Nitrous oxide Air Liquide Sanita': detailed information

Patient Information Leaflet

NITROUS OXIDE AIR LIQUIDE SANITÀ

Nitrous Oxide
Please read this leaflet carefully before you are given this medicine, as it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist, or nurse.
If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

What AZOTO PROTOSSIDO AIR LIQUIDE SANITÀ is and what it is used for
What you need to know before you are given AZOTO PROTOSSIDO AIR LIQUIDE SANITÀ
How AZOTO PROTOSSIDO AIR LIQUIDE SANITÀ will be administered to you
Possible side effects
How to store AZOTO PROTOSSIDO AIR LIQUIDE SANITÀ
Contents of the pack and other information

1. What AZOTO PROTOSSIDO AIR LIQUIDE SANITÀ is and what it is used for

Azoto protossido AIR LIQUIDE SANITÀ contains nitrous oxide, a medicinal gas
belonging to the group of general anesthetics.
Azoto protossido AIR LIQUIDE SANITÀ is indicated in patients of all ages:

to induce general anesthesia, i.e. to eliminate pain accompanied by loss of consciousness, in combination with other anesthetic drugs administered by inhalation or intravenous injection.
to provide rapid-onset pain relief and to induce a state of relaxation (sedation) with rapid offset of effect, for example during short surgical procedures, treatments involving physical injuries (traumatology), severe burns (burns), dental and oral procedures (dentistry), ear, nose and throat procedures (otorhinolaryngology), and during childbirth.

2. What you need to know before you are given NITROUS OXIDE AIR LIQUIDE SANITÀ

LIQUIDE SANITÀ
You must not be given NITROUS OXIDE AIR LIQUIDE SANITÀ if:

you are allergic to nitrous oxide;
you suffer from intestinal distension and/or intestinal obstruction;
you are about to undergo surgery involving a risk of gas bubbles forming in the bloodstream (gas embolism);
you are about to undergo surgery on the middle ear, to avoid severe damage to all structures in this part of the ear;
you suffer from severe chronic lung diseases such as presence of air or other gas in lung tissue (emphysema), lung collapse (pneumothorax), etc.;
you suffer from ear diseases (otitis) and from inflammation of the facial sinuses near the nose (sinusitis);
you are in the first or second trimester of pregnancy (see section “Pregnancy and breastfeeding”);
your doctor has prescribed you to breathe pure oxygen or if you have breathing difficulties;
you suffer from conditions associated with air-filled cavities (pneumothorax, bullous emphysema, gas embolism, etc.) to prevent blockage of a blood vessel by a gas or liquid bubble (embolism) which may expand following administration of nitrous oxide;
you have dived within the last 48 hours, to avoid decompression sickness;
you have recently undergone extracorporeal blood circulation (using heart-lung machine) or if you suffer from severe cranial diseases, or if you have free air in the abdomen;
you have recently had gas injected into your eye (e.g. SF6, C3F8), to avoid an increase in intraocular pressure which may lead to loss of vision;
you have intestinal obstruction (ileus) to prevent further intestinal distension;
you have middle ear obstruction due to reduced passage to the nose and throat (through the Eustachian tube) caused by inflammation;
there is suspicion or confirmation that you suffer from increased intracranial pressure;
you have sustained a severe head injury (closed head trauma);
there is a risk that you may develop vitamin B and/or folate deficiency and low levels of hemoglobin, the protein that carries oxygen in the blood, associated with reduced red blood cell formation (megaloblastic anemia);
you have vitamin B deficiency for which treatment has not yet been established, if you suffer from a specific type of anemia known as Biermer's anemia, or if you suffer from a specific intestinal disease known as Crohn's disease;
you have a defect in the synthesis of the amino acid methionine;
you show severe mental confusion or other signs of cognitive disorders, which may be related to increased intracranial pressure, which may be worsened by nitrous oxide;
you have already been administered nitrous oxide for longer than 24 hours.

Warnings and precautions
Warnings
Consult your doctor or pharmacist before you are given Nitrous Oxide AIR LIQUIDE SANITÀ.
Your doctor will administer nitrous oxide with caution in the following situations:

thoracic surgery, due to the risk of lung collapse (pneumothorax), expansion of emphysematous bullae, and risk of eliminating hypoxic vasoconstriction;
presence of uneliminated fluid accumulation in the airways;
endoscopic procedures using carbon dioxide as insufflation gas;
neurosurgery, because nitrous oxide reduces the protective effect provided by barbiturates, increases cerebral blood flow and pressure in any air bubble or pocket present within the skull;
low levels of hemoglobin, the oxygen-carrying protein in the blood, due to a specific type of anemia called sickle cell anemia;
after an intraocular injection: a sufficient time interval must elapse, due to the risk of visual disturbances;
prolonged anesthesia (longer than 6 hours);
high risk of nausea and vomiting;
in patients treated with bleomycin, a drug used for certain tumors;
vegetarian patients;
if you are in the third trimester of pregnancy (see section “Pregnancy and breastfeeding”).

Nitrous Oxide AIR LIQUIDE SANITÀ may be mixed with air, medical oxygen, and other types of inhaled anesthetics.
Nitrous Oxide AIR LIQUIDE SANITÀ should not be used during laser surgery of the airways due to the risk of explosive combustion.
Nitrous Oxide AIR LIQUIDE SANITÀ is a colorless gas with a faintly sweet odor, barely noticeable even at high concentrations, heavier than air, and may cause asphyxiation. Although not flammable, it supports and accelerates combustion; therefore, the following instructions must be strictly observed.

Precautions
During gas use

It is absolutely forbidden to tamper in any way with container connections, delivery equipment, or related accessories or components (oils and greases may spontaneously ignite upon contact with nitrous oxide).
Do not use oil or grease in contact with the gas.
It is absolutely forbidden to handle equipment or components with hands, clothing, or face contaminated with grease, oil, creams, or ointments.
Do not use greasy creams or lipsticks.
Do not smoke.
Do not approach the container with open flames.
Do not use any electrical equipment that may produce sparks near patients receiving oxygen.
Do not use oils or greases on connectors, taps, valves, or any material in contact with the gas.
Never introduce nitrous oxide into a device that might contain materials capable of catching fire, especially fatty substances.

Other medicines and NITROUS OXIDE AIR LIQUIDE SANITÀ
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
In particular, inform your doctor if you are taking:

medicines belonging to the group of opioids, benzodiazepines, barbiturates, and sedatives, used mainly to treat pain and nervous system disorders;
inhaled anesthetics;
warfarin, a medicine used to prevent blood clot formation;
methotrexate, an anticancer medicine;
sodium nitroprusside, a medicine used to significantly lower blood pressure;
medicines belonging to the group known as depolarizing muscle relaxants used to relax muscles during surgery (e.g. succinylcholine) and non-depolarizing muscle relaxants.

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, planning to become pregnant, or breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy
The use of Nitrous Oxide AIR LIQUIDE SANITÀ is contraindicated during the first and second trimesters of pregnancy.
Nitrous Oxide AIR LIQUIDE SANITÀ may be used during the third trimester of pregnancy only if the doctor considers it strictly necessary.
Nitrous Oxide AIR LIQUIDE SANITÀ may be used during childbirth.
The use of nitrous oxide should be avoided in cases of fetal distress. In any case, the newborn must be monitored for signs of possible respiratory difficulties.

Breastfeeding
It is not necessary to interrupt breastfeeding if you have been administered Nitrous Oxide AIR LIQUIDE SANITÀ for a short period of time.

Driving and using machines
Nitrous oxide impairs cognitive and motor abilities. Avoid driving, operating machinery, or performing other activities requiring special attention for 24 hours after anesthesia with Nitrous Oxide AIR LIQUIDE SANITÀ.
After short-term administration of Nitrous Oxide AIR LIQUIDE SANITÀ for pain relief, your doctor will monitor you to ensure that all effects have worn off and that you are sufficiently alert to drive or operate machinery.

3. How will NITROUS OXIDE AIR LIQUIDE SANITÀ be administered to you

This medicine will always be administered to you exactly as instructed by your doctor. If you
have any doubts, consult your doctor.
Your doctor will decide whether the medicine can be administered and at what dose, primarily based
on clinical parameters indicating your health status, and taking into account the simultaneous
administration of other anaesthetic medicines to induce general anaesthesia.
Your doctor will administer Nitrous Oxide AIR LIQUIDE SANITÀ to you in combination with
oxygen through a tube inserted into your mouth or nose in the operating room, or via a close-fitting
face or nasal mask in other settings. You may breathe spontaneously or with the assistance of a
respirator (assisted or mechanical ventilation).
Medical personnel will monitor you throughout the administration and until you regain consciousness.
If you are given more NITROUS OXIDE AIR LIQUIDE SANITÀ than you should
It is highly unlikely that you will receive more Nitrous Oxide AIR LIQUIDE SANITÀ than required,
as your doctor or nurse will monitor you during treatment.
In case of excessive dosage or prolonged exposure to Nitrous Oxide AIR LIQUIDE SANITÀ,
neurological disturbances due to the drug's toxicity towards Vit. B will always occur.
In general, symptoms you may experience include:

headache,
dizziness,
confusion,
weakness,
uncoordinated movements,
vertigo,
memory loss (amnesia),
loss of language comprehension or expression (aphasia),
sudden and temporary loss of consciousness, with disturbances in circulation and respiration (syncope),
alteration of normal heart rhythm (arrhythmia),
loss of consciousness,
death due to suffocation (asphyxia).

Treatment
The doctor will stop administration, maintain airway patency, and provide assisted oxygenation. The doctor must always have appropriate equipment for cardiopulmonary resuscitation readily available in areas where Nitrous Oxide AIR LIQUIDE SANITÀ is used. The doctor will monitor oxygen-related parameters until you have regained consciousness and are no longer oxygen-deficient (hypoxic). There is no specific antidote for nitrous oxide.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience any of the following reactions, your doctor will STOP
IMMEDIATELY and will start an appropriate treatment:

bluish discoloration of the skin and mucous membranes due to inadequate oxygenation of the blood (cyanosis) occurring unexpectedly during anaesthesia or during the induction phase of anaesthesia

The evaluation of side effects is based on the following frequency data.
Common (may affect up to 1 in 10 people):

nausea, vomiting
dizziness
headache, including severe headache

Uncommon (may affect up to 1 in 100 people):

swelling, increased volume of gas in the intestine
feeling of intense well-being (euphoria), dependence on nitrous oxide
sensation of pressure in the middle ear, damage to the middle ear, rupture of the eardrum (tympanic membrane)
low levels of haemoglobin (the protein that carries oxygen in the blood), associated with reduced formation of red blood cells (severe megaloblastic anaemia)
decrease, even severe, in the number of blood cells, particularly white blood cells (leucopenia, granulopenia/agranulocytosis)

Rare (may affect up to 1 in 1,000 people):

bone marrow disorders (myelopathies)
nerve disorders (polyneuropathies)
spinal cord disorders (subacute combined degenerations)

Very rare (may affect up to 1 in 10,000 people):

movement disorders, complete loss of movement in the upper or lower limbs (paraplegia), incomplete loss of movement in the upper or lower limbs (paraparesis), condition characterised by uncontrolled body movements and loss of consciousness (epilepsy), increased pressure inside the head, disorder of the peripheral nervous system (peripheral neuropathy), disorder of the brain (encephalopathy)
sensory disturbances, altered reflexes, decreased level of consciousness, seeing or perceiving things that do not exist (hallucinations), mental illness (psychotic disorder), confusion, anxiety
increased pressure inside the eye (ocular hypertension), eye pain, blockage of the retinal artery (retinal artery occlusion), loss of vision (blindness)
changes in the normal heart rhythm (arrhythmias), weak heart (heart failure)
death of liver cells (hepatic necrosis)
severe headache following brain surgery (cerebral hyperperfusion syndrome), increased pressure in inflated balloons
vitamin B deficiency, increased concentration of homocysteine in the blood (hyperhomocysteinaemia)
muscle weakness, sudden and dangerously high increase in body temperature (malignant hyperthermia)
birth defects
infertility
lack of oxygen in the body (hypoxia) for several minutes after stopping nitrous oxide administration, lung collapse (pneumothorax)
decrease in blood pressure (hypotension) with or without reduction in all physical and mental functions (shock)

Not known (frequency cannot be estimated from the available data)

damage to the trachea or to any other inflated balloon used in other procedures (balloons for vessel occlusion) due to increased pressure in the endotracheal tube cuff.

Reporting of side effects
If you get any side effects, including any not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the website http://www.agenziafarmaco.gov.it/it/responsabili.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store NITROUS OXIDE AIR LIQUIDE SANITÀ

Store below 50°C.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after EXP.
The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package Contents and Other Information

What AZOTO PROTOSSIDO AIR LIQUIDE SANITÀ Contains
The active substance is Nitrous oxide 100%.
Description of the Appearance of AZOTO PROTOSSIDO AIR LIQUIDE SANITÀ and Contents of the
Packaging
AZOTO PROTOSSIDO AIR LIQUIDE SANITÀ is a colourless gas with a faintly sweet odour,
packaged in cylinders and cylinder packs (blue shoulder marked with “N O” or “nitrous oxide” and white cylinder) with a shut-off valve, and in fixed cryogenic containers.
It is available in the following pack sizes:

Steel cylinders of 3.75 - 7.50 - 30 - 37.5 kg
Cylinder pack of 12 steel cylinders of 30 kg each
Fixed cryogenic steel containers of 880, 1600, 3300, 5500 kg

Marketing Authorization Holder
Air Liquide Santé International, 75 Quai d’Orsay 75007
Paris (France)
Manufacturer
Cylinders and cylinder packs
Air Liquide Sanità Service S.p.A. - Via Campobello, 7 bis – 00071 Pomezia (Rome)
Air Liquide Sanità Service S.p.A. - Via Lussemburgo, 17 – 37135 Verona
Fixed cryogenic containers
Air Liquide Santé France - 7558 Rue du Grand Marais – 59500 Douai (France)
Eurogas S.r.l. - Via Pradazzo, 22 - 26012 Castelleone (CR)

The following information is intended exclusively for physicians or healthcare professionals:
Precautions for Use
The fraction of inspired oxygen (FiO₂) in the inhaled mixture must be at least 21% v/v during the induction phase. In practice, a lower limit of 30% v/v is often used. The oxygen tension must remain above physiological values (100 mmHg), with hemoglobin oxygen saturation exceeding 97%, and in any case always above 60 mmHg, with hemoglobin oxygen saturation exceeding 90%. Regular monitoring is required, through measurement of arterial oxygen tension (PaO₂) or pulse oximetry (arterial oxygen saturation SpO₂), along with clinical parameter assessment. The minimum effective concentration of oxygen in the inhaled air should be established for each individual patient.
Nitrous oxide concentrations exceeding 50% v/v may impair protective reflexes and levels of consciousness. Concentrations above 60–67% v/v often cause unconsciousness and increase the risk of impaired protective reflexes.
If unexpected cyanosis occurs during anaesthesia or during the induction phase, it is recommended to stop the administration of nitrous oxide and increase the inhaled oxygen fraction to 100%.
If cyanosis does not resolve rapidly, or if the episode recurs during anaesthesia, possible causes include equipment malfunction (delivery of a hypoxic mixture) or accidental interchange of medical gas tubing supplying the anaesthetic machine. It is therefore advisable to attempt ventilation of the patient using a bag filled with ambient air.
After general anaesthesia involving high concentrations of nitrous oxide, the gas may diffuse from the blood into the alveoli, diluting alveolar oxygen. This may cause hypoxia (diffusion hypoxia), caused not only by the alveolar gas mixture but also by the reflex response to hypoxia, hypercapnia, and hypoventilation. To prevent this, 100% oxygen should be administered at the end of nitrous oxide delivery instead of air.
Monitoring of oxygen tension and oxygen saturation should continue for 15 minutes after discontinuation of nitrous oxide administration.
Administration of nitrous oxide may increase pressure in the endotracheal tube cuff, potentially causing tracheal injury, or in any other inflated balloon used in procedures (e.g., vascular occlusion balloons). Additionally, when using nitrous oxide with a Swan-Ganz catheter, the generated pressure may displace the catheter into an occlusive position, thereby altering pressure readings.
Medical devices filled with air may malfunction (e.g., rupture) when exposed to nitrous oxide.
Nitrous oxide should not be used during laser airway surgery due to the risk of explosive combustion.
Nitrous oxide should not be used for prolonged periods (e.g., for sedation in intensive care patients) due to the potential risk of vitamin B₁₂ (cofactor of methionine synthase) dysfunction. Nitrous oxide interferes with vitamin B₁₂ and folate metabolism, particularly in elderly patients. Inhibition of methionine synthase impairs the conversion of homocysteine to methionine. This enzyme inhibition reduces thymidine formation, an essential DNA component. Inhibition of methionine synthase may lead to defective or reduced myelin formation, resulting in spinal cord damage. The effects on DNA explain the potential negative impact on haematopoiesis and fetal damage observed in animal studies.
Nitrous oxide may increase pressure in the middle ear.
Administration of nitrous oxide more than once every 4 days should be accompanied by blood cell count monitoring, including assessment for megaloblastic changes or alterations in red blood cells and possible hypersegmentation of neutrophils.
Nitrous oxide should be administered with caution in the following situations:

Thoracic surgery, due to the risk of pneumothorax, expansion of emphysematous bullae, and elimination of hypoxic vasoconstriction.
Presence of undrained airway collections.
Endoscopic procedures using carbon dioxide as the insufflation gas.
Neurosurgery, because nitrous oxide reduces the protective effect provided by barbiturates, increases cerebral blood flow, and increases pressure in any intracranial air pocket or bubble.
Sickle cell anaemia.
After intraocular injection: a sufficient time interval must elapse due to the risk of visual disturbances.
Prolonged anaesthesia (>6 hours).
High risk of nausea and vomiting.
In patients treated with bleomycin, because increased oxygen concentration during inhalational sedation increases the risk of pulmonary toxicity.
Vegetarian patients.

Interactions
No studies on pharmacokinetic interactions between drugs are known. Interactions of nitrous oxide with other medicinal products may be explained by receptor-mediated mechanisms.
Nitrous oxide acts directly on opioid receptors (subtypes OP2 and OP3), GABA receptors (subtype A), and glutamate receptors (NMDA subtype).
Opioids, benzodiazepines, and barbiturates have an additive effect, enhancing the analgesic and sedative action of nitrous oxide.
All inhaled anaesthetics interact with GABA and glutamate receptors and have an additive effect on the sedative action of nitrous oxide.
Nitrous oxide reduces the minimum alveolar concentration (MAC) of inhaled anaesthetics and is used to reduce the required dose of other anaesthetics and to shorten induction time when inhaled anaesthetics are used.
Haemoglobin may not become fully saturated if nitrous oxide is combined with sedatives.
Nitrous oxide potentiates the action of warfarin.
Concomitant use of nitrous oxide and methotrexate should be avoided, as nitrous oxide potentiates the cytotoxic effects of methotrexate. Concurrent administration of nitrous oxide and methotrexate may affect blood cell counts.
The antiproliferative effect of nitrous oxide is based on the inactivation of vitamin B₁₂ by nitrous oxide. This effect disappears when nitrous oxide administration is discontinued and concomitant vitamin B₁₂ therapy is initiated. Inactivation of vitamin B₁₂ by nitrous oxide potentiates the toxicity of sodium nitroprusside and methotrexate.
Nitrous oxide increases neuromuscular blockade caused by succinylcholine and potentiates the effect of non-depolarizing muscle relaxants.

Special Warnings
Nitrous oxide may be mixed with air, medical oxygen, and inhaled halogenated anaesthetics.
Nitrous oxide is a colourless gas with a faintly sweet odour, barely detectable even at high concentrations. It is heavier than air, asphyxiant, and accumulates in lower areas of the workplace. Although non-flammable, it supports and accelerates combustion (it is an oxidizing agent).
The degree of compatibility of various materials depends on the pressure at which the gas is used. The greatest combustion risks involve materials such as greases (lubricating oils) and organic matter (fabrics, wood, paper, plastics, etc.), which may spontaneously ignite upon contact with nitrous oxide at sufficient pressure, especially when exposed to an ignition source (spark, open flame, etc.).
Explosive mixtures may form with flammable anaesthetic gases or vapours, even in the absence of oxygen.
Nitrous oxide exhaled by the patient gradually accumulates in the ambient air of the area where it is used. The use of so-called “double” masks and a sufficiently high air exchange rate in operating rooms (20 times per hour), together with active scavenging of excess gas from anaesthetic equipment, should ensure that the average concentration remains below the maximum acceptable level established by current regulations.
Furthermore, compliance with regulations regarding the use of nitrous oxide-based products is required. In principle, healthcare personnel should avoid prolonged direct inhalation of exhaled air from patients.
Chronic exposure to low concentrations of nitrous oxide has been identified as a potential health risk. At present, it is not possible to establish whether there is a causal relationship between chronic exposure to low concentrations of nitrous oxide and specific pathologies, but a possible link between chronic exposure and the development of tumours or other chronic diseases, reduced fertility, spontaneous abortion, and fetal malformations cannot be excluded.
Prior to and during administration of nitrous oxide, safety precautions outlined in section 6.6 must be followed.

Pregnancy and Lactation
Pregnancy
Skeletal abnormalities have been observed in rat embryos exposed to high concentrations of nitrous oxide during organogenesis.
Animal studies involving long-term exposure to high concentrations of nitrous oxide have demonstrated reproductive toxicity (teratogenic effects) (see section 5.3).
Nitrous oxide may interfere with folate metabolism (see section 4.4).
Epidemiological data collected during pregnancy are insufficient to define the risk of adverse effects on embryonic-fetal development. Limited data on short-term use of nitrous oxide in human pregnancy have not shown an increased risk of congenital anomalies.
Nevertheless, anaesthetic techniques involving nitrous oxide are contraindicated during the first and second trimesters of pregnancy.
During the third trimester, the inhaled mixture should not exceed 50% v/v nitrous oxide. In any case, pregnant women should be exposed to nitrous oxide with great caution and only if strictly necessary. Prolonged or frequent use should be avoided.
Nitrous oxide may be used during childbirth.
The use of nitrous oxide should be avoided in cases of fetal distress. In any case, the newborn must be monitored for signs of possible respiratory depression.
Lactation
There are no data on the excretion of nitrous oxide-based products in breast milk. However, after short-term administration of nitrous oxide-based products, breastfeeding need not be interrupted.

Effects on Ability to Drive and Use Machines
Nitrous oxide impairs cognitive and psychomotor function. It is rapidly eliminated after administration. Nevertheless, as an additional safety measure, driving, operating machinery, and other activities requiring full attention should be avoided for 24 hours following nitrous oxide anaesthesia.
After short-term administration of nitrous oxide for analgesia, outpatient patients who intend to drive or operate machinery should be monitored until all effects have subsided and the patient is sufficiently alert.

Dosage, Method and Duration of Administration
As an anaesthetic
Nitrous oxide, used exclusively in operating rooms or delivery rooms, must be administered in a mixture with oxygen at concentrations below 79%, using appropriate equipment that includes oxygen concentration monitoring and a safety system preventing administration of a hypoxic mixture (FiO₂ <21% v/v).
Nitrous oxide must not be administered at concentrations exceeding 79% v/v to ensure an adequate oxygen fraction. In patients with reduced oxygen saturation, an appropriate oxygen fraction must be used.
In pregnant women, the nitrous oxide concentration in the oxygen mixture must not exceed 50% v/v due to the drug's inherent toxicity.
Induction time is 2–5 minutes with a nitrous oxide concentration of 70–75% v/v. After induction, nitrous oxide is typically used at 50–70% v/v, supplemented with medical oxygen. The nitrous oxide percentage may be reduced according to clinical parameters and the anaesthetic plan.
Nitrous oxide at the maximum permitted concentration cannot induce anaesthesia alone and is therefore used in combination with other anaesthetics administered intravenously or by inhalation.
Dosage information for nitrous oxide and inhaled anaesthetics used to maintain anaesthesia is generally available in the respective product leaflets. When combined with intravenous anaesthetics, the intravenous dose should be adjusted accordingly.
In general, the effects of nitrous oxide, if used as the sole active substance, do not depend on patient age.
Nitrous oxide should not be administered for more than 12 consecutive hours due to its myelotoxicity. Continuous exposure (>24 hours) increases the risk of bone marrow depression.

As an analgesic
Nitrous oxide used as a single analgesic/anaesthetic/sedative (always combined with oxygen) at concentrations below 50% v/v relieves pain, produces sedation, and reduces agitation, typically without affecting awareness or the ability to hold a conversation. At these concentrations, respiration and reflexes remain unchanged.
The pain-relieving and sedative effects are dose-dependent, as are the effects on cognitive functions.
Patient exposure to nitrous oxide as an analgesic should not exceed 1 hour and should not be repeated for more than 15 consecutive days.

Method of Administration – General Rules
Nitrous oxide must always be administered in the presence of medical personnel who determine whether the medicinal product can be administered and at what dose, in a setting equipped for emergency cardiorespiratory resuscitation.
Instructions from medical personnel must be followed when administering the gas.
Personnel using nitrous oxide must be adequately trained and updated on its use, and the gas must be administered using appropriate equipment in well-ventilated rooms ensuring rapid air exchange, with ventilation systems preventing excessive ambient gas concentrations, and using, for example, so-called “double” masks (active nasal masks), particularly recommended for dental procedures.
In ambulances, the delivery device may be connected to an extraction system or a double mask may be used.
Air quality must be monitored according to local regulations, and occupational exposure to nitrous oxide must remain below the hygienic limits established by professional guidelines and health and safety legislation, especially for pregnant personnel.
Nitrous oxide is normally administered via orotracheal or nasotracheal tube in the operating room and via a close-fitting facial or nasal mask in other settings. The patient may breathe spontaneously or with ventilator assistance (assisted or mechanical ventilation).
Nitrous oxide must be administered in combination with oxygen, using equipment that ensures delivery of a non-hypoxic mixture of nitrous oxide and oxygen. This equipment must include oxygen concentration monitoring and a safety system preventing administration of a hypoxic mixture (FiO₂ <21% v/v).
Due to the risk of loss of consciousness and coma, when nitrous oxide is used outside the operating room, analgesic administration is acceptable only in a 50% v/v oxygen mixture. The device used must prevent administration of mixtures with nitrous oxide concentrations exceeding 50% v/v.
Throughout the period of nitrous oxide use, both the patient and the administration method must be monitored to ensure safe inhalation.
The patient must be monitored by medical personnel until administration ends and consciousness is fully regained.

Instructions for Use and Handling
Cylinders and fixed cryogenic containers are intended exclusively for containing/transporting nitrous oxide for inhalation, for therapeutic use.
NOTE: FOR MORE DETAILS, CONSULT THE CONTAINER’S USER MANUAL
Storage

Read the container’s instruction and user manual carefully.
Ensure all equipment is in good condition.
Store outdoors or in well-ventilated areas, in fenced and protected zones, sheltered from rain and direct sunlight, and away from heat sources (locked spaces reserved for medicinal gases).
Do not expose to heat sources or high temperatures (above 50°C).
Protect from electrical lines and ensure proper grounding.
Store away from combustible materials and flammable substances (contact with combustible materials may cause fire).
No smoking or open flames near the product.
Keep the container (cylinder) clean and dry; avoid any contact with greases or oils (do not lubricate valves or fittings).
Ensure containers are undamaged; avoid impacts and product leakage.
Close valves to block delivery when not in use.
Keep cylinders and cylinder packs upright, with valves closed, protective caps and heat-shrink sleeves in place, and securely fastened to prevent accidental impact or falls.
Do not use damaged packages.
Empty and full containers must be stored separately.
Containers containing other types of gases must be stored separately.
Excessive storage of full containers should be avoided.
In case of fire risk, move to a safe area after closing valves.
In case of leakage, close the cylinder valve immediately if safe to do so. If the valve cannot be closed, move the container to a safe outdoor location to allow gas release.
Vapours may cause drowsiness and dizziness.

Transport of Cylinders
Cylinders must be transported using appropriate means (e.g., trolley equipped with chains, barriers, or rings) to protect against impact, falling, and gas leakage. Handling of cylinders must always be done with the protective cap in place. During vehicle transport, cylinders must be securely fastened, preferably in an upright position. Permanent vehicle ventilation must be ensured, and smoking is prohibited.

During Gas Use

Cylinders and fixed containers must not be used if visibly damaged, suspected of damage, or exposed to extreme temperatures.
Before opening the cylinder valve, place the cylinder upright and maintain this position during administration.
Open and close container closure systems gradually and carefully (do not use pliers or other tools to open or close the cylinder valve) to prevent damage.
Do not force valves during opening or closing. Do not alter the container shape.
Never stand directly in front of the gas outlet; always stand to the side. Do not expose yourself or the patient to direct gas flow.
Nitrous oxide must be administered at appropriate pressure, with controlled flow rate between container and patient.
Do not use oil or grease in contact with the gas.
Handle equipment with clean hands, free of grease or oil traces.
Do not completely empty the container.
After use, close the cylinder valve.
In case of gas leakage, close the valve and notify the technical service of the supplier indicated in the container’s user manual.
Use only containers suitable for the product and intended operating temperatures.
Use specific, nitrous oxide-compatible connectors, connecting tubes, or flexible hoses.
It is strictly prohibited to modify container fittings, delivery equipment, or associated accessories or components (OIL AND GREASE MAY SPONTANEOUSLY IGNITE ON CONTACT WITH NITROUS OXIDE).
Do not lubricate or attempt to repair defective valves.
It is strictly prohibited to handle equipment or components with hands, clothing, or face contaminated with grease, oil, creams, or ointments.
Do not use greasy creams or lipsticks.
No smoking.
Do not approach the container with open flames.
No electrical equipment capable of emitting sparks should be used near patients receiving oxygen.
Do not use oils or greases on fittings, valves, or any material in contact with the gas.
Never introduce nitrous oxide into equipment that may contain combustible materials, especially greasy substances.

Disposal

Store empty cylinders with valves closed.
Do not discharge into sewers, basements, or pits where accumulation may be hazardous. Pressurized gas release is not permitted.
Return empty or unused containers, even if only partially empty, to the supplier. Any residual medicinal product in the cylinder will be eliminated through appropriate procedures in a well-ventilated area by the company responsible for subsequent refilling.
Unused medicinal product and waste derived from this medicinal product must be disposed of in accordance with local regulations.

Overdose
Undesirable effects due to overdose may occur in patients exposed to high amounts of nitrous oxide over long periods or at concentrations exceeding 80% v/v.
Early signs of nitrous oxide toxicity include headache, dizziness, confusion, weakness, incoordination, vertigo, amnesia, aphasia, syncope, arrhythmia, unconsciousness, and ultimately death by asphyxiation.
Emergency and supportive measures in case of nitrous oxide overdose include discontinuation of administration, maintenance of airway patency, and provision of assisted oxygenation with supplemental oxygen to achieve adequate oxygen saturation. It is therefore recommended to always have appropriate cardiopulmonary resuscitation equipment available in areas where nitrous oxide is used.
Pulse oximetry monitoring is recommended until the patient regains consciousness and is no longer hypoxic.
Overexposure or prolonged exposure to nitrous oxide always results in neurological disorders due to the drug’s toxicity towards vitamin B₁₂.
There is no specific antidote for nitrous oxide.

Storage
Store at temperatures not exceeding 50°C, in well-ventilated areas or well-ventilated sheds, in an upright position with valves closed, protected from rain, adverse weather, direct sunlight, heat or ignition sources, and combustible materials. Empty containers or containers containing other types of gases must be stored separately.
Fixed containers installed at healthcare facilities must be placed outdoors as specified in Circular 99/1964, in confined and protected zones with restricted access for authorized personnel only, and managed and maintained according to the manufacturer's instructions. These are pressure equipment and therefore subject to the CE PED Directive and/or the Italian Ministerial Decree of 21/11/1972.
Unused medicinal product and waste derived from this medicinal product must be disposed of in
accordance with local regulations (see also Instructions for Use and Handling – Disposal).