Fomepizole for Acetaminophen Overdose

Overseen By Arsen Ghasabyan, MD, MPH

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Richard Dart, MD, PhD

Must be taking: Acetylcysteine

Must not be taking: CYP2E1 activators, High-dose iron

Disqualifiers: Pregnancy, Liver cirrhosis, Seizure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 5 days

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are taking certain substances like acetone, cimetidine, or high dosage iron preparations. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Fomepizole for acetaminophen overdose?

Research suggests that Fomepizole, when used alongside N-acetylcysteine (NAC), may help in cases of severe acetaminophen overdose by blocking harmful pathways and reducing liver and kidney damage. Case studies and animal research indicate it could be beneficial, especially when NAC alone is less effective. ^{1 2 3 4 5}

Is fomepizole safe for use in humans?

Fomepizole has been shown to have an excellent safety profile in humans, particularly when used for methanol and ethylene glycol poisoning, and it has been used safely in cases of acetaminophen overdose as well. It has been reported to prevent liver and kidney damage in animal studies and has been used successfully in both adults and children with acetaminophen toxicity. ^{2 3 4 5 6}

How is the drug combination of fomepizole and N-acetylcysteine unique for treating acetaminophen overdose?

The combination of fomepizole and N-acetylcysteine (NAC) is unique because fomepizole can extend the treatment window and provide additional protection against liver and kidney damage in severe or late-presenting acetaminophen overdoses. Fomepizole works by blocking harmful metabolic pathways and reducing oxidative stress, which NAC alone may not fully address in such cases. ^{2 3 4 5 6}

What is the purpose of this trial?

This study is a randomized, placebo-controlled double-blinded clinical trial of patients presenting with acetaminophen poisoning who are at increased risk of developing liver injury. With this trial the investigators are hoping to show the superiority of acetylcysteine (NAC) + fomepizole (4-MP) compared to treatment with acetylcysteine alone. The primary objective of this trial is to determine the effect of fomepizole on the severity of acute liver injury in patients with acetaminophen poisoning.

Research Team

Richard Dart, MD, PhD

Principal Investigator

Rocky Mountain Poison and Drug Safety, division of Denver Health and Hospital Authority

Eligibility Criteria

This trial is for people aged 10 or older who have taken too much acetaminophen and are at risk of liver injury. They must have a certain level of acetaminophen in their blood and be admitted to the hospital. Pregnant women, those with severe liver damage, recent seizures, heart issues, or other serious health problems can't join.

Inclusion Criteria

Provision of signed and dated informed consent form

I started receiving NAC treatment more than 8 hours after ingestion.

I will start the study medication within 24 hours after beginning my NAC treatment.

Exclusion Criteria

Previous participation in this study

Serum ALT greater than 10,000 IU/L or serum AST greater than 20,000 IU/L at time of screening

I have had a liver transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive acetylcysteine and either fomepizole or placebo for acetaminophen overdose

5 days

Continuous monitoring during hospitalization

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-3 weeks

Treatment Details

Interventions

• Fomepizole (4-MP)
• N-acetylcysteine

Trial Overview The study tests if adding Fomepizole (4-MP) to the standard treatment with N-acetylcysteine (NAC) is better for treating acetaminophen overdose than using NAC alone. Participants will receive either both drugs or just NAC through an IV in this randomized and blinded trial.

Participant Groups

Group I: N-acetylcysteine (NAC) and Fomepizole (4-MP) (Study) Experimental Treatment 2 Interventions

Patients randomized to Study group will receive fomepizole (diluted in D5W) in addition to N-acetylcysteine. Study participants will receive study drug (fomepizole or placebo) throughout the study. If randomized to Study group, the infusion of the study medication should be initiated as soon as feasible but no later than 24 hours after the commencement of acetylcysteine therapy.

Group II: N-acetylcysteine (NAC) only (Control) Active Control 1 Intervention

Patients randomized to Control group will receive placebo (D5W) in addition to N-acetylcysteine. Study participants will receive study drug (fomepizole or placebo) throughout the study.

Fomepizole (4-MP) is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Antizol for:

• Ethylene glycol poisoning
• Methanol poisoning

Approved in European Union as Antizol for:

• Ethylene glycol poisoning
• Methanol poisoning

Approved in Canada as Antizol for:

• Ethylene glycol poisoning
• Methanol poisoning

Who Is Running the Clinical Trial?

Richard Dart, MD, PhD

Lead Sponsor

Trials

1

Recruited

40+

Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division

Industry Sponsor

Trials

9

Recruited

2,500+

Findings from Research

A case study of a 20-year-old female who ingested over 120 grams of acetaminophen demonstrated that a combination treatment of N-acetylcysteine (NAC), fomepizole, and hemodialysis can effectively manage massive overdoses, leading to complete clearance of acetaminophen within 32 hours.

The patient showed significant improvement in her condition, including normalization of acid-base balance and hemodynamic status, without experiencing organ failure, suggesting that this triple treatment strategy may reduce the need for prolonged mechanical ventilation and intensive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Massive Acetaminophen Overdose Treated Successfully with N-Acetylcysteine, Fomepizole, and Hemodialysis. Chiu, MH., Jaworska, N., Li, NL., et al.[2021]

Fomepizole is emerging as a safe and effective adjunct treatment to N-acetylcysteine for patients suffering from paracetamol poisoning.

Clinical and basic science evidence suggests that fomepizole may be particularly beneficial for patients with severe poisoning cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fomepizole should be used more liberally in paracetamol overdose. Filip, AB., Mullins, ME.[2023]

Fomepizole shows potential as an adjunct treatment for acetaminophen (APAP) toxicity by inhibiting CYP2E1, which may reduce liver injury caused by oxidative stress, based on evidence from 11 preclinical studies and 14 case reports.

While NAC remains the standard treatment for APAP overdose, fomepizole has a favorable safety profile and may be considered off-label in specific cases where NAC is insufficient, although more research is needed to establish its clinical benefits in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of fomepizole (4-methylpyrazole) for acetaminophen poisoning: A scoping review. Pourbagher-Shahri, AM., Schimmel, J., Shirazi, FM., et al.[2022]

N-acetylcysteine (NAC) is effective in preventing liver injury from acetaminophen overdose, especially when administered promptly, but delays can lead to severe liver damage and the need for a transplant.

In a case study of a 7-month-old girl with acute liver failure from acetaminophen overdose, the use of fomepizole alongside NAC resulted in her full recovery, suggesting that fomepizole may offer additional safety and efficacy benefits in treating severe pediatric acetaminophen toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fomepizole Therapy for Acetaminophen-Induced Liver Failure in an Infant. Pepin, L., Matsler, N., Fontes, A., et al.[2023]

Fomepizole shows promise as a potential antidote for acetaminophen (APAP) overdose, demonstrating mechanisms that prevent liver injury and kidney damage, which are not addressed by the current standard treatment, N-acetylcysteine (NAC).

In animal studies, fomepizole was effective in both early and late treatment scenarios, suggesting it could extend the therapeutic window for patients who present late after an overdose, warranting further clinical trials to confirm its efficacy in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose. Akakpo, JY., Ramachandran, A., Curry, SC., et al.[2023]

A 33-year-old male with severe acetaminophen toxicity was treated with a combination of intravenous N-Acetylcysteine (NAC) and fomepizole, which led to significant recovery and stabilization of liver function tests.

This case is notable as it represents the first documented instance of using both NAC and fomepizole together in a human for treating acetaminophen poisoning, suggesting potential hepatoprotective benefits of fomepizole in such cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fomepizole as an Adjunctive Treatment in Severe Acetaminophen Toxicity. Shah, KR., Beuhler, MC.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Massive Acetaminophen Overdose Treated Successfully with N-Acetylcysteine, Fomepizole, and Hemodialysis. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Fomepizole should be used more liberally in paracetamol overdose. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Use of fomepizole (4-methylpyrazole) for acetaminophen poisoning: A scoping review. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Fomepizole Therapy for Acetaminophen-Induced Liver Failure in an Infant. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Fomepizole as an Adjunctive Treatment in Severe Acetaminophen Toxicity. [2020]