The role of fomepizole in acetaminophen-related poisoning: a narrative review.

Canada faces nearly 4,500 hospitalizations each year from acetaminophen (APAP)-related poisoning, with 6% of them resulting in liver injuries and acute liver failure requiring liver transplants or leading to death [ 1 ]. At therapeutic doses, 50% to 70% of APAP is metabolized by glucuronidation, 25% to 35% by sulfation, and 2% to 5% is excreted unchanged in urine [ 2 ]. The remainder undergoes liver metabolism, primarily by cytochrome P450 2E1 (CYP2E1), which generates toxic N-acetyl-p-benzoquinone imine (NAPQI), a key driver of APAP-induced hepatotoxicity [ 2 ]. At toxic doses (>4 g/day in adults or >75 mg/kg/day in children), the sulfation process becomes saturated, leading to excessive NAPQI production that depletes intracellular glutathione, causing oxidative liver damage. Fomepizole protects the liver by inhibiting CYP2E1, which reduces NAPQI formation, and blocking JNK activation to mitigate mitochondrial oxidative stress [ 2 ]. As the only available antidote for APAP-related poisoning, N-acetylcysteine (NAC) is most effective if initiated within 8 to 10 hours after an overdose, and it is successful in managing most toxic cases. However, with a massive ingestion (APAP levels above the 300 μg line on the Rumack-Matthew Nomogram or >30 g of ingestion) or late presentation (>8–10 hours), NAC alone might not prevent the need for liver transplantation or fulminant liver failure, prompting inquiries into whether additional therapy could be provided [ 2 ]. In the absence of robust studies, changes in standards of practice rely heavily on the body of evidence available in human case reports and case series. Previous systematic or scoping reviews summarized preclinical in vivo and in vitro data, along with human case studies on fomepizole in APAP-related poisoning only up to July 2021, and they offered preliminary and inconclusive insights into its use. This narrative review focuses on human experiences and includes several new case studies to identify emerging trends and patterns and better inform more specific recommendations for the indications and role of fomepizole in managing APAP poisoning.

This review summarizes the current evidence for the use of fomepizole to manage APAP overdose and toxicity. A systematic literature search was performed in the MEDLINE and Embase databases from their inception to November 2024 to identify relevant studies on this topic. The search strategy, developed with the assistance of a librarian, included Medical Subject Headings (MeSH) terms such as “fomepizole,” “acetaminophen,” “antidote,” “overdose,” and “toxicity” ( Suppl. 1 ). The review included full-text studies and abstracts from conference proceedings that were written in English and involved the use of fomepizole as an antidote for patients with APAP overdoses. Animal studies, non-English publications, and studies exploring other indications of fomepizole, such as toxic alcohol ingestion in the absence of APAP overdose, were excluded. The references of reviews about fomepizole therapy for APAP toxicity management were hand-searched to identify any original articles that might otherwise have been missed. Two independent reviewers screened titles and abstracts, with a third resolving conflicts and discrepancies, and the data were extracted using a standardized form. Each article was thoroughly screened, and the study design, patient characteristics, treatment protocols, and key outcomes (recovery in liver function or injury, acid-base status, mental status, and timing of discharge) were extracted and summarized in tables. The risk of bias in each included study was identified using a full-text review and the JBI critical appraisal tool ( Suppl. 2 , 3 ). A narrative synthesis was performed by identifying key themes that highlight human experiences with fomepizole protocols, including dosing, concomitant use with NAC and dialysis, timing of initiation, place in therapy (i.e., massive ingestion and late presentation), and effects on patient outcomes based on the risk of hepatotoxicity. No statistical analyses of the results were possible because of the large number of case series and heterogeneity in the data found.

The search strategy yielded 214 potentially relevant citations. After the removal of duplicate citations and initial screening, 51 studies were selected for full article review. Twenty-three studies were excluded after the full-text article review. Therefore, 28 publications were included, comprising 18 case reports and 6 case series describing 45 subjects, along with 1 randomized crossover trial, 1 registry-based study, and 2 conference abstracts [ 3 – 31 ]. One patient was excluded from a case series by Link et al. [ 21 ] due to duplication because the same case had already been reported by the same authors in 2020 [ 15 ]. Tables 1 and 2 provide more background on the included case studies. The studies sometimes reported a range of demographic characteristics, including age (mean age, 38.1 years), sex (female sex, 65%), dose of APAP ingested (median dose, 53.1 g), time to presentation from ingestion (median time, 5 hours), and various comorbidities among participants. Among the 24 case reports and case series, most patients were deemed to have a high risk of hepatotoxicity and presented with massive APAP ingestion without other coingestants. In studies that reported the time between ingestion and presentation, the patient distribution was relatively equal between those who presented before and after the 8- to 10-hour mark after APAP ingestion. The most prevalent treatment regimen in these high-risk patients was dual therapy (NAC and fomepizole), with fomepizole most often initiated as a single dose more than 8 to 10 hours after APAP ingestion. Triple therapy (NAC, fomepizole, and dialysis) was also reported, often without indicating a preference for the timing of fomepizole, but in those cases, multidose regimens were seen more frequently than single-dose regimens. Single-dose-fomepizole monotherapy was also used in four of these cases, all of whom had APAP-aminotransferase multiplication product (APAP×AT) of more than 10,000 and developed shock or multiorgan dysfunction following chronic or repeated supratherapeutic APAP ingestions. The few patients who were at possible risk, low risk, or had an undetermined risk of hepatotoxicity typically presented within 8 to 10 hours after consumption and were successfully managed with either dual or triple therapy. In all but one patient, favorable clinical and laboratory outcomes were reported. Specifically, there was consistent resolution of neurocognitive, acid-base, and hemodynamic abnormalities without significant deterioration, organ failure, or the need for a liver transplant. APAP levels declined steadily throughout each patient’s clinical course, and the levels of liver enzymes and markers of liver function rose initially before recovering shortly after fomepizole initiation. Regarding the ordinal aspect of each patient’s therapeutic regimen, fomepizole was most commonly started either at the same time as NAC or after NAC but before dialysis was initiated. On numerous occasions, the use of fomepizole was rationalized by either persistently elevated or increasing APAP and liver enzyme levels or the severity of patient presentation and possible coingestants prompting concerns about a significant risk of morbidity or near-term mortality. In all cases, fomepizole was most frequently administered at the dose standard for treating toxic alcohol poisoning (15 mg/kg intravenous [IV], followed by 10 mg/kg IV every 12 hours as needed). No adverse events associated with fomepizole were reported in any of these case reports or case series. Our search also yielded a single double-blinded, randomized, controlled crossover trial, conducted by Kang et al. [ 27 ], which examined the effect of fomepizole alone on APAP levels in overdoses. The study involved five healthy volunteers. Participants received APAP alone or with fomepizole, with a 2-week washout period between treatments. Fomepizole significantly reduced the formation of oxidative metabolites, indicating its potential to mitigate APAP toxicity. However, that study's short timeline did not capture effects during peak hepatotoxicity, which occurs 72 to 96 hours after ingestion. No adverse events were reported. A secondary analysis of the ToxIC (Toxicology Investigators Consortium) database by Filip et al. [ 28 ] between January 2015 and July 2020 revealed that when fomepizole was explicitly used to manage APAP-overdose patients (n=25) with markers of critical illness (hepatotoxicity/coagulopathy, metabolic acidosis, need for intubation/vasopressors/continuous renal replacement therapy), an overall mortality rate of 24% (6 of 25) was observed. It is interesting to note that this is higher than the mortality rates observed in the case reports and case series included in our review. However, the patients included in that study exhibited severely toxic clinical presentations, so its mortality rate was confounded by critical illness. Filip et al. [ 28 ] also explored prescriber attitudes about the use of fomepizole in that context. Most prescribers indicated that they would consider the use of fomepizole at the standard dose for managing toxic alcohol poisoning in conjunction with dialysis in both acute and chronic APAP overdoses. Most prescribers also agreed that fomepizole is safe in patients with significant metabolic acidosis or hepatotoxicity. No additional patient outcomes were derived from that study. Two abstracts from conference proceedings are also included in this review. An institutional review of the use of fomepizole and NAC in patients with massive APAP ingestion and without co-ingestion of hepatotoxic substances (n=41) by Stott et al. [ 29 ] demonstrated that patients who started fomepizole and NAC on the same day had significantly lower peak AST levels and total days on NAC therapy than those who started the treatments on different days. A trend toward fewer deaths and major outcome designations was also observed in the same-day group. Vottero and Mégarbane [ 30 ] performed an observational retrospective cohort study in which mortality was observed in one of six patients who presented to a non-liver intensive care unit with acute liver failure and received both fomepizole and NAC.

To our knowledge, this review includes all the latest findings since July 2021 and adds to the available body of evidence summarized by recent systematic and scoping reviews by Mullins et al. [ 31 ] and Pourbagher-Shahri et al. [ 2 ]. It presents evolving insights into the hepatoprotective mechanisms, optimal dosing strategies, and safety profile of fomepizole in treating APAP poisoning. Prior to this narrative review, the benefits of adding fomepizole to NAC had been suggested by various in vitro and in vivo studies, but human data were quite limited. Thus, it remained unclear in both systematic or scoping reviews whether fomepizole alone or in combination with NAC was a primary contributor to each patient’s positive clinical outcomes [ 2 , 31 ]. Including studies from previous scoping reviews and new cases allowed for a more comprehensive overview of fomepizole use in APAP poisoning, revealing clinical trends and indications that were not addressed in earlier reviews. Case series and case reports continue to offer insights into how fomepizole fits into patient care in the setting of APAP overdose in a real-life scenario, but observational cohort studies are needed to better understand the clinical outcomes of fomepizole in APAP toxicity management. Most care teams in these case reports did not pre-emptively initiate fomepizole with NAC upon initial toxic presentation. Fomepizole was typically started when APAP concentrations, liver enzyme markers, or a patient’s clinical status were not amenable to an IV NAC infusion. Instances in which fomepizole was initiated close to or at the same time as NAC seemed to occur often in patients who eventually required dialysis. This could imply that the severity of a patient’s toxic presentation factors into whether a clinician chooses to start fomepizole earlier as opposed to later. Beneficial clinical and laboratory effects were observed in these studies, but it remains unclear whether these outcomes can be attributed specifically to fomepizole alone or its use alongside NAC and hemodialysis or if fomepizole offered any significant hepatoprotection. Specifically, APAP concentrations and liver enzyme levels, along with other relevant laboratory markers (lactate, venous blood gas, bilirubin, international normalized ratio), seemed to decrease and become responsive upon the addition of fomepizole, but causality cannot be confirmed. Despite most cases resulting in the resolution of the patient’s general clinical presentation, liver/acid-base disturbances, and altered mental status, these studies did not provide in-depth analyses of their clinically meaningful outcomes. Nonetheless, these results suggest fomepizole’s potential role in improving hepatotoxicity in ways that reduce near-term mortality and the need for liver transplantation. It has become clear that fomepizole is being used more liberally by prescribers for the management of APAP-related poisoning. The systematic review by Mullins et al. [ 31 ] recommended fomepizole as adjunctive therapy in patients with at least one of the following characteristics of severe poisoning: APAP concentration above the 300 line of the APAP treatment nomogram, metabolic acidosis, positive King’s College criteria, or late presentation with evident liver injury and measurable APAP levels. Among the 45 patients in the included case studies, the compiled trends and newly discovered themes across cases provide insight into additional criteria that could be used to determine when fomepizole therapy is warranted and how it could be administered. The severity of a patient’s clinical presentation and risk of mortality/morbidity were among the reasons most commonly cited in these case reports for initiating fomepizole as an adjunct to NAC or dialysis. APAP concentrations and liver enzymes or acid-base abnormalities that were not amenable to NAC infusions were also among the reasons fomepizole was started or multiple doses were administered. Although select cases did report that fomepizole monotherapy provided favorable patient outcomes, the limited clinical experience with this regimen precludes fomepizole from replacing NAC as the standard of care. Limited documentation in each case report makes it difficult to identify a specific timeframe in which the drug should be started. However, it is known that metabolism impairment occurs during an APAP overdose that results in a prolonged half-life of 4 to 8 hours [ 32 ]. That supports early initiation of fomepizole to take advantage of its hepatoprotective mechanisms during the APAP metabolism and post-metabolism phases, sourced from its CYP2E1 and JNK inhibition, respectively [ 33 ]. This consideration was also offered by Stott et al. [ 29 ], who showed that starting fomepizole preemptively on the same day as NAC could limit the severity of hepatotoxicity and reduce the time of NAC therapy. Thus, in addition to the recommendations made by Mullins et al. [ 31 ], fomepizole should be administered within 4 to 8 hours at the standard dose used in alcohol poisoning (15 mg/kg IV, followed by 10 mg/kg IV every 12 hours as needed) in patients at high risk of immediate mortality/morbidity. This includes those with severe clinical presentations, APAP levels above the Rumack-Matthew nomogram line, APAP×AT >10,000, and other markers of severe hepatotoxicity (e.g., refractory metabolic acidosis, coagulopathy, encephalopathy, acute kidney injury). Patients with APAP or liver enzyme levels that are not amenable to NAC infusion with or without dialysis should be considered for fomepizole therapy as well. Although fomepizole is removed by dialysis, there are major discrepancies on its dosing in patients receiving dialysis. Up to 42% of survey respondents in the study by Filip et al. [ 28 ] suggested that fomepizole redosing is required following dialysis. Fomepizole’s drug product monograph suggests that for alcohol intoxication, doses should be administered every 4 hours during dialysis [ 34 ]. No adverse events associated with fomepizole were documented in any case reports or case series included in this review. Furthermore, the lack of adverse events observed in the randomized-controlled trial by Kang et al. [ 27 ] and the extensive positive historical experience using fomepizole to treat toxic alcohol poisoning support its safe use in patients with APAP poisoning. Some common adverse reactions experienced with fomepizole, according to its drug monograph, include headache, nausea, dizziness, drowsiness, and metallic taste [ 34 ]. Less common side effects include abdominal pain, fever, injection site reactions, phlebitis, hypotension, vomiting, diarrhea, and facial flush [ 34 ]. A double-blind randomized-controlled trial by Jacobsen et al. [ 35 ] showed that in healthy volunteers, single doses of 10 and 20 mg/kg of fomepizole did not elicit any adverse effects. Doses above that caused mild to moderate and short-lived nausea, dizziness, and vertigo. No adverse effects linked to changes in objective readings (pulse, blood pressure, temperature, and blood/urine chemistries) were reported. However, the results of that study are limited by a lack of blinding to higher doses of fomepizole due to its poor palatability. The cost of fomepizole as a novel therapy in APAP poisoning warrants consideration. Economic analyses have shown the inflation-adjusted cost of a single dose of fomepizole (15 mg/kg) to be US $748 to $1,123, which is similar to a 20-hour infusion of NAC (US $643 to $735) [ 36 – 40 ]. With the cost of liver transplants in the United States and other countries within the Organization for Economic Co-operation and Development (OECD) often exceeding US $150,000 to $200,000 and the cost of continuous renal replacement therapy, based on data from two tertiary intensive care units in Canada, ranging from CAD $3,486 to $5,117 per week, the potential hepatoprotective benefits of fomepizole could justify a more liberal use of this medication [ 41 , 42 ]. Despite a promising place for fomepizole in patients with APAP overdoses, these results are confounded by a lack of standardization and consistency in treatment protocols, which hinders our ability to identify the main contributor to each patient’s clinical outcome. The assessment of each patient case was also complicated by a lack of documentation of pertinent clinical and laboratory information, which hindered our ability to make general inferences about hepatotoxicity risk stratification, the severity of APAP ingestion and toxic manifestation, the safety of fomepizole therapy, and trends in therapeutic interventions. The small sample sizes and lack of comparators in these case studies also limit their generalizability and undermine our ability to determine causative relationships. Selection bias and publication bias are also possible, with unusual or dramatic patient overdose cases being more likely to be published, so these cases probably do not reflect the entire spectrum of APAP overdose events. The included randomized-controlled trial, observational study, and reviews are also limited by small sample sizes and a lack of analyses for additional patient-centered outcomes. It was difficult to appraise the validity and integrity of each study in the abstracts sourced from conference proceedings. Future observational cohort studies would be an appropriate next step and will be essential to further define the hepatoprotective role of fomepizole and its effects on meaningful clinical outcomes in APAP overdose cases. Human case studies and reports highlight the potential role of fomepizole as an adjunctive therapy in APAP poisoning, particularly in patients for whom intravenous NAC alone is insufficient. Although fomepizole is not a replacement for NAC as the standard of care, it might have contributed to the beneficial outcomes seen in severe poisoning cases, including those with high APAP concentrations, metabolic acidosis, or signs of liver injury. Historical experience with fomepizole in toxic alcohol poisoning and the limited evidence sourced from the randomized, controlled crossover trial suggest that fomepizole exhibits a good safety profile with limited adverse effects. Overall, the evidence supports fomepizole’s consideration in select scenarios, especially in cases with a high risk of hepatotoxicity, severely toxic or refractory clinical status, or late presentation after APAP ingestion. However, in cases of rapid clinical deterioration, a low threshold for hemodialysis remains essential, emphasizing the need for further research to support fomepizole’s role in APAP toxicity management.