Consumer medicine information

Nitrous oxide Medical EP Grade

Nitrous oxide

BRAND INFORMATION

Brand name

BOC Gases Nitrous Oxide

Active ingredient

Nitrous oxide

Schedule

What is in this leaflet

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

It does not take the place of talking to your doctor, anaesthetist, surgeon or dentist.

All medicines have risks and benefits. Your doctor or dentist has weighed the risks of you using nitrous oxide against the benefits they expect it will have for you.

If you have any concerns about using nitrous oxide, ask your doctor or dentist.

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

What Nitrous oxide is used for

Nitrous oxide is a gas used for general anaesthesia or pain relief.

It is usually given with another anaesthetic gas and oxygen during surgery via a tube placed down your throat by an anaesthetist or given with oxygen via a mask by your doctor or dentist.

Nitrous oxide works by causing unconsciousness (deep sleep) before and during surgery and by relieving pain for certain procedures.

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

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

Before you use Nitrous oxide

When you must not use it

Do not use nitrous oxide if:

You have an allergy to nitrous oxide or any other component in the gas or have had an allergic reaction in the past.
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 nitrous oxide without the necessary amount of oxygen.
You are intoxicated.

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

Before you start to use it

You must tell your doctor or dentist if:

You are allergic to any other medicines, foods, dyes or preservatives.
You have had a reaction to nitrous oxide or any other general anaesthetic or pain relief medication in the past.
You have had a general anaesthetic or surgery in the past.
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 or dentist will discuss the risks and benefits of using nitrous oxide when pregnant.

You are breastfeeding or wish to breastfeed.

Your doctor or dentist will discuss the risks and benefits of using nitrous oxide when breastfeeding.

Care should be taken when using nitrous oxide as it is stored under high pressure in gas cylinders. Contact with eyes or skin may result in cold burns. 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 or dentist 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 nitrous oxide include:

Pain relievers
Anaesthetics
Methotrexate
Medicines which may effect your nervous system

These medicines may be affected by nitrous oxide 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 nitrous oxide with other medicines.

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

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

How to use Nitrous oxide

Nitrous oxide should only be used under the supervision of your doctor or dentist.

How much to use and how to use it

The amount of nitrous oxide given to you will be decided by your doctor or dentist, depending on the amount of pain relief or sleep required. It is usually given to you by breathing it through a mask or by a tube placed down your throat during surgery.

If you are elderly or have lung problems, you may need a lower amount of nitrous oxide.

Follow all directions given to you by your doctor or dentist 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 nitrous oxide.

If you use too much (overdose)

As nitrous oxide is most likely to be given to you in hospital under the direction of your doctor, 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 nitrous oxide with more oxygen.

If you have any questions then ask your doctor.

After you have used Nitrous oxide

Things you must not do

Following a general anaesthetic:
Do not drive or operate machinery for at least 24 hours after using nitrous oxide.

General anaesthetics may cause a slight decrease in intellectual function and alertness for 2 to 3 days in some people.

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

Following analgesia:
Ask your doctor or dentist when it is safe for you to drive, operate machinery or perform activities following the use of nitrous oxide.

Side effects

Tell your doctor or dentist as soon as possible if you do not feel well while you are using nitrous oxide.

Nitrous oxide 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 or dentist if you notice any of the following and they worry you:

Nausea, vomiting
Headache, dizziness

These side effects are usually mild.

Tell your doctor or dentist 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 your operation or other medications and anaesthetics received, so check with your doctor or dentist if you have any concerns.

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

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

Ask your doctor or dentist 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 Nitrous oxide

Storage

Nitrous oxide is stored at ambient temperature in cylinders by your doctor or hospital under specific instructions.

Disposal

All cylinders are the property of the manufacturer as indicated on the label . All cylinders are returnable to the manufacturer.

Product Description

What it looks like

Nitrous oxide is a clear, colourless, slightly sweet smelling, non-irritating gas supplied in blue (ultramarine) cylinders as determined by AS4484

Cylinder sizes include: 1.5L, 3.0L, 10L, 25L, 35L, 50L as measured by nominal water capacity.

Ingredients

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

Manufacturer/Distributor/ Supplier

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

AUST R 34466

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 Nitrous Oxide

Active ingredient

Nitrous oxide

Schedule

1 Name of Medicine

Nitrous oxide.

2 Qualitative and Quantitative Composition

Nitrous oxide 99%.
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.
There are no excipients.

3 Pharmaceutical Form

Compressed medical gas (for medicinal use only).
Sweet smelling colourless non-irritating gas.

4 Clinical Particulars

4.1 Therapeutic Indications

Nitrous oxide is indicated in adults and children for:
1. General anaesthesia, usually as an adjuvant to other volatile or intravenous anaesthetics;
2. Analgesia (with oxygen) e.g. dentistry and obstetrics.

4.2 Dose and Method of Administration

Premedication.

Premedication should be selected according to the needs of the individual patient and in consideration of the respiratory depressant effect of nitrous oxide.

General anaesthesia.

The use of nitrous oxide in general anaesthesia is mainly as an adjuvant to other volatile inhalational anaesthetics. Its use as the sole anaesthetic agent can lead to hypoxia and inadequate depth of anaesthesia.
In the average adult, nitrous oxide is administered by inhalation through a suitable anaesthetic apparatus in concentrations up to 70% with oxygen as the balance.
The concentration of nitrous oxide administered during maintenance of anaesthesia must be individualised depending upon the condition of the patient and supplemental medications administered.
The concentrations required in children must be individualised.
The inspired concentration of oxygen may need to be increased in elderly patients or those with pulmonary disease.
The efflux of nitrous oxide from the tissues via the lungs at the end of anaesthesia may lead to diffusion hypoxia if supplemental oxygen is not administered.

Analgesia.

In the average adult, nitrous oxide is administered by inhalation through a suitable face mask in concentrations up to 50% with oxygen as the balance.
The concentrations required in children must be individualised.

Paediatric population.

The potential risk for increased sedation and compromise of protecting reflexes should be considered for the use of nitrous oxide in the paediatric population.

Method of administration.

Nitrous oxide should be administered only in rooms with proper ventilation and/or scavenging equipment in order to avoid excessive ambient air concentrations according to local regulations (see Section 4.4 Special Warnings and Precautions for Use).
Nitrous oxide is inhaled through a face mask or tracheal tube by means of an anaesthetic apparatus. The gas is breathed in by the patient and absorbed through the lungs.
Nitrous oxide should only be administered by medical personnel trained in the appropriate techniques.
Cylinders should only be used in conjunction with medical nitrous oxide gas pressure regulators.

4.3 Contraindications

Nitrous oxide should not be administered without the required level of oxygen (at least 30%).
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 embolism; gas embolus; severe head trauma; decompression sickness; following a recent dive; severe bullous emphysema; during myringoplasty; occluded middle ear; cysts; gross abdominal distension; maxillofacial injuries and 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 patients.
Medicinal nitrous oxide 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 cardiac 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, when used in analgesia, 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.
Nitrous oxide should not be used as an analgesic or anaesthetic agent for prolonged periods without monitoring of peripheral blood for features of megaloblastic anaemia and leukopenia (see Section 4.4; Section 4.8).

4.4 Special Warnings and Precautions for Use

Addiction and abuse of nitrous oxide have been reported. Delirium has been reported upon withdrawal.
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 25ppm 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 Fertility, Pregnancy and Lactation, Use in pregnancy).
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 severe cardiac dysfunction or pronounced cardiac failure (see Section 4.3 Contraindications).

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

Nitrous oxide 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 Adverse Effects (Undesirable Effects)). 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.
Nitrous oxide should be used with caution in patients at risk of vitamin B₁₂ or folic acid deficiency. Risk factors include the elderly, those with poor or vegetarian diet, and previous history of anaemia. Nitrous oxide should therefore not be used for prolonged periods of time. The possibility of vitamin B₁₂/folic acid replacement or substitution therapy should be considered after a prolonged use exceeding 6 h or recurrent use and haematological monitoring should be instituted to minimise risk of potential side effects.
Nitrous Oxide 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. 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.
After inhaling nitrous oxide for 5-7 days, leucopenia and megaloblastic anaemia have been described, in some cases fatal. A poyneuritic type of neuropathy and spinal cord sclerosis can appear during chronic administration of high concentrations of nitrous oxide.
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.

In patients taking other centrally acting medicinal products, such as morphine derivatives and/or benzodiazepines, concomitant administration of nitrous oxide may result in increased sedation, and consequently have effects on respiration, circulation and protective reflexes. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Nitrous oxide in high concentration (> 50%) can lead to the loss of laryngeal reflexes and reduce consciousness. In concentrations higher than 60-70% it often causes unconsciousness and the risk for impairment of the laryngeal reflexes increases.
When nitrous oxide is used in conjunction with other volatile or intravenous anaesthetic agents, the MAC of those agents may be reduced by up to 50%.
Nitrous oxide should never be given with less than 21% oxygen. At high altitude or in the presence of disorders affecting oxygenation, the amount of nitrous oxide required will vary.
Nitrous oxide should not be used during laser surgery in the airways due to the relative risk for explosive fire.
At the end of nitrous oxide/oxygen anaesthesia, ventilation with air may lead to diffusion hypoxia due to the ongoing elimination of nitrous oxide in the alveoli lowering the oxygen partial pressure. Diffusion hypoxia may be minimised by washing out the nitrous oxide with oxygen at the conclusion of the anaesthetic and providing oxygen via facemask for at least 20 minutes while the patient is recovering.
Nitrous oxide passes into gas containing spaces in the body faster than nitrogen passes out. Prolonged anaesthesia may result in bowel distension and expansion of other non-vented gas containing cavities.
Nitrous oxide administration may increase the pressure in catheter balloons e.g. in tracheal intubation.
Nitrous oxide induces increase in middle ear pressure. Prolonged exposure may result in middle ear damage and rupture of ear drums.
Nitrous oxide should be used with caution in patients with severe hypotension.
Evaporating liquid contact with eyes and skin may cause cold burns.

Check the following before use.

Nitrous oxide is non-flammable but strongly supports combustion (including some materials which do not normally burn in air) and should not be used near sources of ignition. It is highly dangerous when nitrous oxide comes into contact with oils, greases and tarry substances due to the risk of spontaneous combustion.
Operability of oxygen mixing apparatus and availability of oxygen.
Dispensing equipment connection matches cylinder valve pin index outlet.
Cylinder pressure is not an indicator of quantity remaining in the cylinder until all liquid has vapourised.
Measure contents by weight.

Use of gas cylinders.

Smoking should be prohibited when using nitrous oxide.
Under no circumstances should oils or grease be used to lubricate any part of the nitrous oxide cylinder or the associated equipment used to deliver the gas to the patient.
Where moisturising preparations are required for use with a facemask, oil based creams should not be used.
Check that hands are clean and free from any oils or grease.
Where alcohol gels are used to control microbiological cross-contamination ensure that all alcohol has evaporated before handling nitrous oxide cylinders or equipment nitrous oxide is stored in high pressure gas cylinders as a liquid under pressure.
Cylinders should be kept out of the reach of children.
Care is needed in the handling and use of medical nitrous oxide gas cylinders.
Nitrous oxide is stored in high pressure gas cylinders as a liquid under pressure at ambient temperature.
Rapid opening of the valve and sustained high flow rates can cause the discharged gas to re-liquefy. This liquid can cause cold burns if in contact with the eyes and skin.
Cylinders should be used in the vertical position with the valve uppermost. If not, liquid may be discharged when the valve is opened.
Additional information is contained in the Material Safety Data Sheet for medical nitrous oxide from the sponsor.

Occupational exposure standard.

Worksafe exposure standard TLV TWA is 25 ppm.

Cold burns.

Burns should not occur if the product is administered correctly (see Section 4.9 Overdose, Accidental contact).

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.

Use in the elderly.

Elderly patients are more susceptible to the effects of nitrous oxide.

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

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.
Nitrous oxide reduces the amount of volatile anaesthetics required for anaesthesia when administered concomitantly.
Nitrous oxide and CNS depressants may lead to increased CNS depression, increased respiratory depression and increased hypotensive effects.
Nitrous oxide and opioids together may lead to further circulatory depression. High dose fentanyl with nitrous oxide may decrease heart rate and cardiac output.
The uptake of an inhalational anaesthetic from the lungs is accelerated by the uptake of nitrous oxide when administered concomitantly. This is known as the second gas effect.

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)
Medicinal nitrous oxide interferes with vitamin B₁₂/folic acid metabolism (see Section 4.4 Special Warnings and Precautions for Use).
Inhibition of the methionine synthase may cause adverse effects during early stages of pregnancy.
There are no adequate data from the use of medicinal nitrous oxide 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.
There was no evidence of teratogenic effects in pregnant women exposed to single, brief anaesthetic exposure to nitrous oxide during pregnancy.
All general anaesthetics carry the potential to produce central nervous system and respiratory depression in the newborn infant. In routine practice this does not appear to be a problem. However, in the compromised fetus, careful consideration should be given to this potential depression and to the selection of particular anaesthetic drugs, doses and techniques.
Inhalation anaesthetics cross the placenta. Treatment of rats with nitrous oxide (75% or 60% for each 24 hour period during organogenesis) resulted in 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.
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 practising 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.
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.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitrous oxide is administered to a nursing woman.

4.7 Effects on Ability to Drive and Use Machines

Nitrous oxide is rapidly eliminated but it is recommended that driving, use of machinery and other psychomotor activities should not be undertaken until 24 hours have elapsed after nitrous oxide anaesthesia and until the patients have returned to their initial mental status as judged by attending healthcare professional.
General anaesthetics may cause a slight decrease in intellectual function for two to three days following anaesthesia.

4.8 Adverse Effects (Undesirable Effects)

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

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, including fatal cases, have been noted.

Cardiovascular.

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

Respiratory.

Hypoxia, diffusion hypoxia, asphyxia.

Gastrointestinal.

Bowel distension following prolonged anaesthesia.

Neurological.

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

Pregnancy and lactation.

See Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation. Prolonged occupational exposure to high levels of nitrous oxide may affect a woman's ability to become pregnant.

General.

Cold burns (see Section 4.9 Overdose, Accidental contact).
Addiction and abuse of nitrous oxide have been reported.

Tabulated summary of adverse reactions.

See Table 1.

Reporting of suspected adverse reactions.

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 nitrous oxide, basic life support, assisted or controlled ventilatory support with oxygen and other symptomatic and supportive treatment.

Accidental contact.

Local pain usually warns of freezing, but sometimes no pain is felt or is short lived. Frozen tissues are painless and appear waxy, with a pale yellowish colour. Thawing of the frozen tissue can cause intense pain.
Shock may occur if the area is large.
Loosen any clothing that may restrict circulation and seek immediate hospital attention for all but the most superficial injuries. Do not apply direct heat to the affected parts, but if possible place the affected part in lukewarm water. Sterile dry dressings should be used to protect damaged tissues from infection or further injury, but they should not restrict circulation. Alcohol and cigarettes should not be given.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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% whilst a concentration of about 70% is usually needed to produce unconsciousness.
Nitrous oxide alone may increase pulse rate and have depressant effects on respiration.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

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.

5.3 Preclinical Safety Data

Genotoxicity.

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.

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).

6 Pharmaceutical Particulars

6.1 List of Excipients

None.

6.2 Incompatibilities

Not applicable.

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 see Commonwealth, State and Territory Dangerous Goods legislation and the appropriate Australian Standards e.g. AS4332. Cylinders should be stored away from sources of ignition, poisons, flammable or combustible materials. They should be stored upright, in a secure area, below 45°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.

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 6 pin index valve outlet.
Cylinder colour: AS4484. Body colour - Ultramarine AS2700 B21. Shoulder colour - Ultramarine AS2700 B21.
Cylinder pressure: 5,700 kPa (max) at 25°C.
Cylinder size (nominal water capacity, Litres): B (1.5 L), C (3 L), D (10 L), E (25 L), F (35 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.
Please consult the Material Safety Data Sheet for medical nitrous oxide from the sponsor.
AUST R 34466.

6.6 Special Precautions for Disposal

The cylinder package must not be disposed, but returned to the supplier.

6.7 Physicochemical Properties

Nitrous oxide, N₂O.

Chemical structure.

A linear but unsymmetrical molecule of the form.

CAS number.

10024-97-2.

Physical data.

Molecular weight: 44.01.
Physical state in the cylinder: High pressure liquefied gas at ambient temperature.
Density of the gas at 15°C and 101.3 kPa: 1.877 kg/m³.
Combustion characteristics: Non flammable, strongly supports combustion.
Boiling point: -88.6°C (at 101.3 kPa).
Critical temperature: 36.4°C.
Nitrous oxide is not very soluble in water and has a low solubility in blood and tissues.

Chemical characteristics.

Nitrous oxide is an oxidising substance which will support combustion of materials which may not normally burn in air. The molecule 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)

S4.

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Consumer medicine information

Nitrous oxide Medical EP Grade

Nitrous oxide

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