A Second Act: Fomepizole in Acetaminophen Toxicity

Acetaminophen (APAP) toxicity is the most common cause of acute liver failure in the United States and carries considerable risk of morbidity and mortality. APAP toxicity arises from the formation of the active metabolite N-acetyl-p-benzoquinonimine (NAPQI), which depletes hepatic glutathione stores and causes hepatocellular necrosis. N-acetylcysteine (NAC) is currently the only FDA-approved antidote for APAP toxicity. However, NAC alone may be insufficient, particularly in patient cases with delayed presentation, massive or repeated supratherapeutic ingestion, or altered APAP pharmacokinetics. Fomepizole (4-methylpyrazole) is currently used off-label as an adjunct to NAC in the management of severe APAP toxicity. Fomepizole inhibits CYP2E1, thereby limiting the oxidative conversion of APAP to NAPQI and preserving existing glutathione stores. The purpose of this case series was to characterize real-world adjunctive use of fomepizole in APAP toxicity.

Electronic health records were reviewed to identify patients who received fomepizole for suspected or confirmed APAP overdose between September 1, 2023, and August 31, 2025. Dosing strategies, laboratory trends, and patient outcomes were collected and are currently undergoing descriptive statistical analysis.

We describe a case series of seven patients treated with fomepizole for suspected and/or confirmed APAP toxicity identified via ICD-10 diagnosis codes. Liver transaminases declined in all patients during hospitalization following fomepizole administration; however, values did not normalize in all cases by discharge. No in-hospital deaths were recorded, and all patients were successfully discharged. No patients received renal replacement therapy. No coagulopathy was observed, with all patients maintaining an INR ≤ 2 throughout hospitalization. There was no documentation of liver transplantation or planned transfer for liver transplant evaluation at the time of discharge. APAP levels decreased to less than 15 mcg/mL by discharge.

This series contributes favorable outcomes to the limited human literature describing NAC and fomepizole use in APAP toxicity.