DESCRIPTION

Fomepizole (Antizol) is an antidote for ethylene glycol and methanol poisoning.

FORMS AND USES

Fomepizole is provided in vials containing 1.5 ml of 1,000 mg/ml (total 1.5 g/vial)

MECHANISM OF ACTION

• Both ethylene glycol and methanol are metabolized by alcohol dehydrogenase to toxic metabolites.
• Before the development of fomepizole, the standard treatment of ethylene glycol or methanol poisonings involved the infusion of ethyl alcohol (ethanol), which blocks the formation of toxic metabolites by competing with ethylene glycol and methanol for metabolism by alcohol dehydrogenase.
• Fomepizole uses the same mechanism as ethanol and is a potent inhibitor of alcohol dehydrogenase; however, it produces more constant inhibition than ethanol and is simpler and safer to use.
• Because metabolism has been blocked, elimination occurs via urine (ethylene glycol) or breath (methanol).
• Patients with large body burdens of either ethylene glycol or methanol may require hemodialysis because the half-life is prolonged.

DRUG AND DISEASE INTERACTIONS

• Fomepizole will block metabolism of ethanol.
• Other drugs metabolized by the cytochrome P450 system may be similarly affected, although they have not been studied (phenytoin, carbamazepine, ketoconozole).

PREGNANCY AND LACTATION

• US FDA Pregnancy Category C. The drug exhibits animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either women or men.
• It is not known if fomepizole is excreted in breast milk.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• MECHANISM OF ACTION
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

ETHYLENE GLYCOL POISONING

• History of possible ethylene glycol ingestion and evidence of toxicity (increased anion gap metabolic acidosis, hematuria, proteinuria)
• Serum ethylene glycol level above 20 mg/dl
• Preparation for dialysis of ethylene glycol poisoning

METHANOL POISONING

• History of possible methanol ingestion and evidence of intoxication or another effect of methanol (visual complaints, increased anion gap metabolic acidosis)
• Serum methanol level above 20 mg/dl
• Preparation for hemodialysis of methanol poisoning

Section Outline:

• ETHYLENE GLYCOL POISONING
• METHANOL POISONING

CONTRAINDICATIONS

• History of allergic response to fomepizole or other agents with pyrazole structure
• Concurrent infusion with ethanol because of accumulation and potential toxicity of ethanol

ADVERSE EFFECTS

• Administration of this compound has been generally free of any serious side effects.
• High doses (50 to 100 mg/kg) are associated with nausea, dizziness, diarrhea, headache, and vertigo; the dose should be decreased or the infusion slowed.
• Low doses (3 mg/kg) for 4 days may cause a slight increase in blood pressure and liver enzymes.

Section Outline:

• CONTRAINDICATIONS
• ADVERSE EFFECTS

ETHYLENE GLYCOL OR METHANOL POISONING

• Loading dose. Adult or pediatric dose is 15 mg/kg.
• Maintenance dose. Adult and pediatric dose is 10 mg/kg every 12 hours for four doses, then 15 mg/kg every 12 hours thereafter until ethylene glycol or methanol level is less than 20 mg/dl (increase in rate is due to self-induction of cytochrome P450 system).
• Method of administration. Each dose should be diluted in 100 cc of normal saline or D5W and infused slowly over 30 minutes. After dilution, fomepizole should be used within 24 hours.

USE OF FOMEPIZOLE IN PATIENTS UNDERGOING HEMODIALYSIS

• Dose at beginning of hemodialysis:
  • If less than 6 hours since last fomepizole dose, do not administer another dose.
  • If more than 6 hours since last dose, administer 10 mg/kg at beginning of dialysis.
• Dosing during hemodialysis:
  • Increase frequency of maintenance dose infusion to every 4 hours instead of 12 hours.
• Dosing at the end of hemodialysis session:
  • If less than 1 hour since last fomepizole dose, do not administer dose at end of hemodialysis session.
  • If 1 to 3 hours since last dose, administer half of next dose.
  • If more than 3 hours since last dose, administer next scheduled dose.

Section Outline:

• ETHYLENE GLYCOL OR METHANOL POISONING
• USE OF FOMEPIZOLE IN PATIENTS UNDERGOING HEMODIALYSIS

• If clinical suspicion is high, fomepizole therapy should not be witheld while awaiting ethylene glycol or methanol levels.
• Overly rapid administration should be avoided; the rate of dose delivery does not affect outcome.

Toxic effect of alcohol: ethylene glycol, methyl alcohol.

See Also: SECTION II, Increased Anion Gap Metabolic Acidosis; SECTION IV, Ethylene Glycol and Methanol chapters.

RECOMMENDED READING

Baud FJ, Galliot M, Astier A, et al. Treatment of ethylene glycol poisoning with intravenous 4-methylpyrazole. N Engl J Med 1988;319:97-100.

Brent J, McMartin K, Phillips S, et al. Fomepizole for the treatment of ethylene glycol poisoning. N Eng J Med 1999;340:832-838.

McMartin KE, Heath A. Treatment of ethylene glycol poisoning with intravenous 4-methylpyrazole. N Engl J Med 1989;320:125.

Author: Scott D. Phillips

Reviewer: Richard C. Dart