NITROUS OXIDE SICO

Package leaflet: Information for the patient

NITROUS OXIDE SICO medicinal gas, liquefied

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:

1. What AZOTO PROTOSSIDO SICO is and what it is used for
2. What you need to know before you are given AZOTO PROTOSSIDO SICO
3. How AZOTO PROTOSSIDO SICO will be given to you
4. Possible side effects
5. How to store AZOTO PROTOSSIDO SICO
6. Contents of the pack and other information

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

Nitrous oxide SICO contains nitrous oxide, a medicinal gas belonging to the group of general anesthetics.
Nitrous oxide SICO 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 pain relief and 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 SICO

You must not be given AZOTO PROTOSSIDO SICO if:

• you are allergic to nitrous oxide;
• you suffer from dilation and/or obstruction in the intestinal tract;
• you are undergoing surgery involving a risk of gas bubble formation in the bloodstream (gas embolism);
• you are undergoing middle ear surgery, to avoid serious damage to all structures of this part of the ear;
• you suffer from severe chronic lung diseases such as presence of air or other gas in lung tissue (emphysema), collapse of a lung (pneumothorax), etc.;
• you suffer from ear diseases (otitis) and 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”) and in cases of fetal distress;
• 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 avoid closure 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 developing decompression sickness;
• you have undergone extracorporeal circulation (extracorporeal circulation) using a heart-lung machine, or if you 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 vision loss;
• you have intestinal obstruction (ileus) to avoid 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);
• 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 therapy has not yet been established, or if you suffer from a specific type of anemia known as Biermer's anemia;
• you suffer from a specific intestinal disease known as Crohn's disease;
• you have a defect in methionine synthesis;
• you experience 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 a period of 24 hours.

Warnings and precautions
Consult your doctor or pharmacist before you are given Azoto protossido SICO.
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 bubbles, and risk of eliminating hypoxic vasoconstriction;
• presence of uneliminated fluid accumulation 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 increases pressure in any air bubble or cavity 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 period of time must elapse, as there is a risk of visual disturbances;
• prolonged anesthesia (lasting more than 6 hours);
• high risk of nausea and vomiting;
• in patients treated with bleomycin;
• vegetarian patients;
• if you are in the third trimester of pregnancy (see section “Pregnancy and breastfeeding”);
• if you have or have had a history of substance abuse, because repeated administration may lead to dependence (see section “Possible side effects”).

Azoto protossido SICO may be mixed with air, medical oxygen, and other types of inhalational anesthetics.
Azoto protossido SICO should not be used during laser surgery of the airways due to the risk of explosive combustion.
Azoto protossido SICO is a colorless gas with a faintly sweet odor, barely noticeable 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 followed.

Safety precautions
During gas use

• It is strictly forbidden to tamper with container connections, delivery equipment, or any 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, particularly fatty substances.

Other medicines and AZOTO PROTOSSIDO SICO
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicine.
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. suxamethonium) 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 SICO is contraindicated during the first and second trimesters of pregnancy.
Azoto protossido SICO may be used during the third trimester of pregnancy only if the doctor considers it strictly necessary. Prolonged or frequent use should be avoided.
Azoto protossido SICO 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
There are no data on the excretion of nitrous oxide-based products in breast milk; however, interruption of breastfeeding is not necessary if Azoto protossido SICO has been administered for a short period of time.

Driving and using machines
Nitrous oxide affects your mental and physical abilities. Avoid driving, operating machinery, or performing other activities requiring special attention within 24 hours after anesthesia with Azoto protossido SICO.
After short-term administration of Azoto protossido SICO for pain relief, your 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 SICO will be administered to you

This medicine will always be administered to you exactly as prescribed by your doctor. If you have any doubts,
please consult your doctor.
Your doctor will decide whether this 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 to induce general anaesthesia.
Your doctor will administer Azoto protossido SICO to you in combination with oxygen through a tube 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 ventilator (assisted or mechanical ventilation).
Medical staff will monitor you throughout the administration and until you regain consciousness.

If you are given more AZOTO PROTOSSIDO SICO than you should have received
It is highly unlikely that you will receive more Azoto protossido SICO than intended, as your doctor or nurse will
monitor you during treatment.
However, in case of excessive dosage or prolonged exposure to Azoto protossido SICO, neurological disorders
due to the drug’s toxicity towards Vit. B__ may 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 circulatory and respiratory disturbances (syncope),
• alteration of the normal heart rhythm (arrhythmia),
• loss of consciousness,
• death due to suffocation (asphyxia).

Treatment in case of overdose
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 SICO is used.
The doctor will continue to 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 oxygenation of the blood (cyanosis), occurring unexpectedly during anaesthesia or during 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, even severe

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

• swelling, increased accumulation of gas in the intestine
• intense feeling of well-being (euphoria)
• 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 carrying oxygen in the blood) associated with reduced red blood cell formation (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):

• nerve diseases (polyneuropathies)

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 disorder (encephalopathy)
• disturbances in sensation, altered reflexes, reduced level of consciousness, visual or perceptual experiences of 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 abnormalities
• infertility
• lack of oxygen in the body (hypoxia) for several minutes after nitrous oxide administration has ended, 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 available data)

• damage to the trachea or to any other inflated balloon used in other procedures (e.g. balloons for vessel occlusion), due to increased pressure in the endotracheal tube cuff
• dependence
• Neuropathy
• Myeloneuropathy
• Subacute degeneration of the spinal cord
• Generalised 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: www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store NITROUS OXIDE SICO

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 SICO contains
The active substance is Nitrous oxide 100%.
Description of the appearance of AZOTO PROTOSSIDO SICO and contents of the package
AZOTO PROTOSSIDO SICO is a colorless gas with a faintly sweet odor, supplied in cylinders and cylinder packs.
Cylinder (blue conical end marked with “N O” or “nitrous oxide”, and white cylinder) with a shut-off valve.

Marketing Authorization Holder
SICO SOCIETA’ ITALIANA CARBURO OSSIGENO SpA
Via Giuseppe Parini, 9 – 20121 – MILANO

Manufacturer
Eurogas S.r.l. – Via Pradazzo, 22, 26012 – Castelleone (CR)
SICO SpA – Via Boscalto, 47 – Resana (TV)

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 greater than 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 must be determined 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 anesthesia or during induction, it is recommended to discontinue nitrous oxide and increase the inhaled oxygen fraction to 100%. If cyanosis does not resolve rapidly, or if the episode recurs during anesthesia, possible causes include equipment malfunction (delivery of a hypoxic mixture) or incorrect connection of gas supply lines to the ventilator. It is therefore advisable to attempt ventilation using a bag filled with ambient air.

After general anesthesia involving high concentrations of nitrous oxide, the gas may diffuse from the blood into the alveoli, diluting pulmonary oxygen. This may cause hypoxia (diffusion hypoxia), caused not only by alveolar gas mixture but also by reflex responses to hypoxia, hypercapnia, and hypoventilation. To prevent this, 100% oxygen should be administered at the end of nitrous oxide administration instead of air.

Monitoring of oxygen tension and oxygen saturation should continue for 15 minutes after discontinuation 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., vascular occlusion balloons). Additionally, when using nitrous oxide with a Swan-Ganz catheter, the generated pressure may displace the catheter into an occluded 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 causes inactivation of vitamin B₁₂, a cofactor of methionine synthase. Prolonged administration consequently alters folate metabolism and impairs DNA synthesis.

Prolonged or frequent use of nitrous oxide may result in megaloblastic bone marrow changes, myeloneuropathy, and subacute combined degeneration of the spinal cord. Nitrous oxide should not be used without close clinical supervision and hematological monitoring. In such cases, consultation with a hematologist is recommended.

Hematological evaluation should include assessment of megaloblastic changes in red blood cells and hypersegmentation of neutrophils. Neurological toxicity may manifest without anemia 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 undergoing anesthesia.

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, assessing for megaloblastic changes, red blood cell alterations, and possible neutrophil hypersegmentation.

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 of barbiturates, increases cerebral blood flow, and raises pressure in any intracranial air pockets or bubbles.
• Sickle cell anemia.
• After intraocular injection: a sufficient time interval must elapse due to the risk of visual disturbances.
• Prolonged anesthesia (>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.
• In patients in the third trimester of pregnancy (see section “Pregnancy and lactation”); or with a history of substance abuse, because repeated administration may lead to dependence (see section “Possible undesirable effects”).

Interactions
No pharmacokinetic interaction studies with other drugs are known. Interactions of nitrous oxide with other medications 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 additive effects, enhancing the analgesic and sedative actions of nitrous oxide.

All inhaled anesthetics 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 anesthetics and is used to reduce the required dose of other anesthetics and to shorten induction time when inhaled anesthetics are used.

Hemoglobin 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 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 halogenated inhaled anesthetics.

Nitrous oxide is a colorless gas with a faintly sweet odor, barely perceptible even at high concentrations. It is heavier than air and asphyxiant. Although non-flammable, it supports combustion (it is an oxidizer: it enables and accelerates burning).

The compatibility of various materials depends on the pressure at which the gas is used. The greatest combustion risks involve greases (lubricating oils) and organic materials (tissues, 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 anesthetic gases or vapors, even in the absence of oxygen.

For healthcare personnel
Nitrous oxide is a colorless gas with a faintly sweet odor; 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 disperses into the surrounding air. Use of so-called “double” masks, adequate air exchange in operating rooms (20 air changes per hour), and active scavenging systems on anesthetic equipment should ensure that average concentrations remain below the maximum allowable exposure levels set by current regulations.

In addition, compliance with regulations regarding nitrous oxide-containing 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 diseases cannot currently be established, a possible link to tumor development or other chronic diseases, reduced fertility, spontaneous abortion, and fetal malformations cannot be excluded.

Prior to and during nitrous oxide administration, 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 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.

However, anesthetic 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 only with great caution and strictly when necessary. Prolonged or frequent use should be avoided.

Nitrous oxide may be used during labor.

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-containing products in human milk. However, after short-term administration of nitrous oxide-containing products, interruption of breastfeeding is not required.

Effects on ability to drive and use machines
Nitrous oxide impairs the ability to drive vehicles or operate machinery due to its effects on 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 anesthesia.

After short-term administration of nitrous oxide for analgesia, outpatient patients who need to drive or operate machinery should remain under observation until all effects have subsided and the patient is sufficiently alert.

Dosage, method and duration of administration
As an anesthetic
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 adequate 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 anesthetic plan.

Nitrous oxide at the maximum allowed concentration cannot induce anesthesia alone and must therefore be used in combination with other anesthetics administered intravenously or by inhalation.

Information on dosing of nitrous oxide and additional inhaled anesthetics for anesthesia maintenance is generally available in the package leaflets of those agents. When combined with intravenous anesthetics, the intravenous anesthetic 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/anesthetic/sedative (always combined with oxygen) at concentrations below 50% v/v relieves pain, provides sedation, and reduces agitation, typically without affecting awareness or the ability to converse. At these concentrations, respiration and reflexes remain unchanged.

The degree of pain relief and sedative effect is dose-dependent, as are 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 setting allowing 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, which must be administered with appropriate equipment in well-ventilated rooms ensuring immediate air exchange, with ventilation systems preventing excessive environmental gas concentrations, and preferably using so-called “double masks” (active nasal masks), especially recommended for dental procedures.

In ambulances, the delivery device may be connected to an evacuation 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, particularly for pregnant personnel.

Nitrous oxide is normally administered via orotracheal or nasotracheal tube in the operating room and via a tight-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. 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 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 regained.

Instructions for use and handling
Cylinders and fixed cryogenic containers are exclusively intended 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 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 cylinders clean and dry, avoiding contact with greases or oils (do not lubricate valves or connectors).
Ensure containers are undamaged and avoid impacts or gas leakage.
Close valves and block gas flow when not in use.
Keep cylinders and cylinder packs upright, with valves closed, protective caps and coverings in place, and securely fastened to prevent accidental impacts 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 to escape.
Vapors 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 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, and smoking is prohibited.

During gas use
Cylinders must not be used if visibly damaged or if damage or exposure to extreme temperatures is suspected.
Before opening the cylinder valve, the cylinder must be placed upright and maintained in 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 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 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 connectors, delivery equipment, or accessories (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.
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 a device 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 discharge 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 refilling.
Unused medicinal product and waste derived from this medicinal product must be disposed of in accordance with current local regulations.

Overdose
Undesirable effects due to overdose may occur in patients exposed to large 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 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. It is therefore recommended to always have 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 disturbances due to drug toxicity toward 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 types of gases must be stored separately.

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).