Adult: For the emergency relief of cases associated with trauma, or pain relief during interventional medical procedures, in conscious patients: 1.5 mL or 3 mL (methoxyflurane 99.9%) as a single dose administered using the inhalation device provided (refer to specific product guideline on directions for use). Dose may be repeated as necessary. Max: 6 mL per day; 15 mL weekly. Daily use is not recommended. To attain adequate analgesia, patients must inhale intermittently; continuous inhalation will reduce the duration of analgesia. Use the lowest effective dose to control pain. Elderly: Use the lowest effective dose.
Special Patient Group
Pharmacogenomics:
Methoxyflurane is presumed to be a triggering agent of malignant hyperthermia (MH). Individuals with malignant hyperthermia susceptibility (MHS) or those carrying certain genetic variants of ryanodine receptor isoform 1 protein (RYR1) and CACNA1S gene are predisposed to severe and sometimes potentially fatal hypermetabolic reaction triggered by potent volatile anaesthetics including methoxyflurane. However, based on product guidelines of methoxyflurane, its use as an anaesthetic agent is currently contraindicated. The prevalence of MHS genetic trait is estimated to be between 1/2,000 and 1/3,000, and approx 70% of individuals with MHS have the RYR1 gene as the primary locus for the pharmacogenetic trait, while approx 1% of patients with MHS have pathogenic variants in CACNA1S.
Clinical Pharmacogenetics Implementation Consortium (CPIC) supplemented the evaluations of the European Malignant Hyperthermia Group (EMHG) consortium which has identified the 50 MH-causative variants in RYR1 or CACNA1S genes that are considered as diagnostic mutations. Genetic testing may be considered prior to initiation of treatment. However, product labelling of methoxyflurane does not specifically recommend performing genetic testing.
RYR1 or CACNA1S phenotype
Phenotype and Genotype
Implication
Recommendation
Malignant hyperthermia susceptible (MHS)
Patients who are heterozygous for or carriers of at least 1 of the 50 identified RYR1 or CACNA1S MH-causative variant (refer to detailed CPIC guideline for the list of causative variants).
Increased risk of developing malignant hyperthermia if administered with methoxyflurane.
Methoxyflurane is relatively contraindicated in these patients, except in instances where the benefits outweigh the risks. In general, the use of alternative agents is recommended.
Uncertain susceptibility
Patients who are negative for RYR1 or CACNA1S MH-causative variant.
Negative or inconclusive results do not eliminate the risk of susceptibility to malignant hyperthermia.
Assess the individual's clinical findings, family history, and other laboratory data, and perform further genetic testing to guide the use of methoxyflurane.
Renal Impairment
Contraindicated.
Contraindications
Clinically evident CV instability, respiratory depression; known or genetic susceptibility to malignant hyperthermia (e.g. presence of RYR1 or CACNA1S pathogenic variants), altered consciousness due to any cause (e.g. head injury, drugs, alcohol). Known personal or family history of severe adverse reactions after inhaled anaesthetic use; history of showing signs of liver impairment after previous use of methoxyflurane or other halogenated anaesthetics. Use as an anaesthetic agent. Renal impairment (clinically significant).
Special Precautions
Patient with known risk factors or predisposition to renal injury; risk factors for hepatic impairment. Obese patient. Occupational exposure. Not applicable for use in relief of exacerbations in chronic pain or break-through pain. Hepatic impairment. Elderly (particularly those with hypotension or bradycardia). Pregnancy and lactation.
Adverse Reactions
Significant: Irreversible nephrotoxicity, bradycardia, hypotension (dose-related), respiratory depression; increased liver enzymes, BUN, and serum uric acid (occupational exposure). Rarely, hepatotoxicity. Eye disorders: Diplopia. Gastrointestinal disorders: Xerostomia, dysgeusia, nausea, vomiting, oral discomfort, oral pruritus, salivary hypersecretion. General disorders and administration site conditions: Fatigue, feeling drunk or abnormal, chills, feeling of relaxation. Infections and infestations: Influenza, viral infection. Injury, poisoning and procedural complications: Fall. Metabolism and nutrition disorders: Increased appetite. Musculoskeletal and connective tissue disorders: Back pain, sprain. Nervous system disorders: Dizziness, headache, drowsiness, peripheral sensory neuropathy, impaired consciousness, dysarthria, migraine, paraesthesia. Psychiatric disorders: Anxiety, euphoria, depression, amnesia, verbigeration, disturbance in attention, inappropriate affect. Reproductive system and breast disorders: Dysmenorrhoea. Respiratory, thoracic and mediastinal disorders: Cough, choking. Skin and subcutaneous tissue disorders: Rash, hyperhidrosis. Vascular disorders: Flushing, hypertension. Potentially Fatal: Hepatic necrosis.
Patient Counseling Information
This drug may cause dizziness or drowsiness, if affected, do not drive or operate machinery.
Symptoms: Drowsiness, pallor, muscle relaxation; nephrotoxicity (dose-related). Management: Replace fluid and electrolyte losses in case of excessive urinary output.
Drug Interactions
May have additive nephrotoxic effect with contrast agents and certain antibiotics (e.g. gentamicin, colistin, polymyxin B, amphotericin B, tetracycline). May increase the rate of metabolism and potential toxicity with inducers of CYP2E1 (e.g. isoniazid), CYP2A6 (e.g. phenobarbital, rifampicin), or CYP2B6 (e.g. carbamazepine, efavirenz, nevirapine) enzymes; avoid concomitant use. Sevoflurane increases serum fluoride levels which may increase the risk of nephrotoxicity of methoxyflurane; avoid sevoflurane use after methoxyflurane analgesia. May cause additive depressant effect with opioids, sedative/hypnotics, general anaesthetics, tranquillisers, phenothiazines, sedating antihistamines, skeletal muscle relaxants.
Food Interaction
May cause additive depressant effects and increased risk of potential toxicity with alcohol.
Action
Description: Mechanism of Action: Methoxyflurane, a volatile halogenated anaesthetic, is given at sub-anaesthetic doses to provide analgesia. Its exact mechanism in producing analgesia has not been fully elucidated, but it has been suggested to be caused by a decrease in substance P and β-endorphin-like immunoreactivity in the brain. Onset: 5 minutes. Duration: Continuous inhalation: 25-30 minutes. Intermittent inhalation: Approx 60 minutes. Pharmacokinetics: Absorption: Absorbed upon inhalation. Time to peak plasma concentration: 2-4 days. Distribution: Highly lipophilic; distributed into fatty tissues and is slowly released over days. Crosses the placenta. Metabolism: Metabolised in the liver via dechlorination and O-demethylation by CYP2E1, 2B6, and 2A6 to free fluoride, oxalic acid, difluoromethoxyacetic acid, and dichloroacetic acid. Excretion: Via urine (approx 60% as metabolites); respiratory (approx 40% as unchanged drug or carbon dioxide).
Chemical Structure
Methoxyflurane Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 4116, Methoxyflurane. https://pubchem.ncbi.nlm.nih.gov/compound/Methoxyflurane. Accessed July 27, 2021.
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