Fomepizole Antidote

Take Home Points

• Fomepizole is a safe and highly effective antidote for toxic alcohol poisoning that has replaced ethanol as a treatment.
• Indications for fomepizole include a clear history of toxic alcohol ingestion, severe unexplained acidosis, or substantially elevated osmolar gap.
• Fomepizole therapy alone is sufficient for patients that present early. Hemodialysis may be required in very large ingestions or those with significant acidosis or end-organ injury.

Methanol and Ethylene Glycol Toxicity

Methanol and ethylene glycol, two of the most common toxic alcohols, are found in many readily available household products. Methanol is a major component of windshield washer fluid and many other industrial solvents, while ethylene glycol is the main component of antifreeze. Toxicity from these compounds is due to their toxic metabolites. Methanol is metabolized to formaldehyde through alcohol dehydrogenase, which is further metabolized to formic acid through aldehyde dehydrogenase. Ethylene glycol is metabolized to glycoaldehyde by alcohol dehydrogenase, which is further metabolized to glycolic acid and oxalic acid by aldehyde dehydrogenase¹. Toxic alcohols can increase the osmolar gap while their toxic metabolites can cause a high anion-gap metabolic acidosis. An osmolar gap and anion gap may be present simultaneously, but as more of the toxic alcohol is metabolized, osmolality will start to fall and anion gap will continue to rise². These abnormal laboratory results are not always present as a low basal serum osmolar gap may obscure an increase due to a toxic alcohol, absence of osmolar gap or anion gap cannot be used to rule out the presence of a toxic alcohol². Delays in treating toxic alcohol poisonings lead to worse outcomes. Treatment with an alcohol dehydrogenase inhibitor should commence expeditiously when there is a strong suspicion of toxic alcohol poisoning or when metabolic acidosis of unknown cause is present³.

Fomepizole

Fomepizole (or 4-methylpyrazole) is a strong inhibitor of alcohol dehydrogenase with an affinity for alcohol dehydrogenase 8,000 times that of ethanol. Fomepizole received FDA approval for the treatment of ethylene glycol and methanol poisoning in 1997 and 2000, respectively³. Fomepizole is effective in the treatment of toxic alcohol ingestions as it blocks alcohol dehydrogenase, inhibiting the conversion of methanol and ethylene glycol into their toxic metabolites^1,3. In the presence of fomepizole blockade, methanol has a half-life of as long as 71 hours, while ethylene glycol has a half-life as long as 16 hours³. In the setting of high initial methanol or ethylene glycol concentrations, fomepizole may need to be continued for days to allow concentrations to fall below the treatment threshold of 20 mg/dL.

Fomepizole Indications

A full discussion of the clinical features and diagnosis of toxic alcohol poisoning is beyond the scope of this article. However, fomepizole should be given as soon as possible when there is a strong suspicion of significant toxic alcohol exposure. Some criteria for empiric administration of fomepizole include:

• Strong history of intentional toxic alcohol ingestion (e.g. patient reported suicide attempt, found with empty container)
• Accidental ingestion of toxic alcohol with a predicted peak toxic alcohol concentration >20 mg/dL
• Significant anion-gap metabolic acidosis without an alternative explanation
• Elevated osmolar gap without an alternative explanation (>20)

Call the Utah Poison Control Center to discuss indications for a specific patient.

Fomepizole Safety

Prior to fomepizole’s FDA approval for ethylene glycol poisoning in 1997, ethanol was the alcohol dehydrogenase inhibitor used in treatment of toxic alcohol poisonings which has been used since the 1940s⁴. Ethanol is administered intravenously or orally to obtain high plasma ethanol levels of 100 to 125 mg/dL to inhibit alcohol dehydrogenase⁵. Throughout the years since fomepizole’s approval, studies have been conducted to compare the safety of the two therapies. A 2011 article looked at medication errors associated with the use of ethanol compared to fomepizole for toxic alcohol poisonings and found that harmful medication errors occurred more frequently with the use of ethanol at 19% compared to 7% with fomepizole⁴. A 2009 study compared adverse drug events between ethylene glycol and fomepizole in the treatment of toxic alcohol poisonings and found that adverse drug events occurred in 57% of the ethanol group and 12% of patients in the fomepizole group⁵. Treatment with fomepizole has been shown to be safer with reduced medication errors and adverse drug reactions compared to ethanol.

Fomepizole Dosing⁶

• An initial loading dose of 15 mg/kg IV
• Maintenance dosing of 10 mg/kg IV every 12 hours for 4 doses
• If additional fomepizole doses are required, the dose should be increased to 15 mg/kg IV every 12 hours thereafter as fomepizole may induce its own metabolism by cytochrome P450 enzymes³
• Treatment with fomepizole is indicated until ethylene glycol or methanol concentrations are undetectable or have been reduced below 20 mg/dL, and the patient is asymptomatic with a normal pH

Dosing During Hemodialysis

Fomepizole only prevents formation of toxic metabolites, while hemodialysis is effective at removing toxic alcohols and their toxic metabolites. Hemodialysis should be used in patients with significant acidosis, elevated anion gap, or evidence of end-organ injury. It can also be used in patients with or without severe side effects to reduce length of fomepizole therapy in patients with very high initial toxic alcohol concentrations. In the presence of hemodialysis, the half-lives of toxic alcohols are cut dramatically, methanol down to approximately 2.5 hours and ethylene glycol to approximately 2.7 hours³. The EXTRIP workgroup provides recommendations for hemodialysis therapy in toxic alcohol ingestions. Some of these recommendations include hemodialysis treatment if coma or seizure occurs, in the presence of reduced kidney function, or if methanol concentration is greater than 70 mg/dL in the presence of fomepizole therapy. For ethylene glycol poisonings, they suggest hemodialysis if the ethylene glycol level is greater than 310 mg/dL in the presence of fomepizole therapy^7,8. For full recommendations on when to start, stop, and consider hemodialysis visit the EXTRIP website or consult the Utah Poison Control Center.

Table 1: Adapted from fomepizole package insert⁶

Toxic Alcohol Lab Ordering Tips and Pitfalls

• Pitfalls in the interpretation of laboratory data include failure to recognize that concentrations may be expressed in milligrams per liter or milligrams per deciliter, with values higher than 200 mg per liter or 20 mg per deciliter indicating the need for treatment³
• Toxic alcohol concentrations help guide therapy and can be instrumental in determining if hemodialysis should be started as well as duration of therapy for both hemodialysis and fomepizole. Ordering these labs correctly and minimizing delays may help make therapy decisions sooner and could reduce unnecessary treatment and hospital length of stay
• Labs should be ordered STAT, but they also must be couriered STAT to ARUP lab to be run
• Ethylene glycol and methanol labs require 2 separate lab orders; methanol is part of the volatile alcohol order test, while an ethylene glycol level must be ordered independent of that panel
• If ordered STAT, toxic alcohol levels will be run on arrival to ARUP laboratories. If ordered routine, samples may sit for days before being analyzed. Typically, once started the test for toxic alcohols takes 4 hours to run. If a lab has not resulted and you suspect a delay at ARUP laboratory, they can be contacted by phone 24/7.
• ARUP Lab contact 800-522-2787

Call the Utah Poison Control Center at 1-800-222-1222 at any time 24/7 for assistance in managing known or suspected toxic alcohol ingestions.

References

1. Gallagher N, Edwards FJ. The Diagnosis and Management of Toxic Alcohol Poisoning in the Emergency Department: A Review Article. Adv J Emerg Med. 2019;3(3): e28. Published 2019 May 22. doi:10.22114/ajem.v0i0.153
2. Mégarbane, B. (2010) Treatment of patients with ethylene glycol or methanol poisoning: Focus on fomepizole, Open access emergency medicine : OAEM. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806829/ (Accessed: 23 May 2023).
3. Kraut JA, Mullins ME. Toxic Alcohols [published correction appears in N Engl J Med. 2019 Jan 10;380(2):202]. N Engl J Med. 2018;378(3):270-280. doi:10.1056/NEJMra1615295
4. Lepik KJ, Levy AR, Sobolev BG, et al. Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole. Ann Emerg Med. 2009;53(4):439-450.e10. doi:10.1016/j.annemergmed.2008.05.008
5. Lepik KJ, Sobolev BG, Levy AR, et al. Medication errors associated with the use of ethanol and fomepizole as antidotes for methanol and ethylene glycol poisoning. Clin Toxicol (Phila). 2011;49(5):391-401. doi:10.3109/15563650.2011.580754
6. Fomepizole package insert. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020696s006lbl.pdf (Accessed: 16 May 2023).
7. Methanol: Extrip-workgroup (no date) extrip. Available at: https://www.extrip-workgroup.org/methanol (Accessed: 16 May 2023).
8. Ethylene Glycol: Extrip-workgroup (no date) extrip. Available at: https://www.extrip-workgroup.org/ethylene-glycol (Accessed: 16 May 2023).

Author: Rochelle Fabian, PharmD, Emergency Medicine Pharmacist, St. Luke’s Meridian Medical Center