SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Xenon Anaesthetic 100% v/v medicinal gas, liquefied medicinal gas, liquefied, for inhalation use

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

-    2 l    aluminium gas cylinder with    1.3    kg of compressed medicinal    gas,

corresponding to a removable volume of 233 litres (at 1.013 bar, 15°C)

-    5 l    aluminium gas cylinder with    3.1    kg of compressed medicinal    gas,

corresponding to a removable volume of 555 litres (at 1.013 bar, 15°C)

-    10 l aluminium gas cylinder with 5.5 kg of compressed medicinal gas, corresponding to a removable volume of 1,000 litres (at 1.013 bar, 15°C)

1 litre gas under standard conditions (1.013 bar, 15°C) contains 1 litre xenon 100% (v/v).

3 PHARMACEUTICAL FORM

Medicinal gas, liquefied.

Colourless and odourless gas

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Xenon is intended for maintaining narcosis in combination with opioids as part of balanced anaesthesia. Xenon Anaesthetic 100% (v/v) is indicated in adults of ASA class I-II.

4.2 Posology and method of administration

Xenon Anaesthetic 100% (v/v) should be administered only under the supervision of an anaesthetist. Adequate apparatus for anaesthesia and ventilation, including resuscitation, must be available during administration. Quantitative determination of the inhaled oxygen concentration during administration is obligatory.

Posology

Premedication

Premedication should be determined according to the individual needs of the patient. Anticholinergics, such as atropine, can be administered.

Induction

Xenon is not intended for induction of anaesthesia. Intravenous anaesthesia induction is preferred.

Maintenance

Adults

Concentrations ranging from 51 to 69% (v/v) of xenon in the inhaled air are recommended in general anaesthesia depending on the individual requirement of the patient, the specific intervention and the dosage of the supplementary anaesthetic*. Muscle relaxants can be given if additional relaxation is required (see section 4.5).

The MAC₅₀ (Minimal Alveolar Concentration which suppresses a defensive reaction to pain stimulus in 50% of patients) is approximately 60 ± 5% (v/v).

*Studies have been conducted using 1 MAC xenon in combination with sufentanil 10 pg boli as required. In combination with fentanyl dosages in a range from 0.05 mg - 1.0 mg were used. In combination with alfentanil 50 pg/kg - 100 pg/kg, in combination with remifentanil 0.2 pg/kg/min.- 0.5 pg/kg/min.

Due to limited clinical experience and lack of available clinical data a concomitant administration of volatile anaesthetics is not recommended at this time.

Elderly

The MAC₅₀ values of xenon in elderly differ in men and women. A MAC₅₀ of 69.3% (v/v) is described for men and a MAC₅₀ of 51.5% (v/v) for women (in 30% oxygen).

Paediatric population

The safety and efficacy of Xenon Anaesthetic 100% (v/v) in children aged 0 to 18 years have not yet been established. No data are available.

Termination of anaesthesia

At the end of the anaesthesia, xenon administration is stopped. Despite less hypoxic dilution with xenon than nitrous oxide, inspired oxygen concentration should be increased to 100 %.

Method of administration

Xenon must be administered only with the addition of at least 30% oxygen.

For inhalation or endotracheopulmonary use.

Xenon is to be administered only by means of conventional anaesthetic apparatus calibrated specifically for xenon. The duration of xenon anaesthesia is dependent upon the type of surgical intervention.

The administration technique must ensure the avoidance of administration of pure xenon (or a mixture with a too high (toxic) partial pressure of the inert gas) in order to maintain a large enough inspired oxygen concentration (see section 6.6).

Due to accumulation of nitrogen when using xenon in a closed-circuit anaesthesia machine and to ensure adequate oxygenation it is recommended to flush the closed system with fresh oxygen-xenon when the xenon concentration decreases to less than 60%. In patients requiring more than 30-35% oxygen to maintain adequate hemoglobine saturation, the accumulation of nitrogen and the needed oxygen concentration will reduce the xenon concentration to significantly less than 1 MAC.

Data regarding long term administration of xenon is not yet available.

4.3 Contraindications

Xenon must not be administered if the patient is known to have a history of hypersensitivity to the active substance.

Xenon must not be administrated to anyone known to be susceptible to malignant hyperthermia.

Xenon must not be used in patients with elevated intracranial pressure.

Xenon must not be used in patients with preeclampsia or eclampsia.

Xenon must not be used in patients with lung and/or airway disease.

Xenon must not be used in patients with a risk of high oxygen demand.

Xenon must not be used in patients with seriously impaired cardiac function.

4.4 Special warnings and precautions for use

Xenon is not intended for use as a monoanaesthetic. Because the MAC value is 5571% (v/v), it is not possible to perform monoanaesthesia with xenon in all patients at a normal ambient air pressure with adequate oxygenation. For this reason, xenon is normally combined with opioids (balanced anaesthesia). If the depth of anaesthesia is uncertain, particularly where there is an increased inhaled oxygen concentration (>35%), the anaesthetic procedure should be changed. Regarding the dosage of the opioids to be used please see section 4.2.

Xenon should only be administered with an anaesthetic device which is suitable for xenon (see section 6.6).

Only little experience has been gained in patients with liver and/or kidney function disorders. Xenon should therefore not be used in these patients until more data are available.

Caution is advised in patients with the risk of PONV as postoperative nausea and vomiting is very common with xenon anaesthesia procedure (up to 45%).

Due to the increase in cerebral blood flow observed with xenon and the lack of available clinical data, utilisation of xenon in neurological surgery is not recommended at this time.

The physical properties of xenon cause an increase of airway pressure.

The incidence of malignant hyperthermia in volatile anaesthetics is 1:20,000. There is no experience with the use of xenon in malignant hyperthermia susceptible patients.

Caution is advised in patients with hypertension.

Xenon must only be used when combined with at least 30% oxygen - danger of asphyxia.

Xenon has a low blood solubility. The risk of elevated pressure in air filled cavities over time cannot be clearly ruled out.

Due to limited clinical experience and lack of available clinical data, a concomitant administration of volatile anaesthetics is not recommended at this time.

Be aware that xenon is heavier than air; it could act as an asphyxiant in low points by displacing oxygen.

4.5 Interaction with other medicinal products and other forms of interaction

In most cases there is no reason for discontinuing treatment with other necessary medicinal products prior to general anaesthesia with xenon. It is sufficient to inform the anaesthetist thereof.

The concomitant administration of xenon and the following medicinal products necessitates strict clinical monitoring of the patient:

Indirect sympathomimetics (amphetamines and their derivatives, psychostimulants, anorectics, ephedrine and its derivatives)

Risk of perioperative hypertension. If surgery is scheduled, then treatment should preferably be discontinued a few days prior to the operation.

Nonselective monoamine oxidase inhibitors

The effect of monoamine oxidase inhibitors on xenon-based anaesthesia is at present unknown. There is as yet no data regarding the concomitant administration of monoamine oxidase inhibitors and xenon.

For safety purposes, treatment with monoamine oxidase inhibitors, as with other inhalation anaesthetic agents, must be stopped 15 days prior to surgery.

Alpha and beta sympathomimetics (e.g. adrenaline [administered as subcutaneous or gingival injections to achieve a local haemostatic effect] and noradrenaline), beta sympathomimetics (orciprenaline)

Clinical studies with xenon revealed no evidence of an increased incidence of ventricular arrhythmias after subcutaneous administration of 0.25 mg adrenaline (50 ml of a dilution of 1:200,000).

Muscle relaxants

Xenon does not have muscle-relaxing effects. The effect of muscle relaxants is not influenced by xenon.

Opioids and other centrally suppressive medicinal products

The narcotic effect of xenon is intensified by the concomitant administration of opioid analgesics and other centrally suppressive medicinal products, as well as under hypothermia; low doses can therefore be sufficient.

Beta blockers and other antihypertensives

Cardiovascular compensatory reactions can be affected by betablockers (they can be diminished by administration of beta sympathomimetics during surgery, however).

As a rule, treatment with betablockers as well as other antihypertensives should not be interrupted, and an abrupt reduction in dosage should be avoided.

Xenon can cause clear hypotension in patients being concomitantly administered calcium antagonists of the dihydropyridine class.

4.6 Fertility, pregnancy and lactation

There are no adequate data from the use of xenon in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

Xenon Anaesthetic 100% (v/v) is not recommended during pregnancy.

An increased uterine bleeding tendency during obstetric intervention cannot be ruled out, since no trials are available at present.

There is no experience regarding the safe use of xenon for anaesthesia in obstetrics.

It is unknown whether xenon is excreted in human breast milk. The excretion of xenon in milk has not been studied in animals.

A decision on whether Xenon Anaesthetic 100% (v/v) should be used during breast-feeding should be made taking into account the benefit for the breastfeeding to the child and the benefit of Xenon Anaesthetic 100% (v/v) narcosis to the woman.

4.7 Effects on ability to drive and use machines

Xenon Anaesthetic 100% (v/v), as all other anaesthetics, has major influence on the ability to drive and use machines.

The patient must not drive a motorised vehicle or operate machines following anaesthesia with xenon. The time period should be decided individually by the physician.

The patient should not return home unaccompanied and should not consume alcohol.

4.8 Undesirable effects

As with other inhalational anaesthetics, xenon will cause respiratory depression more or less in a concentration-dependent manner.

Postoperative nausea and vomiting is very commonly reported in xenon anaesthesia procedures (up to 45 %).

The following rates are used as a basis when assessing undesirable effects.

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:	cannot be estimated from the available data

Immune system disorders:

Common:    Intraoperative or postoperative rise in temperature or sweating

Chills

Cardiac disorders:

Common:    Bradycardia

Vascular disorders:

Very common: Hypertension Common:    Hypotension

Respiratory, thoracic and mediastinal disorders:

Very rare:    Bronchial spasm

Gastrointestinal disorders:

Very common: Postoperative nausea and vomiting

The following events have also been observed in clinical studies, without revealing a direct correlation to xenon anaesthesia:

Arrhythmia Elevated liver enzymes Renal dysfunction Hypersecretion Hypocalcaemia Leucocytosis Metabolic acidosis Tachycardia

4.9 Overdose

In the event of overdose, the supply of xenon should be stopped, assisted or controlled ventilation with pure oxygen temporarily undertaken, and hypertension corrected by supportive measures.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: other general anaesthetics, ATC code: N01A X15

Xenon is an inhalational anaesthetic of the noble gas group. Depending on the dosage, xenon will cause - reversibly - suppression of consciousness, pain sensitivity, vegetative reflexes and motor function. Respiratory drive and circulatory responses are depressed.

5.2 Pharmacokinetic properties

Site of absorption and kinetics

Xenon is absorbed by the pulmonary alveoli. The rate of xenon flow in the brain correlates to the concentration available in the inspiratory air and the ventilation of the patient.

The blood-gas solubility coefficient of xenon is the lowest of all inhalational anaesthetics (xenon: 0.115; other inhalational anaesthetics: 0.115 - 1.14). Hence the induction of anaesthesia is very rapid (the brain saturation concentration is achieved in a few minutes) and the washout phase upon terminating anaesthesia is very fast (detected with ¹³³xenon as a tracer, maximum elimination half-lives in different organs approx 100 min). The uptake is quickest in the highly vascularised organs and likewise strongest in fatty tissue due to the lipophilic properties of xenon. Xenon was found longest in the intestine.

Tissue concentration

The following list of various distribution coefficients reveals on the one hand how diversely the gases are distributed in individual physical compartments and on the other hand how xenon burdens the organism only minimally due to its favourable distribution coefficients.

Distribution coefficients Blood/gas    0.115

Oil/gas    1.9

(All data refers to 37°C)

Liquor patency

Liquor patency is given with xenon.

Metabolism

Xenon is eliminated unchanged by the lungs.

Xenon is an inert gas, hence under normal conditions metabolisation does not occur.

Elimination half-life

Due to the low solubility coefficient of xenon, the anaesthetic already begins to be eliminated during administration.

Elimination under impaired kidney function

Xenon is exhaled only and is not metabolised in humans. Data not available.

Elimination under impaired liver function

Xenon is eliminated solely unchanged in the expiratory air via the alveoli. Data not available.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, repeated dose toxicity, and genotoxicity.

Studies into the possible effects on fertility were carried out in rats given a mixture of xenon and oxygen at a ratio of 80:20 by inhalation over a period of two hours twice per week prior to mating. This had no effect on the fertility of the parental generation.

A study in which rats underwent the same administration regime during the entire gestational period revealed no effect on prenatal progress or postnatal weight development of the offspring. If, however, the rats received xenon over a period of eight hours each day during the organogenesis phase at a concentration of 50, 60 and 75% by inhalation, there was a rise in the embryo-foeto-lethal effects and delayed skeletal and body weight development.

Studies of peri- and postnatal toxicity have not been performed.

Long term carcinogenicity studies have not been performed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 l aluminium gas cylinder: 12 months 5 l aluminium gas cylinder: 12 months 10 l aluminium gas cylinder: 5 years

6.4 Special precautions for storage

Store in the original gas cylinder; do not transfer from the original gas cylinder to another gas cylinder.

Keep the gas cylinder tightly closed.

Store gas cylinders indoors in well-ventilated rooms or outdoors in ventilated sheds where they are protected from rain and direct sunlight.

Protect the gas cylinder from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition.

Before use the gas cylinder has to be stored at room temperature for 24 hours.

Storage in the pharmacy department

The gas cylinders should be stored in an airy, clean and locked place, for storage of medicinal gas only. Inside this place, a separate premise should be dedicated to the storage of xenon gas cylinders.

Storage in the medicinal department

The gas cylinder should be put in an equipped site with appropriate material in order to hold the gas cylinder vertically.

Transport of gas cylinders (please refer to section 6.6)

6.5 Nature and contents of container

2 l, 5 l and 10 l aluminium gas cylinders (bright green shoulder and white body acc. EN 1089 Part 3) with respectively 1.3 kg, 3.1 kg and 5.5 kg of compressed medicinal gas (58.4 bar at 16.6°C, partly liquefied below the critical temperature of 16.6°C), corresponding to a removable volume of

respectively 233 litres, 555 litres and 1,000 litres (at 1.013 bar, 15°C), equipped with brass valve with a specific outlet connection.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Instructions for handling

It should be noticed that below 16.6°C, xenon separates into 2 phases: liquid and gaseous. Above 16.6°C, there is only one gaseous phase.

The installation of a xenon pipeline system with supply station of gas cylinders, fixed network and terminal units is forbidden.

All regulations concerning handling of pressure vessels must be followed.

In order to avoid any incident, the following instructions should be absolutely respected:

The good condition of the material should be checked before use

The gas cylinders should be fixedly stowed away in order to avoid untimely fall

The valve should not be violently opened

A gas cylinder whose valve is not protected by a cap or a shell should not be used

A specific connection complying with DIN 477-1 and a pressure regulator which admits a pressure at least equal to 1.5 the maximum operating pressure (58.4 bar) of the gas cylinder should be used

A defective valve should not be repaired

The pressure regulator should not be tightened with pliers, at the risk of crushing the gasket

Transport of gas cylinders

The gas cylinders should be transported with appropriate material in order to protect them from risks of shocks and falls.

During inter- or within-hospital transfers of patients, treated with Xenon Anaesthetic 100%( v/v), the gas cylinders should be fixedly stowed away in order to hold the gas cylinders vertically and to avoid the risk of fall or untimely modifying output. A particular attention should be also turned to the fastening of the pressure regulator so as to avoid the risks of accidental failures.

Instructions for disposal

When the gas cylinder is empty, it should not be discarded. Empty gas cylinders will be collected by the supplier. To avoid contamination and ensure proper functioning after refilling, they are to be drained down to a residual pressure of at least 3 bars.

Any backflow is to be prevented (risk of penetration of water, moisture or foreign matter). It has to be ensured that the valve of the gas cylinder is always closed when not in use. Maintenance of the residual pressure must be ensured.

Physical constants Appearance:

Odour:

Molar mass:

State at 20°C:

Melting point:

Boiling point:

Critical temperature:

Critical pressure:

Ignition temperature:

Explosion limit (in air):

Density, gaseous (15°C,1.013 bar):

Relative density, gaseous (air=1):

Vapour pressure at 15°C:

Solubility in water (20°C, 1 bar):

Purity determined by mass spectrometry >

Anaesthesia system An anaesthetist should supervise the administration of xenon.

Xenon is delivered to the patient via an approved anaesthesia system. The anaesthesia system must provide ventilation of patient and a control of the inhaled gas mixture. The gas delivery system must provide the desired dosage of xenon irrespective of the ventilator settings. To insure safe anaesthesia the anaesthesia system shall have the following characteristics:

- Non specific to xenon

o Gas specific inlet connexion for the anaesthesia system in compliance EN 739. o Oxygen supply failure protection and alarm system

o The anaesthesia system shall be equipped with means of connection to a reserve oxygen supply.

o The anaesthesia system shall be equipped with an oxygen flush (supply of 100% oxygen at high flow).

o Protection again selection of oxygen concentration below ambient air. o Oxygen monitoring in gas administered to patient.

o Carbon dioxide monitoring in gas administered to patient.

o Anaesthetic vapour delivery devices with the corresponding anaesthetic agents monitoring systems.

o Means of pressure limitation (at patient connection port). o Exhaled volume monitoring. o Breathing system integrity alarm. o Continuing pressure alarm.

o As a general requirement the alarm system shall comply with ISO 9703-1, 2 and 3. o Anaesthetic gas scavenging system.

- And some additional specific features in order to achieve a safe anaesthesia with xenon:

o A specific gas inlet connexion for xenon in compliance with EN 739:1998 -connector NIST B16.

o A gas mixer calibrated for xenon in order to allow adequate dosage of xenon.

o Measurement of xenon concentration in the breathing circuit by a dedicated sensor.

o An alarm on xenon concentration.

o Means of measurement of oxygen concentration in a mixture containing xenon within the breathing circuit and its associated alarms.

o Antihypoxic coupling system.

o Conventional scavenging used for xenon.

7 MARKETING AUTHORISATION HOLDER

AIR LIQUIDE Sante INTERNATIONAL 75, Quai d'Orsay F-75321 Paris cedex 07 France

8    MARKETING AUTHORISATION NUMBER(S)

PL 27513/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

12/10/2010

10 DATE OF REVISION OF THE TEXT

20/08/2014