Consumer medicine information

Entonox

Nitrous oxide; Oxygen

BRAND INFORMATION

Brand name

BOC Gases Entonox

Active ingredient

Nitrous oxide; Oxygen

Schedule

What is in this leaflet

This leaflet answers some common questions about Entonox. It does not contain all the available information.

It does not take the place of talking to your doctor,, anaesthetist or appropriate healthcare professional.

All medicines have risks and benefits. Your doctor or healthcare professional has weighed the risks of you using Entonox against the benefits they expect it will have for you.

If you have any concerns about using Entonox, ask your doctor.

Keep this leaflet with you, you may want to read it again.

What Entonox is used for

Entonox is a nominal gas mixture of 50% nitrous oxide and 50% oxygen used for pain relief.

It is usually given by a doctor, anaesthetist, dentist, ambulance officer or nurse via a mask or mouthpiece in which you breathe in the gas.

Entonox works by relieving pain for certain procedures.

Your doctor may prescribe Entonox for another purpose. Ask your doctor if you have any questions about why Entonox has been prescribed for you.

This medicine is available only with a doctor's prescription.

Before you use Entonox

When you must not use it

Do not use Entonox if:

You have an allergy to Entonox or nitrous oxide or any other gas component or have had an allergic reaction in the past.
You have emphysema, chronic bronchitis or if it is for a premature infant.
You have a condition where air is entrapped within your body and it might expand when given nitrous oxide (eg bowel obstruction, blocked middle ear, following a recent dive). Ask your doctor for full details of these conditions.
You have been using it for a prolonged period without proper monitoring of your blood.

Do not use Entonox if the cylinder is damaged or shows signs of tampering or it has degraded.

You are smoking or there are naked flames nearby. You must not smoke or light any flames whilst using Entonox.
You are intoxicated or heavily sedated.

Before you start to use it

You must tell your doctor if:

You are allergic to any other medicines, foods, dyes or preservatives.
You have had a reaction to Entonox or any other general anaesthetic or pain relief medication in the past.
You have had a general anaesthetic.
You have or have had any other health problems or medical conditions, including:

A condition known as malignant hyperthermia or a family history of it.
Low blood pressure
Low vitamin B12 levels
Problems with addiction to medicines
Bone marrow problems including various cells in the blood
Neurological diseases
Conditions in which air is entrapped within the body

You are pregnant or intend to become pregnant.

Your doctor will discuss the risks and benefits of using Entonox when pregnant.

You are breastfeeding or wish to breastfeed.

Your doctor will discuss the risks and benefits of using Entonox when breastfeeding.

Care should be taken when using Entonox as it is stored under high pressure in gas cylinders. There are also safe working exposure levels and important storage instructions. Please discuss these with your doctor if you have any questions.
You have had long term usage or been chronically exposed to nitrous oxide.
You have had eye surgery within the last four weeks and a gas was used in your eye during the procedure.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

Some commonly used medicines that may interfere with Entonox include:

Pain relievers
Anaesthetics
Methotrexate
Medicines which may effect your nervous system

These medicines may be affected by Entonox or may affect how well it works. You may need to take different amounts of your medicine or you may need to take different medicines.

Some medicines may affect the way others work. Ask what to do when using Entonox with other medicines.

Your doctor may have more information on medicines to avoid while using Entonox.

If you have not told your doctor about any of the above, tell them before you start using Entonox.

How to use Entonox

Entonox should only be used under the supervision of your doctor or healthcare professional.

How much to use and how to use it

The amount of Entonox given to you will be decided by your doctor, depending on the amount of pain relief required. It is usually given to you by breathing it through a mask or mouthpiece.

If you are elderly or have lung problems, you may need a lesser amount of Entonox.

Follow all directions given to you by your doctor carefully.

These directions may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor for help.

How long to use it

Your doctor will decide for how long you need to use Entonox.

If you use too much (overdose)

As Entonox is most likely to be given to you under the direction of your doctor, anaesthetist, ambulance officer, dentist or nurse, it is very unlikely you will receive an overdose. However, if this happened, quick action can be taken to maintain your breathing and replace the Entonox with oxygen.

If you have any questions then ask your doctor.

After you have used Entonox

Things you must not do

Ask your doctor when it is safe for you to drive, operate machinery or perform activities following the use of Entonox.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are using Entonox.

Entonox may have unwanted side effects in some people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

Nausea, vomiting
Headache, dizziness

These side effects are usually mild.

Tell your doctor immediately if you notice any of the following:

Confusion, excitation, depression
Breathing problems
Heart problems
Pins and needles, changes in sensation
Bleeding, fits
Abdominal pain, bloating
Addiction

These are serious side effects. You may need urgent medical attention. Serious side effects are rare. Other side effects may occur as a result of other medications received, so check with your doctor if you have any concerns.

If any of the above happen, tell your doctor immediately or go to casualty at your nearest hospital

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Ask your doctor if you don’t understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using Entonox

Storage

Entonox is stored at ambient temperature in cylinders by your doctor, dentist, ambulance or hospital under specific instructions.

Disposal

All cylinders are the property of the manufacturer as defined on the cylinder label and are to be returned to the manufacturer.

Product Description

What it looks like

Entonox is a clear, colourless, slightly sweet smelling, nonirritating gas supplied in blue (ultramarine) and white cylinders as determined by AS4484

Cylinder sizes include 1.5L, 3.0L, 10L, 25L, 50L as measured by nominal water capacity.

Ingredients

Nitrous oxide component

Active
Nitrous oxide- 98% v/v min

Other
Carbon dioxide- 300ppm v/v max
Carbon monoxide- 5ppm v/v max
Oxides of nitrogen- 2ppm v/v max
Water (vapour)- 67ppm v/v max

Oxygen component

Oxygen- 99.5% v/v min

Other
Carbon dioxide- 300ppm v/v max
Carbon monoxide- 5ppm v/v max
Water (vapour)- 67ppm v/v max

Manufacturer/Distributor/ Supplier

BOC Gases Australia Limited
Riverside Corporate Park
10 Julius Ave.
North Ryde NSW 2113

AUST R 34470

This leaflet was prepared in September 2001 and modified on the 27 March 2008.

Published by MIMS September 2019

BRAND INFORMATION

Brand name

BOC Gases Entonox

Active ingredient

Nitrous oxide; Oxygen

Schedule

1 Name of Medicine

Nitrous oxide and oxygen.

2 Qualitative and Quantitative Composition

Nitrous oxide 50% v/v.
Oxygen 50% v/v.
Entonox is a homogenous gas mixture of oxygen and nitrous oxide in equal volumetric proportions. Nitrous oxide is the active ingredient.
There are no excipients.

3 Pharmaceutical Form

Compressed medical gas mixture (for medicinal use only).
Nitrous oxide is a sweet smelling colourless non-irritating gas. Oxygen is a colourless, odourless and tasteless gas. Nitrous oxide is not very soluble in water and has a low solubility in blood and tissues.

4 Clinical Particulars

4.1 Therapeutic Indications

Nitrous oxide with oxygen (Entonox) is indicated in adults and children for analgesia.

4.2 Dose and Method of Administration

Entonox should only be administered by medical personnel trained in the appropriate techniques and in an adequate environment with access to adequate resuscitation equipment.
Cylinders should only be used in conjunction with special Entonox gas pressure regulators and demand valves.
Entonox is self administered and inhaled via a demand valve through a face mask or mouthpiece. The gas is breathed in by the patient on demand and absorbed through the lungs.
In dentistry, the use of a double mask is recommended, alternatively, a mask with adequate scavenging/ventilation should be used.

4.3 Contraindications

Hypersensitivity to nitrous oxide or any other component in the gas is a contraindication.
Nitrous oxide should not be used with any condition where air is entrapped within a body and where its expansion might be dangerous, such as: the presence of intracranial air; artificial, traumatic or spontaneous pneumothorax; pneumopericardium; air (or gas) embolism; severe head trauma; decompression sickness; following a recent dive; severe bullous emphysema; during myringoplasty; occluded middle ear; cysts; gross abdominal distension; maxillofacial injuries, following cardiopulmonary bypass or air encephalography and after intraocular gas injection in ophthalmic surgery, for example with sulphur hexafluoride (SF₆) or perfluoropropane (C₃F₈), until the intraocular gas had been completely absorbed (due to the risk of further expansion of the gas bubble possibly leading to blindness).
Nitrous oxide should not be used on intoxicated or heavily sedated patients.
Entonox is also contraindicated:
In patients with cardiac failure or severely impaired cardiac function (e.g. after cardiac surgery), since the mild myocardio-depressive effect may cause further deterioration in heart function.
In patients presenting persistent signs of confusion, changed cognitive function or other signs that could be related to increased intra-cranial pressure as nitrous oxide may further increase the intra-cranial pressure.
In patients presenting decreased consciousness and/or co-operability because of the risk for loss of protecting reflexes.
In patients presenting with a vitamin B12 or folic acid deficiency or genetic perturbation in this system.
In patients with facial injury where use of a face mask may present difficulties or risks.
There are no absolute contraindications to the use of oxygen, but the inspired concentration should be limited in the case of premature infants and patients with chronic bronchitis and emphysema or whose respiration is dependent upon hypoxic drive.

4.4 Special Warnings and Precautions for Use

Entonox should only be administered by medical personnel with access to adequate resuscitation equipment (see Section 4.2).
Addiction and abuse of nitrous oxide have been reported. Delirium has been reported upon withdrawal.
Nitrous oxide is a simple asphyxiant in the absence of oxygen. Classified as hazardous according to the criteria of Worksafe Australia.
Reduced fertility in medical and paramedical personnel has been reported after repeated exposure to nitrous oxide in inadequately ventilated rooms. It is not currently possible to confirm or exclude the existence of any causal connection between these cases and nitrous oxide exposure. It is important that the nitrous oxide content in the ambient air is kept as low as possible and well below the nationally set limit value.
Scavenging of waste nitrous oxide gas should be used to reduce operating theatre and equivalent treatment room levels to a level below 25 ppm exposure limit of nitrous oxide (Worksafe exposure standard TLV TWA). Rescue personnel are advised to monitor nitrous oxide concentration before entering confined spaces and poorly ventilated areas which have been contaminated by a nitrous oxide leak. Chronic occupational exposure to nitrous oxide may lead to bone marrow or neurological impairment (see Section 4.6, Use in pregnancy).

Interference with vitamin B12 metabolism leading to neurological and bone marrow toxicity.

The nitrous oxide component of Entonox causes inactivation of vitamin B12 (a co-factor of methionine synthesis), which interferes with folic acid metabolism. Nitrous oxide 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. Thus, DNA synthesis is impaired following prolonged nitrous oxide administration. These disturbances can result in megaloblastic bone marrow changes and possibly polyneuropathy and/or subacute combined degeneration of the spinal cord (see Section 4.8). The effect on DNA synthesis is one of the probable reasons for the influence of nitrous oxide on blood formation and the foetal damage seen in animal studies.
After inhaling nitrous oxide for 5-7 days, leucopenia and megaloblastic anaemia have been described, in some case fatal. A polyneuritic type of neuropathy and spinal cord sclerosis can appear during chronic administration of high concentrations of nitrous oxide.
Continuous administration for periods of more than 6 hours should be applied with caution because of the potential risk for clinical manifestations from the inhibitory effects on the methionine synthase. Prolonged continuous use or recurrent use should be accompanied by haematological monitoring to minimise risk of potential side effects. Thus intermittent Entonox inhalations should not be used for more than a total of 24 hours, or more frequently than every 4 days, without close clinical supervision and haematological monitoring. Where there is prolonged exposure, monitoring of peripheral blood for features of megaloblastic anaemia and leucopenia is recommended. Specialist advice should be sought from a haematologist in such cases.
Haematological assessment should include an assessment for megaloblastic change in red cells and hypersegmentation of neutrophils. Neurological toxicity can occur without anaemia or macrocytosis and with B12 levels in the normal range.
Entonox should be used with caution in patients at risk of vitamin B12 or 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. The possibility of vitamin B12/folic acid replacement or substitution therapy should be considered.
In patients with undiagnosed subclinical deficiency of vitamin B12, neurological toxicity has occurred after single exposures to nitrous oxide during general anaesthesia.
Other analgesic therapies should be considered in patients showing signs of vitamin B12/folate deficiency. See Section 4.3 Contraindications.

Chronic exposure.

Care should be taken with long term usage of nitrous oxide. Chronic exposure to nitrous oxide, such as in abuse, can inactivate vitamin B12 and may result in polyneuropathy, megaloblastic anaemia, bone marrow depression and reproductive effects (see Section 4.8 Adverse Effects (Undesirable Effects)). A full blood examination should be performed in abusers, professionals chronically exposed and patients receiving ongoing therapy for evidence of megaloblastic change in red blood cells and hypersegmentation of neutrophils.

Other precautions.

Nitrous oxide should be used with caution in patients with severe hypotension.
Entonox can, by diffusion of nitrous oxide, induce increase in middle ear pressure. Prolonged exposure may result in middle ear damage and rupture of ear drums.
In patients taking other centrally acting depressant medicinal products, e.g. morphine derivatives and/or benzodiazepines, concomitant administration of Entonox may result in increased sedation, and consequently have effects on respiration, circulation and protective reflexes (see Section 4.5).
Entonox should be used with caution in patients with compromised chemoreceptor sensitivity/function (e.g. chronic obstructive pulmonary disease - COPD) due to the relative high content (50 vol.%) of oxygen. Inhalation of high doses of oxygen may in such patients cause respiratory depression and increase in PaCO₂.
After cessation of Entonox administration, nitrous oxide rapidly diffuses from blood to the alveoli. Due to the rapid wash-out dilution, a decrease of the alveolar oxygen concentration, diffusion hypoxia might occur. This can be prevented by oxygen supplementation.
Nitrous oxide passes into gas containing spaces in the body faster than nitrogen passes out. Prolonged usage may result in bowel distension and expansion of other non-vented gas containing cavities.
At high altitude or in the presence of disorders affecting oxygenation, the amount of nitrous oxide required will vary. Entonox contains 50% nitrous oxide/ 50% oxygen.
Smoking is prohibited when the product is in use and no naked flames should be allowed.

Check the following before use.

Cylinders should not have been stored below 0°C (see Section 6.4 Special Precautions for Storage).
Nitrous oxide is non-flammable but strongly supports combustion (including some materials which do not normally burn in air). It is highly dangerous when nitrous oxide comes into contact with oils, greases and tarry substances due to the risk of spontaneous combustion.
Dispensing equipment connection matches cylinder valve pin index outlet and demand valve is operational.
Cylinder pressure may be used as an indicator of the quantity of the gas remaining in the cylinder.

Use of gas cylinders.

Cylinders should be kept out of the reach of children.
Care is needed in the handling and use of Entonox gas cylinders. Entonox is stored in high pressure gas cylinders under pressure at ambient temperature.
Entonox cylinders must be stored above 0°C. At temperatures below this the nitrous oxide component may separate, leading to risk for potential inhalation of a hypoxic gas mixture. Should this occur, the cylinder should be placed in a warm room for at least 2 hours, then rolled horizontally for at least 5 minutes to remix the components.
Overdose can arise as the result of inappropriate storage of the gas cylinders at temperatures below 0°C.
Additional information is contained in the material safety data sheet for Entonox from the sponsor.
For further information, see Section 6.4.

Occupational exposure standard.

Worksafe exposure standard TLV TWA is 25 ppm.

Use in the elderly.

No data available.

Paediatric use.

Paediatric neurotoxicity.

Some published studies in children have observed cognitive deficits after repeated or prolonged exposures to anaesthetic agents early in life. These studies have substantial limitations, and it is not clear if the observed effects are due to the anaesthetic/analgesic/sedation drug administration or other factors such as the surgery or underlying illness.
Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy. The clinical significance of these nonclinical finding is yet to be determined.
With inhalation or infusion of such drugs, exposure is longer than the period of inhalation or infusion. Depending on the drug and patient characteristics, as well as dosage, the elimination phase may be prolonged relative to the period of administration.

Effects on laboratory tests.

There are no known significant effects on laboratory tests, other than those associated with megaloblastic anaemia.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Nitrous oxide and CNS depressants may lead to increased CNS depression, increased respiratory depression and increased hypotensive effects.
The pulmonary toxicity associated with drugs such as bleomycin, amiodarone, (paraquat), furadantin and similar antibiotics may be exacerbated by inhalation of increased concentration of oxygen.
Nitrous oxide and opioids together may lead to further circulatory depression. High dose fentanyl with nitrous oxide may decrease heart rate and cardiac output.

Methotrexate.

Nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression, stomatitis and neurotoxicity with intrathecal administration. Avoid concomitant use of nitrous oxide in patients receiving methotrexate.
The pharmacokinetic activity of oxygen is modified by changes in the blood carbon dioxide tension but this has little clinical significance.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The germ cells of mice exposed to nitrous oxide for 14 weeks (50% nitrous oxide, 4 hours/day) showed no evidence of toxic effects due to nitrous oxide.
The fecundity of female dental assistants was reduced by 60% for those women working greater than or equal to 5 hours per week with unscavenged nitrous oxide. Similarly, fecundity was reduced in a Swedish study of midwives in those women assisting at more than 30 deliveries per month.
(Category A)
The Nitrous oxide component 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 adequate data from the use of Entonox in pregnant women to assess the potential harmful effects on human embryonic/foetal development.
Animal studies have demonstrated that high concentration or prolonged exposure during particular stages of pregnancy can induce teratogenic effects. The potential risk for humans is unknown.
Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy.
Published studies in pregnant and juvenile animals demonstrate that the use of anaesthetic/analgesic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of rapid brain growth or synaptogenesis may result in neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis when used for longer than 3 hours. These studies included anaesthetic agents from a variety of drug classes.
Inhalation anaesthetics cross the placenta. Treatment of rats with nitrous oxide (75% or 60% for each 24 hour period during organogenesis) resulted increased incidences of resorptions (days 8 and 11 of gestation), visceral abnormalities (day 8, right sided aortic arch and left-sided umbilical artery) and minor skeletal anomalies (days 8 and 9). Increased rates of resorptions, decreased fetal size and skeletal abnormalities have been reported in rats exposed to nitrous oxide concentrations of 0.1% throughout gestation. There were no adverse effects on the fetuses of mice exposed to 50% nitrous oxide during organogenesis.
There was no evidence of teratogenic effects in pregnant women exposed to single, brief anaesthetic exposure to nitrous oxide during pregnancy.
Studies of operating room personnel chronically exposed to low concentrations of inhalation anaesthetics show that pregnancies in female personnel and the wives of male personnel may be subject to increased incidences of spontaneous abortions, stillbirths and possibly birth defects. However, the methods used in obtaining and interpreting the data in these studies have been questioned. Studies on dental staff's exposure to anaesthetic gases had conflicting results. One study showed an increased risk of spontaneous abortion among dental assistants exposed to nitrous oxide. Another showed no increased risk for dental assistants either practicing in private clinics or working in dental school services (OR 0.4). Others demonstrated increased risk of spontaneous abortion among dental assistants exposed to nitrous oxide for 3 or more hours weekly in places without scavenging systems. A study of Swedish midwives exposed to nitrous oxide in more than 50% of deliveries showed no increased risk of spontaneous abortion (OR 0.95). The effect of scavenging was excluded because many midwives were unsure about whether such equipment had been present in the delivery rooms. Several animal studies (in which operating room conditions were simulated) have failed to show fetotoxic or teratogenic effects following chronic exposure of male and/or female animals to low concentrations of inhalation anaesthetics prior to and/or during gestation.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, nitrous oxide should not be administered to a nursing woman.

4.7 Effects on Ability to Drive and Use Machines

The nitrous oxide component of Entonox is rapidly eliminated from the body after brief inhalation and adverse psychometric effects will normally cease shortly after the administration has stopped while its influence on the cognitive capabilities can persist for several hours.
When used as the sole analgesic/sedative agent, driving and use of complex machinery is not recommended for at least 30 minutes after cessation of the administration of Entonox and until the patient has returned to their initial mental status as judged by the attending healthcare professional.
Additional care is needed when Entonox is administered to a patient who has been given concomitant medication.

4.8 Adverse Effects (Undesirable Effects)

The undesirable effects listed are derived from public domain scientific medical literature and post marketing safety surveillance.
Tabulated summary of adverse reactions. See Table 1.

Haematological.

Inactivation of vitamin B12 (a cofactor in methionine synthesis). Folate metabolism is consequently interfered with and DNA synthesis is impaired following prolonged nitrous oxide administration. This results in symptoms similar to vitamin B12 deficiency and megaloblastic bone marrow changes. Bone marrow depression with resultant leukopenia, thrombocytopenia and severe megaloblastic anaemia have been noted.

Cardiovascular.

Cardiovascular depression, hypotension, arrhythmia, increased pulmonary vascular resistance.

Respiratory.

Hypoxia, diffusion hypoxia, asphyxia, pulmonary toxicity.

Neurological.

Confusion, CNS excitation and depression, raised intracranial pressure, anxiolytic effects, euphoria, neuropathy, seizures/convulsions, drowsiness. Exceptionally heavy occupational exposure or frequent use and addiction have resulted in myeloneuropathy (including polyneuropathy) and subacute combined degeneration of the cord.

Gastrointestinal.

Bowel distension following prolonged usage.

Pregnancy and lactation.

See Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation.
Prolonged occupational exposure to high levels of nitrous oxide may affect a woman's ability to become pregnant.
Addiction and abuse of nitrous oxide have been reported.
Retrolental fibroplasia can occur in premature infants exposed to oxygen concentrations of greater than 40%.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms and signs.

Inappropriate or deliberate inhalation of nitrous oxide will ultimately result in unconsciousness, passing through stages of increasing light-headedness and intoxication, and, if the person were to be within a confined space, death from anoxia could result.
Other signs may include: bradycardia, respiratory depression, cardiovascular depression and severe hypotension.

Treatment.

There is no specific antidote. Treatment measures include: discontinuation of Entonox, basic life support, assisted or controlled ventilatory support with oxygen and other symptomatic and supportive treatment.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Oxygen.

Oxygen comprises approximately 21% of atmospheric air and acts in the maintenance of various metabolic processes in the body.

Mechanism of action.

Nitrous oxide.

Nitrous oxide is an inhalational anaesthetic. The MAC (minimum alveolar concentration) in oxygen is greater than 100%.
Nitrous oxide has analgesic and weak anaesthetic properties. It has no dose related muscle relaxant effect. Onset and recovery from its effects are relatively rapid. Pain reduction may be achieved at a concentration of around 25%.
Nitrous oxide alone may increase pulse rate and have depressant effects on respiration.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Nitrous oxide.

Nitrous oxide is rapidly absorbed via inhalation.
The alveolar concentration of N₂O rises rapidly due to its low blood:gas partition coefficient. Likewise, its elimination is very rapid.
The blood:gas partition coefficient of nitrous oxide at 37°C is 0.47 compared with that of nitrogen of 0.015, causing nitrous oxide to expand into internal gas spaces.
The metabolism of nitrous oxide is minimal.
Nitrous oxide is eliminated from the body mostly by the lungs.

Oxygen.

Oxygen is rapidly absorbed via inhalation, distributed mostly in combination with haemoglobin, consumed and exhaled along with carbon dioxide.

5.3 Preclinical Safety Data

Carcinogenicity.

Nitrous oxide was tested for carcinogenic potential in rats and mice. No carcinogenic effect was seen in mice exposed to nitrous oxide (40%, 4 hours per day) or rats exposed to low concentrations of halothane-nitrous oxide (10 ppm:500 ppm, 7 hours per day).

Mutagenicity.

Nitrous oxide gave mixed results in limited assays for genotoxicity. In assays for gene mutations nitrous oxide was negative in the Ames test and sex-linked recessive lethal assay in Drosophilia melanogaster, but was positive in Chinese hamster lung cells. The potential to cause chromosomal damage has not been investigated. An increased frequency of chromosomal aberrations was observed in bone marrow cells and spermatogonia of rats treated with a mixture of nitrous oxide and halothane. Nitrous oxide also caused an increased incidence of sister chromatid exchanges (SCE) in human lymphocytes in vitro.
Clinical studies have suggested that nitrous oxide may be associated with genotoxic events. DNA strand breaks were reported in surgical patients treated with isoflurane-nitrous oxide-oxygen, 1 day after surgery. An increased frequency of SCE, but not micronuclei, was found in the lymphocytes of operating room personnel exposed to nitrous oxide and isoflurane. An increase in SCE was also found in operating room personnel exposed to halothane and nitrous oxide.

6 Pharmaceutical Particulars

6.1 List of Excipients

None.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

Not applicable.

6.4 Special Precautions for Storage

The normal precautions required in the storage and use of medical gas cylinders are applicable. Please refer to Commonwealth, State and Territory Dangerous Goods legislation and the appropriate Australian Standards e.g. AS 4332. Cylinders should be stored away from sources of ignition, poisons, flammable or combustible materials. They should preferably be stored upright, in a secure area, below 45°C but above 0°C, in a dry well ventilated area constructed of non-combustible material with a firm, level floor (preferably concrete) away from heavy traffic and emergency exits.
At temperatures below 0°C the nitrous oxide component may separate. Should this occur, the cylinder should be placed in a warm room for at least 2 hours, then rolled horizontally for at least 5 minutes to remix the components.

6.5 Nature and Contents of Container

Compressed medical gas (for medicinal use only) supplied in cylinders in accordance with AS2030 and fitted with AS2472, figure 11 single pin index valve outlet.
Cylinder colour: AS4484. Body colour - white. Shoulder colour - Ultramarine AS2700 B21 and white quadrants.
Cylinder pressure: 12000 kPa (max) at 15°C.
Cylinder size (nominal water capacity, litres): B (1.5 L), C (3.0 L), D (10 L), E (25 L), G (50 L).
Combinations of the above cylinders may be supplied in a unit called a pack (or bundle). Actual water capacity may vary about the nominal figures indicated.

6.6 Special Precautions for Disposal

Cylinders are returned to BOC.

Other handling.

General.

Do not smoke or use flame in areas where medicinal gases are stored or administered.
Never use oil or grease, even if the cylinder valve sticks or if the regulator is difficult to connect.
Handle valves and devices belonging to them with clean and grease-free (hand-cream etc.) hands.
In case of cleaning of cylinder or attached equipment, do not use combustible products and especially oil-based material. In case of doubt, check compatibility.
Prior to any use, ensure the sufficient quantity of product remains to allow completion of the planned administration. During use, ensure that sufficient quantity of product remains to allow sufficient necessary flow.
Use only standard devices that are designed for nitrous oxide - oxygen mixture administration.

Preparation for use.

Remove the seal from the valve before use.
The instructions below are applicable for Entonox cylinders where a separate pressure regulator shall be connected before use.
Ensure that an appropriate Entonox regulator is selected for connection to the cylinder.
Check that the connection on the coupling or regulator is clean and that the connections are in good condition.
Never use pliers to force pressure/flow regulators that are designed to be connected manually, as this can damage the joint.
Check that the pressure regulator is properly attached before opening the valve.
Open the cylinder valve gently and check for leaks.
Leaks:
Should leaks occur this will usually be evident by a hissing noise.
Should a leak occur between the valve outlet and the regulator or manifold yoke, depressurise and remove the fitting and fit an approved sealing washer. Reconnect the fitting to the valve with moderate force only, fitting a replacement regulator or manifold tailpipe as required.
Sealing or jointing compounds must never be used to cure a leak.
Never use excessive force when connecting equipment to cylinders.
If leak persists. Close the valve and disconnect the regulator. Mark the defective cylinder, keep it separate and return to BOC.
In the event of leakage, close the valve and uncouple the regulator. Label defective cylinders, put them aside, and return them to the supplier.

Use of the gas cylinder.

Only used for medicinal purposes.
Close the cylinder in the event of fire (if safe to do so).
Turned off, when not in use, using moderate force to close the valve.
Ensure Entonox cylinders are secured to a suitable cylinder support in vertical position when in use, to prevent them from falling.
Only moved with the appropriate size and type of trolley or handling device.
Handled with care and not knocked violently or allowed to fall.
Not used in the vicinity of persons smoking or near naked lights.
Use in a well ventilated area with waste gas scavenging systems in place. See Section 4.4 Special Warnings and Precautions for Use.
When the medical nitrous oxide cylinder is empty ensure that:
the cylinder valve is closed using moderate force only and the pressure in the regulator is released.
the empty cylinders are immediately returned to the empty cylinder store for return to BOC.

6.7 Physicochemical Properties

Chemical structure.

Nitrous oxide, N₂O is a linear but unsymmetrical molecule of the form:

Oxygen has a molecular structure of:

CAS number.

Nitrous oxide, N₂O, CAS number 10024-97-2.
Oxygen, O₂, CAS number 7782-44-7.
The specifications for each of the main components are presented separately.

Nitrous oxide.

Complies with the requirements of the current European Pharmacopoeia monograph for nitrous oxide.
Nitrous oxide: 98.0% v/v minimum.
Carbon dioxide: 300 ppm v/v maximum.
Carbon monoxide: 5 ppm v/v maximum.
Oxides of nitrogen (NO/NO₂): 2 ppm v/v maximum.
Water (vapour): 67 ppm v/v maximum.

Oxygen.

Complies with the requirements of the current European Pharmacopoeia monograph for oxygen.
Oxygen: 99.5% v/v minimum.
Carbon dioxide: 300 ppm v/v maximum.
Carbon monoxide: 5 ppm v/v maximum.
Water (vapour): 67 ppm v/v maximum.

Physical data.

Molecular weight: N₂O 44.01, O₂ 32.00.
Physical state in the cylinder: High pressure gas at ambient temperature.
Combustion characteristics: Non flammable, strongly supports combustion.
Nitrous oxide and oxygen are oxidising substances which will support combustion of materials which may not normally burn in air. Nitrous oxide is stable and comparatively unreactive at ordinary temperatures and pressures. At elevated temperatures it decomposes to nitrogen and oxygen. Nitrous oxide will react with powerful reducing agents such as phosphine, stannous chloride and hydrogen. Rust and other impurities, especially oil and grease may cause ignitions.

7 Medicine Schedule (Poisons Standard)

Schedule 4 Prescription Medicine.

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Nitrous oxide; Oxygen

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