Version May 2024
Pain (moderate to severe, acute): Inhalation: Initial: 3 mL inhaled intermittently to achieve adequate analgesia; typical duration of analgesia is ~25 to 60 minutes depending on frequency of inhalation. May repeat an additional 3 mL dose if needed; maximum: 6 mL/day. Do not use on consecutive days. Use lowest effective dosage to provide analgesia. A treatment course should be limited to a total dose of 15 mL/week (no more than 6 mL/48 hours). Treatment courses should not be repeated at an interval of less than 3 months.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution at the lowest effective dose. Use is contraindicated in patients with clinically significant renal impairment.
There are no dosage adjustments provided in the manufacturer's labeling; however, methoxyflurane is metabolized in the liver. Use with caution in patients with hepatic impairment. Use is contraindicated in patients who have shown signs of liver dysfunction after previous methoxyflurane use or other halogenated anesthetics.
Refer to adult dosing; use minimum effective dose.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Central nervous system: Dizziness (8% to 30%), headache (22%)
1% to 10%:
Cardiovascular: Flushing (2%), hypertension (2%)
Central nervous system: Drowsiness (≤5%), euphoria (4%), anxiety (2%), depression (2%), neuropathy (sensory: 2%), impaired consciousness (≤2%), amnesia (1%), dysarthria (1%), falling (1%), intoxicated feeling (1%), migraine (1%)
Dermatologic: Skin rash (1%)
Endocrine & metabolic: Increased lactate dehydrogenase (1%)
Gastrointestinal: Xerostomia (2%)
Genitourinary: Dysmenorrhea (1%)
Infection: Influenza (1%), viral infection (1%)
Neuromuscular & skeletal: Back pain (2%), sprain (1%)
Respiratory: Cough (1%)
<1%, postmarketing, and/or case reports: Agitation, altered blood pressure (fluctuation), blurred vision, choking sensation, diplopia, disorientation, dissociative reaction, drug abuse, dysgeusia, emotional lability (includes inappropriate affect), fatigue, feeling abnormal, hepatic injury, hangover effect, hepatic failure, hepatitis, hunger, hypoxia, increased blood urea nitrogen, increased liver enzymes, increased serum creatinine, increased uric acid, jaundice, nystagmus, oral discomfort, oxygen saturation decreased, paresthesia, relaxation, renal failure syndrome, respiratory depression, restlessness, shivering
Hypersensitivity to methoxyflurane, other halogenated anesthetics, or any component of the formulation; use as an anesthetic agent; renal impairment (clinically significant); hemodynamic instability (clinically evident); respiratory impairment (clinically evident); altered consciousness due to any cause, including head injury, drugs, or alcohol; history of liver dysfunction after previous methoxyflurane or other halogenated anesthetics; malignant hyperthermia or genetic susceptibility to malignant hyperthermia or a history of severe adverse reactions in either patient or relatives.
Concerns related to adverse effects:
• Cardiovascular effects: May cause dose-related bradycardia and hypotension; use with caution in elderly patients with hypotension or bradycardia. Effects are likely not significant with analgesia doses.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating heavy machinery).
• Hepatic effects: [Canadian Boxed Warning]: Very rare cases of hepatotoxicity have been reported when used for analgesic purposes. Avoid use in patients who show signs of liver damage after previous exposure to methoxyflurane or halogenated anesthetics. Use with caution in patients with underlying hepatic conditions or risk factors for hepatic dysfunction.
• Renal toxicity: [Canadian Boxed Warning]: Supratherapeutic doses have led to serious, irreversible nephrotoxicity in a dose-related manner; dosing limitations should be followed meticulously to prevent or limit the risk of nephrotoxicity. Consecutive day use is not recommended due to nephrotoxic potential. Risk may also be increased when the rate of metabolism is increased, such as with coadministration with hepatic enzyme inducers or genetic variations that result in rapid metabolism. Use with caution and at the lowest effective dose in geriatric patients and patients with known risk factors or clinical conditions that would predispose to renal injury.
• Respiratory depression: May cause respiratory depression.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; systemic exposure and risk of toxicity may be increased.
• Renal impairment: Use with caution in patients with renal impairment; use lowest effective dose due to risk of nephrotoxicity.
Special populations:
• Older adult: Use with caution in older adults; use lowest effective dose due to risk of nephrotoxicity.
• Obesity: Use with caution in obese patients due to the distribution into and slow release from fat tissue.
Special handling:
• Occupational exposure: Elevation of liver enzymes, blood urea nitrogen and serum uric acid have been reported in health workers regularly exposed to patients using methoxyflurane. To reduce occupational exposure, always attach the activated carbon chamber to inhaler, which adsorbs exhaled methoxyflurane.
Other warnings/precautions:
• Abuse/misuse/diversion: Use of higher than recommended doses may be a risk factor for substance use disorder, abuse, and misuse, potentially leading to overdose and death (Porter 2018; manufacturer's labeling).
• Appropriate use: Methoxyflurane is not appropriate for relief of chronic or repetitive pain.
• Butylated hydroxytoluene: Contains butylated hydroxytoluene, a stabilizer, which may cause local skin reactions (eg, contact dermatitis) or irritation to the eyes and mucous membranes.
Not available in the US
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Inhalation:
Penthrox: 99.9% (3 mL)
Inhalation: May be self-administered under supervision of health care provider. Attach activated carbon chamber to dilutor hole on inhaler. Holding the methoxyflurane bottle upright, separate the inhaler from the bottle and remove the cap by hand. Tilt the inhaler to a 45° angle and pour the contents of one bottle into the base while rotating to ensure wick is adequately saturated. Inhale and exhale through the inhaler mouthpiece. First few breaths should be gentle, then patient can breathe normally through inhaler. If stronger analgesia is required, cover diluter hole on the activated carbon chamber with finger during inhalation. Inhale intermittently; continuous administration will reduce time of analgesia.
Note: Not approved in the United States.
Pain (moderate to severe, acute): Short-term relief of moderate to severe acute pain, associated with trauma or interventional medical procedures, in conscious adults
Penthrox brand name for methoxyflurane [Australia, New Zealand, United Kingdom] may be confused with Penamox brand name for amoxicillin [multiple international markets].
ALERT: Canadian Boxed Warning: Health Canada-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.
Substrate of CYP2A6 (minor), CYP2E1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May enhance the CNS depressant effect of Methoxyflurane. Alcohol (Ethyl) may increase the metabolism of Methoxyflurane. Specifically, this increased metabolism may lead to increased production of nephrotoxic metabolites. Risk X: Avoid combination
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Aminoglycosides: May enhance the nephrotoxic effect of Methoxyflurane. Risk X: Avoid combination
Amphotericin B: Methoxyflurane may enhance the nephrotoxic effect of Amphotericin B. Risk X: Avoid combination
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Barbiturates: May enhance the nephrotoxic effect of Methoxyflurane. Barbiturates may increase the metabolism of Methoxyflurane. Risk X: Avoid combination
Beta-Blockers: Methoxyflurane may enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Colistimethate: May enhance the nephrotoxic effect of Methoxyflurane. Risk X: Avoid combination
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Doxylamine: CNS Depressants may enhance the CNS depressant effect of Doxylamine. Risk C: Monitor therapy
DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Isoniazid: May increase the metabolism of Methoxyflurane. Specifically, this increased metabolism may lead to increased production of nephrotoxic metabolites. Risk X: Avoid combination
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Polymyxin B: Methoxyflurane may enhance the nephrotoxic effect of Polymyxin B. Risk X: Avoid combination
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Tetracyclines: May enhance the nephrotoxic effect of Methoxyflurane. Risk X: Avoid combination
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
Methoxyflurane crosses the placenta (Clark 1970; Siker 1968); serum fluoride concentrations may be increased in neonates at birth.
Use during labor may cause dose-related central nervous system or respiratory depression in the newborn (Clark 1970).
Methoxyflurane is not indicated for use during pregnancy or the peripartum period, including labor.
It is not known if methoxyflurane is present in breast milk.
The manufacturer recommends that caution be exercised when administering methoxyflurane to breastfeeding patients.
Liver function; renal function; blood pressure; heart rate; pain relief; signs/symptoms of CNS depression (drowsiness, pallor, and muscle relaxation).
Halogenated volatile anesthetic, when inhaled at low concentrations, produces an analgesic effect. Exact mechanism in analgesia has not been elucidated; potential factors contributing to the analgesic activity include effects on substance P and beta-endorphin.
Onset of action: Rapid (5 minutes)
Duration of action: 25 to 30 minutes (continuous inhalation); ~60 minutes (intermittent inhalation)
Distribution: Highly lipophilic; diffuses into fatty tissues and is released slowly over days
Metabolism: Hepatic; dechlorination and o-demethylation via CYP 2E1 and 2A6 to free fluoride, oxalic acid, difluoromethoxyacetic acid and dichloroacetic acid
Excretion: Urine (~60%, as metabolites); respiratory (~40%, unaltered or as carbon dioxide)
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