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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a new combination treatment for individuals who have overdosed on acetaminophen, a common pain reliever. The researchers aim to determine if adding fomepizole, an alcohol dehydrogenase inhibitor, to the standard acetylcysteine treatment can more effectively reduce liver damage from acetaminophen poisoning. Participants may receive either the combination treatment or acetylcysteine with a placebo. Suitable candidates for this trial include those who have taken excessive acetaminophen and are at risk for liver injury. As a Phase 2 trial, this research focuses on assessing the treatment's efficacy in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that fomepizole is generally safe and well-tolerated. Studies have found a strong safety record, particularly with single doses. In cases of acetaminophen overdose, fomepizole is often used with N-acetylcysteine (NAC) to help prevent liver damage. Clinical data supports its use as an effective additional treatment in this context. Although fomepizole is considered a safe antidote, following the recommended dosing guidelines is crucial to avoid serious effects from excessive intake. Overall, its safety record makes fomepizole a promising option for treating acetaminophen poisoning. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about using fomepizole for acetaminophen overdose because it offers a new way to protect the liver. Most existing treatments, like N-acetylcysteine, work by replenishing the antioxidant glutathione to detoxify the harmful byproducts of acetaminophen. However, fomepizole targets a different mechanism by inhibiting the enzyme that converts acetaminophen into its toxic metabolite, potentially reducing liver damage more effectively. This dual approach, combining the protective effects of both fomepizole and N-acetylcysteine, could enhance patient outcomes and provide a more robust defense against liver injury in overdose situations.

What evidence suggests that this trial's treatments could be effective for acetaminophen overdose?

This trial will compare the use of N-acetylcysteine (NAC) alone with the combination of NAC and Fomepizole for treating acetaminophen (Tylenol) overdose. Research has shown promising results for using Fomepizole and NAC together. Specifically, a study found that this combination could help reduce liver damage in severe cases. While NAC effectively treats acetaminophen poisoning, adding Fomepizole might offer extra liver protection. A case study demonstrated success with this combination, especially when used with other treatments like early dialysis. More patients are now receiving this combo, indicating growing confidence in its potential benefits. ^{3 6 7 8 9}

Who Is on the Research Team?

Richard Dart, MD, PhD

Principal Investigator

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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40745148/

Trends in Fomepizole Use for Acetaminophen Poisoning ... 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- ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05517668

NCT05517668 | Evaluation of the Efficacy of Fomepizole in ... Acetylcysteine is the only FDA approved drug indicated for clinical use in acetaminophen overdose. It is highly effective when patients seek medical attention ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8289598/

Massive Acetaminophen Overdose Treated Successfully ... This case highlights the potential benefit of a triple strategy of NAC, fomepizole, and early hemodialysis in massive acetaminophen overdose.

4. medrxiv.org medrxiv.org/content/10.1101/2025.04.25.25326441v1.full.pdf

Trends in Fomepizole Use for Acetaminophen Poisoning in ... 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 ...

5. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2808062

Management of Acetaminophen Poisoning in the US and ... The addition of fomepizole to acetylcysteine in the treatment of serious acetaminophen ingestions has been proposed. The panel concluded that ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36471569/

Fomepizole should be used more liberally in paracetamol ... Growing clinical and basic science data support the use of fomepizole as an adjunct to N-acetylcysteine in paracetamol poisoning. This safe antidote may be

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05517668

NCT05517668 | Evaluation of the Efficacy of Fomepizole in ... The maximal recommended therapeutic dose of 4 g per day is safe and is well tolerated. Unintentional and intentional overdoses occur and can cause serious ...

8. vumc.org vumc.org/poison-control/sites/default/files/Fomepizole_as_an_Adjunctive_Treatment_in_Severe_Acetaminophen_Toxicity_2020.pdf

Fomepizole as an Adjunctive Treatment in Severe ... Finally, fomepizole has an impressive safety profile, especially at a single dose of 15 mg/ kg [15]. This is now the second human case report of fomepizole use.

9. emedicine.medscape.com emedicine.medscape.com/article/820200-treatment

Acetaminophen Toxicity Treatment & Management Fomepizole is gaining increased off-label use as an adjunct to NAC in patients with high-risk acetaminophen overdose.