ALFAPROT 3.75 KG Ингаляционный газ

OSSIGENO FARMA GAS MEDICAL AND TECHNICAL GASES
liquefied medical gas
Pharmacotherapeutic category
Medical gases, general anesthetics

Therapeutic indications
In anesthesia, in combination with other anesthetics administered by inhalation or intravenously.
In analgesia/sedation in all conditions where pain relief/sedation with rapid onset and rapid offset is required (short-duration surgical procedures, traumatology,
burns, dentistry, otorhinolaryngology, childbirth).

Contraindications

• Hypersensitivity to the active ingredient.
• Intestinal dilatation and/or obstruction.
• Any surgical intervention where there is a risk of gas embolism.
• Middle ear surgery, due to the risk of serious damage to all structures of this sector of the ear.
• Severe extensive chronic lung diseases (emphysema, pneumothorax, etc.).
• Otitis and sinusitis.
• First and second trimester of pregnancy (see section 6.6).
• Patients in whom the administration of pure oxygen or with respiratory difficulties is indicated.
• Disorders associated with air-containing cavities (pneumothorax, bullous emphysema, gas embolism, etc.) due to the risk of embolism that may expand following the administration of nitrous oxide.
• After immersion in the last 48 hours, due to the risk of decompression sickness, and after extracorporeal circulation with a heart-lung machine or severe cranial pathologies, free air in the abdomen, recent intraocular gas injection (e.g. SF6, C3F8), due to the risk of increased intraocular pressure that can cause blindness, intestinal obstruction (ileus) due to the risk of further intestinal dilation, obstruction of the middle ear due to reduced patency of the Eustachian tube due to an inflammatory pathology.
• Suspected or known increase in intracranial pressure.
• Closed head trauma.
• Potential risk of vitamin B12 and/or folate deficiency and megaloblastic anemia.
• Patients with untreated vitamin B12 deficiency, with Biermer's anemia, Crohn's disease. Megaloblastic anemia may develop due to the interference of nitrous oxide with vitamin B12; regression of the effect can be induced by administering folic acid. Neurological pathologies may also occur that can compromise the methylation of basic proteins in the myelin sheaths.
• Known deficiency of an enzyme or substrate belonging to the methionine synthesis metabolic pathway.
• Severe confusion or other signs of cognitive dysfunction, potentially related to increased intracranial pressure, which may be aggravated by nitrous oxide.
• Administration for a period longer than 24 hours.

Precautions for use
The oxygen fraction (FiO2) in the inhaled mixture must be at least 21% v/v during the induction phase.
In practice, a concentration of 30% v/v is often used as a lower limit. The oxygen tension must remain above physiological values (100 mmHg), with hemoglobin oxygen saturation greater than 97% and always greater than 60 mmHg, with hemoglobin oxygen saturation greater than 90%. Regular monitoring is necessary, by measuring arterial oxygen tension (PaO2) or by pulse oximetry (arterial oxygen saturation SpO2) and an assessment of clinical parameters. The minimum effective oxygen concentration in the inhaled air for the individual patient must be established.
Nitrous oxide concentrations greater than 50% v/v can alter protective reflexes and levels of consciousness. Concentrations above 60-67% v/v often cause unconsciousness and an increased risk of loss of protective reflexes.
If unexpected cyanosis appears during anesthesia or in the induction phase of anesthesia, it is advisable to stop the flow of nitrous oxide and increase the inhaled oxygen fraction to 100%.
If cyanosis does not disappear quickly, or if the episode recurs during anesthesia, remember, among the possible causes, a malfunction of the equipment (delivery of a hypoxic mixture) or an exchange between the tubes that supply the medical gases to the ventilation machine. It is therefore suggested to try to ventilate the patient using a balloon filled with room air.
After general anesthesia in which a high concentration of nitrous oxide has been used, it may diffuse from the blood into the alveoli, diluting the oxygen in the lung. This can produce hypoxia (diffusion hypoxia), caused not only by the gaseous mixture in the alveoli but also by the reflex response to hypoxia, hypercapnia and hypoventilation. To prevent this from happening, at the end of the administration of nitrous oxide, 100% O2 should be administered instead of air. Monitoring of oxygen tension and oxygen saturation must be continued for 15 minutes after the end of nitrous oxide administration.
The administration of nitrous oxide can increase the pressure in the cuff of the endotracheal tube, generating damage to the trachea or in any other balloon used for other procedures (balloons for occlusion of vessels). Furthermore, during the use of nitrous oxide with the Swan Ganz catheter, the pressure generated can move the catheter into an occlusion position, thus altering the pressure reading.
Medical devices filled with air may present problems (e.g. they may break) when exposed to nitrous oxide.
Nitrous oxide should not be used during laser surgery of the airways due to the risk of explosive combustion.
Nitrous oxide should not be used for long periods (e.g. for sedation in patients in intensive care), due to the risk of potential alteration of vitamin B12 functions (cofactor of methionine synthetase). Nitrous oxide alters the metabolism of vitamin B12 and folates, especially in elderly patients. Inhibition of methionine synthetase contributes to the conversion of homocysteine to methionine. Inhibition of this enzyme reduces the formation of thymidine, an important component of DNA. Inhibition of methionine synthetase can lead to defects or reduced formation of myelin, and therefore damage to the spinal cord. The effects on DNA explain the possible negative influence on hematopoiesis and fetal damage observed in animal experiments.
Nitrous oxide can cause an increase in pressure in the middle ear.
The administration of nitrous oxide more than once every 4 days should be accompanied by a blood cell count with an assessment of any megaloblastic alterations or changes in red blood cells and possible neutrophil hypersegmentation.
The administration of nitrous oxide must be carried out with caution in the following situations:

• Thoracic surgery, due to the danger of pneumothorax, expansion of emphysematous bullae and the risk of elimination of hypoxic vasoconstriction.
• Presence of undrained effusions of the airways.
• Endoscopic procedures using carbon dioxide as the gas.
• Neurosurgery, because nitrous oxide reduces the protective effect guaranteed by barbiturates, increases cerebral blood flow and pressure in any air bubble present within the skull.
• Sickle cell anemia.
• After an intraocular injection: a sufficient amount of time must pass because there is a risk of visual disturbances.
• Prolonged anesthesia (> 6 hours).
• High risk of nausea and vomiting.
• In patients treated with bleomycin, because the increase in oxygen concentration during inhalational sedation technique determines an increased risk of pulmonary toxicity.
• Vegetarian patients.

Interactions
No studies on pharmacokinetic interactions between drugs are known. The interactions of nitrous oxide with other drugs can be explained by receptor-type mechanisms.
Nitrous oxide acts directly on opioid receptors (OP2 and OP3 subtypes), GABA receptors (subtype A) and glutamate receptors (subtype NMDA).
Opioids, benzodiazepines and barbiturates have an additive effect by enhancing the analgesic and sedative action of nitrous oxide.
All anesthetics administered by inhalation interact with GABA and glutamate receptors and have an additive effect on the sedative action of nitrous oxide.
Nitrous oxide reduces the minimum alveolar concentration of inhaled anesthetic and is used to reduce the dose required of other anesthetics, but also to shorten the induction time when anesthetics are used by inhalation.
Hemoglobin may not saturate if nitrous oxide is associated with sedatives.
Nitrous oxide potentiates the action of warfarin.
The concomitant use of nitrous oxide and methotrexate should be avoided as nitrous oxide potentiates the cytotoxic effects of methotrexate. The concomitant assumption of nitrous oxide and methotrexate can have effects on the blood cell count.
The antiproliferative effect of nitrous oxide is based on the inactivation of vitamin B12 by nitrous oxide. This effect disappears when its administration is stopped and vitamin B12-based therapy is introduced. The inactivation of vitamin B12 by nitrous oxide potentiates the toxicity of sodium nitroprusside and methotrexate.
Nitrous oxide increases neuromuscular blockade from succinylcholine and potentiates the effect of non-depolarizing muscle relaxants.

Special warnings
Nitrous oxide can be mixed with air, medical oxygen and inhaled halogenated anesthetics.
Nitrous oxide is a colorless gas with a slightly sweet odor, poorly perceptible even at high concentrations, heavier than air, asphyxiating. Although it is not flammable, it supports combustion (it is a combustant: it allows and accelerates combustion).
The degree of compatibility of different materials depends on the pressure at which the gas is used. The greatest risk of combustion concerns materials such as fats (lubricating oils) and organic matter (fabrics, wood, paper, plastics, etc.) which can ignite on contact with nitrous oxide at sufficient pressure, spontaneously due to an ignition point (spark, open flame, etc.).
Explosive mixtures can be created with flammable anesthetic gas or vapor gases, even in the absence of oxygen.

For operators
Nitrous oxide is a colorless gas with a slightly sweet odor; it is not toxic and is not flammable, but it is a gas that supports combustion; it is heavier than air and accumulates in the lower areas of the work environment.
Nitrous oxide emitted by the patient gradually ends up in the air of the environment where it is used. The use of so-called "double" masks and a sufficiently high level of air exchange in operating rooms (20 times per hour) together with the active suction of excess gas from anesthetic equipment must ensure that the average concentration remains below the maximum acceptable concentration, as established by current regulations.
Furthermore, operators must act in accordance with the rules regarding the use of nitrous oxide-based products. And in principle, operators must avoid prolonged direct inhalation of exhaled air from patients.
Chronic exposure to low concentrations of nitrous oxide has been identified as a possible health risk. It is not currently possible to establish whether there is a causal relationship between chronic exposure to low concentrations of nitrous oxide and particular pathologies, but the risk of a connection between chronic exposure and the development of tumors or other chronic pathologies, reduced fertility, spontaneous abortion and fetal malformations cannot be ruled out.
Before and during the administration of nitrous oxide, it is necessary to follow the safety precautions reported in paragraph 6.6.

Pregnancy and breastfeeding
Pregnancy
Skeletal changes have been observed in rat embryos exposed to high concentrations of nitrous oxide during the period of organogenesis.
Experiments conducted on animals exposed to nitrous oxide at high concentrations for long periods have demonstrated reproductive toxicity (teratogenic effects) (see section 5.3).
Nitrous oxide can interfere with folic acid metabolism (see section 4.4).
Epidemiological data collected during pregnancy are insufficient to define the risk of adverse effects on embryonic-fetal development. Limited data on short-term use of nitrous oxide in human pregnancy have not shown an increased risk of congenital anomalies.
The use of anesthetic techniques involving nitrous oxide is, however, contraindicated in the first and second trimester of pregnancy.
During the third trimester of pregnancy, it is recommended not to exceed 50% v/v of nitrous oxide in the inhaled mixture. In any case, pregnant women should be exposed to nitrous oxide with great caution and only if strictly necessary. Prolonged or frequent use should be avoided.
Nitrous oxide can 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.
Breastfeeding
There are no data on the excretion of nitrous oxide-based products into breast milk. However, after short-term administration of nitrous oxide-based products, it is not necessary to interrupt breastfeeding.
Effects on the ability to drive and operate machinery. Nitrous oxide alters cognitive and psychomotor function. It is rapidly eliminated after administration.
Despite this, as a further safety measure, driving, operating machinery and other activities requiring particular attention should be avoided for 24 hours after anesthesia with nitrous oxide.
After short-term administration of nitrous oxide for analgesia, in ambulatory patients who need to drive vehicles or operate machinery, they should be kept under observation until all effects have disappeared and the patient is sufficiently alert.

Dosage, method and duration of administration
As an anesthetic
Nitrous oxide, used exclusively in the operating room or delivery room, must be administered in a mixture with oxygen at concentrations below 79% using suitable equipment, which must include monitoring of oxygen concentration and a system that makes it impossible to administer a hypoxic mixture (FiO2 < 21% v/v).
Nitrous oxide must not be administered at concentrations greater than 79% v/v so that an adequate fraction of oxygen is always guaranteed. In patients with reduced oxygen saturation, an adequate fraction of oxygen must be used.
In pregnant women, the percentage of nitrous oxide must not exceed 50% v/v in the mixture with oxygen due to the drug's own toxicity.
The time to induction is 2-5 minutes with a concentration of nitrous oxide of 70-75% v/v.
After induction, nitrous oxide between 50 and 70% v/v is usually used, with oxygen supplementation. The percentage of nitrous oxide can be decreased in line with clinical parameters and in consideration of the anesthetic plan implemented.
Nitrous oxide at the maximum permitted concentration cannot induce anesthesia on its own and is, therefore, used in association with other anesthetics, administered intravenously or by inhalation.
Information regarding the dosage of nitrous oxide and additional inhalational anesthetics for maintenance of anesthesia is generally available in the package leaflets of the latter. In the case of association with intravenous anesthetics, it will be calculated how much to reduce the dosage of the intravenous anesthetic.
In general, the effects of nitrous oxide, if used as the sole active ingredient, do not depend on the patient's age.
Nitrous oxide should not be administered for more than 12 consecutive hours, due to its bone marrow toxicity. Continuous exposure (>24 hours) to nitrous oxide increases the risk of bone marrow depression.
As an analgesic
Nitrous oxide used as a single analgesic/anesthetic/sedative (always associated with oxygen) at concentrations below 50% v/v relieves pain, has a sedative effect and reduces agitation, and normally does not affect the degree of awareness or the ability to sustain speech. Breathing, circulation and reflexes remain unchanged at these concentrations.
The effect on pain reduction and the sedative effect are dose-dependent as are the effects on cognitive functions.
Exposure of the patient to nitrous oxide as an analgesic should last a maximum of 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 decide whether the medicine can be administered and at what dose, in a suitable facility that allows for emergency cardio-respiratory resuscitation.
It is necessary to follow the instructions of the medical personnel when administering the gas.
Personnel using nitrous oxide must be adequately prepared and updated on the use of the gas, which must be administered with appropriate equipment, in well-ventilated rooms suitable for ensuring immediate air exchange, with ventilation systems that do not allow excessive concentrations of gas in the ambient air, for example, by using so-called "double masks" (active nasal masks), particularly recommended for dental interventions.
In ambulances, the delivery device can be connected to an extraction system or a double mask can be used.
Air quality must be monitored in accordance with local laws and occupational exposure to nitrous oxide must be below the hygienic limits established nationally by professional guidelines and legislation relating to health and safety, especially for pregnant personnel.
Nitrous oxide is normally administered through the orotracheal or nasotracheal tube in the operating room and via a tight-fitting facial or nasal mask in other settings. The patient can breathe spontaneously or with the help of a respirator (assisted or mechanical ventilation).
Nitrous oxide must be administered in combination with oxygen, using equipment that requires the delivery of a non-hypoxic mixture of nitrous oxide and oxygen. This equipment must include monitoring of oxygen concentration and a safety system that prevents the administration of a hypoxic mixture (FiO2<21% v/v).
Due to the risk of loss of consciousness and coma, if nitrous oxide is used outside the operating room, administration for analgesic purposes is acceptable only in a mixture with oxygen at 50% v/v. The device used must make it impossible to administer mixtures with concentrations of nitrous oxide greater than 50% v/v.
Throughout the period of use of nitrous oxide, both the patient and the method of administration must be monitored to ensure that the gas is inhaled safely.
The patient must be monitored by medical personnel until the end of administration and until regaining consciousness.

Instructions for use and handling
Cylinders, as well as fixed cryogenic containers, are reserved exclusively for containing/transporting nitrous oxide for inhalation, for therapeutic use.

NOTE: FOR MORE DETAILS CONSULT THE MANUAL OF USE OF THE
CONTAINER
Storage

• Read the container's instruction and use manual carefully.
• Verify that all material is in good condition.
• Place in the open air or in well-ventilated areas, in fenced areas and protected from rain and exposure to direct sunlight and away from heat sources (locked spaces, reserved for medicinal gases).
• Do not expose to heat sources and in any case to high heat (over 50°C).
• Protect from power lines and with grounding systems.
• Place away from deposits of combustible products and in general from combustible material (contact with combustible material can cause fire).
• Do not smoke or use open flames near the product.
• Keep the cylinder clean and dry and avoid any contact with greases or oils (do not lubricate valves and fittings).
• Be careful that the containers are not damaged and avoid shocks and leaks of product.
• Block the dispensing if not in use, closing the valves.
• Keep the cylinders in a vertical position, with the valves closed, with the protective cap and covering in place, properly secured to prevent accidental shocks or falls.
• Do not use non-integral packaging.
• Empty containers and full containers must be stored separately.
• Containers containing other types of gases must be stored separately.
• Excessive storage of full containers must be avoided.
• If there is a fire hazard, move to a safe space after closing the valves.
• In case of leakage, the cylinder valve must be closed immediately, if it can be done safely. If the valve cannot be closed, the container must be taken to a safer place outdoors to allow the gas to escape.
• The vapors can cause dizziness and vertigo.

Transport of cylinders
Cylinders must be transported using appropriate means (e.g. trolley with chains, barriers or rings) to protect them from the risk of shocks and falls and gas leaks. Handling of the cylinders must always take place with the protective cap fitted. During transport on vehicles, the cylinders must be firmly secured, preferably in a vertical position. Permanent ventilation of the vehicle and a ban on smoking must be guaranteed.
During the use of the gas

• The cylinders and fixed containers cannot be used if there is evident damage or if they are suspected of being damaged or have been exposed to extreme temperatures.
• Before opening the cylinder valve, it must be placed in a vertical position and kept in that position during administration.
• Open and close the closing systems of the containers gradually and carefully (do not use pliers or other tools to open or close the cylinder valve), in order to prevent the risk of damage.
• Do not force the valves during opening and closing. Do not change the shape of the container.
• Never position yourself in front of the gas outlet from the valve, but always on the opposite side. Do not expose yourself or the patient to the direct flow of gas.
• The administration of nitrous oxide must take place with adequate pressure and controlling the flow rate between the container and the patient.
• Do not use oil or grease in contact with the gas.
• Handle the material with clean hands, free of traces of grease or oil.
• Do not completely empty the container.
• After use, close the cylinder valve.
• In case of gas leakage, close the valve and notify the technical intervention service of the supplier indicated on the Container Use Manual.
• Use only containers suitable for the product, at the expected operating temperatures.
• Use fittings, connecting tubes or flexible connecting hoses specific and compatible with nitrous oxide.
• It is strictly forbidden to intervene in any way on the fittings of the containers, on the dispensing equipment and related accessories or components (OIL AND GREASESCAN SPONTANEOUSLY IGNITE IN CONTACT WITH NITROUSOXIDE).
• Do not grease or attempt to repair defective valves.
• It is strictly forbidden to handle the equipment or components with hands or clothes or face soiled with grease, oil, creams and various ointments.
• Do not use greasy creams and lipsticks.
• Do not smoke.
• Do not approach the package with open flames.
• No electrical equipment that can emit sparks should be used near patients receiving oxygen.
• Do not use oils or greases on fittings, valve and on any material in contact with the gas.
• Never introduce nitrous oxide into an appliance that could contain combustible materials and in particular fatty substances.

Disposal

• Store empty cylinders with the valves closed.
• Do not discharge into sewers, basements or excavations where accumulation may be dangerous. It is not permitted to let the gas flow under pressure.
• Return empty or no longer usable containers, even if only partially empty, to the supplier. Any unused medicinal product residues present in the cylinder will be eliminated, through appropriate procedures, in a well-ventilated area by the company that will proceed to refill the same container.
• The unused medicine and waste derived from such medicine must be disposed of in accordance with local regulations.

Overdosage
Adverse effects due to overdosage may occur in patients exposed to quantities of
nitrous oxide for long periods of time or with concentrations higher than 80% v/v.
The first signs of nitrous oxide toxicity include headache, dizziness, confusion,
weakness, incoordination of movements, vertigo, amnesia, aphasia, syncope, arrhythmia, unconsciousness
and then death by asphyxia.
Emergency and supportive measures in case of nitrous oxide overdosage are those of
stopping administration, keeping the airways open, providing assisted oxygenation
aided by the delivery of supplemental oxygen to achieve sufficient oxygen saturation.
It is therefore advisable to always have suitable equipment available for cardiopulmonary resuscitation in the premises where nitrous oxide is used.
Monitoring by pulse oximetry is recommended until the patient has regained consciousness
and is no longer hypoxic.
Overexposure or prolonged exposure to nitrous oxide always results in neurological disorders due to the toxicity of the drug to Vitamin B12.
There is no specific antidote for nitrous oxide.

Undesirable Effects

Like all medicines, nitrous oxide can cause side effects, although not everyone

experiences them.
The following convention has been used for the classification of undesirable effects in terms
of frequency: very common ≥ 1/10, common ≥ 1/100 and < 1/10, uncommon ≥1/1000 and < 1/100,
rare ≥ 1/10.000 and < 1/1000, very rare < 1/10.000.
Gastrointestinal disorders:

common:nausea and vomiting.

uncommon:bloating, increased volume of gas in the intestine.
Nervous system disorders:

common:dizziness, migraine, headache.

rare:myelopathies, polyneuropathies, subacute combined degeneration of the spinal cord.

very rare:movement disorders, paraplegia, paraparesis, epilepsy, increased intracranial pressure, peripheral neuropathy, encephalopathy.
Psychiatric disorders:

uncommon:euphoria, nitrous oxide dependence

very rare:sensory disturbances, altered reflexes, depression of the level of consciousness, hallucinations
(psychodysleptic effects may occur in the absence of association with another anesthetic),
psychotic pathology, confused state, anxiety.
Ear and labyrinth disorders:

uncommon:sensation of pressure in the middle ear, damage to the middle ear, rupture of the
tympanic membrane.
Blood and lymphatic system disorders:

uncommon:severe megaloblastic anemia, leukopenia, granulopenia/agranulocytosis (following
administration for more than 24 hours. It is assumed that a single exposure of up to 6 hours poses
no risk or does so in very rare cases in subjects without a history of
hematological pathologies).
Eye disorders:

very rare:ocular hypertension, eye pain, retinal artery occlusion, blindness.
Cardiac disorders:

very rare:arrhythmias, heart failure.
Hepatobiliary disorders:

very rare:hepatic necrosis
Injury, poisoning and complications of procedure:

very rare:cerebral hyperperfusion syndrome, increased pressure in inflated balloons.
Metabolism and nutrition disorders:

very rare:vitamin B12 deficiency, hyperhomocysteinemia.
Musculoskeletal and connective tissue disorders:

very rare:muscle weakness, malignant hyperthermia.
Congenital, familial and genetic disorders:

very rare:multiple congenital anomalies (in medical and paramedical personnel following
repeated exposure).
Reproductive system and breast disorders:

very rare:infertility (in medical and paramedical personnel following repeated exposure)
Respiratory, thoracic and mediastinal disorders:

very rare:hypoxia (for several minutes after the end of nitrous oxide administration),
pneumothorax.
Vascular disorders:

very rare:hypotension, shock

EXPIRY DATE AND STORAGE
Expiry date:see the expiry date indicated on the packaging.
The expiry date indicated refers to the product in intact packaging, stored correctly.

Warning:Do not use the medicine after the expiry date indicated on the packaging.

Storage
Store at a temperature not exceeding 50°C, in well-ventilated areas, or in well-ventilated sheds, in an upright position with the valves closed, protected from rain, weather,
from exposure to direct sunlight, away from sources of heat or ignition and from combustible materials. Empty containers or those containing other types of gas must be stored
separately.
Fixed containers, installed in healthcare facilities, must be placed outdoors in accordance with
the provisions of Circular 99/1964, in confined and protected areas, with access limited to
authorized personnel, managed and maintained according to the instructions provided by each Manufacturer. These are
pressure equipment and are therefore subject to the CE PED Directive and/or the Ministerial Decree of
21/11/1972.

Unused medicine and waste derived from this medicine must be disposed of in
accordance with local regulations (see also Instructions for use - Disposal).
Keep the medicine out of the reach and sight of children
Composition
Active ingredient: Nitrous oxide 100%

Pharmaceutical form and content
Liquefied medicinal gas
FARMA GAS MEDICAL AND TECHNICAL GASES is packaged in cylinders
(blue ogive marked with “N2O” or with "nitrous
oxide" and white cylinder) with a closing valve and in fixed cryogenic containers.

Marketing Authorisation Holder
FARMA GAS - MEDICAL AND TECHNICAL GASES SRL
via A. Fortunato 22
84084 PENTA (SA) – ITALY

Manufacturer

Cylinders
Alfa Ossigeno S.r.L. - Via delle Industrie, 9 - Fisciano (Sa)

Fixed cryogenic containers
Alfa Ossigeno S.r.L. - Via delle Industrie, 9 - Fisciano (Sa)