Alfaprot

PACKAGE LEAFLET

OSSIGENO FARMA GAS MEDICAL AND TECHNICAL GASES
Medicinal liquefied gas
Pharmacotherapeutic category
Medicinal gases, general anaesthetics
Therapeutic indications
In anaesthesia, in combination with other anaesthetics administered by inhalation or intravenous route.
In analgesia/sedation in all conditions requiring rapid onset and rapid offset of pain relief/sedation (short surgical procedures, trauma, burns, dentistry, otorhinolaryngology, childbirth).

Contraindications

• Hypersensitivity to the active substance.
• Bowel dilation and/or obstruction.
• Any surgical procedure where there is a risk of gas embolism.
• Middle ear surgery, due to the risk of serious damage to all structures in this area 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 breathing of pure oxygen is indicated or who have respiratory difficulty.
• Conditions associated with air-filled cavities (pneumothorax, bullous emphysema, gas embolism, etc.) due to the risk of embolism expansion following nitrous oxide administration.
• After diving within the last 48 hours, due to the risk of decompression sickness, and after extracorporeal circulation with 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 which may cause blindness, intestinal obstruction (ileus) due to the risk of further intestinal dilation, middle ear obstruction due to reduced patency of the Eustachian tube caused by inflammatory disease.
• Suspected or known increased intracranial pressure.
• Closed head trauma.
• Potential risk of vitamin B12 and/or folate deficiency and megaloblastic anaemia.
• Patients with untreated vitamin B12 deficiency, pernicious anaemia (Biermer's anaemia), Crohn's disease. Megaloblastic anaemia may develop due to interference of nitrous oxide with vitamin B12; regression of effect may be induced by folic acid administration. Neurological disorders may also occur, potentially affecting methylation of basic proteins in myelin sheaths.
• Known deficiency of enzyme or substrate involved in the metabolic pathway of methionine synthesis.
• Severe mental confusion or other signs of cognitive dysfunction, potentially related to increased intracranial pressure, which may be aggravated by nitrous oxide.
• Administration for 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 lower limit of 30% v/v is often used. Oxygen tension must remain above physiological values (100 mmHg), with haemoglobin saturation with oxygen exceeding 97%, and in any case always above 60 mmHg, with haemoglobin oxygen saturation exceeding 90%. Regular monitoring is required, via measurement of arterial oxygen tension (PaO2) or pulse oximetry (arterial oxygen saturation SpO2), along with clinical parameter assessment. The minimum effective oxygen concentration in the inhaled air should be established for each individual patient.
Nitrous oxide concentrations exceeding 50% v/v may impair protective reflexes and levels of consciousness. Concentrations above 60–67% v/v often cause unconsciousness and increase the risk of impaired protective reflexes.
If unexpected cyanosis occurs during anaesthesia or during induction, it is recommended to stop nitrous oxide administration and increase the inhaled oxygen fraction to 100%.
If cyanosis does not resolve rapidly, or if the episode recurs during anaesthesia, possible causes include malfunction of equipment (delivery of hypoxic mixture) or incorrect connection of medical gas lines to the anaesthesia machine. It is therefore suggested to attempt ventilation of the patient using a bag filled with ambient air.
After general anaesthesia involving high concentrations of nitrous oxide, the gas may diffuse from blood to alveoli, diluting oxygen in the lungs. This may cause hypoxia (diffusion hypoxia), caused not only by the alveolar gas mixture but also by reflex response to hypoxia, hypercapnia and hypoventilation. To prevent this, 100% O2 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 cessation of nitrous oxide administration.
Nitrous oxide administration may increase pressure in the cuff of the endotracheal tube, causing tracheal damage, or in any other inflated balloon used for other procedures (e.g. vessel occlusion balloons). Additionally, when using nitrous oxide with a Swan-Ganz catheter, generated pressure may displace the catheter into an occlusive position, altering pressure readings.
Medical devices containing air may present problems (e.g. may 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. for sedation in intensive care patients), due to the potential risk of vitamin B12 function impairment (cofactor of methionine synthase). Nitrous oxide alters vitamin B12 and folate metabolism, particularly in elderly patients. Inhibition of methionine synthase affects homocysteine conversion to methionine. Inhibition of this enzyme reduces thymidine formation, an important DNA component. Inhibition of methionine synthase may lead to defective or reduced myelin formation, and thus spinal cord damage. DNA effects explain potential negative impacts on haematopoiesis and fetal damage observed in animal studies.
Nitrous oxide may cause increased pressure in the middle ear.
Administration of nitrous oxide more than once every 4 days should be accompanied by blood cell count with evaluation for possible megaloblastic changes or alterations in red blood cells and possible neutrophil hypersegmentation.
Nitrous oxide administration should be performed with caution in the following situations:

• Thoracic surgery, due to the risk of pneumothorax, expansion of emphysematous bullae, and risk of 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 provided by barbiturates, increases cerebral blood flow and pressure in any intracranial air bubble or cavity.
• Sickle cell anaemia.
• After intraocular injection: a sufficient time interval must elapse due to the risk of visual disturbances.
• Prolonged anaesthesia (> 6 hours).
• High risk of nausea and vomiting.
• In patients treated with bleomycin, because increased oxygen concentration during inhalation sedation technique increases the risk of pulmonary toxicity.
• Vegetarian patients.

Interactions
No pharmacokinetic interaction studies with other drugs are known. Interactions of nitrous oxide with other medicinal products may be explained by receptor-mediated mechanisms.
Nitrous oxide acts directly on opioid receptors (subtypes OP2 and OP3), GABA receptors (subtype A), and glutamate receptors (NMDA subtype).
Opioids, benzodiazepines and barbiturates have an additive effect, enhancing the analgesic and sedative action of nitrous oxide.
All inhaled anaesthetics interact with GABA and glutamate receptors and have an additive effect on the sedative action of nitrous oxide.
Nitrous oxide reduces the minimum alveolar concentration (MAC) of inhaled anaesthetic and is used to reduce the required dose of other anaesthetics, as well as to shorten induction time when inhaled anaesthetics are used.
Haemoglobin may not become saturated if nitrous oxide is combined with sedatives.
Nitrous oxide potentiates the action of warfarin.
Concomitant use of nitrous oxide and methotrexate should be avoided, as nitrous oxide potentiates the cytotoxic effects of methotrexate. Concomitant administration of nitrous oxide and methotrexate may affect blood cell count.
The antiproliferative effect of nitrous oxide is based on inactivation of vitamin B12 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-depolarising muscle relaxants.

Special warnings
Nitrous oxide may be mixed with air, medicinal oxygen, and inhaled halogenated anaesthetics.
Nitrous oxide is a colourless gas with a faintly sweet odour, barely perceptible even at high concentrations, heavier than air, and asphyxiant. Although non-flammable, it supports combustion (it is an 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 substances (fabrics, wood, paper, plastics, etc.), which may ignite upon contact with nitrous oxide at sufficient pressure, spontaneously due to an ignition point (spark, open flame, etc.).
Explosive mixtures with flammable anaesthetic gases or vapours may form, even in the absence of oxygen.

For operators
Nitrous oxide is a colourless gas with a faintly sweet odour; it is non-toxic and non-flammable, but supports combustion; it is heavier than air and accumulates in lower areas of the workplace.
Nitrous oxide exhaled by the patient gradually enters the ambient air where it is used. Use of so-called “double” masks and a sufficiently high air exchange rate in operating rooms (20 times per hour), together with active scavenging of excess gas from anaesthetic equipment, should ensure that average concentration remains below the maximum acceptable concentration established by current regulations.
Furthermore, operators must comply with regulations regarding the use of nitrous oxide-based products. In principle, operators 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 whether there is a causal relationship between chronic exposure to low concentrations of nitrous oxide and specific diseases, but a risk of association between chronic exposure and development of tumours or other chronic diseases, reduced fertility, spontaneous abortion and fetal malformations cannot be excluded.
Precautions for safety as reported in section 6.6 must be observed before and during nitrous oxide administration.

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 pregnancy are insufficient to define the risk of adverse effects on embryonic-fetal development. Limited data on short-term use of nitrous oxide in human pregnancy have not shown an increased risk of congenital anomalies.
However, anaesthetic techniques involving nitrous oxide use are contraindicated during the first and second trimesters of pregnancy.
During the third trimester of pregnancy, 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 if strictly necessary. Prolonged or frequent use should be avoided.
Nitrous oxide may be used during childbirth.
Nitrous oxide use should be avoided in cases of fetal distress. In any case, the newborn must be monitored for signs of possible respiratory depression.

Lactation
There are no data on excretion of nitrous oxide-based products in breast milk. However, after short-term administration of nitrous oxide-based products, interruption of breastfeeding is not necessary.

Effects on ability to drive or use machines
Nitrous oxide alters cognitive and psychomotor function. It is rapidly eliminated after administration.
Despite this, as an additional safety measure, driving, operating machinery and other activities requiring particular attention should be avoided within 24 hours following nitrous oxide anaesthesia.
After short-term administration of nitrous oxide for analgesia in outpatients who need to drive or operate machinery, patients must be kept under observation until all effects have disappeared and the patient is sufficiently alert.

Dosage, method and duration of administration
As anaesthetic
Nitrous oxide, used exclusively in operating rooms or delivery rooms, must be administered in mixture with oxygen at concentrations below 79%, using appropriate equipment, which must include oxygen concentration monitoring and a system that prevents administration of a hypoxic mixture (FiO2 < 21% v/v).
Nitrous oxide must not be administered at concentrations exceeding 79% v/v to ensure adequate oxygen fraction is always maintained. In patients with reduced oxygen saturation, an adequate oxygen fraction must be used.
In pregnant women, the nitrous oxide percentage must not exceed 50% v/v in the oxygen mixture due to the drug's inherent toxicity.
Induction time is 2–5 minutes with a nitrous oxide concentration of 70–75% v/v. After induction, nitrous oxide is typically used between 50% and 70% v/v, supplemented with medicinal oxygen. The nitrous oxide percentage may be reduced according to clinical parameters and the anaesthetic plan.
Nitrous oxide at the maximum allowed concentration cannot induce anaesthesia alone and is therefore used in combination with other anaesthetics administered intravenously or by inhalation.
Information regarding nitrous oxide and additional inhaled anaesthetic dosing for maintenance of anaesthesia is generally available in the package leaflets of the latter. In case of combination with intravenous anaesthetics, the intravenous anaesthetic dose should be adjusted accordingly.
In general, the effects of nitrous oxide, if used as the sole active substance, do not depend on patient age.
Nitrous oxide should not be administered for more than 12 consecutive hours due to its myelotoxicity. Continuous exposure (>24 hours) to nitrous oxide increases the risk of bone marrow depression.

As analgesic
Nitrous oxide used as a single analgesic/anaesthetic/sedative (always combined with oxygen) at concentrations below 50% v/v relieves pain, has sedative action and reduces agitation, and normally does not affect level of awareness or ability to converse. At these concentrations, circulation and reflexes remain unchanged.
The effect on pain reduction and sedation is dose-dependent, as are effects on cognitive functions.
Patient exposure to nitrous oxide as an analgesic should last no longer than 1 hour and should not be repeated for more than 15 consecutive days.

Method of administration – General rules
Nitrous oxide must always be administered in the presence of medical personnel, who decide whether the medicinal product can be administered and at what dose, in an appropriate facility 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 gas use, which must be administered with appropriate equipment in well-ventilated rooms allowing immediate air exchange, with ventilation systems preventing excessive gas concentrations in ambient air, using, for example, so-called “double” masks (active nasal masks), particularly recommended for dental procedures.
In ambulances, the delivery device may be connected to an extraction system or a double mask may be used.
Air quality must be monitored according to local laws, and occupational exposure to nitrous oxide must remain below nationally established hygiene limits defined by professional guidelines and health and safety legislation, especially regarding 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 support (assisted or mechanical ventilation).
Nitrous oxide must be administered in combination with oxygen, using equipment that enforces 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 mixture with 50% v/v oxygen. The device used must make it impossible to administer mixtures with nitrous oxide concentrations exceeding 50% v/v.
Throughout the period of nitrous oxide use, both the patient and the method of administration must be monitored to ensure safe inhalation of the gas.
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 protected areas sheltered from rain and 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 product stores and in general from combustible materials (contact with combustible materials may cause fire).
• Do not smoke or use open flames near the product.
• Keep the cylinder clean and dry and avoid any contact with fats or oils (do not lubricate valves and fittings).
• Ensure containers are not damaged and avoid impacts and product leakage.
• Block gas delivery when not in use by closing valves.
• Keep cylinders in upright position, with valves closed, protective cap and coating in place, properly secured to prevent accidental impacts or falls.
• Do not use packages that are not intact.
• 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, the cylinder valve must be closed immediately, if this can be done safely. If the valve cannot be closed, the container must be moved to a safer outdoor location to allow gas to escape.
• Vapours may cause drowsiness and dizziness.

Cylinder transport
Cylinders must be transported using appropriate means (e.g. trolley equipped with chains, barriers or rings) to protect them from impact, falling and gas leakage. Cylinder handling must always be performed with the protective cap in place. During transport in vehicles, cylinders must be securely fastened, preferably in upright position. Permanent vehicle ventilation and smoking prohibition must be ensured.

During gas use

• Cylinders and fixed containers must not be used if there are evident damages or if damage is suspected or if they have been exposed to extreme temperatures.
• Before opening the cylinder valve, it must be placed in upright position 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 risk.
• Do not force valves during opening and closing. Do not modify the container shape.
• 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 direct gas flow.
• Nitrous oxide administration must occur at adequate pressure, with controlled flow rate between container and patient.
• Do not use oil or grease in contact with the gas.
• Handle materials with clean hands, free of fat 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 intervention service of the supplier indicated in the container’s user manual.
• Use only containers suitable for the product and intended operating temperatures.
• Use specific and compatible connectors, connecting tubes or flexible couplings for nitrous oxide.
• It is absolutely forbidden to modify in any way the container connectors, delivery equipment and related accessories or components (OIL AND GREASE MAY SPONTANEOUSLY IGNITE ON CONTACT WITH NITROUS OXIDE).
• Do not lubricate or attempt to repair defective valves.
• It is absolutely forbidden to handle equipment or components with hands, clothing or face contaminated with grease, oil, creams or ointments.
• Do not use greasy creams or lipsticks.
• Do not smoke.
• Do not approach the package with open flames.
• No electrical equipment capable of emitting sparks must 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 might contain combustible materials, especially fatty substances.

Disposal

• Store empty cylinders with valves closed.
• Do not discharge into sewers, basements or pits where accumulation may be dangerous. Discharge of pressurized gas is not permitted.
• Return empty or unusable containers, even if only partially empty, to the supplier. Any residual unused medicinal product in the cylinder will be eliminated via appropriate procedures in a well-ventilated area by the company responsible for subsequent refilling of the same container.
• Unused medicinal product and waste derived from such medicinal product must be disposed of in accordance with current local regulations.

Overdose
Adverse effects due to overdose may occur in patients exposed to nitrous oxide quantities for prolonged periods or at concentrations exceeding 80% v/v.
Early signs of nitrous oxide toxicity include headache, dizziness, confusion, weakness, incoordination, vertigo, amnesia, aphasia, syncope, arrhythmia, unconsciousness and ultimately death by asphyxia.
Emergency and supportive measures in case of nitrous oxide overdose include stopping administration, maintaining airway patency, providing assisted oxygenation supplemented with additional 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 towards vitamin B12.
There is no specific antidote for nitrous oxide.

Undesirable effects
Like all medicines, nitrous oxide can cause adverse effects, although not everyone experiences them.
The following convention has been used to classify adverse effects by 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 intestinal gas volume.

Nervous system disorders:
common: dizziness, migraine, headache.
rare: myelopathies, polyneuropathies, subacute combined degenerations 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 consciousness level, hallucinations (psychodysleptic effects may occur in absence of association with another anaesthetic), psychotic disorder, confusion, anxiety.

Ear and labyrinth disorders:
uncommon: sensation of pressure in middle ear, damage to middle ear, tympanic membrane rupture.

Haematopoietic and lymphatic system disorders:
uncommon: severe megaloblastic anaemia, leucopenia, granulopenia/agranulocytosis (after administration for more than 24 hours. A single exposure up to 6 hours is presumed not to pose any risk or to do so only very rarely in subjects without history of haematological disorders).

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 procedural complications:
very rare: cerebral hyperperfusion syndrome, increased pressure in inflated balloons.

Metabolism and nutrition disorders:
very rare: vitamin B12 deficiency, hyperhomocysteinaemia.

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 staff following repeated exposure).

Reproductive system and breast disorders:
very rare: infertility (in medical and paramedical staff following repeated exposure).

Respiratory, thoracic and mediastinal disorders:
very rare: hypoxia (for several minutes after cessation of nitrous oxide administration), pneumothorax.

Vascular disorders:
very rare: hypotension, shock.

Adhering to the instructions in this leaflet reduces the risk of adverse effects.

EXPIRY DATE AND STORAGE
Expiry date: see expiry date indicated on the packaging.
The indicated expiry date refers to the product in intact packaging, correctly stored.
Caution: Do not use the medicinal product after the expiry date indicated on the packaging.

Storage
Store at temperature not exceeding 50°C, in well-ventilated areas, or in well-ventilated sheds, in upright position with valves closed, protected from rain, weather, direct sunlight, heat sources or ignition sources, and away from 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 limited access for authorized personnel, managed and maintained according to each Manufacturer's instructions. These are pressure equipment and therefore subject to the PED CE Directive and/or Ministerial Decree of 21/11/1972.

Unused medicinal product and waste derived from such medicinal product must be disposed of in accordance with current local regulations (see also Instructions for use - Disposal).
Keep the medicinal product out of the reach and sight of children.

Composition
Active substance: Nitrous oxide 100%

Pharmaceutical form and contents
Liquefied medicinal gas
OSSIGENO FARMA GAS MEDICAL AND TECHNICAL GASES is packaged in cylinders (blue shoulder marked with “N2O” or “nitrous oxide” and white cylinder) with closure valve and in fixed cryogenic containers.

Marketing Authorization 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)