Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Medical Developments UK Limited, c/o Price Bailey LLP, Causeway House, 1 Dane Street, Bishops Stortford, Herts CM23 3BT, United Kingdom
Use as an anaesthetic agent.
Hypersensitivity to methoxyflurane, any fluorinated anaesthetic or to any of the excipients listed in section 6.1.
Malignant hyperthermia: patients who are known to be or genetically susceptible to malignant hyperthermia.
Patients or patients with a known family history of severe adverse reactions after being administered with inhaled anaesthetics.
Patients who have a history of showing signs of liver damage after previous methoxyflurane use or halogenated hydrocarbon anaesthesia.
Clinically significant renal impairment.
Altered level of consciousness due to any cause including head injury, drugs, or alcohol.
Clinically evident cardiovascular instability.
Clinically evident respiratory depression.
To ensure the safe use of PENTHROX as an analgesic the following precautions should be observed.
Methoxyflurane causes significant nephrotoxicity at high doses. Nephrotoxicity is thought to be associated with inorganic fluoride ions, a metabolic breakdown product. When administered as instructed for the analgesic indication, a single dose of 3 ml methoxyflurane produces serum levels of inorganic fluoride ions below 10 micromol/l. In the past when used as an anaesthetic agent, methoxyflurane at high doses caused significant nephrotoxicity, which was determined to occur at serum levels of inorganic fluoride ions greater than 40 micromol/l. Nephrotoxicity is also related to the rate of metabolism. Therefore factors that increase the rate of metabolism such as drugs that induce hepatic enzymes can increase the risk of toxicity with methoxyflurane as well as sub-groups of people with genetic variations that may result in fast metaboliser status (see section 4.5).
Methoxyflurane is metabolised in the liver, therefore increased exposures in patients with hepatic impairment can cause toxicity. PENTHROX must not be used in patients who have a history of showing signs of liver damage after previous methoxyflurane use or halogenated hydrocarbon anaesthesia (see section 4.3). PENTHROX should be used with care in patients with underlying hepatic conditions or with risks for hepatic dysfunction (such as enzyme inducers – see also section 4.5).
It has been reported that previous exposure to halogenated hydrocarbon anaesthetics (including methoxyflurane when used in the past as an anaesthetic agent), especially if the interval is less than 3 months, may increase the potential for hepatic injury.
Cautious clinical judgement should be exercised when PENTHROX is to be used more frequently than on one occasion every 3 months.
Potential effects on blood pressure and heart rate are known class-effects of high dose methoxyflurane used in anaesthesia and other anaesthetics. They do not appear to be significant at the analgesic doses. There is no particular pattern to the patients' systolic blood pressure levels after methoxyflurane administration as an analgesic across age groups. However, as the risk may potentially be increased for older people with hypotension and bradycardia, caution should be exercised in the elderly due to possible reduction in blood pressure.
Secondary pharmacodynamic effects including potential CNS effects such as sedation, euphoria, amnesia, ability to concentrate, altered sensorimotor co-ordination and change in mood are also known class-effects. Self-administration of methoxyflurane in analgesic doses will be limited by occurrence of CNS effects, such as sedation. Whilst the possibility of CNS effects may be seen as risk factor for potential abuse, reports are very rare in post marketing use.
Due to the limitations on the dose of PENTHROX and the duration of pain relief, PENTHROX is not appropriate for providing relief of break-through pain/exacerbations in chronic pain conditions. PENTHROX is also not appropriate for relief of trauma related pain in closely repeated episodes for the same patient.
PENTHROX contains the excipient, butylated hydroxytoluene (E321), a stabiliser. Butylated hydroxytoluene may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes. See section 6.1.
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 always be used with the Activated Carbon (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 are no reported drug interactions when used at the analgesic dosage (3–6 mL).
The metabolism of methoxyflurane is mediated by the CYP 450 enzymes particularly CYP 2E1 and to some extent CYP 2A6. It is possible that enzyme inducers (such as alcohol or isoniazid for CYP 2E1 and phenobarbital or rifampicin for CYP 2A6) which increase the rate of methoxyflurane metabolism might increase its potential toxicity and they should be avoided concomitantly with methoxyflurane.
Concomitant use of methoxyflurane with medicines (e.g. contrast agents and some antibiotics) which are known to have a nephrotoxic effect should be avoided as there may be an additive effect on nephrotoxicity. Antibiotics with known nephrotoxic potential include tetracycline, gentamicin, colistin, polymyxin B and amphotericin B. It is advisable to avoid using sevoflurane anaesthesia following methoxyflurane analgesia, as sevoflurane increases serum fluoride levels and nephrotoxicity of methoxyflurane is associated with raised serum fluoride.
Concomitant use of PENTHROX with CNS depressants, such as opioids, sedatives or hypnotics, general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants, sedating antihistamines and alcohol 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.
When methoxyflurane was used for anaesthesia at the higher doses of 40–60 mL, there were reports of:
No clinical data on effects of methoxyflurane on fertility are available. Limited data from animal studies do not indicate any effects on sperm morphology.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
Where methoxyflurane has been used for obstetric analgesia in pregnant women, there has been a single report of neonatal respiratory depression associated with a high fetal level of methoxyflurane. However, when low concentrations were administered, or the duration of higher concentrations was kept short, per recommended posology, methoxyflurane was found to have little effect on the fetus. No fetal complications were reported to result from methoxyflurane analgesia in the mother in all the studies completed in obstetric analgesia.
As with all medicines care should be exercised when administered during pregnancy especially the first trimester.
There is insufficient information on the excretion of methoxyflurane in human milk. Caution should be exercised when methoxyflurane is administered to a nursing mother.
Methoxyflurane may have a minor influence on the ability to drive and use machines. Dizziness, somnolence and drowsiness may occur following the administration of methoxyflurane (see section 4.8). Patients should be advised not to drive or operate machinery if they are feeling drowsy or dizzy.
The common non-serious reactions are CNS type reactions such as dizziness, and somnolence, and are generally easily reversible.
'Serious dose-related nephrotoxicity has only been associated with methoxyflurane when used in large doses over prolonged periods during general anaesthesia. Methoxyflurane is therefore no longer used for anaesthesia. See section 4.4 under renal disease. The recommended maximum dose for PENTHROX should therefore not be exceeded.'
The following table consists of adverse drug reactions:
The following frequencies are the basis for assessing undesirable effects: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1000); Very rare (<1/10,000); and Not known (cannot be estimated from the available data).
Uncommon: Increased appetite
Common: Euphoric mood
Uncommon: Anxiety, Depression, Inappropriate affect
Not known: Affect lability^, Agitation^, Confusional state^, Dissociation^, Restlessness^
Very common: Dizziness
Common: Amnesia, Dysarthria, Dysgeusia, Headache, Somnolence
Uncommon: Paraesthesia, Peripheral sensory neuropathy
Not known: Altered state of consciousness^, Nystagmus^
Uncommon: Diplopia
Not known: Vision blurred^
Common: Hypotension
Uncommon: Flushing
Not known: Blood pressure fluctuation^
Common: Cough
Not known: Choking^, Hypoxia^
Common: Dry mouth, Nausea
Uncommon: Oral discomfort
Not known: Vomiting^
Not known: Hepatic failure*, Hepatitis*, Jaundice^, Liver injury^
Uncommon: Hyperhidrosis
Not known: Renal failure^
Common: Feeling drunk
Uncommon: Fatigue, Feeling abnormal, Chills, Feeling of relaxation
Not known: Hepatic enzyme increased^, Blood urea increased, Blood uric acid increased^, Blood creatinine increased^
* *isolated post-marketing reports that have been observed with analgesic use of methoxyflurane
^ Other events linked to methoxyflurane use in analgesia found in post marketing experience and in scientific literature
Reporting suspected adverse reactions after authorisation 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 suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Not applicable.
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