit milk production).

Warnings and precautions

Talk to your doctor or nurse before you are given Esketamine Sintetica:

in the case of chest pain (angina pectoris) or in the case of heart attack (myocardial infarction)

during the last 6 months,

in the case of a weak heart (cardiac insufficiency),

if you have an increased brain pressure, except under appropriate ventilation, and in the case of

damage or diseases of the central nervous system,

if you have or have had severe psychiatric problems,

if you have an increased eye pressure (glaucoma) and eye injuries, as well as if you need an eye

examination or eye surgery in which eye pressure must not be increased,

in the case of surgery in the upper respiratory tract,

if you are under the influence of alcohol (chronic or acute alcohol),

if you have liver disease,

if you have a history of drug abuse or addiction.

Out-patient treatment

Adequate continuous monitoring of the patient must be ensured until discharge.

You should be accompanied home after out-patient anaesthesia and you should not drink alcohol

within the next 24 hours.

You are not allowed to drive, operate machinery or operate dangerous activities for at least 24 hours

following esketamine administration.

In diagnostic and therapeutic procedures of the upper respiratory tract , laryngeal spasms

(laryngospasms) are possible, especially in children. Controlled ventilation may be necessary.

Long-Term Use

In patients who used ketamine during long term therapy (1 month to several year), cases of urinary

disorders (such as bladder inflammation) and liver toxicity have been reported. Similar effects may

also occur following esketamine abuse.

Drug Abuse and Dependence

There are reports of drug abuse with ketamine which suggest that ketamine abuse causes a variety of

symptoms such as flashbacks, hallucinations, anxiety, dissatisfaction feeling, insomnia or

disorientation. Urinary symptoms such as bladder inflammation and disorders of the liver were also

reported after use of ketamine. Same symptoms may occur with Esketamine in individuals with a

history of drug abuse or dependence. Therefore esketamine should be prescribed and administered

with caution only under the supervision of a doctor.

Other medicines and Esketamine Sintetica

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

Xanthine derivatives (for example aminophylline, theophylline) Ergometrine (used during or after

childbirth and to inhibit milk production)

Sympathomimetics (for example adrenaline or noradrenaline), thyroid hormones and vasopressin

may lead to an increase in blood pressure and in heart rate or heart rhythm disorders.

In combination with sleeping pills (hypnotics), benzodiazepines (for example diazepam) or

neuroleptics used for mental disorders, as the duration of effect of Esketamine Sintetica may be

prolonged.

Barbiturates and opiates (such as morphine) given together with Esketamine Sintetica may prolong

the recovery phase after the application of esketamine .

The anaesthetic effect of some gas anaesthetics (for example, isoflurane, desflurane, sevoflurane)

is increased by administration of Esketamine Sintetica so lower doses may be needed.

The effect of muscle relaxants such as pancuronium-or suxamethonium- may be prolonged due to

the use of Esketamine Sintetica.

Concomitant administration of esketamine with medicines that inhibit the enzyme CYP3A4 may

require a reduced dose of esketamine to achieve the desired clinical outcome.

Concomitant administration of esketamine with medicines that induce the enzyme CYP3A4 may

require an increased dose of esketamine to achieve the desired clinical outcome.

Esketamine Sintetica with alcohol

You should not drink alcohol within 24 hours after receiving this anaesthetic.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before you are given this medicine.

Pregnancy

This medicine will not be used during pregnancy unless your doctor comes to the conclusion that the

therapeutic benefit for you outweighs any possible hazard for the child. It may negatively affect the

baby’s breathing rate (respiratory depression) if used during delivery.

Breast-feeding

Esketamine can pass into breast-milk, however, it is unlikely to affect the baby when it is used at the

recommended doses.

Driving and using machines

You should not drive or operate machinery for at least 24 hours after receiving this medicine.

Esketamine Sintetica results in reduced response times which are important in situations requiring

special alertness, e.g., when driving a car.

You should only go home if you are accompanied.

Esketamine Sintetica contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium-

free’.

3.

How to use Esketamine Sintetica

For hospital use only. Esketamine Sintetica will only be given to you by or under the supervision of an

anaesthetist.

You will be asked to fast for 4 to 6 hours before you are due to receive Esketamine Sintetica.

Method of administration

Esketamine is given as a slow injection into your vein (intravenous) or muscle (intramuscular). If

necessary, the injection can be repeated or it can be given as an infusion.

If you are given more Esketamine Sintetica than you should

At very high doses, life-threatening symptoms such as seizures abnormal heart rhythm a respiratory

arrest are to be expected but as the product is given only by trained specialists, those overdoses with

these symptoms are very unlikely.

If you have further questions on the use of this medicine ask your doctor, anaesthetist, pharmacist or

nurse.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Side effects usually depend on the dose and speed of injection and usually get better without treatment.

Very common side effects (may affect more than 1 in 10 patients) are:

recovery reactionsincluding vivid dreams, including nightmares, dizziness and restlessness

increase in blood pressure and heart rate

Common side effects (may affect up to 1 in 10 patients) are:

blurred vision;

temporary increase in heartbeat;

effects

breathing

during

anaesthesia

increased

oxygen

consumption,

laryngeal

spasms

(laryngospasm), and temporary respiratory depression

being sick, increased salivation (drooling);

Uncommon side effects (may affect up to 1 in 100 patients) are:

Increased body movements (for example muscle twitching), which can resemble seizures, and

increased eye movements;

double vision, increased pressure in the eye;

skin redness (rash), and skin rash (exanthema);

pain and/or redness at the injection site.

Rare side effects (may affect up to 1 in 1,000 patients) are:

severe allergic reaction;

irregular heart beat or slower heart beat;

low blood pressure.

Very rare side effects (may affect up to 1 in 10,000 patients) are:

hypersensitivity reactions (anaphylactoid reactions).

Not known side effects (frequency can not be estimated from the available data) are:

hallucinations, feeling of dissatisfaction, anxiety and disorientation;

abnormal liver function test results,

liver injury.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via

HPRA Pharmacovigilance

Earlsfort Terrace

IRL – Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: medsafety@hpra.ie

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Esketamine Sintetica

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton/ampoule after "Exp". The

expiry date refers to the last day of that month.

Do not freeze.

The chemical and physical in-use stability of ready-to-use infusion solutions prepared with sodium

chloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%) infusion solution has been demonstrated over 24

hours under storage at 25°C.

From

microbiological

point

view,

product

should

used

immediately.

used

immediately, in-use storage times and conditions prior to use are the responsibility of the user and

would normally be no longer than 24 hours at 2 to 8°C, for dilution not under controlled and validated

aseptic conditions.

The content is intented for single use only. Any unused residue should be discarded. Only a clear and

colourless solution should be used.

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines

you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Esketamine Sintetica contains

The active substance is esketamine

Esketamine Sintetica 5 mg/ml, solution for injection/infusion

1 ml solution for injection/infusion contains 5 mg esketamine as 5.77 mg of esketamine hydrochloride.

1 ampoule of 5 ml solution for injection/infusion contains 25 mg of esketamine as 28.83 mg

esketamine hydrochloride.

Esketamine Sintetica 25 mg/ml, solution for injection/infusion

1 ml solution for injection/infusion contains 25 mg of esketamine as 28.83 mg of esketamine

hydrochloride.

1 ampoule of 2 ml solution for injection/infusion contains 50 mg of esketamine as 57.66 mg of

esketamine hydrochloride.

1 ampoule containing 10 ml solution for injection/infusion contains 250 mg of esketamine as 288.30

mg of esketamine hydrochloride.

The other ingredients are sodium chloride, hydrochloric acid 0.36% (for pH-adjustment), and

water for injections.

What Esketamine Sintetica looks like and contents of the pack

Esketamine Sintetica is a clear, colourless solution for injection/infusion.

Pack sizes:

Esketamine Sintetica 5 mg/ml

10 ampoules each containing 5 ml of solution for injection/infusion.

Esketamine Sintetica 25 mg/ml

10 ampoules each containing 2 ml of solution for injection/infusion.

10 ampoules each containing 10 ml of solution for injection/infusion.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Sintetica Ireland Limited

BEAUCHAMPS

Riverside Two

Sir John Rogerson’s Quay

Dublin 2

D02 KV60

Manufacturer

Sintetica GmbH

Albersloher Weg 11

48155 Münster

Germany

HAUPT PHARMA LIVRON

1 rue Comte de Sinard

26250 Livron-sur-Drôme - France

This medicinal product is authorised in the Member States of the EEA under the following names:

Member States

Proposed (Invented) Names

Germany

Esketamin Sintetica 5 mg/ml Injektions-/Infusionslösung

Esketamin Sintetica 25 mg/ml Injektions-/Infusionslösung

Netherlands

Esketamine IDD 5 mg/ml, oplossing voor injectie/infusie

Esketamine IDD 25 mg/ml, oplossing voor injectie/infusie

Sweden

Esketamin IDD, 5 mg/ml, injektions-/infusionsvätska, lösning

Esketamin IDD, 25 mg/ml, injektions-/infusionsvätska, lösning

France

Esketamine IDD 5 mg/ml solution injectable/pour perfusion

Esketamine IDD 25 mg/ml solution injectable/pour perfusion

Austria

Esketamin Sintetica 5 mg/ml Injektions-/Infusionslösung

Esketamin Sintetica 25 mg/ml Injektions-/Infusionslösung

Ireland

Esketamine Sintetica 5 mg/ml solution for injection/infusion

Esketamine Sintetica 25 mg/ml solution for injection/infusion

Esketamine Sintetica 5 mg/ml solution for injection/infusion

Esketamine Sintetica 25 mg/ml solution for injection/infusion

This leaflet was last revised in August 2020

------------------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

Esketamine should be administered only by specialist of anaesthesiology or emergency medicine.

Esketamine is for hospital use only.

As aspiration cannot be completely excluded and due to the possibility of respiratory depression,

intubation and ventilation equipment must be available.

Posology

For induction of general anaesthesia 0.5 to 1 mg/kg of esketamine is given intravenously or 2 to

4 mg/kg intramuscularly, half the initial dose is re-injected as needed, generally every 10 to 15

minutes.

As an alternative to injection, esketamine can be administered as a continuous infusion at a dose of 0.5

to 3 mg esketamine/kg/h. In case of multiple injuries (polytrauma) and in patients with poor general

condition a dose reduction may be necessary.

For analgesic supplementation of regional and local anaesthesia 0.125 to 0.25 mg esketamine/kg/h is

administered as intravenous infusion.

For analgesia in artificial respiration (intubated intensive care patients), 0.25 mg esketamine/kg is

generally used as a bolus with a subsequent continuous infusion of 0.2 to 0.5 (up to 1.5) mg

esketamine/kg/h with simultaneous benzodiazepine administration.

When

used as

permanent

infusion

analgesia

artificial

respiration,

the duration

application should not exceed 4 to 6 weeks.

For analgesia in emergency medicine 0.25 to 0.5 mg esketamine/kg is administered intramuscularly or

0.125 to 0.25 mg/kg as a slow intravenous injection.

Increased salivation should be prophylactically treated with atropine.

The risk of psychological reactions occurring during recovery from anaesthesia can be greatly reduced

by the co-administration of a benzodiazepine.

Where possible, the use of esketamine should follow the ordinary guidelines regarding fasting, 4 to 6

hours before anaesthesia.

In case of hepatic impairment, a dose reduction may be required.

Paediatric population

In paediatric surgery, as well as in emergency medicine, esketamine hydrochloride is generally used as

monotherapy; in case of other indications, a combination with hypnotics is recommended.

Dosage of esketamine across subgroups of paediatric patients of different ages has not been adequately

studied. Based on the information available, dosage in paediatric patients is not expected to differ

substantially from that in adults.

Method of administration

Esketamine is for intravenous or intramuscular use. It can be injected slowly or administered as an

infusion. For infusion, either the undiluted injection solution can be used or it can be diluted

beforehand.

Overdose

Above

25-fold

usual

anaesthetic

dose,

life-treatening

symptoms

expected.

clinical

symptoms of overdose are convulsion, cardiac arrhythmia and respiratory arrest.

Respiratory arrest must be treated by assisted or controlled ventilation until sufficient spontaneous

respiration is achieved. Convulsions should be treated with intravenous administration of diazepam. If

treatment with diazepam does not result in sufficient response, administration of phenytoin or

phenobarbital is recommended.

No specific antidote is presently known.

Incompatibilities

Esketamine must not be mixed with barbiturates, diazepam, 4-hydroxybutyric acid (sodium salt),

theophylline, furosemide sodium or sodium bicarbonate since they are chemically incompatible and

precipitation may occur.

Precautions for side effects

If high doses are administered and the injection is carried out more quickly, a respiratory standstill is to

be expected, which must be bridged by means of assisted ventilation until the resetting of sufficient

spontaneous breathing. The administration of hypnotics, especially benzodiazepines or neuroleptics,

reduces the side effects of Esketamine Sintetica.

Read the complete document

Health Products Regulatory Authority

05 March 2021

CRN00C75W

Page 1 of 8

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Esketamine Sintetica 25 mg/ml solution for injection/infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution for injection/infusion contains 25 mg of esketamine as 28.83 mg of esketamine hydrochloride.

1 ampoule of 2 ml solution for injection/infusion contains 50 mg of esketamine as 57.66 mg of esketamine hydrochloride.

1 ampoule containing 10 ml solution for injection/infusion contains 250 mg of esketamine as 288.30 mg of esketamine

hydrochloride.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection/infusion.

Clear, colourless solution.

pH 3.0 – 4.0.

Osmolality = 270 – 310 mOsmol/kg.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

- Induction and maintenance of general anaesthesia, as the only anaesthetic or possibly in combination with hypnotics.

- Supplementation of regional or local anaesthesia.

- Anaesthesia and pain relief (analgesia) in emergency medicine.

- Pain control in artificial respiration (intubation).

4.2 Posology and method of administration

Esketamine should be administered only by specialist of anaesthesiology or emergency medicine.

Esketamine is for hospital use only.

As aspiration cannot be completely excluded and due to the possibility of respiratory depression, intubation and ventilation

equipment must be available.

Posology

For induction of general anaesthesia 0.5 to 1 mg/kg of esketamine is given intravenously or 2 to 4 mg/kg intramuscularly, half

the initial dose is re-injected as needed, generally every 10 to 15 minutes.

alternative

injection,

esketamine

administered

continuous

infusion

dose

3 mg

esketamine/kg/h. In case of multiple injuries (polytrauma) and in patients with poor general condition a dose reduction may be

necessary.

For analgesic supplementation of regional and local anaesthesia 0.125 to 0.25 mg esketamine/kg/h is administered as

intravenous infusion.

For analgesia in artificial respiration (intubated intensive care patients), 0.25 mg esketamine/kg is generally used as a bolus

with a subsequent continuous infusion of 0.2 to 0.5 (up to 1.5) mg esketamine/kg/h with simultaneous benzodiazepine

administration.

When used as a permanent infusion for analgesia in artificial respiration, the duration of the application should not exceed 4 to

6 weeks.

For analgesia in emergency medicine 0.25 to 0.5 mg esketamine/kg is administered intramuscularly or

0.125 to 0.25 mg/kg as a slow intravenous injection.

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Increased salivation should be prophylactically treated with atropine (see section 4.4).

The risk of psychological reactions occurring during recovery from anaesthesia can be greatly reduced by the co-administration

of a benzodiazepine (see also sections 4.4 and 4.8).

Where possible, the use of esketamine should follow the ordinary guidelines regarding fasting, 4 to 6 hours before anaesthesia.

In case of hepatic impairment, a dose reduction may be required.

Paediatric population

In paediatric surgery, as well as in emergency medicine, esketamine hydrochloride is generally used as monotherapy; in case of

other indications, a combination with hypnotics is recommended.

Dosage of esketamine across subgroups of paediatric patients of different ages has not been adequately studied. Based on the

information available, dosage in paediatric patients is not expected to differ substantially from that in adults.

Method of administration

Esketamine is for intravenous or intramuscular use. It can be injected slowly or administered as an infusion.

For infusion, either the undiluted injection solution can be used or it can be diluted beforehand.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Esketamine Sintetica must not be used:

- in the case of hypersensitivity to the active substance or to any of the excipients listed in section 6.1,

- in patients to whom elevation of blood pressure or intracranial pressure forms a serious risk,

- if hypertension is poorly adjusted or not treated (arterial hypertension - systolic / diastolic blood pressure above 180/100

mmHg at rest),

- in eclampsia and preeclampsia,

- in patients with hyperthyroidism (or insufficiently treated hyperthyroidism),

- in situations which require relaxed uterus myometrium (eg threatening uterus rupture, prolapsed umbilical cord),

- as sole anesthetic agent in patients with manifest ischemic cardiac disorders.

- in combination with xanthine derivatives (e.g. aminophylline or theophylline) (the convulsion threshold may become lower).

- in combination with ergometrine.

4.4 Special warnings and precautions for use

Esketamine should be used with caution in the following situations:

- unstable angina pectoris or myocardial infarction in the last 6 months,

- cardiac insufficiency

- elevated intracranial pressure, except under appropriate ventilation, and in the case of central nervous system damages or

diseases, since elevation of cerebrospinal pressure has been described in connection with ketamine anaesthesia,

- in patients who have or have had severe psychiatric disturbances,

- increased eye pressure (glaucoma) and perforating eye injuries as well as in connection with eye examinations or eye surgery

in which intraocular pressure should not increase,

- surgery in the upper respiratory tract,

- in patients under chronic or acute influence of alcohol,

- in patients who have liver disease,

- in patients who have a history of drug abuse or addiction.

Esketamine is metabolized in the liver, and hepatic clearance is required for a termination of the clinical effects. Abnormal liver

function tests associated with esketamine use have been reported, particularly with extended use (> 3 days) or drug abuse. A

prolonged duration of action may occur in patients with cirrhosis or other types of liver impairment. Dose reductions should be

considered in these patients.

In case of high dose and rapid intravenous injection, respiratory depression may occur.

Increased salivation should be prophylactically treated with atropine.

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The risk of psychological reactions occurring during recovery from anaesthesia can be greatly reduced by the co-administration

of a benzodiazepine (see also section 4.8).

In outpatient surgery, adequate patient monitoring must be ensured until discharge.

The patient should be accompanied home and should not consume alcohol within the next 24 hours.

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

In surgical procedures that may involve visceral pain, muscle relaxation and supplemental analgesia (controlled ventilation and

administration of nitrous oxide / oxygen) are indicated.

In patients with alcohol intoxication, care should be taken when using esketamine.

In patients with known history of severe angina pectoris, caution should be taken when using esketamine.

When using esketamine in patients in shock, the basic principles of shock therapy (volume replenishment, O

intake) must be

observed. In the most severe patients in shock, with hardly or not measurable blood pressure, caution should be taken when

using esketamine.

In diagnostic and therapeutic procedures of the upper respiratory tract, hyperreflexia and laryngospasm are possible, especially

in children. In the case of interventions on the pharynx, larynx and bronchial tree, a muscle relaxation with adequate ventilation

may therefore be necessary.

Long-Term Use

In patients who received racemic ketamine as long-term therapy (1 month to several years), cases of cystitis, including

haemorrhagic cystitis, have been reported. Similar effects may also occur following esketamine abuse. Furthermore,

hepatotoxicity has been reported in patients after extended use (> 3 days).

Drug Abuse and Dependence

Racemic ketamine has been reported being used as a drug abuse. Reports suggest that abuse of ketamine produces a variety

of symptoms including, among others, flashbacks, hallucinations, dysphoria, anxiety, insomnia or disorientation. Cases of

cystitis, including haemorrhagic cystitis, and cases of hepatotoxicity have also been reported after use of ketamine racemic.

Similar effects therefore cannot be ruled out following esketamine use. Esketamine dependence may be developed by

individuals with history of drug abuse. Therefore, esketamine should be prescribed and administered with caution only under

the supervision of a doctor.

This medicinal product contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interactions

Concomitant administration contraindicated:

The convulsion threshold may become lower in combination with xanthine derivatives (e.g. aminophylline or theophylline). This

combined administration should be avoided.

Esketamine Sintetica should not be used in combination with ergometrine.

Concomitant administration with precaution:

Sympathomimetics (directly or indirectly acting), thyroid hormones, and vasopressin may lead to an increase in blood pressure

(arterial hypertension) and in heart rate acceleration (tachycardia), which should be taken into consideration in concurrent

administration with esketamine.

In combination with hypnotics, especially benzodiazepines or neuroleptics, there is a reduction in adverse effects, but also a

prolongation of the duration of effect of esketamine.

Barbiturates and opiates given concurrently with esketamine may prolong the recovery phase.

The anaesthetic effect of halogenated hydrocarbons (e.g. isoflurane, desflurane, sevoflurane) is potentiated by administration

of esketamine, so lower doses of halogenated hydrocarbons may be needed.

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The effect of certain muscle relaxants (depolarizing or non-depolarizing muscle relaxants, e.g. suxamethonium, pancuronium)

may be prolonged due to the combined use of esketamine.

Diazepam is known to increase the half-life of racemic ketamine and prolongs its pharmacodynamic effect. Therefore, dose

adjustments may also be needed for esketamine.

The risk of cardiac arrhythmia after administration of adrenaline may increase in concurrent administration of esketamine and

halogenated hydrocarbons.

Medicinal

products

that

inhibit

CYP3A4

activity

generally

decrease

hepatic

clearance,

resulting

increased

plasma

concentration of CYP3A4 substrates medicinal products, such as esketamine. Co-administration of esketamine with medicinal

products that inhibit the enzyme CYP3A4 enzyme may require a decrease in esketamine dosage to achieve the desired clinical

outcome.

Medicinal products that induce CYP3A4 activity generally increase hepatic clearance, resulting in decreased plasma

concentration of CYP3A4 substrate medicinal products, such as esketamine. Co-administration of esketamine with medicinal

products that induce CYP3A4 enzyme may require an increase in esketamine dosage to achieve the desired clinical outcome.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data on the use of esketamine in pregnant women. The informative value of the present animal

reproduction studies is insufficient, but the available data do not indicate any adverse effects on pregnancy, embryofetal

development, parturition or postnatal development. The potential risk for humans is unknown. Esketamine must not be used

during pregnancy unless, after careful consideration, the benefit for the mother is judged to outweigh the possible hazard for

the child.

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

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

Treatment with Esketamine Sintetica may result in reduced reaction ability. This should be taken into consideration in

connection with situations requiring special alertness, e.g. when driving. The patient is not allowed to drive, operate machinery

or operate dangerous activities for at least 24 hours following esketamine administration.

The patient should go home only if accompanied.

4.8 Undesirable effects

Adverse effects are usually dependent on the dose and speed of injection and are spontaneously reversible.

Nervous system (CNS) and psychiatric adverse effects are more common if esketamine is administered as the only anaesthetic.

The risk of psychic reaction occuring during recovery from anaesthesia can be greatly reduced by the co-administration of a

benzodiazepine.

The adverse reaction terms were categorized utiliszing the incidence rate as follows:

Very common (≥ 1/10)

Common (≥ 1/100, < 1/10)

Uncommon (≥ 1/1,000, < 1/100)

Rare (≥ 1/10,000, < 1/1,000)

Very rare (< 1/10,000)

Not known (frequency cannot be estimated from the available data)

Immune system disorder

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05 March 2021

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Page 5 of 8

Rare

Anaphylaxis

Very rare

Hypersensitivity reactions (anaphylactoid reactions). In patients with

shock, there may also be a further reduction in blood pressure.

Psychiatric disorders

Very common

Recovery reactions

. These include vivid dreams, including

nightmares, dizziness and motor restlessness

Not known

Hallucinations, dysphoria, anxiety and disorientation

Nervous system disorders

Uncommon

Tonic and clonic movements, which can resemble convulsions (as a

result of increased muscle tonus), and nystagmus

Eye disorders

Common

Blurred vision

Uncommon

Diplopia, increased intraocular pressure

Cardiac disorders

Very common

Increase in blood pressure and heart rate (an increase of about 20 %

of the starting level is common)

Common

Temporary tachycardia

Rare

Arrhythmia, bradycardia

Vascular disorders

Rare

Hypotension (especially in connection with circulatory shock)

Respiratory, thoracic and mediastinal disorders

Common

Especially in patients with restricted coronary reserve, increase in

vascular resistance in pulmonary circulation, and increase in mucus

secretion. Increased oxygen consumption, laryngospasm, and

temporary respiratory depression. (The risk of respiratory depression

usually depends on the dose and the speed of the injection)

Gastrointestinal Disorders

Common

Nausea and vomiting, increased salivation

Hepatobiliary Disorders

Not Known

Liver function test abnormal

Drug-induced liver injury*

Skin and subcutaneous tissue disorders

Uncommon

Morbilliform rash, and exanthema

General disorders and administration site conditions

Uncommon

Pain and erythema at the injection site

Injury, poisoning and procedural complications

Common

Diagnostic and therapeutic interventions in the area of the upper

respiratory tract (especially in children) may lead to reflex

(hyperreflexia) and laryngeal spasms (laryngospasm). In the case of

interventions on the pharynx, larynx and bronchial tree, a muscle

relaxation with adequate ventilation may therefore be necessary.

Under inadequate ventilation, there is often an increase in brain

pressure, an increase in intraocular pressure, and an increase in

muscle tone.

1 When esketamine is administered as the only anesthetic, up to 30% of patients may experience dose-dependent reactions

during the recovery phase.

2 The incidence of these events can be greatly reduced by the co-administration of a benzodiazepine.

* Extended period use (>3 days) or drug abuse.

Reporting of suspected adverse reactions

Reporting

suspected

adverse

reactions

after

authorisation

medicinal

product

important.

allows

continued

monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected

adverse reactions via HPRA Pharmacovigilance, Website: http://www.hpra.ie

4.9 Overdose

Above the 25-fold usual anaesthetic dose, life-treatening symptoms are expected.

The clinical symptoms of overdose are convulsion, cardiac arrhythmia and respiratory arrest.

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Respiratory arrest must be treated by assisted or controlled ventilation until sufficient spontaneous respiration is achieved.

Convulsions should be treated with intravenous administration of diazepam. If treatment with diazepam does not result in

sufficient response, administration of phenytoin or phenobarbital is recommended.

No specific antidote is presenty known.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other general anesthetics, ATC code: N01AX14

Esketamine is a chiral cyclohexanone derivative with strong analgesic activity. At the same time it causes a so-called

dissociative anaesthesia. The analgesic effect already occurs at sub-dissociative doses and persists anaesthesia.

The ketamine-racemate consists of the enantiomers esketamine ((S)-ketamine) and (R)-ketamine. The analgesic effect of

Esketamine is mainly due to the blockade of N-methyl-D-aspartate (NMDA) receptors. The analgesic-anesthetic potency

between

S-isomer

about

1:4.

potency

esketamine

approximately

twice

high

racemic

(R),(S)-ketamine in the same dose. Esketamine has a marked local anaesthetic effect on the spinal cord and on peripheral

nerves.

In the EEG, the signs of attenuation of the bioelectrical cerebral cortex activity can be observed under esketamine anaesthesia,

especially the frontal areas, and an activation of subcortical structures can be detected. Muscle tone is maintained or becomes

increased so that the protective reflexes are generally not impaired. The convulsion threshold is not lowered. Spontaneous

respiration is followed by an elevation of intracranial pressure that can be avoided by adequate pulmonary ventilation.

Due to a sympathomimetic effect, esketamine produces an increase in blood pressure and heart rate, resulting in an increase in

myocardial oxygen consumption and in coronary blood flow. Esketamine hydrochloride has a negative inotropic and

antiarrhythmic effect on the heart. Peripheral resistance is barely changed due to contradictory effects.

After administration of esketamine, moderate hyperventilation can be observed without substantial impairment of the blood

gases. Esketamine has a relaxing effect on the bronchial musculature.

Metabolism, endocrine, kidney and intestinal function as well as the coagulation system are not influenced by esketamine.

5.2 Pharmacokinetic properties

In contrast to the pharmacodynamic differences, the pharmacokinetic properties of the enantiomers of ketamine are very

similar, i.e., there are also no significant differences in the pharmacokinetics of esketamine and racemic (±) ketamine

hydrochloride. Thus reference can be made to the pharmacokinetic experience with the racemic ketamine (called "ketamine"

below). The pharmacokinetic of ketamine is linear.

After intravenous bolus delivery, ketamine is rapidly distributed into strongly perfused tissues (e.g. heart, lung and brain),

followed by muscles and peripheral tissue, followed by adipose tissue; the peak concentrations are reached within 1 minute.

There are approximately 6.5-fold higher concentrations in the brain tissue than in the plasma. Ketamine passes through the

placenta. It is resorbed rapidly (half-life resorption: 2 to 17 minutes) after intramuscular administration into the deltoid muscle.

After an intravenous bolus delivery of 2.5 mg/kg, the distribution phase of ketamine takes about 45 minutes at a half-life of 10

to 15 minutes, which is associated with the duration of the anaesthetic effect (about 20 minutes). After an intravenous bolus

injection

mg/kg

esketamine,

plasma

concentrations

around

micrograms/ml

after

minute

micrograms/ml after 5 minutes.

After

intramuscular

dose

mg/kg

esketamine,

plasma

esketamine

peak

concentration

around

0.14

micrograms/ml after 25 minutes.

Ketamine is 93% bioavailable after intramuscular administration. The binding to plasma protein is about 47%.

Metabolism

rapid

largely

complete.

Metabolic

clearance

therefore

high

1200

1500 ml/min.

N-demethylation, (±)-norketamine (via the cytochrome P-450 system) and a (±)-cyclohexenone derivative resulting from

dehydration are obtained, which are about 1/3 to 1/10 and 1/10 to 1/100 respectively of the anaesthetic effect of ketamine. In

human

liver

microsomes,

CYP3A4

enzyme

main

enzyme

responsible

N-demethylation

ketamine

norketamine, with CYP2B6 and CYP2C9 enzymes as minor contributors.

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The terminal elimination half-life for ketamine is between 79 minutes (following continuous infusion) and 186 minutes

(following low-dose intravenous administration), for (±)-norketamine, 240 minutes were measured.

Ketamine and its metabolites are eliminated predominantly by the kidneys. After administration of

H-ketamine, 91 to 97% of

the total radical activity was found in the urine and only 3% in the faeces in the 120 h. urine. In the 72 h. urine, only 2.3% or

1.6% of the dose is excreted as free ketamine or as free (±)-norketamine and 16% of the dose as dehydronoketamine.

In a clinical-therapeutic study (7 to 8 patients per group), plasma concentrations of the unchanged substance as well as the

metabolites I (norketamine) and II (cyclohexenone derivative) were measured after intravenous administration of 2mg/kg

ketamine racemate, 1 mg/kg Esketamine and 3 mg/kg of (R)-ketamine, respectively. In all cases, the plasmas mirror curves of

the unchanged substance as well as the metabolites I and II were largely parallel, that is, without apparent pharmacokinetic

differences. Likewise, the withdrawal profiles were comparable in all three groups.

In two more recent studies, the similarity of the pharmacokinetic profile of esketamine with that of ketamine racemate and

(R)-ketamine was confirmed.

Esketamine only had the tendency to faster elimination with greater total clearance than (R)-ketamine and ketamine racemate,

which promises improved controllability in clinical use.

5.3 Preclinical safety data

Acute and chronic toxicity

studies

with

single

repeated

intravenous

administration

symptoms

toxicity

were

exaggerated

pharmacodynamic effects of esketamine.

Studies on animals have shown that racemic (R),(S)-ketamine can cause a NMDA antagonist-induced neuronal cell death

(apoptosis) in juvenile animals when used in high doses and/or over a long period of time. S-ketamine uses the same

pharmacological target structure. The relevance of these results for human use is not known.

Mutagenic and tumor-inducing potential

In vitro

in vivo studies on genotoxicity revealed no evidence of genotoxic potential. Long-term studies on carcinogenicity

were not carried out.

Reproductive toxicity

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 0.36% (pH adjustment)

Water for injections

6.2 Incompatibilities

Esketamine must not be mixed with barbiturates, diazepam, 4-hydroxybutyric acid (sodium salt), theophylline, furosemide

sodium or sodium bicarbonate since they are chemically incompatible and precipitation may occur.

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

6.3 Shelf life

3 years.

The chemical and physical in-use stability of ready-to-use infusion solutions prepared with sodium chloride 9 mg/ml (0.9%) or

glucose 50 mg/ml (5%) infusion solution has been demonstrated over 24 hours under storage at 25°C.

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From a microbiological point of view, 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 and would normally be no longer than 24 hours at 2 to 8°C, for

dilution not under controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not freeze.

6.5 Nature and contents of container

Ampoules: glass type I (Ph. Eur.)

10 ampoules with 2 ml of solution for injection/infusion.

10 ampoules with 10 ml of solution for injection/infusion.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

For single use only.

Parenteral medicinal products must always be visually checked prior to administration. Only a clear and colourless solution may

be used.

When diluting the solution for injection/infusion before application as an infusion:

Esketamine can be mixed with glucose 50 mg/ml (5 %) or sodium chloride 9 mg/ml (0.9 %).

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

7 MARKETING AUTHORISATION HOLDER

Sintetica Ireland Limited

BEAUCHAMPS

Riverside Two

Sir John Rogerson’s Quay

Dublin 2

D02 KV60

Ireland

8 MARKETING AUTHORISATION NUMBER

PA22903/004/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 2

October 2020

10 DATE OF REVISION OF THE TEXT

February 2021

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