Sections View Full Chapter Figures Tables Videos Full Chapter Figures Tables Videos Supplementary Content + Fomepizole (4-Methylpyrazole, 4-MP) Download Section PDF Listen ++ Pharmacology Fomepizole (4-methylpyrazole) is a potent competitive inhibitor of alcohol dehydrogenase, the first enzyme in the metabolism of ethanol and other alcohols. Fomepizole can prevent the formation of toxic metabolites after methanol or ethylene glycol ingestion. Furthermore, early treatment with fomepizole for ethylene glycol or methanol poisoning (before the appearance of a significant acidosis) may obviate the need for dialysis. Since the introduction of fomepizole, most patients with ethylene glycol or methanol poisoning probably will be treated with this drug instead of ethanol, particularly in cases involving small children, patients taking disulfiram, patients with altered consciousness and ingestion of multiple substances, patients with pancreatitis or active liver disease, and hospitals lacking laboratory support to perform rapid ethanol levels (for monitoring treatment). Economic models have suggested that fomepizole may be more cost-effective than ethanol despite the high acquisition cost of fomepizole. Fomepizole is eliminated mainly via zero-order kinetics, but cytochrome P-450 metabolism can undergo auto-induction within 2–3 days. The drug is dialyzable. It is well absorbed and has been used successfully with PO administration but is not approved for this route in the United States.Indications are suspected or confirmed methanol (methyl alcohol [See Methanol]) or ethylene glycol (See Ethylene Glycol and Other Glycols) poisoning with one or more of the following: A reliable history of ingestion of a toxic dose but no available blood concentration measurements (when used empirically, allows a 12-hour “window” after one dose to assess the patient);Metabolic acidosis and an unexplained elevated osmolar gap (See Diagnosis of Poisoning); orSerum methanol or ethylene glycol concentration of 20 mg/dL or higher.Other substances that are metabolized by alcohol dehydrogenase to toxic metabolites include propylene glycol, diethylene glycol, triethylene glycol, glycol ethers (eg, ethylene glycol ethyl ether, ethylene glycol butyl ether), and 1,4-butanediol. The criteria for fomepizole therapy and evidence for improved outcomes are lacking for all these substances. However, case reports of poisonings from some of these other glycols (eg, propylene glycol, diethylene glycol) have suggested benefit when fomepizole therapy is coupled with dialysis to remove the potentially toxic parent compound and concomitantly prevent the formation of toxic metabolites. Disulfiram reaction (or risk for): to halt progression or the production of acetaldehyde, assuming that ethanol is still present (based on case reports).Contraindications. History of allergy to the drug or to other pyrazoles.Adverse effectsVenous irritation and phlebosclerosis after intravenous injection of the undiluted product.Headache, nausea, and dizziness are the most commonly reported side effects. Less common effects are vomiting, tachycardia, hypotension, feeling of inebriation, rash, fever, and eosinophilia.Transient non–dose-dependent elevation of hepatic transaminases has been reported after multiple doses.Although safety and effectiveness in children have not been established by the manufacturer, fomepizole has been used successfully and reported for pediatric poisonings (in children as young as 8 months).Use in pregnancy. FDA Category C (indeterminate). Has been used in pregnant patients without immediate adverse effects on the mother or fetus (See Introduction in Section III).Drug or laboratory interactionsDrugs or chemicals metabolized by alcohol dehydrogenase (eg, chloral hydrate, ethanol, isopropyl alcohol) will also have impaired elimination. Fomepizole inhibits the metabolism of ethanol, and vice versa.Drugs or chemicals metabolized by cytochrome P-450 enzymes may compete with fomepizole for elimination. Also, induction of cytochrome P-450 activity by these drugs or by fomepizole may alter metabolism.Dosage and method of administration. Note: The interval between the initial dose and subsequent maintenance doses, 12 hours, provides an opportunity to confirm the diagnosis with laboratory testing. Initial dose. Give a loading dose of 15 mg/kg (up to 1.5 g). Dilute in at least 100 mL of normal saline or 5% dextrose and infuse intravenously slowly over 30 minutes. (Oral administration may be considered for patients lacking IV access.) Patients weighing more than 100 kg may receive a loading dose of 1500 mg (one vial) to avoid wastage from opening a second vial of fomepizole. However, it is unknown if sufficient enzyme blockade will be achieved in all patients, and additional doses are recommended if there is evidence of a worsening acidosis before the next maintenance dose 12 hours later. Note: The drug may solidify at room temperature and should be inspected visually before administration. If there is any evidence of solidification, hold the vial under a stream of warm water or roll between the hands.Maintenance therapy. Give 10 mg/kg every 12 hours for four doses, then increase to 15 mg/kg (to offset increased metabolism resulting from auto-induction) until methanol or ethylene glycol serum levels are below 20 mg/dL.Adjustment for hemodialysis. To offset loss of fomepizole during dialysis, the manufacturer recommends increasing the frequency of dosing to every 4 hours. It is probably sufficient to administer one additional dose of fomepizole at the beginning of dialysis (if 6 hours or more has elapsed since the last dose) and administer another dose at the completion of dialysis, then continue with usual dosing every 12 hours thereafter. (Note: With newer, high-flux hemodialysis equipment, fomepizole half-life averages 1.7 hours, compared with 3 hours with standard dialysis.)FormulationsParenteral. Fomepizole (Antizol, Paladin Labs; generic, X-Gen Pharmaceuticals), 1 g/mL in 1.5-mL vials, prepackaged in tray packs containing four vials.Suggested minimum stocking levels to treat a 100-kg adult for the first 8 hours and 24 hours: fomepizole, first 8 hours: 1.5 g or one vial of either product; first 24 hours: 6.0 g or four vials of either product. Note: Manufacturers will replace free of charge or provide a credit for any expired vials of fomepizole if they are in the original packaging and returned within 12 months of the expiration date.