� Is Fomepizole efficacious in the treatment of toxic acetaminophen overdoses?
Acetaminophen (N-acetyl-para-aminophenol, paracetamol, or APAP) overdose is the leading cause of liver transplantation in the United States. Acetaminophen ingestions greater than 4000 mg (adults) or 60 mg/kg per day are typically hepatotoxic. When ingested, Acetaminophen is rapidly absorbed by the GI tract. It undergoes 90% metabolism by glucuronidation and sulfuration via cytochrome P450 to non-toxic substrates. Once saturated, these pathways shunt towards CYP2E1, which results in the depletion of glutathione and the production of an irreversible hepatoxic substance known as NAPQI (N-acetyl-p-benzoquinone imine).
Acetaminophen Toxicity is broken into 4 known stages:
Stage 1: Asymptomatic or emesis (12 to 24 hours post-ingestion)
Stage 2: Emesis, RUQ abdominal pain, and hypotension (24-72 hours post-ingestion)
Stage 3: Hepatic failure, renal failure, coagulopathy, encephalopathy, acidosis. (72 to 96 hours post-ingestion) [Mortality is highest during this stage]
Stage 4: Recovery (96 hours+)
N-acetylcysteine (NAC) remains the standard of therapy for Tylenol overdose when indicated in conjunction with the Rumack Matthew Nomogram, clinical picture, and liver enzymes. What about the role of 4-methylpyrazole (Fomepizole) as adjunctive therapy?
A recent secondary retrospective metanalysis analyzed 25 cases reported to the Toxicology Investigators Consortium (ToxIC) database.
� Meta-analysis:
➊ The study:
25 total cases met the inclusion criteria as outlined:
Cases reviewed from the ToxIC database from 2015-2020.
APAP was noted to be the ingested substance for clinical presentation.
Fomepizole was co-administered.
Exclusion criteria:
APAP was not the primary substance ingested.
NAC was not administered
Fomepizole was administered for an indication different than adjunctive therapy.
➋ Let's break it down!:
68% of cases were acute APAP ingestions.
72% of patients had hepatotoxicity (AST or ALT > 1000 IU/L)
40% developed coagulopathy (PT > 15s)
Ill patient population
72%) developed metabolic acidosis (pH <7.20),
48% were intubated
36% received vasopressors
24% received CRRT
Mortality:
Of the cases included, there was a mortality of 24%.
Areas of improvement for study:
Relatively small population size
Many confounding variables
Stages of acute APAP toxicity were not accounted for.
Those enrolled in stage 1 vs stage 3 are likely to show improved clinical outcomes due to early initiation of therapy before hepatic cell necrosis.
➌ So Does It Work? Further Studies Say Yes!:
Following this analysis with many confounding variables, Fomepizole became strongly recommended in conjunction with NAC. Fomepizole competitively inhibits alcohol dehydrogenase and is a potent inhibitor of CYP2E1. This blocks the formation of NAPQI, which in conjunction with NAC restores glutathione, allowing for non-toxic glucuronidation and sulfuration hepatic clearance. It has also been shown to prevent kidney injury, extend the therapeutic window of NAC, and even promote hepatic regeneration in mice. It is relatively safe, well tolerated, and is conveniently given as a one-time loading dose of 15 mg/kg followed by a 5 mg/kg maintenance dose Q12hr.
� Conclusions:
Fomepizole has shown strong pharmacologic evidence to support its use as adjunctive therapy to NAC in APAP overdoses. It is growing in popularity and developing strong case-based support for improved patient outcomes.
Implementation of NAC and fomepizole during acute ingestions could represent a critical step in improving APAP overdose outcomes worldwide.
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