Fomepizole 1.5g/1.5ml solution for infusion vials

Ethylene glycol (EG) is metabolized into glycolate and oxalate and may cause metabolic acidemia, neurotoxicity, acute kidney injury (AKI), and death. Historically, treatment of EG toxicity included supportive care, correction of acid-base disturbances and antidotes (ethanol or fomepizole), and extracorporeal treatments (ECTRs), such as hemodialysis. With the wider availability of fomepizole, the indications for ECTRs in EG poisoning are debated. We conducted systematic reviews of the literature following published EXTRIP methods to determine the utility of ECTRs in the management of EG toxicity. The quality of the evidence and the strength of recommendations, either strong ("we recommend") or weak/conditional ("we suggest"), were graded according to the GRADE approach. A total of 226 articles met inclusion criteria. EG was assessed as dialyzable by intermittent hemodialysis (level of evidence = B) as was glycolate (Level of evidence = C). Clinical data were available for analysis on 446 patients, in whom overall mortality was 18.7%. In the subgroup of patients with a glycolate concentration ≤ 12 mmol/L (or anion gap ≤ 28 mmol/L), mortality was 3.6%; in this subgroup, outcomes in patients receiving ECTR were not better than in those who did not receive ECTR. The EXTRIP workgroup made the following recommendations for the use of ECTR in addition to supportive care over supportive care alone in the management of EG poisoning (very low quality of evidence for all recommendations): i) Suggest ECTR if fomepizole is used and EG concentration > 50 mmol/L OR osmol gap > 50; or ii) Recommend ECTR if ethanol is used and EG concentration > 50 mmol/L OR osmol gap > 50; or iii) Recommend ECTR if glycolate concentration is > 12 mmol/L or anion gap > 27 mmol/L; or iv) Suggest ECTR if glycolate concentration 8-12 mmol/L or anion gap 23-27 mmol/L; or v) Recommend ECTR if there are severe clinical features (coma, seizures, or AKI). In most settings, the workgroup recommends using intermittent hemodialysis over other ECTRs. If intermittent hemodialysis is not available, CKRT is recommended over other types of ECTR. Cessation of ECTR is recommended once the anion gap is < 18 mmol/L or suggested if EG concentration is < 4 mmol/L. The dosage of antidotes (fomepizole or ethanol) needs to be adjusted during ECTR.

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N-acetylcysteine (NAC) as the gold standard antidote in cases of acetaminophen (APAP)-related poisoning might not be sufficient with delayed presentation or massive ingestion. Human reports published up to July 2021 suggest that fomepizole could play a role in APAP overdoses by inhibiting cytochrome P450 2E1 (CYP2E1)-mediated N-acetyl-p-benzoquinone imine (NAPQI) production and JNK-mediated oxidative damage. This narrative review builds on previous systematic and scoping reviews by adding the latest evidence about the use of fomepizole in APAP poisoning to better understand the hepatoprotective role and safety profile of this medication, as well as its practical place in therapy. A systematic search of MEDLINE and Embase was completed through November 2024. Studies involving human patients with APAP toxicity who received fomepizole treatment were included. Each case was summarized in tables to identify clinical trends, particularly the risk of hepatotoxicity, quantity of ingestion, time of presentation since ingestion, therapeutic and dosing regimens, and clinical outcomes. This review covers 28 studies and 45 patients across 18 case reports and 6 case series. When used with NAC, fomepizole seemed to result in favorable laboratory and clinical outcomes in most patients at high risk of hepatotoxicity because of late presentation or massive APAP ingestion. The available data suggest that fomepizole might complement NAC in treating severe APAP toxicity. Though they lack detailed clinical outcome analyses, case studies suggest that fomepizole could improve hepatotoxicity, survival, and transplant-free days.

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Acetaminophen (APAP) overdose can cause liver injury and is the leading cause of acute liver failure in Western countries. Hepatocellular necrosis induced by APAP involves the formation of a reactive metabolite, triggering mitochondrial oxidant stress and peroxynitrite formation. Iron-catalyzed protein nitration is critical for mitochondrial dysfunction and cell death in the absence of lipid peroxidation (LPO). However, co-treatment of APAP and ferrous sulfate aggravated protein nitration and liver injury but also triggered extensive LPO (measured as malondialdehyde and hydroxy eicosatetraenoic acid (HETE) species). The objective of this study was to evaluate whether the aggravated injury under these conditions is caused by a combination of protein nitration and LPO or if LPO is now the dominant injury mechanism. To test this, C57BL/6 J mice were co-treated with APAP (300 mg/kg) and a moderate dose of ferrous sulfate (0.15 mmol/kg) for 6 h. Some animals also received a dose of Mito-TEMPO, the mitochondria-targeted SOD mimetic, or minocycline, an inhibitor of mitochondrial iron uptake. Although Mito-TEMPO and minocycline eliminated protein nitration and liver injury after APAP alone, these interventions did not affect LPO and only had a moderate effect on protein nitration and liver injury in the APAP+Fe 2+ group, suggesting LPO as the main mechanism of cell death. Consistent with these findings, delayed treatment with clinically relevant antidotes N-acetylcysteine and fomepizole did not reduce LPO or liver injury. Thus, liver injury after APAP+Fe 2+ is no longer primarily driven by mitochondrial oxidant stress and peroxynitrite-mediated necrosis but by lipid peroxidation and a ferroptosis-like cell death.

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INTRODUCTION: c-Jun N-terminal kinases or superoxide generation; and other specific targets, such as nuclear factor-erythroid factor 2-dependent gene induction and autophagy. With this range of potential additional therapies, how should the speciality of clinical toxicology approach the development of new antidotes for this common poisoning? HISTORICAL BACKGROUND: When the first treatments for paracetamol toxicity were developed, the clinical trial and ethical basis of practice were different from today. Acetylcysteine was never subjected to placebo-controlled studies, even by the United States Food and Drug Administration, as it was presumed that the toxicity of high paracetamol concentrations was so evident that placebo-controlled studies were unethical. Thus, the absolute benefit of acetylcysteine remains unknown. In addition, no dose-ranging studies of acetylcysteine in patients were ever done. The weakness of assessing the efficacy of additional antidotes in small groups of patients with moderate poisoning is illustrated by the use of cimetidine in paracetamol poisoning. CURRENT APPROACHES TO DRUG (AND ANTIDOTE) DEVELOPMENT: The approach required by regulatory authorities today relies on several important steps. First, a clear target for therapeutic effect is sought, normally in a laboratory model. Next, a 'proof of principle' study is required to demonstrate that the target is 'druggable'. Finally, clinical studies to confirm proof of principle applies in humans, followed by a controlled trial with matched patient groups with sufficient power to demonstrate the clinical outcome being sought. Such patient studies can be expensive to conduct, and non-commercial groups suffer the risk of not being funded. FOMEPIZOLE: Fomepizole prevents paracetamol-induced hepatic toxicity in mice by inhibiting cytochrome P4502E1, thereby preventing the conversion of paracetamol to its toxic metabolite. Fomepizole also inhibits c-Jun N-terminal kinases, a key pathway in the downstream toxicity on the mitochondria. The present evidence of efficacy in humans is based on small case series with no control groups. The availability of a licensed indication has facilitated off-label use of fomepizole in an unproven indication. CONCLUSIONS: Paracetamol poisoning is common, and randomized, controlled clinical trials are possible. The benefit of fomepizole can only be shown by such a study. As clinical trials using fomepizole as an added therapy to acetylcysteine are recruiting in the United States, these should be supported by all clinical toxicologists. In the interim, the publication of small case series using fomepizole should be discouraged by journals.

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BACKGROUND: Fomepizole has been suggested as adjunctive therapy for severe acetaminophen poisoning though clinical efficacy is unknown. We sought to determine trends in the use of fomepizole for acetaminophen poisoning. METHODS: This is a cross-sectional analysis of hospitalized patients with acetaminophen poisoning from January 2013 through December 2024, using Epic Cosmos, a research database of 298 million patients nationally. We identified encounters involving acetaminophen poisoning by International Classification of Diseases, version 10 (ICD-10-CM) code. Data extracted included administration of N-acetylcysteine (NAC) and fomepizole, demographic data, and outcomes of death and liver transplantation. Data were analyzed using descriptive statistics to identify trends and multivariable logistic regression to determine associations with death. RESULTS: There were 114,111 hospital encounters involving acetaminophen poisoning with 64,957 (56.92%) receiving NAC, and 1,552 (1.36%) receiving fomepizole. In 2013, 0.44% of NAC-treated acetaminophen poisoning cases also received fomepizole. This rose to 6.27% in 2024. From 2013 to 2019, the proportion of NAC-treated acetaminophen cases receiving fomepizole was stable, but from 2019 to 2024, there was a 1029.64% increase in fomepizole use. Regression modeling indicated increased odds for death (OR = 5.88, aOR = 5.32 [95% CI: 4.52, 6.27]) among those who received fomepizole in addition to NAC, indicating increased fomepizole use in patients with severe toxicity. CONCLUSION: Fomepizole use in acetaminophen poisoning has risen dramatically since 2019, particularly among patients at highest risk for death and liver transplantation. It is of critical importance to determine the efficacy of fomepizole for acetaminophen poisoning.

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