No

Antidote

Ethylene glycol and methanol toxicity; may be useful in propylene glycol; unclear whether it is useful in disulfiram-ethanol reactions

C

Clinical effects on the fetus: Animal reproduction studies have not been conducted and it is not known whether fomepizole can cause fetal harm when administered to pregnant women; should only be used in pregnant women if the benefits clearly outweigh the risks

Fomepizole should not be administered to patients with a documented serious hypersensitivity reaction to fomepizole or other pyrazoles

Should not be given undiluted or by bolus injection. It is not known whether this drug is excreted in human milk, therefore, caution should be exercised when given to a nursing woman; safety and effectiveness in pediatric patients have not been established. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function and because elderly patients are more likely to have decreased renal function, care should be taken in geriatric dose selection. Hemodialysis can accumulate the drug and as a result dosage adjustments may be required and patients with liver disease may accumulate fomepizole.

Unless noted, all adverse reactions have a reported incidence of less than or equal to 6%:

Central nervous system: Dizziness (7%), seizures, headache (12%), vertigo, lightheadedness, feeling of drunkenness, strange feelings, slurred speech, decreased environmental awareness, somnolence, hangover

Dermatologic: Rash

Gastrointestinal: Vomiting, nausea (11%), diarrhea, anorexia, heartburn, abdominal pain, bad metallic taste

Hematologic: Lymphangitis, eosinophilia, anemia

Local: Injection site reactions

Ocular: Nystagmus, blurred vision, visual problems

Respiratory: Pharyngitis, abnormal smell

Miscellaneous: Phlebosclerosis, hiccups

Nausea, dizziness, and vertigo were noted in healthy volunteers receiving 3-6 times the recommended dose. This dose-dependent CNS effect was short-lived in most subjects and lasted up to 30 hours in one subject.

Because fomepizole is dialyzable, dialysis may be useful in treating cases of overdosage

Inhibitory effects on alcohol dehydrogenase are increased in presence of ethanol; ethanol also decreases metabolism of 4-MP; 4-MPO induces cytochrome P-450 mixed function oxidases in vitro; 4-MP may worsen the ethanol-chlorohydrate central nervous system interaction

Fomepizole diluted in 0.9% sodium chloride injection or dextrose 5% injection is stable for at least 48 hours when stored refrigerated or at room temperature; although, it is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservatives.

After dilution, do not use beyond 24 hours. Fomepizole solidifies at temperatures <25°C (77°F). If the fomepizole solution has become solid in the vial, the solution should carefully be warmed by running the vial under warm water or by holding in the hand. Solidification does not affect the efficacy, safety, or stability of the drug.

Complexes and inactivates alcohol dehydrogenase thus preventing formation of the toxic metabolites of the alcohols

Maximum effect: 1.5-2 hours

Absorption: Oral: Readily absorbed

Distribution: V_d: 0.6-1.02 L/kg; rapidly distributes into total body water

Protein binding: Negligible

Elimination: Nonlinear elimination; at suggested therapeutic doses of 10-20 mg/kg, the apparent elimination rate is 4-5 mmol/L/hour

A loading dose of 15 mg/kg should be administered, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until ethylene glycol levels have been reduced <20 mg/dL

Fomepizole is dialyzable and the frequency of dosing should be increased to every 4 hours during hemodialysis

Dose at the beginning of hemodialysis:

If <6 hours since last fomepizole dose: Do not administer dose

If greater than or equal to 6 hours since last fomepizole dose: Administer next scheduled dose

Dosing during hemodialysis: Dose every 4 hours

Dosing at the time hemodialysis is complete, based on time between last dose and the end of hemodialysis:

<1 hour: Do not administer dose at the end of hemodialysis

1-3 hours: Administer 1/2 of next scheduled dose

>3 hours: Administer next scheduled dose

Maintenance dose when off hemodialysis: Give next scheduled dose 12 hours from last dose administered.

Fomepizole plasma levels should be monitored as well as the response of ethylene glycol intoxication to fomepizole; monitor plasma/urinary ethylene glycol, urinary oxalate, plasma/urinary osmolality, renal/hepatic function, serum electrolytes, arterial blood gases; look for continued signs of severe metabolic acidosis, elevated anion and osmolar gaps, significant creatinine increases and resolution of clinical signs and symptoms of ethylene glycol intoxication (eg, arrhythmias, seizures, coma)

Concentrations >10 mmol/L should result in enzyme inhibition

Dizziness is common; may cause drowsiness

None reported

No information available to require special precautions

No effects or complications reported

This agent is intended as an antidote for ethylene glycol poisoning, the main ingredient in antifreeze and coolants, which can cause severe CNS depression, severe metabolic acidosis, renal failure, coma, and possibly death. The most common reactions to be aware of with the use of this agent are minor allergic reactions, headache, nausea, and dizziness.

Injection: 1 g/mL (1.5 mL)

Borron SW and Baud FJ, "Intravenous 4-Methylpyrazole as an Antidote for Diethylene Glycol and Triethylene Glycol Poisoning: A Case Report," Vet Hum Toxicol, 1997, 37(1): 26-8.

Brent J, McMartin K, Phillips S, et al, "4-Methylpyrazole (Fomepizole) Therapy of Ethylene Glycol Poisoning: Preliminary Results of the Meta Trial," J Toxicol Clin Toxicol, 1997, 35(5):507.

Brent J, McMartin K, Phillips S, et al, "4-Methylpyrazole (Fomepizole) Therapy of Methanol Poisoning: Preliminary Results of the Meta Trial," J Toxicol Clin Toxicol, 1997, 35(5):507.

Hung O, Kaplan J, Hoffman R, et al, "Improved Understanding of the Ethanol-Chloral Hydrate Interaction Using 4-MP," J Toxicol Clin Toxicol, 1997, 35(5):507-8.

Jacobsen D and McMartin KE, "4-Methylpyrazole - Present Status," J Toxicol Clin Toxicol, 1996, 34(4):379-81.

Jacobsen D and McMartin KE, "Antidotes for Methanol and Ethylene Glycol Poisoning," J Toxicol Clin Toxicol, 1997, 35(2):127-43.

Jacobsen D, Ostensen J, Bredesen L, et al, "4-Methylpyrazole (4-MP) Is Effectively Removed by Haemodialysis in the Pig Model," Hum Exp Toxicol, 1996, 15(6):494-6.

Jacobsen D, Sebastian CS, Barron SK, et al, "Effects of 4-Methylpyrazole, Methanol/Ethylene Glycol Antidote in Healthy Humans," J Emerg Med, 1990, 8(4):455-61.

Jobard E, Harry P, Turcant A, et al, "4-Methylpyrazole and Hemodialysis in Ethylene Glycol Poisoning," J Toxicol Clin Toxicol, 1996, 34(4):373-7.

McMartin KE and Heath A, "Treatment of Ethylene Glycol Poisoning With Intravenous 4-Methylpyrazole," N Engl J Med, 1989, 320(2):125.