PEDIATRICS Vol. 107 No. 1 January 2001, pp. 170

COMMENTARY:
Fomepizole in the Treatment of Poisoning

Alcohol dehydrogenase. It is unique in clinical toxicology as the enzyme that changes relatively benign agents into dangerous, even lethal, toxicants. Without alcohol dehydrogenase, methanol is merely irritating and inebriating. With alcohol dehydrogenase, methanol becomes formaldehyde, then formic acid. These cause anion gap metabolic acidosis, blindness, seizures, coma, and death. Without alcohol dehydrogenase, ethylene glycol is a gastrointestinal irritant, and a more potent inebriant than ethanol. With alcohol dehydrogenase, ethylene glycol becomes glycoaldehyde then glycolic and oxalic acids. Profound metabolic acidosis results; calcium oxalate precipitates in soft tissues, damaging the kidneys and the heart; hypocalcemia contributes to seizures, tetany, and dysrhythmia; coma and death can occur.

Alcohol dehydrogenase is an obvious target in the treatment of victims of methanol or ethylene glycol poisoning. Ethanol is a competitive inhibitor of alcohol dehydrogenase. Ethanol is a logical choice, as the preferred substrate for alcohol dehydrogenase, and it works: serum ethanol levels of 100 mg/dL block metabolism of ethylene glycol and methanol in their usual overdose concentrations.¹

Unfortunately for patients, ethanol has its own toxicity. At therapeutic concentrations, ethanol is inebriating and may cause hypoglycemia. Unfortunately for clinicians, ethanol is difficult to use. Kinetics vary widely among individuals, and in the same individual over time. Published dosing schemes vary widely among sources. Oral absorption is erratic; intravenous preparations are rarely shelved² in most hospitals, and some emergency departments obtain the antidote from the local liquor store. Even the math is challenging: ethanol concentrations may be reported with units of proof or percent; percent sometimes refers to mass:mass, mass:volume, or volume:volume, and even 100% solutions don't have as much as one might guess, because the density of ethanol is <1. All of these problems add up to delays in acquiring, calculating, preparing, and administering the dose, and too many opportunities for error in the process. Ethanol dosing usually means drawing hourly ethanol and glucose levels from an intoxicated patient in the intensive care unit, with frequent changes in the ethanol dose.³

In 1986 fomepizole was introduced as a safer and more effective blocker of alcohol dehydrogenase.⁴ Administration is simple: a 15-mg/kg loading dose is given intravenously over 30 minutes, followed by 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours. Treatment is continued until methanol or ethylene glycol levels are <20 mg/dL. Fomepizole is approved by the Food and Drug Administration for treatment of confirmed or suspected ethylene glycol poisoning in adults; it appears equally safe and effective in methanol poisoning,⁵ and in children.

Because it only blocks further conversion of methanol and ethylene glycol to toxic metabolites, fomepizole does not replace bicarbonate in acidotic patients, nor dialysis in patients with acidosis, renal insufficiency, or massive overdose. Side effects seem to be minimal; seizures reported in 2 patients shortly after the fomepizole administration may have been attributable to the underlying ethylene glycol intoxication,⁶ and both patients received additional doses without problems. At $1000 per 1500-mg vial ($4000 per 4-vial pack, wholesale cost direct from manufacturer), drug acquisition cost is the major problem with this drug. Although fomepizole may lower other costs (by allowing less dialysis, intensive care unit admissions, blood ethanol and glucose measurements, and by eliminating the delays and risks of ethanol dosing), a formal pharmacoeconomic study is needed.⁷

Fomepizole improves the care of the methanol- or ethylene glycol-poisoned patient and makes the physician's job easier, too.

Marcel J. Casavant, MD, FACEP, FACMT
Ohio State University
Clinical Pharmacology/Toxicology
Pediatric Pharmacology Research Unit
Children's Hospital
Columbus, OH 43205

FOOTNOTES

Received for publication Apr 4, 2000; accepted Apr 4, 2000.

Reprint requests to (M.J.C.) Clinical Pharmacology/Toxicology, Ohio State University, Children's Hospital, 700 Children's Dr, Columbus, OH 43205. E-mail: casavant{at}chi.osu.edu

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