Dosage / Administration:
The loading dose of fomepizole in both adult and pediatric patients is 15 mg/kg IV (intravenous). The maintenance dose is 10 mg/kg IV every 12 hours (with the first dose given 12 hours after loading dose) for 4 doses, then the maintenance dose increases to 15 mg/kg every 12 hours for the duration of therapy. The dose adjustment is necessary because fomepizole plays a role in its own metabolism. The duration of therapy depends on the amount of toxic alcohol ingested and should be continued until the serum toxic alcohol concentration is measured or predicted (based on half-life) to be below 25 mg/dL. Methanol, in particular, has an extended half-life (54 hours), so treatment duration is often over the course of days.

Fomepizole requires dilution in 100 mL normal saline or dextrose 5% in water (D5W) prior to administration. Each dose should be given over 30 minutes to avoid venous irritation.

Special considerations:
Fomepizole is dialyzable. In patients undergoing hemodialysis, the loading dose of fomepizole is the same (15 mg/kg) and maintenance doses should be given at 15 mg/kg every 4 hours while dialysis is underway.

Indications:
Fomepizole (4-methylpyrazole) is primarily used for toxic alcohol poisoning, specifically with methanol and ethylene glycol. Fomepizole is a competitive inhibitor of alcohol dehydrogenase, one of the enzymes responsible for converting these alcohols into their toxic metabolites (formic acid and oxalic acid, respectively). Fomepizole has a very high affinity for this enzyme, making it highly useful in the prevention of toxic metabolite formation.

Off-label uses of fomepizole include preventing toxicity from diethylene glycol and various xenobiotics, improving symptoms of disulfiram reactions, and potentially in treating acetaminophen toxicity. Diethylene glycol and several xenobiotics are also metabolized via alcohol dehydrogenase to toxic metabolites. In one study, patients were given a small amount of both ethanol and disulfiram, and the adverse reaction was significantly improved with fomepizole treatment. More recently, fomepizole has shown potential benefit in improving outcomes of massive acetaminophen poisoning, although there is a paucity of data, and its use is debated.

The dose of fomepizole to treat acetaminophen toxicity is 15 mg/kg as a one-time infusion.

There have been no reported significant adverse events with fomepizole administration. It should be noted that, due to the mechanism of action of fomepizole, the patient will remain intoxicated for a longer period. This is due to prevention of methanol and ethylene glycol conversion to toxic metabolites by inhibiting the enzyme alcohol dehydrogenase.

Contraindications:
The only absolute contraindication to fomepizole is known allergy to the drug or other pyrazoles.

Fomepizole is pregnancy category C, and minimal studies have been done related to its safety in pregnancy. Because toxic alcohol poisoning is highly consequential (blindness, renal failure [acute, chronic], neonatal death), it is recommended that fomepizole be given to pregnant patients who ingest these alcohols.

Monitoring:
Patients receiving fomepizole should be admitted to the hospital to receive serial doses, preferably for the duration of 5 half-lives of the specific toxic alcohol ingested. It is not necessary to obtain repeat serum toxic alcohol levels as the half-life can be reliably calculated. No other laboratory monitoring is required.

Adverse Effects:
Fomepizole has been well studied, and the recommended dose has not been shown to have any significant adverse effects. At doses above 30-40 mg/kg/dose (up to 100 mg/kg), some study participants reported mild nausea, headache, and light-headedness. A less common adverse effect is phlebitis, which is more likely to occur if the dose is given too quickly or not properly diluted.

Toxicity:
There has been no evidence of toxicity from fomepizole use.

Mechanism of Action:
Mechanism: Fomepizole is a competitive inhibitor of alcohol dehydrogenase, an enzyme that converts toxic alcohols to their toxic metabolites.

Metabolism: Fomepizole is rapidly absorbed and undergoes hepatic metabolism. The primary metabolite is 4-carboxypyrazole (80%-85% of dose). Elimination half-life varies with the dose given and with the duration of therapy. In general, fomepizole follows zero-order kinetics until duration of therapy reaches 96 hours, after which it follows first-order kinetics. This is thought to be secondary to multiple metabolic pathways that each predominate at different concentrations of the antidote.

Excretion: Fomepizole is renally excreted at a low level – 3% of the dose is excreted unchanged.