Acetaminophen with Isoniazid Interaction Details

Brand Names Associated with Isoniazid

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Feb 25, 2024

Interaction Effect

An increased risk of hepatotoxicity

Interaction Summary

Concomitant use of acetaminophen and isoniazid has led to hepatotoxicity in isolated cases[1][2][3]. Isoniazid may demonstrate biphasic effects on CYP2E1, initially inhibiting then inducing CYP2E1 activity [4]. Variations in CYP2E1 activity with isoniazid therapy may also depend on a patient's genetic predisposition as a rapid or slow acetylator. Use caution with concomitant administration of acetaminophen and isoniazid as this may lead to induction of CYP2E1 and increased exposure to toxic acetaminophen metabolites [5]. Due to differing genetic predisposition in acetylator status, variable effects of isoniazid on CYP2E1, the potential for increased formation of toxic acetaminophen metabolites, and the additive risk of hepatotoxicity, the use of acetaminophen in isoniazid-treated patients should be avoided or limited.

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Use caution with concomitant administration due to the potential for isoniazid to induce CYP2E1, which may increase exposure to toxic acetaminophen metabolites[5]. Acetaminophen use should be avoided or limited in patients taking isoniazid.

Mechanism Of Interaction

Initial inhibition of CYP2E1-mediated metabolism of acetaminophen by isoniazid; induction of CYP2E1-mediated metabolism of acetaminophen by isoniazid

Literature Reports

A) Isoniazid may have variable effects on CYP2E1, as determined in a pharmacokinetic study in patients with tuberculosis (N=11). Following 14 days of isoniazid therapy, CYP2E1 activity was significantly reduced in 8 patients, by a median of 71.7%, while 3 patients demonstrated an increase in CYP2E1 activity, by a median of 176% [6].

B) In a group of slow-acetylator volunteers given isoniazid 300 mg daily for 7 days (N=10), administration of acetaminophen 500 mg led to reduced then increased production of acetaminophen metabolites. When acetaminophen was given on day 1 or 3 of isoniazid, reduced levels of acetaminophen thioether metabolites were observed compared with acetaminophen monotherapy. However, when acetaminophen was given on day 8 or 10, increased levels of acetaminophen thioether metabolites were observed, compared with monotherapy or coadministration on days 1 or 3. Isoniazid may bind with CYP2E1 to reduce enzyme activity via ligand stabilization, with a compensatory increase in CYP2E1 production. After time, and especially following withdrawal of isoniazid, the increased levels of free CYP2E1 increased the enzyme activity. Thus, the interaction may be biphasic, with an initial reduction in CYP2E1 activity and reduced production of toxic acetaminophen metabolites, followed by an increase in CYP2E1 activity and greater production of toxic acetaminophen metabolites [4].

C) One study reported the cases of 3 patients who experienced hepatotoxicity after self-medication with acetaminophen that was taken concurrently with antituberculosis agents including isoniazid and rifampin. Although clinical signs and symptoms varied among the 3 patients, all had greatly increased serum levels of hepatic enzymes. All signs and symptoms of hepatotoxicity resolved after discontinuation of all medications, and, when antituberculosis treatment was resumed, no further adverse effects were seen [1] .

References

1 ) Nolan CM, Sandblom RE, Thummel KE, et al: Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis. Chest 1994; 105:408-411.

2 ) Murphy R, Swartz R, & Watkins PB: Severe acetaminophen toxicity in a patient receiving isoniazid. Ann Intern Med 1990; 113:799-802.

3 ) Moulding TS, Redeker AG, & Kanel GC: Acetaminophen, isoniazid, and hepatic toxicity (letter). Ann Intern Med 1991; 114:431.

4 ) Zand R, Nelson SD, Slattery JT, et al: Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans. Clin Pharmacol Ther 1993; 54(2):142-149.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

5 ) Product Information: isoniazid oral tablets, isoniazid oral tablets. West-ward Pharmaceutical Corp. (per DailyMed), Eatontown, NJ, 2011.

6 ) Walubo A, Coetsee C, Arti D, et al: The effect of isoniazid containing regimen on CYP2E1 during antituberculosis therapy. Res Commun Mol Pathol Pharmacol 2005; 117-118:137-151.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

Isoniazid Overview

• Isoniazid is used with other drugs to treat tuberculosis (TB; a serious infection that affects the lungs and sometimes other parts of the body). Isoniazid is also used with other drugs to treat people with latent (resting or nongrowing) TB including those in close contact with people who have active TB, a positive tuberculin skin test, human immunodeficiency virus (HIV), and those with pulmonary fibrosis (scarring of the lungs with an unknown cause). Isoniazid is in a class of medications called antituberculosis agents. It works by killing the bacteria that cause tuberculosis.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.