Package leaflet: Information for the patient

NITROUS OXIDE SOL medicinal liquefied gas

Nitrous oxide
Please read this leaflet carefully before using 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 get any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

What AZOTO PROTOSSIDO SOL is and what it is used for
What you need to know before using AZOTO PROTOSSIDO SOL
How to use AZOTO PROTOSSIDO SOL
Possible side effects
How to store AZOTO PROTOSSIDO SOL
Contents of the pack and other information

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

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

to induce anaesthesia (loss of sensation, consciousness and pain, associated with muscle relaxation) during surgical procedures, in combination with other anaesthetics administered by inhalation (inhalational route) or by intravenous injection (intravenous route)
to provide rapid-onset pain relief (analgesia) and to induce a state of relaxation (sedation) with rapid offset of effect, for example during short surgical procedures, treatments involving physical injuries (traumatology), severe burns (burns), dental and oral procedures (dentistry), ear, nose and throat procedures (otorhinolaryngology), and during childbirth.

2. What you need to know before you are given NITROUS OXIDE SOL

You must not be given NITROUS OXIDE SOL if:

you are allergic to nitrous oxide;
you suffer from dilation and/or obstruction and/or perforation of the intestine;
you are due to undergo surgery that carries a risk of gas bubbles forming in the blood (gas embolism);
you are due to undergo surgery on the middle ear;
you have recently received an injection of gas into the eye;
you suffer from severe chronic lung diseases (emphysema, pneumothorax);
you are in the first or second trimester of pregnancy (see section “Pregnancy and breastfeeding”);
pure oxygen needs to be administered to you or you have difficulty breathing;
you have dived within the last 48 hours;
you have undergone surgery requiring the use of a heart-lung machine, a device used to maintain blood circulation;
you have inflammation of the ear (otitis), ear obstruction, or sinusitis (infection of the nose and paranasal sinuses);
there is suspicion or confirmation that you have increased intracranial pressure; this may be associated with reduced consciousness and cooperation, which may worsen with the use of nitrous oxide;
you have suffered head trauma (closed head injury) or have serious head diseases;
you are at risk of developing vitamin B12 and/or folate deficiency and anemia (reduction in hemoglobin, the protein that carries oxygen in the blood);
you have vitamin B12 deficiency for which therapy has not yet been established;
you have Biermer's anemia, a type of anemia;
you have Crohn’s disease (a bowel disease);
you have diseases that may affect myelin sheaths (nerve coverings);
you have impaired methionine synthesis (a deficiency in an amino acid);
you have already been administered nitrous oxide for longer than 24 hours.

Warnings and precautions
Talk to your doctor or pharmacist before you are given Nitrous Oxide SOL.
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 non-resorbed 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 raises pressure within any air-filled cavity or bubble inside the skull;
after an intraocular injection into the eye: a sufficient period of time must elapse, as there is a risk of visual disturbances;
prolonged anesthesia (longer than 6 hours);
high risk of nausea and vomiting;
if you have sickle cell anemia (a blood disorder causing abnormal shape of red blood cells);
if you are being treated with bleomycin (a medicine used in cancer treatment);
if you are a vegetarian.

Children and adolescents
Do not administer this medicine to neonates (preterm or term infants).
Safety precautions
During use of the gas:

It is absolutely forbidden to tamper in any way with container connections, delivery equipment, or their accessories or components (oils and greases may spontaneously ignite upon contact with nitrous oxide).
Do not use oil or grease in contact with the gas.
It is absolutely forbidden to handle equipment or components with hands, clothing, or face contaminated with grease, oil, creams, or 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, especially fatty substances.

Other medicines and NITROUS OXIDE SOL
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:

opioids (medicines used for pain);
benzodiazepines (medicines used to treat anxiety and insomnia);
psychotropic medicines (medicines used to treat psychiatric disorders);
anesthetics (medicines used to induce anesthesia or reduce pain);
warfarin, a medicine that slows blood clotting;
methotrexate, a medicine used in immune diseases or cancer;
succinylcholine and other muscle relaxants (medicines that relax muscles);
sodium nitroprusside, a medicine used to significantly lower blood pressure.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
Limited data on short-term use of Nitrous Oxide SOL do not indicate an increased risk of congenital malformations. In rare cases, Nitrous Oxide SOL may cause respiratory problems in the newborn.
Nitrous Oxide SOL may be used during pregnancy only if strictly necessary. Frequent or long-term use should be avoided.
The use of Nitrous Oxide SOL is contraindicated during the first and second trimesters of pregnancy (see section “Do not use NITROUS OXIDE SOL”).
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 known whether Nitrous Oxide SOL is excreted in breast milk. It is not necessary to interrupt breastfeeding after short-term administration.
Fertility
There are no data available in humans regarding the effects of nitrous oxide on fertility. Animal studies suggest potential impairment of male and female fertility following exposure to low concentrations (≤1%).
Driving and using machines

Do not drive or operate tools or machinery for 24 hours after receiving Nitrous Oxide SOL in combination with anesthetics, as Nitrous Oxide SOL significantly affects your ability to drive and operate machinery.
Exercise particular caution following short-term administration of Nitrous Oxide SOL for pain relief. Do not drive or operate machinery until any adverse effects have disappeared and your previous level of alertness has returned.

3. How AZOTO PROTOSSIDO SOL will be administered to you

This medicine will always be administered to you exactly as instructed by your doctor. If you have any doubts,
consult your doctor.
Your doctor will decide whether the medicine can be administered and at what dose, primarily based on clinical
parameters indicating your health status and taking into account the simultaneous administration of other
anaesthetic medicines to induce general anaesthesia.
Your doctor will administer Azoto protossido SOL 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 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 SOL than you should receive
It is highly unlikely that you will be given more Azoto protossido SOL than intended, as your doctor or nurse will
monitor you during treatment.
In case of excessive dosage or prolonged exposure to Azoto protossido SOL, the following may occur:

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

Treatment
The doctor will stop the administration, maintain the airways open, and provide assisted oxygenation. The doctor must always have available the necessary equipment for cardiopulmonary resuscitation in any location where Azoto protossido SOL 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 gets them.
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):

swelling, increased intestinal gas
exaggerated 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)
a type of anaemia due to vitamin B12 deficiency caused by nitrous oxide (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)
malfunction of peripheral nerves (peripheral neuropathies)
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), incomplete loss of movement in the upper or lower limbs (paraparesis), condition characterised by uncontrolled body movements and loss of consciousness (epilepsy), increased pressure inside the head, disease of the peripheral nervous system (peripheral neuropathy), brain disease (encephalopathy).
sensory disturbances, altered reflexes, decreased level of consciousness, seeing or perceiving things that do not exist (hallucinations), mental illness (psychotic disorder), confusion, anxiety.
increased pressure inside the eye (ocular hypertension), eye pain, blockage of the retinal artery (retinal artery occlusion), loss of vision (blindness).
disturbances in the normal heart rhythm (arrhythmias), inability of the heart to supply adequate blood flow according to the body's actual needs (heart failure).
liver cell death (hepatic necrosis).
severe headache following brain surgery (cerebral hyperperfusion syndrome), increased pressure in inflated balloons.
vitamin B12 deficiency, increased concentration of homocysteine in the blood (hyperhomocysteinaemia).
muscle weakness, sudden and dangerously high increase in body temperature (malignant hyperthermia).
birth defects (congenital anomalies) in medical and paramedical staff following repeated exposure.
infertility in medical and paramedical staff following repeated exposure.
lack of oxygen in the body (hypoxia) for several minutes after the end of nitrous oxide administration.
accumulation of air in the pleural cavity, a space between the lungs and the pleura, a membrane surrounding the lungs (pneumothorax).
decrease in blood pressure (hypotension) with or without reduction of all physical and mental functions (shock).

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

injury 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.
Sedation.
Dizziness.
Tingling.
generalized epileptic seizures.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, please inform 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 SOLUTION

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

6. Package Contents and Other Information

What AZOTO PROTOSSIDO SOL Contains
The active substance is Nitrous oxide 100%.
Description of the Appearance of AZOTO PROTOSSIDO SOL and Package Contents
AZOTO PROTOSSIDO SOL is a colorless gas with a slightly sweet odor, packaged in cylinders and cylinder packs (blue shoulder marked with “N O” or “nitrous oxide” and white cylinder) with a closure valve, and in fixed cryogenic containers.

Marketing Authorization Holder
SOL S.p.A – Via Borgazzi, 27 – 20900 Monza (MB)

Manufacturer
Cylinders and cylinder packs
SOL SpA – Zona Interconsortile ASI – Marcianise (CE)
SOL SpA – Via XVI^ Strada s.n. z.i. – Catania
SOL SpA – Via Acquaviva, 4, Via Oldoini, 3 – Cremona

Fixed cryogenic containers
SOL SpA – Zona Interconsortile ASI – Marcianise (CE)
SOL SpA – Via Acquaviva, 4, Via Oldoini, 3 – Cremona
N.T.G. Nederlandse Technische Gasmaatschappij B.V.,
Swaardvenstraat 11, 5048 Tilburg, Netherlands

The following information is intended exclusively for physicians or healthcare professionals:

Precautions for Use
Nitrous oxide must be administered only by trained professional personnel.
The fraction of inspired oxygen (FiO₂) in the inhaled mixture must be at least 21% v/v during the induction phase. In practice, a lower limit of 30% v/v is often used. The oxygen tension must remain above physiological values (100 mmHg), with hemoglobin oxygen saturation exceeding 97%, and in any case always above 60 mmHg, with hemoglobin oxygen saturation exceeding 90%. Regular monitoring is required, either by measuring arterial oxygen tension (PaO₂) or by pulse oximetry (arterial oxygen saturation SpO₂), along with clinical parameter assessment. The minimum effective oxygen concentration in the inhaled air should be determined for each individual patient.

Nitrous oxide concentrations exceeding 50% v/v may impair protective reflexes and levels of consciousness. Concentrations above 60–70% v/v often cause unconsciousness and increase the risk of impaired protective reflexes.

If unexpected cyanosis occurs during anesthesia 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 resolve rapidly, or if the episode recurs during anesthesia, possible causes include equipment malfunction (delivery of a hypoxic mixture) or incorrect connection of medical gas 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 alveolar oxygen. This may result in 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 for other procedures (e.g., vascular occlusion balloons). Additionally, when using nitrous oxide with a Swan-Ganz catheter, the generated pressure may displace the catheter into an occlusive position, altering pressure readings.

Medical devices containing air may malfunction (e.g., rupture) when exposed to nitrous oxide.

Nitrous oxide should not be used during laser airway surgery due to the risk of explosive combustion.

Nitrous oxide should not be used for prolonged periods (e.g., sedation in intensive care patients) due to the potential risk of vitamin B₁₂ dysfunction (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, a key DNA component. Inhibition of methionine synthase may lead to defective or reduced myelin formation, resulting in spinal cord damage. DNA effects explain the potential negative impact on hematopoiesis and fetal abnormalities 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 to assess for possible megaloblastic changes, red blood cell alterations, or hypersegmentation of neutrophils.

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 insufflation gas.
Neurosurgery, because nitrous oxide reduces the protective effect of barbiturates, increases cerebral blood flow, and raises pressure in any intracranial air pocket or bubble.
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.
Patients treated with bleomycin, as increased oxygen concentration during inhalation sedation increases the risk of pulmonary toxicity.
Vegetarian patients.

Interactions
No pharmacokinetic interaction studies are known. Interactions between nitrous oxide and other drugs are 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 become fully saturated 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 its inactivation of vitamin B₁₂. This effect reverses upon discontinuation of nitrous oxide and initiation of concomitant vitamin B₁₂ therapy. Inactivation of vitamin B₁₂ by nitrous oxide potentiates the toxicity of sodium nitroprusside and methotrexate.

Nitrous oxide increases succinylcholine-induced neuromuscular blockade and potentiates the effects 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 detectable even at high concentrations, heavier than air, and asphyxiant. Although non-flammable, it supports combustion (it is an oxidizer: it enables 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 (fabrics, wood, paper, plastics, etc.), which may ignite spontaneously upon contact with nitrous oxide at sufficient pressure, triggered by 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 patients gradually disperses into the ambient air. The use of so-called “double” masks, adequate air exchange in operating rooms (20 times per hour), and active scavenging of excess gas from anesthetic equipment should ensure that average concentrations remain below the maximum allowable limit established by current regulations.

In addition, personnel must comply with regulations regarding the use of nitrous oxide-containing products. In principle, healthcare workers should avoid prolonged direct inhalation of exhaled air from patients.

Chronic exposure to low concentrations of nitrous oxide has been identified as a potential health risk. At present, it is not possible to establish a causal relationship between chronic low-level exposure to nitrous oxide and specific diseases, but a potential link between chronic exposure and tumor development or other chronic diseases, reduced fertility, spontaneous abortion, and fetal malformations cannot be excluded. 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.

Prior to and during nitrous oxide administration, safety precautions outlined in section 6.6 of the Summary of Product Characteristics must be followed.

Pregnancy and Lactation
Pregnancy
Extensive data from pregnant women (outcomes from over 1,000 first-trimester exposures) do not indicate teratogenicity or fetal/neonatal toxicity following a single administration of nitrous oxide. Animal studies have shown reproductive toxicity.

Nitrous oxide Medicinal SOL may be used during pregnancy when clinically necessary. If nitrous oxide is used shortly before labor, the neonate should be monitored for potential adverse effects.

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 with great caution and only when strictly necessary. Prolonged or frequent use should be avoided. Nitrous oxide should be avoided in cases of fetal distress.

Lactation
It is not known whether nitrous oxide is excreted in breast milk. However, short-term administration of medicinal nitrous oxide does not require interruption of breastfeeding.

Effects on Ability to Drive and Use Machines
Nitrous oxide impairs cognitive and psychomotor function. It is rapidly eliminated after administration. Nevertheless, as an additional safety measure, driving, operating machinery, and other activities requiring high 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 be monitored until all effects have resolved 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 that prevents delivery 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.

Dosage information for nitrous oxide and additional inhaled anesthetics for anesthesia maintenance is generally available in the respective product leaflets. When combined with intravenous anesthetics, the intravenous anesthetic dose must 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, reduces agitation, and normally does not affect awareness or the ability to maintain conversation. Circulation and reflexes remain unchanged at these concentrations.

The pain-reducing 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 drug may be administered, in a 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 preferably using so-called “double masks” (active nasal masks), especially recommended for dental procedures.

In ambulances, the delivery device may be connected to an exhaust system or a double mask may be used.

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 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. 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 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 in open areas or well-ventilated rooms, 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 material deposits and combustible materials in general (contact with combustible material may cause fire).
Do not smoke or use open flames near the product.
Keep the container (cylinder) clean and dry; avoid any contact with fats or oils (do not lubricate valves or connectors).
Ensure containers are undamaged; avoid impacts and product leakage.
Close valves to block gas release when not in use.
Store cylinders and cylinder packs upright, with valves closed, protective caps and heat-shrink sleeves in place, securely fastened to prevent accidental impact or falls.
Do not use damaged packages.
Empty and full containers must be stored separately.
Containers containing other types of gases must be stored separately.
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.
Vapors 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, and smoking is prohibited.

During Gas Use

Cylinders and fixed containers must not be used if visible damage is present or if damage is suspected, or if they have been exposed to extreme temperatures.
Before opening the cylinder valve, place the cylinder upright and maintain this position during administration.
Open and close container closure systems gradually and carefully (do not use pliers or other tools to open or close the cylinder valve) to prevent damage.
Do not force valves during opening or closing. Do not alter the container shape.
Never stand directly in front of the gas outlet; always stand to the side. Do not expose yourself or the patient to direct gas flow.
Nitrous oxide administration must occur at appropriate pressure, with controlled flow rate between container and patient.
Do not use oil or grease in contact with the gas.
Handle equipment with clean hands, free from grease or oil traces.
Do not completely empty the container.
Close the cylinder valve after use.
In case of gas leakage, close the valve and contact 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, connection tubes, or flexible hoses.
It is absolutely prohibited to modify container 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 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 bring open flames near the container.
Do not use any electrical equipment that may produce sparks 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 only partially empty, 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 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 appropriate cardiopulmonary resuscitation equipment available in areas where nitrous oxide is used.
Pulse oximetry monitoring is recommended until the patient regains consciousness and is no longer hypoxic.
Overexposure or prolonged exposure to nitrous oxide always results in neurological disorders due to the drug’s toxicity 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, upright 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.
Fixed containers installed at 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 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).

Nitrous oxide Sol

Package leaflet: Information for the patient