Description of Fomepizole
Fomepizole is a competitive inhibitor of alcohol dehydrogenase. It is FDA-approved for the treatment of ethylene glycol and methanol poisoning. The drug must be diluted and administered by intravenous infusion over 30 minutes; administration as an undiluted intravenous bolus is associated with venous irritation and phlebosclerosis. If given with hemodialysis, which should be considered in addition to fomepizole in patients with renal failure, worsening metabolic acidosis, or a measured ethylene glycol or methanol concentration 50 mg/dL or greater, the dosing frequency must be increased as fomepizole is dialyzable. Assess treatment success by monitoring blood gases, pH, electrolytes, BUN, creatinine, urinalysis, ethylene glycol concentrations (serum and urine) or methanol concentrations (serum), hepatic enzymes, and white blood cell counts.
Mechanism of Action of Fomepizole
Fomepizole is a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites. Ethylene glycol is metabolized to glycoaldehyde which is further oxidized to glycolate, glyoxylate, and oxalate. Glycolate and oxalate are primarily responsible for the metabolic acidosis and renal damage seen in ethylene glycol poisoning. The lethal dose of ethylene glycol is approximately 1.4 mL/kg. Methanol is metabolized to formaldehyde which is further oxidized to formic acid. Formic acid is primarily responsible for the metabolic acidosis and visual disturbances associated with methanol poisoning. The lethal dose of methanol is approximately 1 to 2 mL/kg. By inhibiting alcohol dehydrogenase, fomepizole prevents the metabolism of ethylene glycol and methanol to their toxic metabolites. Since ethanol is also metabolized by this enzyme, fomepizole can also inhibit its metabolism.
Pharmacokinetics of Fomepizole
Fomepizole is administered via intravenous infusion. Once in systemic circulation, fomepizole rapidly distributes to total body water with a volume of distribution between 0.6 and 1.02 L/kg. Metabolism is the major route of elimination and is characterized by Michaelis-Menten kinetics after acute doses, with saturable elimination occurring at therapeutic blood concentrations. With multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system, which produces a significant increase in the elimination rate after about 30 to 40 hours. Following enzyme induction, fomepizole elimination follows first-order kinetics. Since fomepizole is metabolized via the P-450 enzyme system, significant drug interactions may occur, although these have not been systematically investigated. The primary metabolite is 4-carboxypyrazole (approximately 80% to 85% of an administered dose). Other metabolites observed are 4-hydroxymethylpyrazole and the N-glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole. Fomepizole and its metabolites are eliminated via the urine. In healthy volunteers, only 1% to 3.5% of the administered dose was excreted unchanged in the urine. The plasma half-life varies with dose (irrespective of renal function) and has not been calculated
Generic Name
- Fomepizole
- Antizol
- Alcohol Dehydrogenase Inhibitor
- Antidote
- Ethylene glycol toxicity: Adult
- Methanol toxicity: Adult
- Cardiovascular: Lightheadedness
- Endocrine metabolic: Hypertriglyceridemia (30%)
- Gastrointestinal: Heartburn, Loss of appetite, Nausea (11%)
- Neurologic: Dizziness (7%), Headache (12%), Nystagmus, Seizure, Vertigo
- Ophthalmic: Visual disturbance
- Otic: Roaring in ear
- Psychiatric: Agitation, Anxiety, Consciousness and/or awareness finding
- Other: Disorder of smell
- Hematologic: Disseminated intravascular coagulation (rare)
- Renal: Anuria (3%)
- Intravenous: dilute in 100 mL of NS or D5W
- Intravenous: administer by slow IV infusion over 30 minutes
- Intravenous: stable for 24 hours after dilution
- Intravenous Solution: 1 GM/1 ML
- Important Note: Orphan drug designation: Treatment of methanol or ethylene glycol poisoning
- Important Note: Orphan drug designation: Treatment of acetaminophen overdose
- Ethylene glycol toxicity: 15 mg/kg IV loading dose, followed by 10 mg/kg every 12 hr for 4 doses, then 15 mg/kg every 12 hr until ethylene glycol or methanol concentrations are below 20 mg/dL; all doses should be administered as a slow IV infusion over 30 minutes
- Methanol toxicity: 15 mg/kg IV loading dose, followed by 10 mg/kg every 12 hr for 4 doses, then 15 mg/kg every 12 hr until ethylene glycol or methanol concentrations are below 20 mg/dL; all doses should be administered as a slow IV infusion over 30 minutes
- Important Note: Orphan drug designation: Treatment of methanol or ethylene glycol poisoning
- Important Note: Orphan drug designation: Treatment of acetaminophen overdose
- General Dosage Information: safety and effectiveness in pediatric patients have not been established