SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Nitrous oxide (medical)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Consists solely of nitrous oxide Ph Eur

3. PHARMACEUTICAL FORM

Inhalation gas

4    CLINICAL PARTICULARS

4.1.    Therapeutic Indications

Nitrous oxide mixed with 30% oxygen is used as an adjuvant in general anaesthesia. With nitrous oxide providing background anaesthesia, the concentration of potent inhalation agents (e.g. halothane and enflurane) can be reduced, so that there is less circulatory and respiratory depression, and more rapid recovery.

Nitrous oxide mixed with 50% oxygen is used as an analgesic agent in a number of situations, the most common being dental surgery and childbirth. Other uses include provision of analgesia for short painful procedures like insertion of IV needles, dressing changes and physiotherapy.

It is occasionally used in laparoscopy as an insufflating agent, and in cryosurgery as a refrigerant. Nitrous oxide has also been used in the treatment of withdrawal symptoms in alcoholism and drug addiction.

4.2 Posology and Method of Administration

To avoid hypoxia, nitrous oxide should always be given with at least 20% oxygen. In obstetric anaesthesia at least 30% oxygen is required. Higher levels of oxygen are required in patients with disorders affecting oxygenation of the blood.

Nitrous oxide is inhaled and absorbed through the lungs. It is administered through a facemask or tracheal tube, by means of an anaesthetic apparatus. In labour, the patient should self administer nitrous oxide by holding the facemask.

Nitrous oxide should only be administered under the direct supervision of suitably trained medical personnel.

Cylinders should only be used with appropriate gas pressure regulators.

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 for features of megaloblastic anaemia and leukopenia. (see sections 4.4 and 4.8)

4.3    Contra-indications

Oxynox should not be used in any condition where air is entrapped within the body and where its expansion might be dangerous, e.g:

•    Artificial, traumatic or spontaneous pneumothorax.

•    Air embolism

•    Decompression sickness

•    Following a recent dive

•    Following air encephalography

•    Severe bullous emphysema

•    Use during myringoplasty

•    Gross abdominal distension

4.4    Special Warnings and Precautions for Use

Use no oil or grease on valve or associated equipment. Do not allow naked flames near the container. Do not smoke when using nitrous oxide.

While routine use of nitrous oxide is without significant adverse effects, prolonged exposure at anaesthetic levels may have severe adverse effects, as may chronic exposure to low levels of the agent (e.g. occupational exposure).

Occupational exposure is a consideration for dentists, dental assistants and operating theatre staff. The Occupational Exposure Standard (OES) long-term exposure limit is 100ppm (ref. HSE EH40/94).

Measures to reduce levels of occupational exposure:

1.    Achieve levels of nitrous oxide no higher than 100 ppm.

2.    Minimise patient conversation during use of nitrous oxide.

3.    Check delivery system for leakage monthly.

4.    Vent exhaust gases to outside.

5.    Monitor levels of N20 in the surgery regularly, using a dosimeter.

6.    Use a scavenging system.

Individuals who should avoid exposure to N20:

1.    Women in the first trimester of pregnancy.

2.    Infertile individuals using in vitro fertilisation procedures.

3.    Individuals with neurological complaints.

4.    Immunocompromised individuals who are at risk of bone marrow suppression.

Nitrous oxide causes inactivation of vitamin B12, which is a co-factor of methionine synthase. Folate metabolism is consequently interfered with and DNA synthesis is impaired following prolonged nitrous oxide administration. Prolonged or frequent use of nitrous oxide may result in megaloblastic marrow changes, myeloneuropathy and sub acute combined degeneration of the spinal cord

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. 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.

In patients with undiagnosed subclinical deficiency of vitamin B12, neurological toxicity has occurred after single exposures to nitrous oxide during general anaesthesia.

Assessment of vitamin B12 levels should be considered in people with risk factors for vitamin B12 deficiency prior to using nitrous oxide anaesthesia. Risk factors include the elderly, those with poor or vegetarian diet, and previous history of anaemia.

4.5 Interaction with other medicinal products and other forms of interaction

Methotrexate interacts with nitrous oxide. Methotrexate acts by blocking the enzyme dihydrofolate reductase. This results in inhibition of several processes that require reduced folates, including the conversion of homocysteine to methionine. This is catalysed by the B12 -dependent methionine synthase enzyme which is also inhibited by nitrous oxide. As a result, nitrous oxide and methotrexate appear to have a synergistic effect, so that nitrous oxide may potentiate the therapeutic effects of methotrexate. Caution should therefore be exercised with patients on methotrexate therapy.

4.6 Fertility, pregnancy and lactation

Clinical studies have not shown the use of nitrous oxide anaesthesia in pregnancy to have any teratogenic effects. However, studies on rats have shown nitrous oxide to have teratogenic effects. For this reason, the use of nitrous oxide anaesthesia is probably best avoided in the first trimester of pregnancy, although it is not absolutely contraindicated. The attending physician should weigh the risk : benefit ratio of nitrous oxide as compared with other forms of anaesthesia in the first trimester.

Clinical studies have shown that chronic occupational exposure to high levels of nitrous oxide is linked to decreased fertility, increased incidence of spontaneous abortions and an increased incidence of congenital malformations (particularly musculoskeletal disorders). Avoidance of occupational exposure to nitrous oxide is therefore particularly important during pregnancy and especially in the first trimester.

There are no known deleterious effects on mother or child, specifically associated with use during lactation.

4.7. Effects on Ability to Drive and Use Machines

A slight but quantifiable impairment of driving ability has been found up to 30 minutes after inhalation of 50% nitrous oxide/50% oxygen for 15 minutes. Driving, use of machinery, and other psychomotor activities should not be undertaken for 12 hours following nitrous oxide anaesthesia.

4.8 Undesirable Effects

Events such as euphoria, disorientation, sedation, nausea, vomiting, dizziness and generalised tingling are commonly described. These events are generally minor and rapidly reversible.

During anaesthesia, nitrous oxide exchanges with nitrogen, which is less soluble than nitrous oxide. As a result more nitrous oxide is delivered than nitrogen removed, and this results in an increased volume and pressure of air trapped in pockets

within the body. Prolonged exposure may result in bowel distension, middle ear damage and rupture of ear drums.

When administration of nitrous oxide is discontinued, its elimination from blood to alveoli may take place as rapidly as its uptake. Consequently, alveolar oxygen is diluted by the outflow of nitrous oxide, which gives rise to “diffusion hypoxia”.

Diffusion hypoxia may last as long as 30 minutes after termination of anaesthesia, and so it has been recommended that oxygen be administered both before and after extubation.

Evidence from one study suggests that chronic occupational exposure to high levels of nitrous oxide is associated with increased incidence of liver disease, renal disease and cervical cancer.

Prolonged or frequent use of nitrous oxide, including heavy occupational exposure and addiction, may result in megaloblastic anaemia. Agranulocytosis has been reported following prolonged nitrous oxide administration (see section 4.4)

Myeloneuropathy and sub acute combined degeneration have also been reported following prolonged or frequent use.

However in patients with undiagnosed subclinical deficiency of vitamin B12, neurological toxicity has occurred after a single exposure to nitrous oxide for anaesthesia (see section 4.4)

Addiction may occur.

4.9 Overdose

Inhalation of nitrous oxide in the absence of oxygen will lead to unconsciousness and ultimately death due to anoxia. Treatment is removal to fresh air, mouth to mouth resuscitation and if necessary, the use of an oxygen resuscitator.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Nitrous oxide is a non-halogenated, non-carbon containing, inhalation anaesthetic and analgesic.

Whilst nitrous oxide has often been regarded as effectively chemically inert within the body, it does produce unwanted side-effects.

Oxidative inactivation of vitamin B12 can result both in megaloblastic

anaemia and in peripheral neuropathy. The latter occurs after prolonged exposure (including abuse). Megaloblastic anaemia is seen after chronic exposure (see section 4 for advice on chronic usage). Particular care should be exercised in exposing patients who may be deficient in vitamin B₁₂.

5.2. Pharmacokinetic Properties

Bio-transformation of nitrous oxide is minimal. Whilst the little that does occur has safety implications (see above) for considerations of disposition and kinetics, it may be considered inert within the body.

Nitrous oxide is an asphyxiant. Adequate oxygen supply must be ensured at all times.

Nitrous oxide selectively replaces nitrogen in any air-filled cavities of the body. There is a resultant increase in gas pressure within the cavity and/or distension of the cavity. Care should be exercised with patients with obvious amounts of gas associated with the intestinal tract (evidenced by abdominal distension). Also in those with gas in abnormal body sites whether traumatic (head injuries), pathological (air embolism, severe bullous emphysema, pneumothorax, pneumopericardium) or iatrogenic (air encephalography, during myringoplasty). It should also not be used in those suffering from decompression sickness or who have recently dived.

Transient hypoxia on withdrawal of the gas may be seen as nitrous oxide flows from the tissues to the lungs. Ventilation with oxygen, after completion of nitrous oxide administration, will eliminate the risk of such "diffusion hypoxia".

5.3. Preclinical Safety Data

Exposure of pregnant rats caused foetal resorption, skeletal anomalies and a variety of macroscopic lesions. Whilst it now seems that there is more than one mode of action (that is modes other than the inactivation of vitamin B₁₂) that cause teratogenicity and other effects in laboratory species, current thinking is that the inactivation of vitamin B₁₂ is seen at lower exposures.

The best assessment of human risk currently comes from epidemiological data rather than laboratory studies.

Other information:

Nitrous oxide is an asphyxiant. This should be kept in mind by those that use the gas or are responsible for its transport and storage.

Nitrous oxide is not flammable, but will itself support the combustion of flammable materials. Oils and greases should not be used on supply equipment.

Chronic exposure to nitrous oxide by theatre staff, dental surgery staff, or others is considered deleterious to their health. Proper 'scavenging systems' and other precautions should be employed. The OES (Occupational Exposure Standard) for nitrous oxide is 30mg/m³ for long-term exposure and 45mg/m³ for short-term.

Rapid venting of gas from a cylinder may result in its chilling and reliquification. The resulting liquid nitrous oxide can cause cold burns to operators.

PHARMACEUTICAL PARTICULARS List of Excipients

There are no excipients.

Incompatibilities

Nitrous oxide has no major incompatibilities.

Shelf Life

Thirty six months after the date of filling.

Special Precautions for Storage

Nitrous oxide should be stored in a well-ventilated place at a temperature not exceeding 30°C

Nature and contents of container

The container is a cylinder of high-strength chromium-molybdenum steel, designed for a charge pressure of up to 300 bar. It is fitted with a brass valve conforming to BS341 part 2 and BS1319.

The tabulation below shows the water capacities of cylinders and the corresponding gas volumes.

Water capacity of cylinder    Corresponding volume of gas at 15°C

806 litres 2,014 litres 4,028 litres 8,056 litres 12,084 litres 18,392 litres

6.6. Instruction for Use, Handling and Disposal

Use in accordance with the doctor's instructions.

Cylinders must be used in the vertical position with the valve uppermost so as to avoid the discharge of liquid nitrous oxide. Avoid rapid opening of the valve as this could lead to reliquification of the discharged gas. In its liquid form the substance in contact with the skin can cause cold burns.

Nitrous oxide supports combustion more vigorously than does air. There is danger of spontaneous combustion when organic substances come into contact with the high pressure gas. This applies to substances such as grease, oil and some plastics.

7 MARKETING AUTHORISATION HOLDER

Air Products PLC 2 Millennium Gate Westmere Drive Crewe CW1 6AP

8.    MARKETING AUTHORISATION NUMBER

PL 06183/0012

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15^th October 2003

10 DATE OF REVISION OF THE TEXT

05/01/2009