Patient Information Leaflet

NITROUS OXIDE SIAD medicinal liquefied gas

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

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

Azoto protossido SIAD contains nitrous oxide, a medicinal gas belonging to the group of general anesthetics.
Azoto protossido SIAD is indicated:

to induce general anesthesia, i.e. the elimination of pain accompanied by loss of consciousness, in combination with other anesthetic drugs administered by inhalation or intravenous injection.
to provide rapid pain relief and to induce a state of relaxation (sedation) with rapid onset and rapid offset, for example during short-duration 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 should know before you are given AZOTO PROTOSSIDO SIAD

You will not be given AZOTO PROTOSSIDO SIAD if:

you are allergic to nitrous oxide;
you suffer from dilation and/or obstruction in the intestinal passage;
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 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) or sinus cavities of the facial bones near the nose (sinusitis);
you are in the first or second trimester of pregnancy (see section “Pregnancy and breastfeeding”);
your doctor has prescribed breathing pure oxygen or if you have breathing difficulties;
you suffer from conditions involving air-filled cavities (pneumothorax, bullous emphysema, gas embolism, etc.) to prevent blockage of a blood vessel by a gas or liquid bubble (embolism) that may expand following administration of nitrous oxide;
you have dived within the last 48 hours, to avoid developing decompression sickness;
you have undergone extracorporeal blood circulation (using a heart-lung machine) or suffer from severe skull disorders, have free air in the abdomen, or have recently had gas injected into the eye (e.g. SF6, C3F8), to prevent an increase in intraocular pressure that could lead to vision loss;
you have an intestinal blockage (ileus), to avoid further intestinal distension;
you have a 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 cranial 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 vitamin B12 deficiency for which treatment has not yet been established, suffer from a specific type of anemia known as Biermer's anemia (pernicious anemia), or suffer from a specific intestinal disease known as Crohn's disease;
you have a defect in methionine synthesis;
you show severe mental confusion or other signs of cognitive disturbances, which may be related to increased intracranial pressure that could be worsened by nitrous oxide;
you have already been administered nitrous oxide for longer than 24 hours.

Warnings and precautions
Consult your doctor or pharmacist before you are given Azoto protossido SIAD.
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 provided by barbiturates, increases cerebral blood flow, and raises pressure in any air-filled cavity or bubble 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 into the eye: 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;
if you are being treated with bleomycin;
if you are a vegetarian;
if you have a history of substance abuse.

Azoto protossido SIAD can be mixed with air, medical oxygen, and other types of inhaled anesthetics.
Azoto protossido SIAD should not be used during laser surgery of the airways due to the risk of explosive combustion.
Azoto protossido SIAD is a colorless gas with a faintly sweet odor, even at high concentrations, heavier than air, and may cause suffocation. Although non-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 various 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, particularly fatty substances.

Other medicines and AZOTO PROTOSSIDO SIAD
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 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, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
The use of Azoto protossido SIAD is contraindicated during the first and second trimesters of pregnancy.
Azoto protossido SIAD may be used during the third trimester of pregnancy only if the doctor considers it strictly necessary.
Azoto protossido SIAD 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 SIAD has been administered for a short period of time.

Driving and using machines
Nitrous oxide affects mental and physical abilities. Avoid driving, operating machinery, or performing other activities requiring special attention within 24 hours after anesthesia with Azoto protossido SIAD.
After short-term administration of Azoto protossido SIAD for pain relief, the doctor will monitor you to ensure all effects have worn off and that you are sufficiently alert to drive or operate machinery.

3. How AZOTO PROTOSSIDO SIAD will be administered to you

This medicine will always be administered exactly as instructed by your doctor. If you have any doubts,
please consult your doctor.
Your doctor will decide whether the medicine can be administered and at which 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 Azoto protossido SIAD to you in combination with oxygen through a cannula
inserted into your mouth or nose in the operating room, or via a close-fitting mask to the face or nose 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 SIAD than you should
It is highly unlikely that you will be given more Azoto protossido SIAD than required, as your doctor or nurse
will monitor you during treatment.
However, in case of excessive dosage or prolonged exposure to Azoto protossido SIAD, neurological
disorders due to the drug's toxicity towards Vitamin B__ will always occur.
In general, symptoms you may experience include:

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

Treatment
The doctor will immediately stop the administration, ensure airways remain open, and provide assisted
oxygenation.
The doctor must always have appropriate equipment for cardiopulmonary resuscitation readily available in
areas where Azoto protossido SIAD is used.
The doctor will monitor oxygen-related parameters until you have regained consciousness and are no
longer lacking oxygen (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 will experience 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 during the induction phase of anaesthesia

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

nausea, vomiting
dizziness
headache, migraine

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

swelling, increased intestinal gas volume
pronounced feeling of 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 red blood cell production (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 skull, disorder of the peripheral nervous system (peripheral neuropathy), brain disorder (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 within the eye (ocular hypertension), eye pain, blockage of the retinal artery (retinal artery occlusion), loss of vision (blindness)
changes 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 defects
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 the available data)

bone marrow disorders affecting also the nervous system (myeloneuropathies), disorder of the nervous system (neuropathy)
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 reporting system at 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 SIAD

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 no longer in use. This will help protect the environment.

6. Package contents and other information

What AZOTO PROTOSSIDO SIAD contains
The active substance is Nitrous oxide 100%.
Description of the appearance of AZOTO PROTOSSIDO SIAD and contents of the pack
AZOTO PROTOSSIDO SIAD is a colourless gas with a slightly sweet odour, supplied in cylinders and cylinder packs (blue conical shoulder marked with “N O” or “nitrous oxide” and white cylinder) with a shut-off valve, and in fixed cryogenic containers.

Marketing Authorisation Holder
SOCIETA’ ITALIANA ACETILENE & DERIVATI “SIAD” S.p.A
Via San Bernardino, 92 - 24126 Bergamo
Manufacturer
Cylinders and cylinder packs
Alfa Ossigeno S.r.l. - Via delle Industrie, 9 - Fisciano (Sa)
Eurogas S.r.l. - Via Pradazzo, 22 - 26012 Castelleone (CR)
Nippon Gases Pharma S.r.l. - Via Martino della Torre, 16 - 28100 Novara
Fixed cryogenic containers
Alfa Ossigeno S.r.l. - Via delle Industrie, 9 - Fisciano (Sa)
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 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 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 induction, 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 to consider include equipment malfunction (delivery of hypoxic mixture) or incorrect connection of medical gas lines to the anaesthetic machine. It is therefore advisable to attempt ventilation 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 administration instead of air.
Oxygen tension and oxygen saturation monitoring must continue for 15 minutes after nitrous oxide administration has ended.
Nitrous oxide administration may increase pressure in the endotracheal tube cuff, potentially causing tracheal damage, or in any other inflated balloon used in procedures (e.g., vascular occlusion balloons). Additionally, during use of 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 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.
Repeated administration or exposure to nitrous oxide may lead to dependence. Caution is advised in patients with a history of substance abuse or in healthcare workers with occupational exposure to nitrous oxide.
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/inactivation (cofactor of methionine synthase). 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. Prolonged nitrous oxide administration consequently disrupts folate metabolism and compromises DNA synthesis. Methionine synthase inhibition may lead to defective or reduced myelin formation, resulting in spinal cord damage. Prolonged or frequent use of nitrous oxide may cause megaloblastic changes in the bone marrow, myeloneuropathy, and subacute combined degeneration of the spinal cord.
The effects on DNA explain the potential negative impact on haematopoiesis. Nitrous oxide should not be used without strict clinical supervision and haematological monitoring. In such cases, consultation with a haematologist is recommended.
Haematological evaluation should include assessment of megaloblastic changes in red blood cells and hypersegmentation of neutrophils. Neurological toxicity may occur without anaemia or macrocytosis and with normal vitamin B₁₂ levels. Neurological toxicity has been reported after a single exposure to nitrous oxide in patients with undiagnosed subclinical vitamin B₁₂ deficiency during anaesthesia.
The effects on DNA explain the 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, red blood cell alterations, and possible neutrophil hypersegmentation.
Nitrous oxide administration should be performed 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 effusions.
Endoscopic procedures using carbon dioxide as the insufflating gas.
Neurosurgery, as nitrous oxide reduces the protective effect of barbiturates, increases cerebral blood flow, and raises 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.
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 (NMDA subtype).
Opioids, benzodiazepines, and barbiturates have additive effects, enhancing the analgesic and sedative actions of nitrous oxide.
All inhaled anaesthetics interact with GABA and glutamate receptors and have additive effects 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.
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 its inactivation of vitamin B₁₂. This effect reverses when 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 may be mixed with air, medical oxygen, and inhaled halogenated 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 oxidant: it promotes and accelerates burning).
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 fats (lubricating oils) and organic matter (tissues, wood, paper, plastics, etc.), which may ignite spontaneously 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 workers
Nitrous oxide is a colourless gas with a faintly sweet odour; it is not toxic and not flammable, but supports combustion. It is heavier than air and accumulates in lower areas of the workplace.
Nitrous oxide exhaled by the patient gradually enters the ambient air. The use of so-called "double" masks, adequate air exchange rates in operating rooms (20 air changes per hour), and active scavenging systems from anaesthetic equipment should ensure that average concentrations remain below the maximum allowable limit set by current regulations.
Additionally, practices must comply with regulations regarding the use of nitrous oxide-containing products. Healthcare workers should, in principle, 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. Although a causal relationship between chronic low-level exposure and specific pathologies cannot currently be established, 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.
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 human pregnancy are insufficient to define the risk of adverse effects on embryofetal 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 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-containing products in breast milk. However, after short-term administration of nitrous oxide-containing 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 high attention should be avoided for 24 hours after nitrous oxide anaesthesia.
After short-term administration of nitrous oxide for analgesia, ambulatory patients who intend to drive or operate machinery should be monitored until all effects have resolved 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 that prevents 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 percentage of nitrous oxide 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 additional inhaled anaesthetics for anaesthesia maintenance is generally available in the product leaflets of the latter. When combined with intravenous anaesthetics, the intravenous anaesthetic 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, provides sedation, and reduces agitation, and normally does not affect the level of awareness or the ability to converse. At these concentrations, circulation and reflexes remain unchanged.
The analgesic 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 and at what dose the medicinal product may 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 its use. The gas must be 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 administration device may be connected to an extraction system or a double mask may be used.
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 mixture of nitrous oxide and oxygen. Such 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 make it impossible to administer mixtures with nitrous oxide concentrations exceeding 50% v/v.
Throughout 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 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 INSTRUCTION MANUAL OF THE CONTAINER

Storage

Read the container instruction and user manual carefully.
Check that all materials are in good condition.
Store outdoors or in well-ventilated areas, in fenced 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, and avoid any contact with fats or oils (do not lubricate valves or connectors).
Ensure containers are undamaged and avoid impacts and product leakage.
Close valves and block gas 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 impacts or falls.
Do not use packages that are not intact.
Store empty and full containers separately.
Store containers containing other types of gases separately.
Avoid excessive storage of full containers.
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 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 and falling risks 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 of damage, or exposed to extreme temperatures.
Before opening the cylinder valve, place the cylinder in an upright position 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 be performed at appropriate pressure, with controlled flow rate between container and patient.
Do not use oil or grease in contact with the gas.
Handle materials with clean hands, free from 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 user manual.
Use only containers suitable for the product and intended operating temperatures.
Use connectors, connecting tubes, or flexible hoses specifically designed and compatible with nitrous oxide.
It is absolutely forbidden to modify connectors, delivery equipment, or their accessories or components (OIL AND GREASE MAY SPONTANEOUSLY IGNITE UPON 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 package 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. Do not release pressurized gas.
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 such medicinal product must be disposed of in accordance with applicable local regulations.

Overdose
Adverse effects due to overdose may occur in patients exposed to large 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 with supplemental oxygen to achieve adequate oxygen saturation. Appropriate cardiopulmonary resuscitation equipment should always be 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 disturbances 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, weather, direct sunlight, heat sources, ignition sources, and combustible materials. Empty containers or containers containing other types of gases 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, and managed and maintained according to each manufacturer's instructions. These are pressure equipment subject to the CE PED Directive and/or the Italian Ministerial Decree of 21/11/1972.
Unused medicinal product and waste derived from such medicinal product must be disposed of in accordance with applicable local regulations (see also Instructions for use and handling – Disposal).

Nitrous oxide SIAD

Patient Information Leaflet