Document: Niontix medicinal gas, liquefied ENG SmPC change

• Niontix medicinal gas, liquefied SmPC
• Niontix medicinal gas, liquefied ENG SmPC

---

SUMMARY OF PRODUCT CHARACTERISTICS

Niontix 100%, medicinal gas, liquefied.

Nitrous oxide (N₂O, medicinal laughing gas) 100%.

For the full list of excipients, see section 6.1.

Medicinal gas, liquefied.

Colourless gas with a slightly sweet taste and smell.

Nitrous oxide is used

• in anaesthesia, in combination with other inhalation anaesthetics or intravenous anaesthetics.

• for the treatment of short-term pain conditions of mild to moderate intensity when rapid analgesic onset and offset effects are wanted.

Personnel who administer nitrous oxide must be adequately trained and practised in using this medicinal product. Nitrous oxide should only be administered where there is adequate equipment available to secure an open airway immediately and commence emergency cardiopulmonary resuscitation if necessary.

Posology

General anaesthesia

When used in general anaesthesia, Nitrous oxide is commonly used in concentrations between 35 and 75 vol.% in mixtures with oxygen and if necessary with other anaesthetics.

Nitrous oxide as sole anaesthetic is usually not sufficiently potent for surgical anaesthesia, but should therefore be combined with other anaesthetics when used in general anaesthesia.

Nitrous oxide has an additive effect when combined with most other anaesthetics (see Section4.5).

The effects of nitrous oxide given as a sole agent are not dependent on the patient’s age, but when co-administered with other anaesthetics the mixture usually has increased effect on older patients compared to younger ones.

Analgesia, conscious sedation

Nitrous oxide exhibits analgesic and sedative properties.

When used as a sole agent, concentrations of 30-60 vol.% nitrous oxide possess dose dependent analgesia and sedative effects.

Nitrous oxide in concentrations of up to 50-60% alleviates pain, sedates, and reduces agitation, but usually without affecting the degree of consciousness or capacity to react to speech.

It should be used during the entire duration of the procedure or for as long as the analgesic effect is desired.

Breathing, circulation and protective reflexes are normally preserved at these concentrations.

Nitrous oxide should not be administered in concentrations greater than 70-75 vol.% so that a safe oxygen fraction can be guaranteed.

In patients with compromised oxygenation, oxygen fraction greater than 30% might be required.

Nitrous oxide can be administered for up to 6 hours without haematological monitoring in patients with no risk factors (see Section 4.4.).

Method of administration

Nitrous oxide should be given by inhalation (either spontaneous breathing by the patient or controlled ventilation).

Nitrous oxide should be given in combination with oxygen, using special equipment that can deliver a mixture of nitrous oxide and oxygen.This equipment should include oxygen concentration monitoring and alarm facilities so that a hypoxic gas mixture (FiO₂< 21 vol.%) is not administered.

When used in anaesthesia, nitrous oxide is administered through special equipment where the exhaled gas is recirculated and can be rebreathed (circular system with rebreathing).

Nitrous oxide should be used only in premises with adequate ventilation and/or exhaust facilities to avoid high gas concentrations in the ambient air. The air quality should accord with local regulations, and exposure to nitrous oxide at work should be below nationally determined hygienic limits.

During inhalation of nitrous oxide, gas bubbles (gas emboli) and enclosed gas filled spaces may expand due to the enhanced diffusivity of nitrous oxide. Consequently, the use of nitrous oxide is contraindicated:

• In patients presenting with symptoms of pneumothorax, pneumoperocardium, severe gas embolus, or severe head trauma

• After a recent dive (with the attendant risk of decompression sickness),

• After a recent cardiopulmonary bypass with heart-lung machine.

• In patients with a recent intraocular injection of gas (e.g. SF₆, C₃F₈) until said gas has been completely reabsorbed, due to the risk of further expansion of the gas bubble possibly leading to blindness.

• In patients with gross abdominal gaseous distension.

Nitrous oxide is also contraindicated:

.

Special warnings:

Effort should be made to keepworking environment with nitrous oxide concentrations as low as possible in accordance with local regulations.

Chronic exposure to low concentrations of nitrous oxide has been implicated as a possible health risk. At present it is not possible to decide whether there is a causal relationship between chronic exposure to low concentrations of nitrous oxide and any disease, but nor is it possible entirely to discount the possibility of a connection between such chronic exposure and the risk of developing tumours or other chronic diseases, impaired fertility, spontaneous abortion and/or foetal deformities. Hygienic limit values currently exist beneath which (even in chronic exposure) no health hazards are considered to exist. The limit value for a non-dangerous environment in regard to nitrous oxide is currently considered to be a mean value during an eight-hour work cycle that is below 25-100 ppm (TWA value below 25-100 ppm = 0.0025-0.01%).

The mechanical ventilation that is normally employed in operating theatres in combination with active extraction of excess gases from anaesthetic equipment is the basis for a good, uncontaminated working environment, ensuring that the concentrations of nitrous oxide and other anaesthetic gases do not exceed the norms imposed (hygienic limit values) for a working day.

Nitrous oxide should only be used where supplemental oxygen can be given and in the presence of personnel trained in emergency procedures.

Special Precautions for use

The effects of nitrous oxide on the cardiovascular system are negligible in cardiovascular healthy patients with good cardiovascular function. In experimental situations, nitrous oxide has been shown to have a slight depressant effect on the contractility of heart muscle, but this is offset by a slight increase in the sympathetic stimulation of the heart, such that there is normally no significant net effect on the circulation. However, due to the potential for myocardial depression,nitrous oxide should be used with caution in patients with mild to moderate cardiac dysfunction and is contraindicated in patients with extant heart failure or severe cardiac dysfunction.

Nitrous oxide interferes with vitamin B₁₂/folatic acid metabolism.

It also inhibits methionine synthetase, which contributes to the conversion of homocysteine to methionine. The inhibition of this enzyme affects/reduces the formation of thymidine, which is an important part of DNA formation. Nitrous oxide’s inhibition of methionine formation may lead to defects and reduced myelin formation, and hence to damage to the spinal cord. The effect on DNA synthesis is the reason for the influence of nitrous oxide on blood formation and the foetal injuries seen in animal studies.

Nitrous oxide should be used with caution in patients at risk of vitamin B₁₂or folic acid deficiency, i.e. those with deficient intake or absorption of vitamin B₁₂/folic acid, or genetic perturbations in this system, and in immunocompromised patients.

Nitrous oxide should therefore not be used for prolonged periods of time, e.g. for sedation in the ICU.

The possibility of vitamin B₁₂/folic acid replacement or substitution therapy should be considered after a prolonged use exceeding 6 hours or recurrent use and haematological monitoring should be instituted to minimise risk of potential side effects.

Nitrous oxide in high concentration (> 50%) may affect protective reflexes and level of consciousness. Concentrations above 60-70% often cause unconsciousness, and the risk of impaired protective reflexes increases.

Nitrous oxide should not be used during laser surgery of the airways because of the risk of explosive combustion.

Nitrous oxide administration may increase the pressure in catheter balloons e.g. in tracheal intubation.

After general anaesthesia in which a high concentration of nitrous oxide has been used, there is a well-known risk of hypoxia (diffusion hypoxia) which is provoked not only by the alveolar gas mixture but also by a reflexive response to hypoxia, hypercapnia and hypoventilation.Supplementary oxygen administration and oxygen saturation monitoring by means of pulse oximetry is recommended after general anaesthesia until the patient is awake.

Nitrous oxide creates an increase in middle ear pressure.

Combination with other medicinal products

Nitrous oxide interacts in an additive manner with inhaled and/or intravenous anaesthetics and/or active substances with effects on the central nervous system (e.g. opiates, benzodiazepines and other psychomimetics).

These interactions have clear clinical effects, reducing the need for other drugs that are combined with nitrous oxide. The combination usually produces less cardiovascular and respiratory depression and improves/hastens emergence.

Nitrous oxide potentiates the effect of methotrexate on folate metabolism.

Other interactions

Nitrous oxide causes inactivation of vitamin B₁₂(a co-factor in methionine synthetase) which interferes with folic acid metabolism. Thus, DNA synthesisis impaired following prolonged nitrous oxide administration. These disturbances can result in megaloblastical bone marrow changes and possibly polyneuropathy and/or a subacute combined degeneration of the spinal cord (see 4.8.).

Pregnancy

Nitrous oxide interferes with vitamin B₁₂/folic acid metabolism (see section 4.4).

Inhibition of the methionine synthase may cause adverse effects during early stages of pregnancy.

There are no adequatedata from the use of nitrous oxide in pregnant woman to assess the potential harmful effects on human embryonic-foetal development.

Animal studies have demonstrated that high concentrations or prolonged exposure during particular stages of pregnancy can induce teratogenic effects (See section 5.3).

The potential risk for humans is unknown.

It is therefore recommended to avoid using nitrous oxide during the first two trimesters ofpregnancy.

Nitrous oxide can be used during later stages of pregnancy, third trimester and delivery. When used close to delivery, newborns should be supervised for any adverse effects.

Lactation

Nitrous oxide may be given during lactation, but should not be given during breastfeeding itself.

Fertility

The potential risk for impaired fertility associated to chronic work place exposure cannot be ruled out (see 4.4).

Nitrous oxide affects both cognitive and psychomotor functions.Nitrous oxide is rapidly eliminated from the body after brief inhalation and adverse psychometric effects are rarely evident 20 minutes after the administration has stopped while its influence on the cognitive capabilities can persist for several hours.

When used as sole agent, driving, and use of complex machinery in not recommended for at least 30 minutes after cessation of administration of Nitrous oxide and until the patients have returned to their initial mental status as judged by attending healthcare professional.

The undesirable effects listed are derived from public domain scientific medical literature and post marketing safety surveillance.

System organ class	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)	Not known (cannot be estimated from the available data)
Blood and lymphatic system disorders	-	-	-	-	-	Leukopenia, megaloblastic anaemia
Psychiatric disorders	-	-	-	-	-	Psychosis
Nervous system disorders	-	-	-	-	Myelopathy, polyneuropathy	-
Ear and labyrinth disorders	-	-	Feeling of pressure in the middle ear	-	-	-
Gastrointestinal disorders	-	Nausea, vomiting	Bloating, increased gas volume in the intestines	-	-	-
General disorders and administration site conditions	-	Dizziness, sense of intoxi-cation *	-	-	-	-

*only when nitrous oxide is used as a sole agent

In suspected or confirmed vitamin B₁₂deficiency, or where symptoms compatible with affected methionine synthetase occur, vitamin B substitution therapy should be given in order to minimize the risk for adverse signs/symptoms associated to methionine synthetase inhibition such as leukopenia, megaloblastic anaemia, myelopathy and polyneuropathy.

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.

Niontix should always be used in combination with sufficient oxygen in order to guarantee adequate oxygenation/oxygen saturation. Administration equipment should not allow concentration of oxygen below 21%.

Excessive concentrations of nitrous oxide will cause oxygen deficiency (hypoxia), which may lead to unconsciousness.

If hypoxaemia occurs as a result of excessive nitrous oxide concentration, the concentration should be reduced or administration suspended. The oxygen content should be increased and adjusted so that the patient recovers adequate oxygen saturation.

If during the use of nitrous oxide in analgesic concentrations the patient shows signs of decreased alertness, does not respond adequately to command, or in some other ways shows signs of pronounced sedation, administration should be suspended and the patient should breathe “fresh air” and/or be given supplementary oxygen if necessary. Monitoring by pulsoximetry is recommended until the patient has recovered consciousness and is no longer hypoxic.

The patient should not receive any further nitrous oxide until full consciousness has been restored.

Nitrous oxide should not be used for more than 6 hours at one time, or repeatedly without monitoring for haematological effects. (see 4.4.)

Reversible neurological toxicity and megaloblastic bone marrow changes have also been observed following exceptionally prolonged inhalation.

Pharmacotherapeutic group:other general anaesthetics, ATC code: N01AX13.

Available data indicate that nitrous oxide has both direct and indirect effects on the transmission of a number of neurotransmitters both in the brain and the spinal cord.Its effect on the endorphin system throughout the CNS is presumably one of the more central mechanisms underlying the analgesic effects.Results have also shown that nitrous oxide affects noradrenaline activity in the posterior horn of the spinal cord and that to some extent its analgesic effects depend on spinal inhibition.

Nitrous oxide has dose-dependent effects on sensory and cognitive functions that start at 15 vol.%.Concentrations exceeding 60-70 vol.% cause unconsciousness.Nitrous oxide has dose-dependent analgesic properties that are clinically perceptible at end-tidal concentrations around 20 vol.%.

Nitrous oxide is administered by inhalation.Its absorption depends on the pressure gradient between inhaled gas and the blood passing through ventilated alveolar sections.

Distribution in different body tissues is dependent on the solubility of nitrous oxide in these tissues.Its low solubility in blood and other tissues generates a rapid equilibrium between the inhaled and exhaled nitrous oxide concentration.Nitrous oxide saturates the blood rapidly and reaches equilibrium faster than other presently available inhalation anaesthetics.

It is not metabolised, but eliminated unchanged by exhalation.Elimination depends entirely on alveolar ventilation.The elimination time after administration of nitrous oxide ceases corresponds to the saturation time.Because of its low solubility in blood and other tissue, both uptake and elimination are rapid.

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

Exposure to nitrous oxide has been shown to induce neuropathy in fruit bats, pigs and monkeys.

Teratogenic effects of nitrous oxide have been observed in rats after chronic exposure to levels higher than 500 ppm.

Pregnant rats exposed to 50 – 75% nitrous oxide for 24 hours on each of days 6 to12 of gestation show higher incidence of foetal wastage and malformations of the ribs and vertebrae.

None.

Medicinal nitrous oxide may be mixed with air, medicinal oxygen and halogenated inhalation anaesthetics.

3 years forcylinders 5 litres

5 years forbundle, “maxi-ball” and cylinders 5 litres

Drug-related storage precautions

This medicinal product does not require any special storage conditions other than those applying to gas containers and gas under pressure (see below).

Store gas cylinders in locked spaces reserved for medicinal gases.

Storage precautions related to gas containers and pressurised gases

Contact with combustible material may cause fire.

Vapours may cause drowsiness and dizziness.

Keep away from combustible material.

Use only in well-ventilated areas.

Keep cylinder in locked storage reserved for medicinal gases. Must not be exposed to strong heat.

If at risk of fire – move to a safe place. No smoking.

Keep the cylinder clean, dry and free of oil and grease.

Make sure the cylinder is not knocked or dropped.

Store and transport upright with valves closed and, where these are present, with the protective cap and cover in place.

The shoulder of the gas cylinder is marked in blue (nitrous oxide). The body of the gas cylinder is white (medicinal gas). In Finland, the body of the gas cylinder can also be turquoise.

Steel cylinder with shut-off valve 2.5 litres, 4 litres, 5 litres, 10 litres, 20 litres, 40 litres, 50 litres.

Maxi-ball/sphere, steel, 450 litres

Bundle 12 x 27 litres, 9 x 50 litres, 12 x 40 litres, 12 x 50 litres.

Not all pack sizes may be marketed

A pack filled with 0.75 kg of nitrous oxide per litre of cylinder volume produces the following number of litres of gas at atmospheric pressure and 15C (a variant of the 10-litre cylinder is filled with 0.74 kg per litre of cylinder volume and maxiball /sphere is filled with 0.70 kg per litre of cylinder volume).

One 2.5 litre cylinder filled with 1.9 kg produces ca. 1000 litres of gas.

One 4 litre cylinder filled with 3.0 kg produces ca. 1600 litres of gas.

One 5 litre cylinder filled with 3.8 kg produces ca. 2000 litres of gas.

One 10 litre cylinder filled with 7.5 kg produces ca. 4100 litres of gas.

One 10 litre cylinder filled with 7.4 kg produces ca. 4000 litres of gas.

One 20 litre cylinder filled with 15 kg produces ca. 8100 litres of gas.

One 40 litre cylinder filled with 30 kg produces ca. 16,200 litres of gas.

One 50 litre cylinder filled with 37.5 kg produces ca. 20,300 litres of gas.

One 12 x 27 litre bundle filled with 240 kg produces ca. 130,000 litres of gas.

One 9 x 50 litre bundle filled with 337.5 kg produces ca. 183,000 litres of gas.

One 12 x 40 litre bundle filled with 360 kg produces ca. 195,000 litres of gas.

One 12 x 50 litre bundle filled with 450 kg produces ca. 244,000 litres of gas.

One 450 litre maxiball/sphere filled with 315 kg produces 182,000 litres of gas.

General

Medicinal gases must be used for medicinal purposes only.

Different gas types and gas qualities must be separated from each other. Full and empty containers must be stored separately.

Never use oil or grease even if the cylinder valve is stiff or if the regulator is difficult to connect. Handle valves and devices to match with clean, grease-free (hand cream etc.) hands.

Use only standard equipment that is intended for nitrous oxide (medicinal laughing gas).

Check that the cylinders are sealed before they are taken into use.

Preparation prior to use

Remove the seal from the valve before use.

Use only regulators intended for nitrous oxide. Check that the quick connector and regulator is clean and that the gaskets are in good condition.

Never use a tool on a stuck pressure/flow regulator intended to be connected manually, as this can damage the coupling.

Open the cylinder valve slowly – at least half a turn.Check for leakage in accordance with the instruction that accompanies the regulator. Do not try to deal with leakage from the valve or device yourself other than by changing the gasket or O-ring.

In the event of leakage, close the valve and uncouple the regulator. Label defective cylinders, put them aside and return them to the supplier.

Using the gas cylinder

Smoking and open flame are absolutely forbidden in rooms in which nitrous oxide treatment is being given.

Close down the equipment in the event of fire or if it is not being used.

Carry to safety in the event of fire.

Larger gas cylinders must be transported by means of a suitable type of cylinder trolley. Take special care that connected devices are not inadvertently loosened.

When the cylinder is in use it must be fixed in a suitable support.

When a small amount of gas is left in the gas cylinder, the cylinder valve must be closed. It is important to leave a little pressure in the cylinder to protect it from contamination.

After use, the cylinder valve must be closed hand-tight. Depressurise the regulator or connection.

AGA AB

SE-181 81 Lidingö, Sweden.

19004

Date of first authorisation: 20 January 2006

Date of latest renewal: 20 January 2011

22 August 2014