What are the indications for fomepizole (antizol) administration in acetaminophen (APAP) toxicity?

Fomepizole is NOT a Standard Indication for Acetaminophen Toxicity

Fomepizole is not currently indicated or recommended by any major guideline for routine use in acetaminophen (APAP) toxicity—N-acetylcysteine (NAC) remains the only FDA-approved and guideline-recommended antidote. However, emerging evidence suggests fomepizole may be considered as an off-label adjunct in select high-risk cases where NAC alone may be insufficient.

Standard of Care: N-Acetylcysteine Only

• NAC is the only proven antidote for APAP toxicity and should be administered to all patients with possible or probable risk on the Rumack-Matthew nomogram 1
• NAC should be given to patients with hepatic failure due to acetaminophen (Level B recommendation) 1
• NAC should be administered to patients with hepatotoxicity and suspected or known APAP overdose, including repeated supratherapeutic ingestions (Level C recommendation) 1
• No guideline currently recommends fomepizole for APAP toxicity 2

Emerging Off-Label Use: When Fomepizole May Be Considered

While not guideline-supported, fomepizole has been used in highly selected cases based on mechanistic rationale and case series data:

Potential Clinical Scenarios (Based on Case Series, Not Guidelines)

• Massive APAP overdoses with persistently elevated levels despite NAC therapy, where altered half-life suggests ongoing toxicity 3
• Critically ill patients with established severe hepatotoxicity (AST/ALT >1000 IU/L) and coagulopathy (PT >15s) despite NAC 4
• Patients with metabolic acidosis (pH <7.20) and multi-organ dysfunction from APAP toxicity 4
• Late-presenting patients (>24 hours) with fulminant hepatic failure where NAC efficacy is diminished 5, 6
• Repeated supratherapeutic ingestions with acute liver failure in high-risk populations 7

Mechanism Supporting Adjunctive Use

• Fomepizole inhibits CYP2E1, blocking formation of toxic APAP metabolite NAPQI 3, 5, 6
• Fomepizole inhibits c-Jun N-terminal kinase (JNK), preventing mitochondrial oxidative stress even after metabolism phase 3, 5, 6
• Unlike NAC, fomepizole may prevent APAP-induced kidney damage and promote hepatic regeneration 5
• Fomepizole has an extended therapeutic window compared to NAC, remaining effective after the metabolism phase 5, 6

Critical Caveats and Limitations

• Fomepizole use in APAP toxicity is experimental and off-label—no randomized controlled trials exist 6
• Current evidence consists only of animal studies, case reports/series, and one healthy volunteer study 5, 6
• Mortality in reported cases was 24%, reflecting the critically ill population selected for fomepizole use 4
• NAC must always be given first and continued—fomepizole is only considered as adjunctive therapy, never as monotherapy 3, 4, 6
• Use should be restricted to experienced toxicologists in rare circumstances with increased hepatotoxicity risk despite standard NAC dosing 6
• Increasing frequency of use (8 cases in 2020 vs 1-4 cases/year 2015-2019) suggests growing clinical interest, but this does not constitute evidence of efficacy 4

Practical Approach

For routine APAP overdose: Use NAC only per established guidelines 1, 2

For consideration of fomepizole (consultation with toxicology required):

• Patient has massive overdose with persistently elevated APAP levels despite NAC 3
• Patient develops severe hepatotoxicity (AST/ALT >1000) with coagulopathy despite NAC 4
• Patient has metabolic acidosis (pH <7.20) and multi-organ failure from APAP 4
• Continue NAC therapy regardless of fomepizole use 3, 6