PENTHROX^®

MIMS Revision Date: 01 November 2023

1 Name of Medicine

Methoxyflurane.

2 Qualitative and Quantitative Composition

Each bottle contains 99.9% methoxyflurane.
Methoxyflurane belongs to the fluorinated hydrocarbon group of volatile anaesthetic agents. It is a volatile liquid intended for vaporisation and administration by inhalation using the Penthrox Inhaler. At low concentrations the inhaled vapour is used to provide analgesia in stable, conscious patients.

3 Pharmaceutical Form

Methoxyflurane is a clear, almost colourless mobile liquid, with a characteristic odour that is mildly pungent (also see Section 6.7 Physicochemical Properties).

4 Clinical Particulars

4.1 Therapeutic Indications

1. For emergency relief of pain by self administration in conscious haemodynamically stable patients with trauma and associated pain, under supervision of personnel trained in its use (see Section 4.2 Dose and Method of Administration).
2. For the relief of pain in monitored conscious patients who require analgesia for surgical procedures such as the change of dressings (see Section 4.2 Dose and Method of Administration).
Note. The total maximum dose must not be exceeded.

4.2 Dose and Method of Administration

For use only as an analgesic agent (see Section 4.3 Contraindications).
Dosage. One bottle of Penthrox (3 mL) to be vaporised in a Penthrox Inhaler. On finishing the initial bottle, another bottle may be used. Up to 6 mL may be administered per day. The refilling must be conducted in a well ventilated area to reduce environmental exposure to methoxyflurane vapour.
To maximise safety, the lowest effective dosage of Penthrox (methoxyflurane) to provide analgesia should be used, particularly for children and the elderly. The total weekly dose should not exceed 15 mL. Administration on consecutive days is not recommended.
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.
Method of administration. Penthrox (methoxyflurane) is self administered under supervision (and assisted if necessary) by a person trained in its administration using the handheld Penthrox Inhaler.
Instructions on the preparation of the Penthrox Inhaler and correct administration are provided below.
How to use the Penthrox inhaler. 1. Ensure the activated carbon (AC) chamber (where applicable) is inserted into the dilutor hole on the top of the Penthrox Inhaler.
2. Holding the methoxyflurane bottle upright, use the base the Penthrox Inhaler to loosen the cap with a ½ turn. Separate the inhaler from the bottle and remove the cap by hand.
3. Tilt the Penthrox Inhaler to a 45° angle and pour the contents of one bottle into the base whilst rotating.
4. Place wrist loop over patient's wrist. Patient inhales through the mouthpiece of inhaler to obtain analgesia. First few breaths should be gentle and then breathe normally through inhaler.
5. Patient exhales into inhaler. The exhaled vapour passes through the AC chamber to adsorb any exhaled methoxyflurane.
6. If stronger analgesia is required, patient can cover dilutor hole with finger during inhalation.
7. Patient should be instructed to inhale intermittently to achieve adequate analgesia. Continuous administration will reduce time of analgesia. Patients should be administered minimum dose.
8. Replace cap onto Penthrox bottle. Place used Penthrox Inhaler and used bottle in sealed plastic bag and dispose of responsibly (see Section 6.6 Special Precautions for Disposal).

4.3 Contraindications

Use as an anaesthetic agent.
Renal impairment, including reduced glomerular filtration rate (GFR), urine output and reduced renal blood flow.
Renal failure.
Hypersensitivity to methoxyflurane, any fluorinated anaesthetic or to any of the excipients listed in Section 6.1.
Cardiovascular instability.
Respiratory depression.
Head injury or loss of consciousness.
A history of possible adverse reactions in either patient or relatives.
Malignant hyperthermia: patients with known or genetically susceptible to malignant hyperthermia.

4.4 Special Warnings and Precautions for Use

Use in hepatic impairment. It is advisable not to administer methoxyflurane to patients who have shown signs of liver damage, especially after previous methoxyflurane or halothane anaesthesia.
There have also been occasional reports of hepatic dysfunction, jaundice, and fatal hepatic necrosis associated with methoxyflurane use.
Renal impairment. Methoxyflurane impairs renal function in a dose related manner due to the effect of the released fluoride on the distal tubule and may cause polyuric or oliguric renal failure, oxaluria being the prominent feature.
Because of the potential nephrotoxic effects methoxyflurane must not be used as an anaesthetic agent. The risk is related to the total dose (time and concentration) and frequent exposure. Methoxyflurane impairs renal function in a dose related manner.
Nephrotoxicity is greater with methoxyflurane than with other halogenated anaesthetics because of the slower metabolism over several days resulting in prolonged production of fluoride ions and metabolism into other potentially nephrotoxic substances. Therefore the lowest effective dose of methoxyflurane should be administered, especially in elderly or obese patients.
Daily use of methoxyflurane is not recommended because of nephrotoxic potential.
Diabetic patients. 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.
Use in the elderly. Caution should be exercised in the elderly due to possible reduction in blood pressure or heart rate.
Respiratory depression. Respiratory depression has been reported also from analgesic doses of methoxyflurane. Respiration should be monitored due to the risk of respiratory depression and hypoxia.
Paediatric use. Limited data is available regarding the administration of methoxyflurane using the Penthrox Inhaler. The minimum effective dose to produce analgesia should be administered to children.
Paediatric neurotoxicity. Some published studies in children have observed cognitive deficits after repeated or prolonged exposures to anaesthetic agents early in life. These studies have substantial limitations, and it is not clear if the observed effects are due to the anaesthetic/analgesic/sedation drug administration or other factors such as the surgery or underlying illness.
Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy. The clinical significance of these nonclinical finding is yet to be determined.
With inhalation or infusion of such drugs, exposure is longer than the period of inhalation or infusion. Depending on the drug and patient characteristics, as well as dosage, the elimination phase may be prolonged relative to the period of administration.
Occupational exposure. Healthcare professionals 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 agents. To reduce occupational exposure to methoxyflurane, the Penthrox Inhaler should be used with the activated carbon (AC) chamber. Patients should be instructed to exhale into the Penthrox Inhaler so the exhaled vapour passes through the AC chamber which adsorbs exhaled methoxyflurane. Multiple use of Penthrox Inhaler without the AC chamber creates additional risk. Elevation of liver enzymes, blood urea nitrogen and serum uric acid have been reported in exposed maternity ward staff in delivery wards when methoxyflurane was used in the past in obstetric patients at the time of labour and delivery.
There have been reports of non-serious and transient reactions such as dizziness, headache, nausea or malaise, and reports of hypersensitivity reactions to methoxyflurane or other ingredients in healthcare professionals exposed to Penthrox.
Effects on laboratory tests. No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The concurrent use of tetracycline and methoxyflurane for anaesthesia 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.
Concomitant use of Penthrox with CNS depressants e.g. opioids may produce additive depressant effects. If opioids are given concomitantly with Penthrox, the patient should be observed closely, as is normal clinical practice with opioids.
It is possible that enzyme inducers (such as barbiturates, alcohol, isoniazid, phenobarbital or rifampicin) which increase the rate of methoxyflurane metabolism might increase its potential toxicity and they should be avoided concomitantly with methoxyflurane.
Intravenous adrenaline or nor-adrenaline should be employed cautiously during methoxyflurane administration.
Interactions may occur with β-blockers, with an increased risk of hypotension.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility. No data available.
Use in pregnancy. (Category C)
Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy.
Published studies in pregnant and juvenile animals demonstrate that the use of anaesthetic/analgesic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of rapid brain growth or synaptogenesis may result in neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis when used for longer than 3 hours. These studies included anaesthetic agents from a variety of drug classes.
All general anaesthetics cross the placenta and carry the potential to produce central nervous system and respiratory depression in the newborn 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 anaesthetic drugs, doses and techniques.
Neonates delivered of mothers who used methoxyflurane analgesia for childbirth had a briefly raised serum uric acid, not requiring further intervention.
Toxaemia of pregnancy. It is advisable not to administer methoxyflurane due to the possibility of existing renal impairment.
Use in lactation. Caution should be exercised when methoxyflurane is administered to a nursing mother.

4.7 Effects on Ability to Drive and Use Machines

The decision as to when patients may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualised. Patients should be warned to take extra care as a pedestrian and not to drive a vehicle or operate a machine until the patient has completely recovered from the effects of the drug, such as drowsiness. The treating doctor should decide when activities such as driving a vehicle or operating a machine may be resumed.

4.8 Adverse Effects (Undesirable Effects)

There are no data on the dose dependency of most of the adverse drug reactions.
Use of Penthrox in patients with trauma and associated pain. Table 1 provides treatment emergent adverse events experienced by ≥ 1% of the safety population of a placebo controlled study in patients with trauma and associated pain, of which 149 had Penthrox.

In listings below, are adverse reactions (adverse effects that are related to the treatment) which occurred at a rate lower than in Table 1. They are listed by system organ class and frequency (common ≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 to < 1/100; and rare ≥ 1/10,000 to < 1/1,000).
Nervous system disorders. Uncommon: dysgeusia, paraesthesia.
Gastrointestinal disorders. Uncommon: oral discomfort.
General disorders and administration site conditions. Uncommon: fatigue, feeling abnormal, feeling of relaxation, hangover, hunger, shivering.
Eye disorders. Uncommon: diplopia.
Psychiatric disorders. Uncommon: inappropriate affect.
Use of Penthrox for pain relief in patients who require it for surgical procedures. Table 2 provides drug associated events (adverse reactions) experienced by ≥ 2% of the safety population of a placebo controlled study in patients in a minor surgical procedure, of which 49 had Penthrox for the relief of pain.
Post-marketing. The following additional adverse effects have also been reported in the literature and patients receiving analgesia.
Nervous system disorders. Altered state of consciousness, nystagmus.
Respiratory, thoracic and mediastinal disorders. Choking, hypoxia, respiratory depression.
Hepatobiliary disorders. Hepatic failure, hepatitis, jaundice, liver injury.
Renal and urinary disorders. Renal failure.
Eye disorders. Vision blurred.
Psychiatric disorders. Affect lability, agitation, confusional state, dissociation, restlessness.
Vascular disorders. Blood pressure fluctuation.
Investigations. Blood uric acid increased, blood urea increased, blood creatinine increased, hepatic enzymes increased.
Hepatic toxicity in association with methoxyflurane is rare but has been observed with analgesic use.
The following adverse effects have been reported in association with historical use as an anaesthetic.
(i) Common: retrograde amnesia, nausea, vomiting, coughing, drowsiness, sleeping, dizziness, dislike of odour, fever, polyuria, headache.
ii) Rare: nonspecific hepatitis, malignant hyperthermia.
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.
Reporting suspected adverse effects. Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspect adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Adverse effects will include those for anaesthetic doses, see Section 4.8 Adverse Effects (Undesirable Effects).
In the event of overdose, anaesthetic effects may occur with signs of excessive drowsiness, (including loss of consciousness), lowering of blood pressure, respiratory depression, pallor and muscle relaxation. After Penthrox discontinuation such overdose effects usually resolve quickly often with no other intervention required but cardiorespiratory supportive measures can be implemented if necessary.
High doses of methoxyflurane cause dose related nephrotoxicity. High output renal failure has occurred several hours or days after the administration of repeated high analgesic or anaesthetic doses of methoxyflurane.
In the event of excessive urinary output following overdosage, fluid and electrolyte losses should be promptly replaced.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action. 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 sensitised to adrenaline by methoxyflurane. In light planes of anaesthesia 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.
Clinical trials. No data available.

5.2 Pharmacokinetic Properties

Distribution. 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.
Metabolism. Biotransformation of methoxyflurane occurs in man. As much as 50-70% of the absorbed dose is metabolised to free fluoride, oxalic acid, difluoromethoxyacetic acid, and dichloroacetic acid. Both the free fluoride and the oxalic acid can cause renal damage in large doses, however dose related nephrotoxicity seen with clinical doses appears related to a combination of free fluoride and dichloroacetic acid.
Excretion. 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 nonobese and in the elderly.

5.3 Preclinical Safety Data

Genotoxicity. No data available.
Carcinogenicity. No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Butylated hydroxytoluene.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Penthrox (methoxyflurane) is supplied in the following presentations:
a) Pack of ten 3 mL bottles;
b) Combination Pack containing one 3 mL bottle, one Penthrox Inhaler and Activated Carbon (AC) Chamber;
c) Combination Pack (Starter Pack) containing one 3 mL bottle, one Penthrox Inhaler and Activated Carbon (AC) Chamber;
d) Single Combination Pack containing ten 3 mL bottles and ten Penthrox Inhalers;
e) Double Combination Pack containing two 3 mL bottles, one Penthrox Inhaler and Activated Carbon (AC) Chamber (Pack of ten);
f) Combination Pack containing one 1.5 mL bottle, one Penthrox Inhaler and Activated Carbon (AC) Chamber;
g) Single Combination Pack containing ten 1.5 mL bottles and ten Penthrox Inhalers.
Not all packs may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Methoxyflurane is known chemically as 2,2-dichloro-1,1-difluoro-1-methoxyethane. The molecular formula is C₃H₄Cl₂F₂O and the molecular weight is 164.97. Methoxyflurane is soluble 1 in 500 of water; miscible with alcohol, acetone, chloroform, ether and fixed oils. It is soluble in rubber. The flash point in oxygen is 32.8°C. The concentration to reach flash point is usually not achieved under normal circumstances.
Some of the physical constants are in Table 3.

Methoxyflurane is stable and does not decompose in contact with soda lime. An antioxidant, butylated hydroxytoluene (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 vaporisation. 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 and oxygen at ordinary room temperature.
Chemical structure.
CAS number. 76-38-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Date of First Approval

18 January 1993

Date of Revision

06 October 2023