Humerox® inhal

INSTRUCTIONS for medical use of the medicinal product UMEROX® Inhal (UMEROX®Inhal)

Composition:

Active substance: methoxyflurane;

1 ml contains methoxyflurane 99.9%;

Excipient: butylated hydroxytoluene (E 321).

Medicinal form. Inhalation vapours, liquid.

Main physicochemical properties: clear, colorless liquid with a sweet fruity odor.

Pharmacotherapeutic group. Analgesics. Other analgesics and antipyretics. Methoxyflurane. ATC code N02BG09.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Methoxyflurane belongs to the fluorinated hydrocarbon group of volatile anaesthetics. It is a volatile liquid intended for vaporization and administration by inhalation using a personal inhaler device for methoxyflurane.

Methoxyflurane vapour provides analgesia upon inhalation at low concentrations. Drowsiness may occur following administration of methoxyflurane. During administration of methoxyflurane, cardiac rhythm is usually regular. Myocardial sensitivity to adrenaline is minimally increased following administration of methoxyflurane. At superficial levels of analgesia, some reduction in arterial blood pressure may occur. This may be accompanied by bradycardia. The observed arterial hypotension is associated with decreased myocardial contractility and reduced cardiac output.

Clinical studies

Data are lacking.

Pharmacokinetics.

Distribution

Methoxyflurane undergoes more extensive metabolism than other halogenated methyl ethers and has a greater tendency to diffuse into fatty tissues. Therefore, methoxyflurane is slowly released from this depot and becomes available for biotransformation over many days.

Metabolism

Methoxyflurane undergoes biotransformation in the human body. Approximately 50–70% of the absorbed dose is metabolized to inorganic fluoride, oxalic acid, difluoromethoxyacetic acid, and dichloroacetic acid. Both inorganic fluoride and oxalic acid may cause renal damage when administered in high doses; however, dose-dependent nephrotoxicity observed with clinical doses appears to be related to the combination of inorganic fluoride and dichloroacetic acid.

Elimination

Approximately 20% of absorbed methoxyflurane is eliminated via exhaled air, while urinary excretion of organic fluoride, fluoride, and oxalic acid accounts for approximately 30% of the elimination of absorbed methoxyflurane. Study results indicate that higher peak blood fluoride levels are reached earlier in obese individuals compared to non-obese individuals, and in elderly patients.

Clinical characteristics.

Indications.

For emergency pain relief in hemodynamically stable patients with trauma and associated pain who are conscious, via self-administration under supervision of trained personnel (see section "Dosage and administration").

For pain relief in conscious patients under supervision requiring analgesia during surgical procedures such as dressing changes (see section "Dosage and administration").

Note: The total maximum dose must not be exceeded.

Contraindications.

• Use as an anesthetic agent.
• Impaired kidney function, including reduced glomerular filtration rate (GFR), diuresis, and renal blood flow.
• Renal insufficiency.
• Hypersensitivity to methoxyflurane, fluorinated anesthetics, or any components of the medicine Yumerox**®** Ingal.
• Cardiovascular instability.
• Respiratory depression.
• Head injury or loss of consciousness.
• History of adverse reactions in the patient or family history.
• Malignant hyperthermia: patients with known malignant hyperthermia or genetic predisposition to it.

Interaction with other medicinal products and other forms of interaction.

Concomitant administration of tetracycline and methoxyflurane for anesthesia has been reported to cause fatal renal toxicity. There is a potential for methoxyflurane to enhance the undesirable nephrotoxic effects of other drugs, including certain antibiotics known to have nephrotoxic potential, such as gentamicin, kanamycin, colistin, polymyxin B, cephaloridine, and amphotericin B. The dose of subsequent narcotic agents may be reduced.

Concomitant use of Yumerox**®** Ingal with central nervous system (CNS) depressants such as opioids may result in additive CNS depression. If opioids are administered concurrently with Yumerox**®** Ingal, careful monitoring of the patient is required, which is standard clinical practice when using opioids.

Enzyme inducers (such as barbiturates, alcohol, isoniazid, phenobarbital, or rifampicin), which accelerate the metabolism of methoxyflurane, may increase its potential toxicity; therefore, concomitant use of these agents with methoxyflurane should be avoided.

Intravenous adrenaline (epinephrine) or noradrenaline (norepinephrine) should be administered with caution during methoxyflurane use.

Interaction with β-blockers may be associated with an increased risk of arterial hypotension.

Special precautions for use.

Hepatic impairment

Methoxyflurane should not be administered to patients showing signs of liver damage, particularly following previous anaesthesia with methoxyflurane or halothane.

There have also been isolated reports of hepatic dysfunction, jaundice, and fatal hepatic necrosis associated with the use of methoxyflurane.

Renal impairment

Due to the effect of released fluoride on the distal tubules, methoxyflurane causes dose-dependent renal dysfunction and may lead to polyuric or oliguric renal failure, with oxaluria being the main characteristic.

Because of its potential nephrotoxic effect, methoxyflurane should not be used as an anaesthetic agent. The risk is related to the total dose (duration and concentration) and repeated administration.

Methoxyflurane causes dose-dependent renal impairment.

The nephrotoxicity of methoxyflurane is higher than that of other halogenated anaesthetics due to its slower metabolism over several days, resulting in prolonged release of fluoride ions and metabolism into other potentially nephrotoxic substances. Therefore, the lowest effective dose of methoxyflurane should be administered, particularly in elderly patients or those with obesity.

Due to its nephrotoxic potential, daily use of methoxyflurane is not recommended.

Patients with diabetes mellitus

Patients with diabetes mellitus who have renal impairment or polyuria, are obese, or have not achieved optimal disease control may have an increased risk of developing nephropathy.

Elderly patients

Due to the possible reduction in arterial blood pressure or heart rate, methoxyflurane should be used with caution in elderly patients.

Respiratory depression

Respiratory depression has been reported with the use of anaesthetic doses of methoxyflurane. Respiratory function should be monitored due to the risk of respiratory depression and hypoxia.

Neurotoxicity in children

Some published studies in children have reported cognitive deficits following repeated or prolonged exposure to anaesthetics at an early age. These studies have significant limitations, and it is unclear whether the observed effects are due to the use of anaesthetic/sedative/analgesic agents or to other factors such as surgery or the underlying condition.

Published animal studies with certain anaesthetic/sedative/analgesic agents have reported adverse effects on early brain development and during late pregnancy. The clinical relevance of these non-clinical findings has not yet been established.

When inhaled or infused, the effect of such agents lasts longer than the period of inhalation or infusion. Depending on the characteristics of the agent, patient-specific factors, and the dose used, the elimination phase may be prolonged relative to the duration of administration.

Butylhydroxytoluene

Yumerox® Inhale contains the excipient butylhydroxytoluene (E 321), which acts as a stabilizer. Butylhydroxytoluene may cause local skin reactions (e.g. contact dermatitis) or irritation of the eyes and mucous membranes.

Occupational exposure

Healthcare workers who are regularly exposed to patients using inhalation devices for methoxyflurane should follow appropriate occupational health and safety guidelines for handling inhaled anaesthetics. To reduce occupational exposure, the Yumerox® Inhale individual inhaler device contains an integrated activated charcoal (AC) chamber. Patients should be instructed to exhale exclusively into the Yumerox® Inhale individual inhaler device so that exhaled vapours pass through the activated charcoal chamber, which adsorbs residual methoxyflurane. Repeated use of the Yumerox® Inhale individual inhaler device without replacing the AC chamber increases the risk. Increased levels of liver enzymes, blood urea nitrogen, and serum uric acid have been reported in healthcare staff in maternity units when methoxyflurane was previously used in parturient women.

There have been reports of mild and transient reactions such as dizziness, headache, nausea, or malaise, as well as hypersensitivity reactions to methoxyflurane or other components of the medicinal product in healthcare workers exposed to methoxyflurane.

Effect on laboratory test results

No data available.

Use during pregnancy or breastfeeding.

Fertility

No data available.

Pregnancy

Published animal studies with certain anaesthetic/sedative/analgesic agents have reported adverse effects on brain development in early life and during late pregnancy.

Published studies in pregnant and sexually immature animals have shown that the use of anaesthetic/sedative/analgesic agents that block NMDA receptors and/or potentiate gamma-aminobutyric acid (GABA) activity during periods of rapid brain growth or synaptogenesis may lead to neuronal and oligodendrocyte cell loss in the developing brain and changes in synaptic morphology and neurogenesis when administered for more than 3 hours. These studies involved anaesthetics from various classes.

All general anaesthetics cross the placenta and may cause central nervous system and respiratory depression in the newborn. In standard clinical practice, this is not usually a concern; however, in fetuses with abnormalities, the potential for such depression should be considered, and appropriate anaesthetic agents, doses, and methods should be carefully selected.

In newborns whose mothers received methoxyflurane for analgesia during labour, a transient increase in serum uric acid levels has been observed, which did not require further intervention.

Pregnancy toxemia

Due to the potential for renal dysfunction, the use of methoxyflurane is not recommended.

Breastfeeding

Caution should be exercised when administering methoxyflurane to a breastfeeding mother.

Ability to affect reaction speed when driving or operating machinery.

The decision regarding when patients may resume activities requiring full attention, such as operating dangerous machinery or driving, depends on the individual patient. Patients should be advised to be particularly cautious as pedestrians and should refrain from driving or operating machinery until the effects of the medicinal product, such as drowsiness, have completely subsided. The decision to resume such activities as driving or operating machinery remains at the discretion of the physician.

Method of Administration and Dosage

FOR ANALGESIC USE ONLY (SEE SECTION "CONTRAINDICATIONS").

Dosing

One cartridge containing 3 mL of the medicinal product Yumeroks® Ingal should be vaporized using the individual inhalation device Yumeroks® Ingal.

If the content of the first cartridge is exhausted, a second cartridge may be used. Up to 6 mL of the medicinal product may be administered per day. Cartridge replacement should be performed in a well-ventilated area to minimize exposure of the surrounding environment to vapors of the medicinal product Yumeroks® Ingal.

For maximum safety, the lowest effective dose of the medicinal product Yumeroks® Ingal should be used for analgesia, especially in children and elderly patients.

The total dose for a patient should not exceed 15 mL within one week.

It is not recommended to use the medicinal product for several consecutive days.

Cumulative dose received by patients receiving intermittent doses of the medicinal product Yumeroks® Ingal during painful procedures (such as wound dressing) must be carefully monitored to ensure that the recommended dose of Yumeroks® Ingal is not exceeded.

Exceeding the recommended dose of the medicinal product Yumeroks® Ingal may cause renal failure. Renal failure caused by the medicinal product Yumeroks® Ingal is typically irreversible.

Method of Administration

Yumeroks® Ingal should be administered independently under supervision or, if necessary, with assistance from a qualified healthcare professional who has appropriate experience, medical education, and is proficient in the technique of using the individual inhalation device Yumeroks® Ingal.

1. Attach the mouthpiece to the outlet port of the device; place the nose clip on the patient’s nose to prevent nasal breathing.
2. Press the button on top of the device firmly with the thumb until it stops to introduce the inhalation liquid into the device.
3. Prior to use, gently shake (rotate) the device to ensure better distribution and vaporization of the medicinal product Yumeroks® Ingal.
4. The device is ready for use.
5. The patient should begin inhaling the medicinal product Yumeroks® Ingal 5 minutes before the start of the procedure and continue throughout its duration.
6. The first 2–3 inhalations should be shallow; thereafter, inhalations should be performed as usual. Exhalations must be directed only through the mouthpiece into the device, as residual substance from exhalation is retained by the adsorbent in the deactivation chamber within the device housing.
7. The patient should be instructed to inhale intermittently and may independently stop breathing through the device once adequate analgesia is achieved. When pain sensation returns, the patient may independently resume breathing through the device. Continuous administration will shorten the duration of analgesia. The patient should use the lowest effective dose of the medicinal product.
8. After use, the medical device should be disposed of according to local waste disposal regulations.

When using a second cartridge

1. Remove the button from the device.
2. Insert the cartridge containing the medicinal product Yumeroks® Ingal.
3. Reinstall the button into its original position. Continue use according to the instructions provided above, starting from point №1 of the section "Method of Administration and Dosage".

Children

To be used in children aged 6 years and older. Data on the use of methoxyflurane via the inhalation device for methoxyflurane are limited. The lowest effective analgesic dose should be used in children.

Overdose

Adverse reactions include those related to anesthetic doses (see section "Adverse Reactions").

In case of overdose, anesthetic effects may occur, characterized by excessive drowsiness (including loss of consciousness), decreased arterial pressure, respiratory depression, pallor, and muscle relaxation. After discontinuation of methoxyflurane, these effects usually resolve rapidly, often without intervention; however, if necessary, supportive measures for cardiovascular and respiratory functions may be required.

High doses of methoxyflurane cause dose-dependent nephrotoxicity. Severe renal failure has occurred several hours or days after repeated administration of high analgesic or anesthetic doses of methoxyflurane.

In case of excessive diuresis following overdose, fluid and electrolyte losses should be promptly corrected.

Adverse Reactions

Data regarding the dose-dependent nature of most adverse reactions to the medicinal product are lacking.

Use of methoxyflurane in patients with trauma and associated pain

The table below describes treatment-emergent adverse events observed in ≥ 1% of the safety population in a placebo-controlled study involving patients with trauma and associated pain.

Treatment-emergent adverse events occurring in > 1% of the safety population are listed by system organ class and preferred terms.

Gastrointestinal disorders	Dry mouth, nausea, toothache, vomiting
General disorders and administration site conditions	Influenza-like symptoms, feeling drunk
Infections and infestations	Influenza, nasopharyngitis, viral infection
Injury, poisoning and procedural complications	Fall, ligament sprain
Investigations	Increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood lactate dehydrogenase
Musculoskeletal and connective tissue disorders	Back pain
Nervous system disorders	Amnesia, dizziness, dysarthria, headache, migraine, somnolence
Reproductive system and breast disorders	Dysmenorrhea
Respiratory, thoracic and mediastinal disorders	Cough, oropharyngeal pain
Skin and subcutaneous tissue disorders	Rash
Vascular disorders	Arterial hypotension

The list below presents adverse reactions (adverse effects related to treatment) that occurred less frequently than those in the table above. They are listed by system organ class and frequency [common (from ≥ 1/100 to < 1/10), uncommon (from ≥ 1/1000 to < 1/100), and rare (from ≥ 1/10000 to < 1/1000)].

Neurological disorders

Uncommon: dysgeusia, paraesthesia.

Gastrointestinal disorders

Uncommon: oral discomfort.

General disorders and administration site conditions

Uncommon: fatigue, malaise, feeling of relaxation, hangover, hunger, chills.

Eye disorders

Uncommon: diplopia.

Psychiatric disorders

Uncommon: inappropriate affect.

Use of methoxyflurane in patients requiring analgesia during surgical procedures

The table below describes drug-related events observed in ≥ 2% of the safety population in a placebo-controlled study involving patients undergoing minor surgical procedures.

Adverse reactions within 30–45 minutes after the procedure	Dizziness, euphoria, nausea, excessive sweating, dysgeusia, facial flushing, arterial hypertension, anxiety, depression, sensory neuropathy, drowsiness/suppressed level of consciousness, vomiting
Adverse reactions within 48 hours after the procedure	Nausea, drowsiness/suppressed level of consciousness, confusion, anxiety, vomiting, musculoskeletal and connective tissue disorders

Post-marketing experience

Additional adverse reactions associated with analgesia have also been described in the literature.

Neurological disorders: altered state of consciousness, nystagmus.

Respiratory, thoracic and mediastinal disorders: choking, hypoxia, respiratory depression.

Hepatobiliary disorders: hepatic failure, hepatitis, jaundice, liver damage.

Renal and urinary disorders: renal failure.

Eye disorders: blurred vision.

Psychiatric disorders: affective lability, excitement, confusion, dissociation, restlessness.

Vascular disorders: fluctuations in blood pressure.

Investigations: increased blood uric acid level, increased blood urea level, increased blood creatinine level, increased liver enzyme levels.

Hepatotoxicity associated with methoxyflurane is rare but has been observed with the use of analgesic agents.

In the past, the following adverse reactions have been reported with the use of methoxyflurane as an anaesthetic.

Common: retrograde amnesia, nausea, vomiting, cough, drowsiness, sleep, dizziness, smell aversion, fever, polyuria, headache.

Uncommon: non-specific hepatitis, malignant hyperthermia.

Other reported events: cardiac arrest, respiratory depression, laryngospasm, bronchospasm, arterial hypotension, bradycardia, renal failure, increased serum urea level, increased serum creatinine level, increased urinary oxalate excretion, increased serum inorganic fluoride level, pallor, muscle relaxation.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after the registration of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

3 ml in polymer cartridges, supplied with the Yumeroks® Ingal individual inhalation device and Yumeroks® Ingal procedural kit, in a cardboard box, 1 cartridge per box.

3 ml in 1 polymer cartridge № 1 in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and location of operations.

108, Kobzarska Street, Cherkasy, Cherkasy region, Ukraine. Tel.: (044) 281-01-01.

Marketing Authorization Holder.

LLC "Yuria-Pharm".

Address of the Marketing Authorization Holder.

10, M. Amosova Street, Kyiv, 03680, Ukraine.

In case of adverse reactions or questions regarding the safety and efficacy of the medicinal product, please contact the Pharmacovigilance Department of LLC "Yuria-Pharm" at: 10, M. Amosova Street, Kyiv, 03038, Ukraine,
Tel.: +38 (044) 275-15-66, +38 (095) 275-15-66.