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Three Part Question

In a [patient with elevated risk of liver injury following paracetamol overdose]is [fomepizole with NAC better than standard care alone with NAC at standard dose] at [decreasing incidence of liver injury, decreasing incidence of liver failure, decreasing length of hospital stay, decreasing incidence of death and improving patient experience]

Clinical Scenario

A 25-year-old women attends the emergency department having taken a large paracetamol overdose. She reports taking 64x500mg tablets 7 hours ago. On questioning she describes nausea and vomiting with mild abdominal pain. Her examination reveals right upper quadrant tenderness. Blood investigations reveal a high paracetamol level. You start her on IV acetylcysteine as per the SNAP protocol. You are concerned that she is at risk of developing serious liver injury and wonder if there is any other treatment that could be initiated in addition to the NAC minimise this risk.

Search Strategy

Medline from 1966 to 2022 using pubmed interface
Results were filtered to include only papers that were full text, English and involved humans.

(Paracetamol OR acetaminophen OR paracetamol sulphate OR paracetamol derivative) AND (drug overdose OR overdose OR poisoning OR suicide) AND (fomepizole)

Search Outcome

29 Results of which 7 were identified as relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Shah et al 2020 USA	33 y/o male with staggered paracetamol overdose, high risk of significant liver injury. Treated with IV NAC and fomepizole	Case report	Liver injury	Lack of development of significant liver injury despite risk factors	Isolated case report. Non-standardised NAC dose administered Multiple confounding factors for liver injury present (alcohol dependence etc)
Woolum et al 2020 USA	Use of n-acetylcysteine, fomepizole, and hemodialysis to treat a massive paracetamol ingestion in 55 y/o male with features of renal failure.	Case report	Clinical outcome	In addition to other therapies fomepizole may have played a role in deterring the development of paracetamol related hepato-toxicity and death	Individual case report. Likely inconclusive as multiple interventions utilised
Kang et al 2020 USA	5 human volunteers	Cross over trial	Percentage of oxidative paracetamol metabolites detected	The addition of fomepizole resulted in the reduction in the production of oxidative metabolites in urine 4.48 to 0.51% (95% CI = 2.31–5.63%, p = 0.003).	Small sample size. Paracetamol not administered in overdose, supra-therapeutic dose utilised. Fomepizole administered concurrently with paracetamol
Shah et al 2021 USA	Two patients with poor prognostic features from paracetamol overdose. Managed with NAC and fomepizole as an adjunct treatment	Case series	Survival	Both patients survived to hospital discharge	Small case series Non-controlled case series. Variable NAC dosing strategy. Confounding factor for hepatotoxicity (hepatitis C)
			Fomepizole safety in paracetamol overdose	No reported safety issues
Chui et al 2021 Canada	Massive paracetamol overdose treated with NAC, fomepizole and haemodialysis	Case report	Survival	Patient survived to discharge from hospital	Individual case report. Polypharmacy overdose (ibuprofen) Recovery cannot be attributed to paracetamol toxicity treatment alone. Multiple interventions utilised. Dialysis removes NAC and fomepizole. Bespoke re-dosing strategies to account for this.
			Hepatotoxicity	Resolution of biochemical evidence of hepatotoxicity
Cuninghame et al 2021 Canada	Massive paracetamol overdose, delayed presentation and metabolic acidosis refractory to NAC, fomepizole and RRT.	Case report	Survival	Patient did not survive admission due to fulminant liver failure	Individual case report Variable NAC dosing + use of haemodialysis complicating dosing strategy Multiple interventions.
Link et al 2022 USA	14 consecutive, high-risk patients who had elevated paracetamol levels after overdose who were treated with fomepizole as an adjunct to standard IV-NAC	Case series	Safety of fomepizole in paracetamol overdose	No observable side effects	Small case series No specific criteria for identifying side effects No specific criteria for identification of potential participants or administration of fomepizole Variable dosing

Comment(s)

NAC is the only licensed treatment for paracetamol overdose. Unfortunately hepatotoxicity can still occur, especially in those with massive overdose or cases of delayed administration of NAC (1). Fomepizole is usually utilised in toxic alcohol ingestion where it is used to inhibit alcohol dehydrogenase. It is also a potent cytochrome P450 system inhibitor and therefore may reduce the toxic metabolite production in the liver that occurs in paracetamol overdose (3). Early human studies involving small numbers of volunteers support this concept but are limited by their scale (4). Given the theoretical additional benefits of fomepizole a number of authors have published case reports and series detailing clinical outcomes in high-risk paracetamol overdose patients who have received fomepizole (1–3,5,7). None have recorded any serious adverse events and authors have suggested that the levels of hepatotoxicity observed were potentially lower than the presence of risk factors would have predicted. The evidence is low quality, papers identified were individual case studies or uncontrolled case series involving a diverse patient group and often multiple interventions utilised together, making firm conclusions impossible to draw. These reports do suggest that fomepizole is likely to be safe in paracetamol overdose and a high-quality clinical trial is now needed to further confirm safety and establish efficacy.

Clinical Bottom Line

Fomepizole has the potential to be beneficial in paracetamol overdose through its ability to inhibit the production of toxic metabolites in the liver. Current evidence suggests it may be safe but there is no good-quality evidence that reliably demonstrates its safety and efficacy in this situation and therefore administration cannot be recommended at present.

References

1. Shah KR, Beuhler MC. Fomepizole as an Adjunctive Treatment in Severe Acetaminophen Toxicity Am J Emerg Med 2020 Feb 1 [cited 2022 Jun 29];38(2).
2. Woolum JA, Hays WB, Patel KH Use of fomepizole, n-acetylcysteine, and hemodialysis for massive acetaminophen overdose Am J Emerg Med 2020 Mar 1 [cited 2022 Jun 29];38(3):692.e5-692.e7
3. Kang AM, Padilla-Jones A, Fisher ES, Akakpo JY, Jaeschke H, Rumack BH, et al The Effect of 4-Methylpyrazole on Oxidative Metabolism of Acetaminophen in Human Volunteers J Med Toxicol 2020 Apr 1 [cited 2022 Jun 29];16(2):169–76.
4. Shah KR, Fox C, Geib AJ, Murphy C, Kopec K, Kerns W, Fomepizole as an adjunctive treatment in severe acetaminophen ingestions: a case series. Clin Toxicol (Phila) 2021 [cited 2022 Jun 29];59(1):71–2
5. Chiu MH, Jaworska N, Li NL, Yarema M. Massive Acetaminophen Overdose Treated Successfully with N-Acetylcysteine, Fomepizole, and Hemodialysis Case Rep Crit Care 2021 [cited 2022 Jun 29];2021.
6. Cuninghame S, Lotfy K, Cameron P Massive acetaminophen overdose with metabolic acidosis refractory to N-acetylcysteine, fomepizole, and renal replacement therapy Toxicol Rep 2021 Jan 1 [cited 2022 Jun 29];8:804–7.
7. Link SL, Rampon G, Osmon S, Scalzo AJ, Rumack BH Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series Clin Toxicol (Phila) 2022 [cited 2022 Jun 29];60(4):507–13