Nitrous oxide Medicair: detailed information

Package leaflet: Information for the patient

NITROUS OXIDE MEDICAIR medicinal liquefied gas

Nitrous oxide
Please read carefully this leaflet before you are administered this medicine because 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 MEDICAIR is and what it is used for
What you need to know before you are administered AZOTO PROTOSSIDO MEDICAIR
How AZOTO PROTOSSIDO MEDICAIR will be administered to you
Possible side effects
How to store AZOTO PROTOSSIDO MEDICAIR
Contents of the pack and other information

1. What AZOTO PROTOSSIDO MEDICAIR is and what it is used for

Nitrous oxide MEDICAIR contains nitrous oxide, a medicinal gas belonging to the group of general anaesthetics.
Nitrous oxide MEDICAIR is indicated in patients of all ages:

to induce general anaesthesia, i.e. the elimination of pain accompanied by loss of consciousness, in combination with other anaesthetic drugs administered by inhalation or intravenous injection.
to provide pain relief and to induce a state of relaxation (sedation) with rapid onset and rapid offset, 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 AZOTO PROTOSSIDO MEDICAIR

You must not be given AZOTO PROTOSSIDO MEDICAIR if:

you are allergic to nitrous oxide;
you suffer from intestinal distension and/or obstruction;
you are due to undergo surgery involving a risk of gas bubbles forming in the bloodstream (gas embolism);
you are due to undergo middle ear surgery, to avoid serious 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 sinus cavities (sinusitis);
you are in the first or second trimester of pregnancy (see section “Pregnancy and breastfeeding”) or in cases of fetal distress;
your doctor has prescribed pure oxygen breathing or if you have breathing difficulties;
you suffer from conditions associated with air-filled cavities (pneumothorax, bullous emphysema, gas embolism, etc.) to avoid blockage of a blood vessel by a gas or liquid bubble (embolism) that may expand following nitrous oxide administration;
you have dived within the last 48 hours, to avoid decompression sickness;
you have undergone extracorporeal blood circulation (using a heart-lung machine) or suffer from severe cranial diseases, free air in the abdomen, or have recently had gas injected into the eye (e.g. SF6, C3F8), to avoid increased intraocular pressure which may lead to loss of vision;
you have intestinal obstruction (ileus), to avoid further intestinal distension;
you have middle ear obstruction due to reduced passage to the nose and throat (via 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);
you may develop vitamin B12 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 an untreated vitamin B12 deficiency, suffer from a specific type of anemia known as Biermer's anemia, suffer from a specific intestinal disease known as Crohn's disease, or have a defect in methionine synthesis;
you show severe mental confusion or other signs of cognitive impairment, which may be related to increased intracranial pressure that could be worsened by nitrous oxide;
you have already been administered nitrous oxide for a period of 24 hours.

Warnings and precautions
Talk to your doctor or nurse before being given Azoto protossido MEDICAIR if you have or have had drug abuse, as there is a higher risk of developing dependence on nitrous oxide if used repeatedly. Your doctor will decide whether treatment with nitrous oxide is appropriate in your case.
Repeated or long-term use of nitrous oxide may increase the risk of vitamin B12 deficiency, which can lead to bone marrow or nervous system damage. Your doctor may perform blood tests before and after treatment to assess possible consequences of vitamin B12 deficiency.
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 accumulations in the airways;
endoscopic procedures using carbon dioxide as the insufflation gas;
neurosurgery, because nitrous oxide reduces the protective effect of barbiturates, increases cerebral blood flow, and raises pressure in any intracranial air pockets or bubbles;
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 into the eye: a sufficient time interval must elapse due to the risk of visual disturbances;
prolonged anesthesia (lasting more than 6 hours); high risk of nausea and vomiting;
in patients treated with bleomycin;
in vegetarian patients;
if you are in the third trimester of pregnancy (see section “Pregnancy and breastfeeding”).

Azoto protossido MEDICAIR may be mixed with air, medical oxygen, and other types of inhaled anesthetics.
Azoto protossido MEDICAIR should not be used during laser surgery of the airways due to the risk of explosive combustion.
Azoto protossido MEDICAIR is a colorless gas with a faint sweet odor, even at high concentrations, heavier than air, and may cause suffocation. Although not flammable, it supports and accelerates combustion; therefore, the following safety instructions must be observed.

Safety precautions
During gas use

It is strictly forbidden to tamper in any way with container connections, delivery equipment, and 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 strictly 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 AZOTO PROTOSSIDO MEDICAIR
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 clots;
methotrexate, an anticancer medicine;
sodium nitroprusside, a medicine used to significantly lower blood pressure;
medicines belonging to the group called depolarizing muscle relaxants used to relax muscles during surgery (e.g. succinylcholine) and non-depolarizing muscle relaxants.

Pregnancy and breastfeeding
Pregnancy
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
The use of Azoto protossido MEDICAIR is contraindicated during the first and second trimesters of pregnancy.
Azoto protossido MEDICAIR may be used during the third trimester of pregnancy only if the doctor considers it strictly necessary.
Azoto protossido MEDICAIR 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 difficulty.
Breastfeeding
It is not necessary to interrupt breastfeeding if Azoto protossido MEDICAIR has been administered 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 within 24 hours after anesthesia with Azoto protossido MEDICAIR.
After short-term administration of Azoto protossido MEDICAIR for pain relief, your doctor will monitor you until all effects have worn off and you are sufficiently alert to drive or operate machinery.

3. How AZOTO PROTOSSIDO MEDICAIR will be administered to you

This medicine will always be administered exactly according to your doctor's instructions. If you have any doubts, please 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 concomitant administration of other anaesthetic medicines used to induce general anaesthesia.
Your doctor will administer Azoto protossido MEDICAIR to you in combination with oxygen through a cannula 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 AZOTO PROTOSSIDO MEDICAIR than you should
It is highly unlikely that you will receive more Azoto protossido MEDICAIR than intended, as your doctor or nurse will monitor you during treatment.
In case of excessive dosage or prolonged exposure to Azoto protossido MEDICAIR, neurological disorders 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 alterations in circulation and breathing (syncope),
changes in normal heart rhythm (arrhythmia),
loss of consciousness,
death due to suffocation (asphyxia).

Treatment
The doctor will stop the administration, maintain airway patency, and provide assisted oxygenation. The doctor must always have appropriate equipment available for cardiopulmonary resuscitation in areas where Azoto protossido MEDICAIR 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 everyone gets them.
If you experience any of the following reactions, your doctor will IMMEDIATELY STOP treatment and initiate appropriate therapy:

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

The assessment 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):

bloating, increased intestinal gas volume
heightened sense of well-being (euphoria), dependence on nitrous oxide
sensation of pressure in the middle ear, damage to the middle ear, rupture of the eardrum (membrane separating the middle ear)
low levels of haemoglobin (the protein that carries oxygen in the blood) associated with reduced red blood cell production (severe megaloblastic anaemia)
decreased, even severely reduced, 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 diseases (subacute combined degeneration)

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

movement disorders, complete loss of movement in the upper or lower limbs (paraplegia), partial 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 skull, disease of the peripheral nervous system (peripheral neuropathy), brain disease (encephalopathy)
sensory disturbances, altered reflexes, reduced level of consciousness, seeing or perceiving things that do not exist (hallucinations), mental illness (psychotic disorder), confusion, anxiety
increased pressure within the eye (ocular hypertension), eye pain, blockage of the retinal artery (retinal artery occlusion), loss of vision (blindness)
disturbances in 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)
congenital abnormalities
infertility
lack of oxygen in the body (hypoxia) for several minutes after nitrous oxide administration has ended, lung collapse (pneumothorax)
decreased blood pressure (hypotension) with or without reduction in all physical and mental functions (shock)

Not known (frequency cannot be estimated from 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
dependence
effects on nerve function, sensation of numbness and weakness, usually in the legs
generalized epileptic seizures

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse.
You can also report side effects directly via the website
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store NITROUS OXIDE MEDICAIR

Store at a temperature not exceeding 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 no longer in use. This will help protect the environment.

6. Package contents and other information

What AZOTO PROTOSSIDO MEDICAIR contains
The active substance is Nitrous oxide 100%.
Description of the appearance of AZOTO PROTOSSIDO MEDICAIR and package contents
AZOTO PROTOSSIDO MEDICAIR is a colourless gas with a faintly sweet odour, packaged in cylinders (blue shoulder marked with “N O” or “nitrous oxide” and white cylinder) with a shut-off valve, and in fixed cryogenic containers.
Marketing Authorization Holder
MEDICAIR ITALIA S.r.l.
Via T. Tasso 29 – 20010 Pogliano Milanese (MI)
Manufacturer
Cylinders
Eurogas S.r.l. - Via Pradazzo, 22 - 26012 Castelleone (CR)
Medicair Italia srl- Via Torquato Tasso, 29 – 20010 Pogliano Milanese (MI)
Fixed cryogenic containers
Eurogas S.r.l. - Via Pradazzo, 22 - 26012 Castelleone (CR)
Medicair Italia srl- Via Torquato Tasso, 29 – 20010 Pogliano Milanese (MI)

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. Oxygen tension must remain above physiological values (100 mmHg), with haemoglobin oxygen saturation exceeding 97%, and in any case always above 60 mmHg, with haemoglobin 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 oxygen concentration in the inhaled air for each individual patient must be established.
Nitrous oxide concentrations above 50% v/v may impair protective reflexes and levels of consciousness. Concentrations exceeding 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 discontinue nitrous oxide administration and increase the inhaled oxygen fraction to 100%. If cyanosis does not rapidly resolve, or if the episode recurs during anaesthesia, possible causes include equipment malfunction (delivery of hypoxic mixture) or accidental interchange of medical gas tubing supplying the ventilator. It is therefore advisable to attempt ventilating 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 pulmonary oxygen. This may result in 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 must continue for 15 minutes after the end of nitrous oxide administration.
Nitrous oxide administration may increase pressure in the endotracheal tube cuff, potentially causing tracheal injury, or in any other inflated balloon used in procedures (e.g., vessel occlusion balloons). Additionally, when using nitrous oxide with a Swan-Ganz catheter, the generated pressure may displace the catheter into an occlusive position, altering pressure readings.
Medical devices filled with air may experience problems (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., sedation in intensive care patients) due to the potential risk of vitamin B₁₂ function impairment (cofactor of methionine synthase). Nitrous oxide interferes with vitamin B₁₂ and folate metabolism, particularly in elderly patients. Inhibition of methionine synthase affects the conversion of homocysteine to methionine. This enzyme inhibition reduces thymidine formation, a key DNA component. Methionine synthase inhibition may lead to defects or reduced myelin formation, resulting in spinal cord damage. DNA effects explain the potential negative impact on haematopoiesis and fetal damage observed in animal studies.
Nitrous oxide may cause increased pressure in the middle ear.
Administration of nitrous oxide more than once every 4 days should be accompanied by blood cell count monitoring to assess for possible megaloblastic changes or alterations in red blood cells and potential neutrophil hypersegmentation.
Nitrous oxide administration must be performed with caution in the following situations:

Thoracic surgery, due to the risk of pneumothorax, expansion of emphysematous bullae, and loss of hypoxic vasoconstriction.
Presence of undrained airway effusions.
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 within 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, as increased oxygen concentration during inhalational sedation increases the risk of pulmonary toxicity.
Vegetarian patients.

Interactions
No pharmacokinetic interaction studies with other drugs are known. Interactions between nitrous oxide and other medicinal products can be explained by receptor-mediated mechanisms.
Nitrous oxide acts directly on opioid receptors (subtypes OP2 and OP3), GABA receptors (subtype A), and glutamate receptors (subtype NMDA).
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, as well as to shorten induction time when inhaled anaesthetics are used.
Haemoglobin may not fully saturate if nitrous oxide is combined with sedatives.
Nitrous oxide potentiates the effect of warfarin.
Concurrent use of nitrous oxide and methotrexate should be avoided, as nitrous oxide enhances the cytotoxic effects of methotrexate. Concomitant administration of nitrous oxide and methotrexate may affect blood cell counts.
The antiproliferative effect of nitrous oxide is based on vitamin B₁₂ inactivation 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 by succinylcholine and potentiates the effect of non-depolarizing muscle relaxants.
Special warnings
Nitrous oxide can be mixed with air, medical oxygen, and halogenated inhaled anaesthetics.
Nitrous oxide is a colourless gas with a faintly sweet odour, barely perceptible even at high concentrations, heavier than air, and asphyxiant. Although non-flammable, it supports combustion (it is an oxidizing agent: it enables and accelerates burning).
Material compatibility depends on the pressure at which the gas is used. The greatest combustion risks involve materials such as fats (lubricating oils) and organic matter (tissues, wood, paper, plastics, etc.), which may spontaneously ignite upon contact with nitrous oxide at sufficient pressure, especially in the presence of an ignition source (spark, open flame, etc.).
Explosive mixtures may form with flammable anaesthetic gases or vapours, even in the absence of oxygen.
For healthcare personnel
Nitrous oxide is a colourless gas with a faintly sweet odour; it is non-toxic and non-flammable but supports combustion. It is heavier than air and accumulates in lower areas of the workplace.
Nitrous oxide exhaled by the patient gradually disperses into the ambient air of the room where it is used. The use of so-called “double” masks, adequate air exchange in operating rooms (20 times per hour), and active scavenging systems from anaesthetic equipment should ensure that the average concentration remains below the maximum allowable limit set by current regulations.
In addition, compliance with regulations regarding the use of nitrous oxide-based products is required. In principle, 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. While a causal relationship between chronic exposure to low concentrations of nitrous oxide and specific pathologies cannot currently be established, the possibility of a link between chronic exposure and the development of tumours or other chronic diseases, reduced fertility, spontaneous abortion, and fetal malformations cannot be ruled out.
Repeated administration or exposure to nitrous oxide may lead to dependence. Caution must be exercised regarding occupational exposure of healthcare workers to nitrous oxide.
Prior to and during nitrous oxide administration, safety precautions outlined in section 6.6 must be followed.
Pregnancy and breastfeeding
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.
However, anaesthetic techniques involving nitrous oxide use 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 extreme caution and only if strictly necessary. Prolonged or frequent use should be avoided.
Nitrous oxide may be used during labour.
Nitrous oxide use should be avoided in cases of fetal distress. In any case, the newborn must be monitored for signs of possible respiratory depression.
Breastfeeding
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 alters cognitive and psychomotor function. It is rapidly eliminated after administration. Nevertheless, as an additional safety measure, driving, operating machinery, and other activities requiring special attention should be avoided for 24 hours following nitrous oxide anaesthesia.
After short-term administration of nitrous oxide for analgesia, outpatients who must drive or operate machinery should be observed 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 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 adequate oxygen fraction. In patients with reduced oxygen saturation, an appropriate oxygen fraction must be used.
In pregnant women, the nitrous oxide percentage must not exceed 50% v/v in the oxygen mixture 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 allowed concentration cannot induce anaesthesia alone and is therefore used in combination with other anaesthetics administered intravenously or by inhalation.
Information on nitrous oxide and additional inhaled anaesthetic dosing for anaesthesia maintenance is generally available in the respective product leaflets. When combined with intravenous anaesthetics, the intravenous anaesthetic dose must be adjusted accordingly.
Generally, 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. Uninterrupted 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, has sedative effects, and reduces agitation, typically without affecting awareness level or the ability to converse. At these concentrations, respiration and reflexes remain unchanged.
The effect on pain reduction and sedation is dose-dependent, as are effects on cognitive functions.
Patient exposure to nitrous oxide as an analgesic should last no longer than 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 and at what dose the medicinal product can be administered, in an appropriate facility 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 gas use, administered with appropriate equipment in well-ventilated rooms ensuring immediate 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.
Ambient air quality must be monitored according to local laws, and occupational exposure to nitrous oxide must remain below 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 operating rooms and via a tight-fitting facial or nasal mask in other settings. The patient may breathe spontaneously or with ventilator support (assisted or mechanical ventilation).
Nitrous oxide must be administered in combination with oxygen, using equipment that ensures delivery of a non-hypoxic nitrous oxide-oxygen mixture. These devices 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 operating rooms, analgesic administration is acceptable only in a 50% v/v oxygen mixture. The device used must make it impossible to administer mixtures with nitrous oxide concentrations exceeding 50% v/v.
Throughout nitrous oxide use, both the patient and administration methods must be monitored to ensure safe inhalation.
The patient must be monitored by medical personnel until administration ends and consciousness is 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 enclosed and rain-protected areas, shielded from 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 flammable materials and combustible substances (contact with combustible material may cause fire).
Do not smoke or use open flames near the product.
Keep the container (cylinder) clean and dry, avoiding any contact with grease or oils (do not lubricate valves or fittings).
Ensure containers are undamaged and avoid impacts or gas leaks.
Block gas flow when not in use by closing valves.
Keep cylinders and cylinder packs upright, with valves closed, protective caps and heat-shrink sleeves in place, securely fastened to prevent accidental impacts or falls.
Do not use damaged packages.
Store empty and full containers separately.
Store containers containing other gas types separately.
Avoid excessive storage of full containers.
In case of fire risk, move to a safe location 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 to escape.
Vapours may cause drowsiness and dizziness.

Cylinder transport
Cylinders must be transported using appropriate means (e.g., trolley equipped with chains, barriers, or rings) to protect against impact, falling, and gas leakage. Cylinder handling must always be performed 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, with smoking prohibited.
During gas use

Cylinders and fixed containers must not be used if visibly damaged, suspected damage, or exposure 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 the valve 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 administration must occur at adequate 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 support service of the supplier indicated in the container’s user manual.
Use only containers suitable for the product and intended operating temperatures.
Use specific, compatible connectors, connection tubes, or flexible hoses for nitrous oxide.
It is absolutely forbidden to modify container fittings, delivery equipment, or related accessories or components (OIL AND GREASE MAY SPONTANEOUSLY IGNITE IN CONTACT WITH NITROUS OXIDE).
Do not lubricate or attempt to repair defective valves.
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.
No electrical equipment capable of emitting sparks should be used near patients receiving oxygen.
Do not use oils or greases on connectors, valves, or any material in contact with the gas.
Never introduce nitrous oxide into devices 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. Discharging pressurized gas is not permitted.
Return empty or unused containers, even if partially full, to the supplier. Any residual medicinal product in the cylinder will be removed via 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 current local regulations.

Overdose
Adverse effects due to overdose may occur in patients exposed to high amounts of nitrous oxide for prolonged 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 asphyxia.
Emergency and supportive measures in case of nitrous oxide overdose include discontinuing administration, maintaining airway patency, and providing assisted oxygenation supplemented with additional oxygen to achieve adequate oxygen saturation. It is therefore recommended to always have appropriate cardiopulmonary resuscitation equipment readily 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 drug 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 ventilated sheds, in upright position with valves closed, protected from rain, weather, direct sunlight, heat sources, ignition sources, and combustible materials. Empty containers or those containing other gas types must be stored separately.
Fixed containers installed in healthcare facilities must be placed outdoors as specified in Circular 99/1964, in confined and protected areas with restricted access for authorized personnel, managed and maintained according to each manufacturer's instructions. These are pressure equipment and therefore subject to the PED CE Directive and/or the Ministerial Decree of 21/11/1972.
Unused medicinal product and waste derived from this medicinal product must be disposed of in accordance with current local regulations (see also Instructions for use and handling – Disposal).