Humeroxx®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT YUMEROX® (UMEROX®)

Composition:

Active substance: methoxyflurane;

1 vial (3 ml) contains methoxyflurane 99.9 %;

Excipient: butylhydroxytoluene (E 321).

Pharmaceutical form. Inhalation vapours, liquid.

Main physicochemical properties: clear, colourless liquid with a sweet fruity odour.

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

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Methoxyflurane belongs to the group of fluorinated volatile anesthetic hydrocarbons. It is a volatile liquid intended for vaporization and administration by inhalation via a methoxyflurane inhalation device.

Methoxyflurane vapors provide analgesia upon inhalation at low concentrations. Drowsiness may occur following administration of methoxyflurane. During methoxyflurane administration, heart rhythm is usually regular. Following methoxyflurane administration, myocardial sensitivity to adrenaline increases minimally. At superficial levels of analgesia, some reduction in arterial 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 free fluoride, oxalic acid, difluoromethoxyacetic acid, and dichloroacetic acid. Both free fluoride and oxalic acid may cause kidney damage when administered in high doses; however, dose-dependent nephrotoxicity observed with clinical doses appears to be associated with the combination of free fluoride and dichloroacetic acid.

Elimination

Approximately 20% of absorbed methoxyflurane is eliminated via exhaled air, while urinary excretion of organic fluorine, 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 component of Yumerox**®**.
• 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 use 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 with known nephrotoxic potential such as gentamicin, kanamycin, colistin, polymyxin B, cephaloridine, and amphotericin B. The dose of subsequent narcotic agents may need to be reduced.

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

Enzyme inducers (such as barbiturates, alcohol, isoniazid, phenobarbital, or rifampicin) that accelerate methoxyflurane metabolism 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

Administration of methoxyflurane is not recommended in patients with evidence of hepatic impairment, 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 release of fluoride and its effect on the distal tubules, methoxyflurane causes dose-dependent renal dysfunction and may lead to polyuric or oliguric renal failure, with oxaluria being the primary manifestation.

Because of the 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, especially in elderly patients or those with obesity.

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

Diabetic patients

Patients with diabetes mellitus who have renal impairment or polyuria, suffer from obesity, or have not achieved optimal disease control may be at increased risk of developing nephropathy.

Elderly patients

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

Respiratory depression

Respiratory depression has been reported with 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 administration of anaesthetic/analgesic/sedative agents or to other factors such as surgery or the underlying condition.

Published animal studies with certain anaesthetic/analgesic/sedative 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 may last 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 administration period.

Butylhydroxytoluene

Yumerox**®** 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 methoxyflurane inhalation devices should follow appropriate occupational health and safety guidelines for handling inhaled agents. To reduce occupational exposure to methoxyflurane, the inhalation device contains an integrated activated charcoal (AC) chamber. Patients should be instructed to exhale exclusively into the inhalation device so that exhaled vapours pass through the activated charcoal chamber, which adsorbs residual methoxyflurane. Repeated use of the inhalation 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 parturients.

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

Effect on laboratory test results

Data are lacking.

Use during pregnancy or breastfeeding.

Fertility

Data are lacking.

Pregnancy

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

Published studies in pregnant and sexually immature animals have shown that anaesthetic/analgesic/sedative agents that block NMDA receptors and/or potentiate gamma-aminobutyric acid (GABA) activity, when administered during periods of rapid brain growth or synaptogenesis, may result in neuronal and oligodendrocyte cell loss in the developing brain, as well as changes in synaptic morphology and neurogenesis, particularly after exposures exceeding 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 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 techniques should be carefully selected.

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

Pregnancy toxemia

Due to the probable risk of 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 vehicles, depends on the individual patient. Patients should be advised to be particularly cautious as pedestrians and should refrain from driving vehicles 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 physician's discretion.

Method of Administration and Dosage

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

Dosing

One 3 ml vial of Yumerox**®** medicinal product should be vaporized using a methoxyflurane inhalation administration device.

After completion of the first vial, a second vial may be used. Up to 6 ml of the medicinal product may be administered per day. Vial replacement should be performed in a well-ventilated area to minimize exposure to methoxyflurane vapors in the environment.

For maximum safety, the lowest effective analgesic dose of methoxyflurane should be used, particularly in children and elderly patients.

The total weekly dose for a patient should not exceed 15 ml.

The medicinal product is not recommended for consecutive daily use over several days.

Cumulative doses must be carefully monitored in patients receiving intermittent methoxyflurane doses during painful procedures (such as wound dressing changes) to ensure that the recommended methoxyflurane dose is not exceeded.

Exceeding the recommended dose of methoxyflurane may lead to renal failure. Methoxyflurane-induced renal failure is typically irreversible.

Method of Administration

Yumerox**®** should be administered under the supervision of a person (with assistance if necessary) who is trained in its use via a methoxyflurane inhalation administration device. The patient may self-administer the product.

Children

Use in children aged 6 years and older. Data on the use of methoxyflurane via the methoxyflurane inhalation administration device in children 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, manifesting as excessive drowsiness (including loss of consciousness), hypotension, respiratory depression, pallor, and muscle relaxation. After discontinuation of methoxyflurane, these effects usually resolve rapidly, often without intervention; however, supportive measures for cardiovascular and respiratory function may be required if necessary.

Administration of large methoxyflurane doses causes 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 on 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.

The following is a list of adverse reactions (treatment-related adverse effects) that occurred with a lower frequency than those in the table above. They are listed by system organ class and frequency [frequent (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), and rare (≥ 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 population in the safety evaluation from a placebo-controlled study involving patients undergoing minor surgical procedures.

Post-marketing use

Additional adverse reactions related to analgesia have also been described in the literature.

Nervous system disorders: altered state of consciousness, nystagmus.

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

Hepatobiliary disorders: liver 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 were reported when methoxyflurane was used as an anesthetic.

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

Rare: 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 of suspected adverse reactions

Reporting suspected adverse reactions after medicine registration is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, 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 below 30 °C. Keep in the original packaging and avoid exposure to high temperatures.

Keep out of reach of children.

Incompatibilities.

Incompatibility has either not been evaluated or not established during registration of this medicinal product.

Packaging.

3 ml in glass vials. 1 vial in a cardboard box. 5 vials in a blister pack, 2 blister packs in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Yuria-Pharm LLC.

Manufacturer's address and place of business.

108, Kobzarska St., Cherkasy, Cherkasy region, 18030, Ukraine. Tel.: (044) 281-01-01.