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Methoxyflurane is known chemically as 2, 2 - dichloro-1, 1-difluoroethyl methyl ether. The molecular formula is C3H4Cl2F2O and the molecular weight is 164.97.
Structural formula:
CAS registry: 76-38-0
A clear, almost colourless mobile liquid, with a characteristic odour. Soluble 1 in 500 of water; miscible with alcohol, acetone, chloroform, ether and fixed oils. It is soluble in rubber. Store in airtight containers at a temperature not exceeding 40°C. Protect from light. The flash point in oxygen is 32.8°C. The concentration to reach flash point is usually not achieved under normal circumstances.
Methoxyflurane belongs to the fluorinated hydrocarbon group of volatile anesthetic agents. It is a volatile liquid intended for vaporization and administration by inhalation using appropriate equipment or devices. At low concentrations the inhaled vapour is used to provide analgesia in conscious patients or in patients undergoing anesthesia. Methoxyflurane has a mildly pungent odour.
| SOME OF THE PHYSICAL CONSTANTS ARE: | |
|---|---|
| Molecular weight | 164.97 |
| Boiling Point at 760 mm Hg | 104.97°C |
| Partition coefficients at 37°C | |
| Water/gas | 4.5 |
| Blood/gas (mean range) | 10.20 to 14.06 |
| Oil/gas | 825 |
| Vapour pressure 17.7°C | 20 mm Hg |
| Flash points | |
| In air | 62.8°C |
| In oxygen (closed system) | 32.8°C |
| In N2O 50% | 28.2°C |
| Lower limit of flammability of vapour concentration | |
| In air | 7.0% |
| In oxygen | 5.4% |
| In N2O 50% | 4.6% |
Methoxyflurane is stable and does not decompose in contact with soda lime. An antioxidant, Butylated Hydroxy toluene 0.01% w/w is added to ensure stability on standing. As polyvinyl chloride plastics are extracted by methoxyflurane contact should be avoided. Methoxyflurane does not extract polyethylene plastics, polypropylene plastics, fluorinated hydrocarbon plastics or nylon.
The vapour concentration of methoxyflurane is limited by its vapour pressure at room temperature to a maximum of about 3.5% at 23°C. In practice, this concentration is not reached due to the cooling effect of vaporization. Methoxyflurane is not flammable except at vapour concentrations well above those recommended for its use. Recommended concentrations are non flammable and non-explosive in air, oxygen and nitrous oxide mixtures at ordinary room temperature.
Methoxyflurane vapour provides analgesia when inhaled at low concentrations. After methoxyflurane administration, drowsiness may occur. During methoxyflurane administration, the cardiac rhythm is usually regular. The myocardium is only minimally sensitized to adrenaline by methoxyflurane. In light planes of anesthesia some decrease in blood pressure may occur. This may be accompanied by bradycardia. The hypotension noted is accompanied by reduced cardiac contractile force and reduced cardiac output.
Biotransformation of methoxyflurane occurs in man. As much as 50-70% of the absorbed dose is metabolized to free fluoride, oxalic acid, difluoromethoxyacetic acid, and dichloroacetic acid. Both the free fluoride and the oxalic acid can cause renal damage. Methoxyflurane is more susceptible to metabolism than other halogenated methyl ethyl ethers and has greater propensity to diffuse into fatty tissues. Hence methoxyflurane is released slowly from this reservoir and becomes available for biotransformation for many days. Approximately 20% of methoxyflurane uptake is recovered in the exhaled air, while urinary excretion of organic fluorine, fluoride and oxalic acid accounts for about 30% of the methoxyflurane uptake. Studies have shown that higher peak blood fluoride levels are obtained earlier in obese than in non-obese and in the elderly.
Self administration to conscious haemodynamically stable patients with trauma and associated pain, under supervision of personnel trained in its use (see Dosage and Administration)
Monitored conscious patients who require analgesia for the relief of pain in short surgical procedures such as the change of dressings (See Dosage and Administration)
Note: the total maximum dose must not be exceeded.
Renal disease: Methoxyflurane should be used with caution in patients with renal disease. Because of the potential nephrotoxic effects in high concentrations, methoxyflurane must not be used as a sole anesthetic agent. The risk is related to the totals dose (time and concentration). This syndrome is related to the serum concentrations of the oxalate and free fluoride ion, metabolic by-products of methoxyflurane and is generally irreversible. Therefore the lowest effective dose of methoxyflurane should be administered, especially in aged or obese patients.
Liver disease: it is advisable not to administer methoxyflurane to patients who have shown signs of liver damage after previous methoxyflurane or halothane anesthesia.
Diabetic patients: may have an increased likelihood of developing nephropathy if they have impaired renal function or polyuria, are obese, or are not optimally controlled.
Daily use of methoxyflurane is not recommended because of nephrotoxic potential.
In patients under treatment with enzyme inducing drugs (e.g. barbiturates) the metabolism of methoxyflurane may be enhanced resulting in increased fluoride levels.
Adrenaline or nor-adrenaline should be employed cautiously during methoxyflurane administration.
Malignant hyperthermia: Caution in patients with known or genetically susceptibility to malignant hypothermia.
Caution in hot climates: Do not expose to temperatures above 40°C, especially when used in conjunction with oxygen.
Use in the elderly: Caution should be exercised in the elderly due to possible reduction in blood pressure or heart rate.
Caution should be exercised in the following circumstances due to the possibility of increased free fluoride and oxalic acid levels - See Pharmacology
Health workers who are regularly exposed to patients using Penthrox inhalers should be aware of any relevant occupational health and safety guidelines for the use of inhalational anaesthetic agents. The use of methods to reduce occupational exposure to methoxyflurane should be considered.
When discharged after methoxyflurane administration, patients should be cautioned not to drive motor vehicles or bicycles, operate hazardous machinery or engage in hazardous sports for 24 hours or more (depending on total dosage of methoxyflurane, condition of patient and consideration given to other drugs administered).
All general anesthetics cross the placenta and carry the potential to produce central nervous system and respiratory depression in the new born infant. In routine practice this dose does not appear to be a problem; however in a compromised foetus, careful consideration should be given to this potential depression, and to the selection of anesthetic drugs, doses and techniques.
Toxemia of pregnancy: It is advisable not to administer methoxyflurane due to the possibility of existing renal impairment.
Caution should be exercised when methoxyflurane is administered to a nursing mother.
The concurrent use of tetracycline and methoxyflurane for anesthesia has been reported to result in fatal renal toxicity. The possibility exists that methoxyflurane may enhance the adverse renal effects of other drugs including certain antibiotics of known nephrotoxic potential such as gentamicin, kanamycin, colistin, polymyxin b, cephaloridine and amphotericin b. Dosage for the subsequent administration of narcotics may be reduced.
Note: Use in anesthesia is contraindicated. No systemic data have been collected on the frequency or nature of adverse drug reactions of methoxyflurane when used as an analgesic. There are no data on the dose-dependency of the adverse drug reactions, therefore all documented adverse reactions are possible, however no statement regarding frequency can be made.
When used as an anaesthetic:
i)Common: retrograde amnesia, nausea, vomiting, coughing, drowsiness, sleeping, dizziness, dislike of odour, fever, polyuria, headache.
ii)Rare: non-specific hepatitis, malignant hypothermia
iii)Other reported events: cardiac arrest, respiratory depression, laryngospasm, bronchospasm, hypotension, bradycardia, renal failure, increased serum urea, increased serum creatinine, increased urinary oxalate excretion, increased serum inorganic fluoride, pallor, muscle relaxation
Hepatic toxicity in association with methoxyflurane is rare but has been observed with analgesic use.
FOR USE ONLY AS AN ANALGESIC AGENT, SEE "PRECAUTIONS"
Dosage: Up to 6 mL of Penthrox® (methoxyflurane) per day, vaporized in an appropriate device. The lowest effective dosage of Penthrox® (methoxyflurane) to provide analgesia should be used. Intermittent inhalation of vapour concentrations in the range of 0.2 to 0.7% is recommended. The total weekly dose should not exceed 15 mL. Administration of consecutive days is not recommended. (See Precautions).
The cumulative dose received by patients receiving intermittent doses of Penthrox® (methoxyflurane) for painful procedures (such as wound dressings) must be carefully monitored to ensure that the recommended dose of methoxyflurane is not exceeded
Methoxyflurane may cause renal failure if the recommended dose is exceeded. Methoxyflurane-associated renal failure is generally irreversible.
Administration:
Penthrox® (Methoxyflurane) is self-administered under observation (and assisted if necessary) by a person trained in the administration of anesthesia or emergency care., using the hand held inhaler (The Penthrox™ Inhaler) or plenum vaporizer (e.g. the Komesaroff VIC vaporizer). If available, oxygen can be administered simultaneously. (See Precautions and Description)
Adverse effects will include those for anesthetic doses, see Adverse Reactions.
Patients should be observed for signs of drowsiness, pallor and muscle relaxation following methoxyflurane administration. In the event of excessive urinary output following overdosage, fluid and electrolyte losses should be promptly replaced.
Penthrox® (Methoxyflurane) is supplied in a 3 mL sealed bottle with a tear off tamper seal (pack of 10), combination blister pack with one 3 mL sealed bottle and one Penthrox® Inhaler (pack of 10), combination blister pack with two 3 mL sealed bottles and one Penthrox™ Inhaler (pack of 10) and in a 125 mL sealed bottle with tear tamper seal.
Store below 30°C
Prescription Medicine
Medical Developments International Pty. Ltd.
Factory 7, 56 Smith Road
Springvale 3171
Melbourne Australia
Tel: 61-3-9547 1888 Fax: 61-3-9547 0262
New Zealand Medical and Scientific Ltd.
P O Box 24-138
Royal Oak
2A
Fisher Crescent
Mt Wellington
Auckland
New Zealand
Tel: 64-9 259 4062
Fax: 64-9 259 4067
29 May 2007
Issue No. 2