Mechanism of Action: Antizol® (fomepizole) is a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde. Alcohol dehydrogenase also catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites.

Ethylene glycol, the main component of most antifreezes and coolants, is metabolized to glycoaldehyde, which undergoes subsequent sequential oxidations to yield glycolate, glyoxylate, and oxalate. Glycolate and oxalate are the metabolic byproducts primarily responsible for the metabolic acidosis and renal damage seen in ethylene glycol toxicosis. The lethal dose of ethylene glycol in humans is approximately 1.4 mL/kg.

Methanol, the main component of windshield wiper fluid, is slowly metabolized via alcohol dehydrogenase to formaldehyde with subsequent oxidation via formaldehyde dehydrogenase to yield formic acid. Formic acid is primarily responsible for the metabolic acidosis and visual disturbances (e.g., decreased visual acuity and potential blindness) associated with methanol poisoning. A lethal dose of methanol in humans is approximately 1-2 mL/kg.

Fomepizole has been shown in vitro to block alcohol dehydrogenase enzyme activity in dog, monkey, and human liver. The concentration of fomepizole at which alcohol dehydrogenase is inhibited by 50% in vitro is approximately 0.1 μmol/L.

In a study of dogs given a lethal dose of ethylene glycol, three animals each were administered fomepizole, ethanol, or left untreated (control group). The three animals in the untreated group became progressively obtunded, moribund, and died. At necropsy, all three dogs had severe renal tubular damage. Fomepizole or ethanol, given 3 hours after ethylene glycol ingestion, attenuated the metabolic acidosis and prevented the renal tubular damage associated with ethylene glycol intoxication.

Several studies have demonstrated that Antizol® plasma concentrations of approximately 10μmol/L (0.82 mg/L) in monkeys are sufficient to inhibit methanol metabolism to formate, which is also mediated by alcohol dehydrogenase. Based on these results, concentrations of Antizol® in humans in the range of 100 to 300 μmol/L (8.6-24.6 mg/L) have been targeted to assure adequate plasma concentrations for the effective inhibition of alcohol dehydrogenase.

In healthy volunteers, oral doses of Antizol® (10-20 mg/kg) significantly reduced the rate of elimination of moderate doses of ethanol, which is also metabolized through the action of alcohol dehydrogenase (see PRECAUTIONS, Drug Interactions). 

Pharmacokinetics: The plasma half-life of Antizol® varies with dose, even in patients with normal renal function, and has not been calculated.

Distribution: After intravenous infusion, Antizol® rapidly distributes to total body water. The volume of distribution is between 0.6 L/kg and 1.02 L/kg.

Metabolism: In healthy volunteers, only 1-3.5% of the administered dose of Antizol® (7-20 mg/kg oral and IV) was excreted unchanged in the urine, indicating that metabolism is the major route of elimination. In humans, the primary metabolite of Antizol® is 4-carboxypyrazole (approximately 80-85% of administered dose), which is excreted in the urine. Other metabolites of Antizol® observed in the urine are 4-hydroxymethylpyrazole and the N-glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole.

Excretion: The elimination of Antizol® is best characterized by Michaelis-Menten kinetics after acute doses, with saturable elimination occurring at therapeutic blood concentrations [100-300 μmol/L, 8.2-24.6 mg/L].

With multiple doses, Antizol® rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system, which produces a significant increase in the elimination rate after about 30-40 hours. After enzyme induction, elimination follows first-order kinetics.

Special Populations:

Geriatric: Antizol® (fomepizole) Injection has not been studied sufficiently to determine whether the pharmacokinetics differ for a geriatric population.

Pediatric: Antizol® has not been studied sufficiently to determine whether the pharmacokinetics differ for a pediatric population.

Gender: Antizol® has not been studied sufficiently to determine whether the pharmacokinetics differ between the genders.

Renal Insufficiency: The metabolites of Antizol® are excreted renally. Definitive pharmacokinetic studies have not been done to assess pharmacokinetics in patients with renal impairment.

Hepatic Insufficiency: Antizol® is metabolized through the liver, but no definitive pharmacokinetic studies have been done in subjects with hepatic disease.

Clinical Studies: The efficacy of Antizol® in the treatment of ethylene glycol and methanol intoxication was studied in two prospective, U.S. clinical trials without concomitant control groups. Fourteen of 16 patients in the ethylene glycol trial and 7 of 11 patients in the methanol trial underwent hemodialysis because of severe intoxication (see DOSAGE AND ADMINISTRATION). All patients received Antizol® shortly after admission.

The results of these two studies provide evidence that Antizol® blocks ethylene glycol and methanol metabolism mediated by alcohol dehydrogenase in the clinical setting. In both studies, plasma concentrations of toxic metabolites of ethylene glycol and methanol failed to rise in the initial phases of treatment. The relationship to Antizol® therapy, however, was confounded by hemodialysis and significant blood ethanol concentrations in many of the patients. Nevertheless, in the post-dialysis period(s), when ethanol concentrations were insignificant and the concentrations of ethylene glycol or methanol were > 20 mg/dL, the administration of Antizol® alone blocked any rise in glycolate or formate concentrations, respectively.

In a separate French trial, 5 patients presented with ethylene glycol concentrations ranging from 46.5 to 345 mg/dL, insignificant ethanol blood concentrations, and normal renal function. These patients were treated with fomepizole alone without hemodialysis, and none developed signs of renal injury.