Acetaminophen And Codeine and Isoniazid: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 1, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Isoniazid
No brand names on record
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Your pain medicine contains acetaminophen (the same ingredient as Tylenol), and you're also taking isoniazid for TB. Both of these can be hard on the liver. When they're used together, isoniazid can change how your body breaks down acetaminophen in a way that produces more of a harmful byproduct. Over time, this can raise the risk of liver damage.
This doesn't happen to everyone, and it usually builds up slowly rather than all at once. The good news is your care team can manage this. Please talk with your pharmacist or doctor before using any acetaminophen, and don't stop either medicine on your own.
Effect: Increased risk of hepatotoxicity with concurrent acetaminophen (in the acetaminophen/codeine product) and isoniazid.
Mechanism: Isoniazid exerts biphasic effects on CYP2E1, initially inhibiting then inducing it. Induction increases conversion of acetaminophen to the hepatotoxic metabolite NAPQI, depleting glutathione. Effect is modulated by acetylator genotype (slow vs rapid).
- Direction: Increased formation of toxic acetaminophen metabolites plus additive hepatotoxicity.
- Onset: Delayed. Evidence: Established (isolated case reports).
- Management: Avoid or limit acetaminophen; monitor LFTs and for signs of hepatic injury.
Note: the codeine component is not implicated in this interaction.
What happens
An increased risk of hepatotoxicity
Interaction Deep Dive
Hepatotoxicity has been reported in isolated instances when acetaminophen and isoniazid were taken together456. On CYP2E1, isoniazid can produce biphasic effects, first suppressing and later inducing the activity of this enzyme 3. How CYP2E1 activity changes during isoniazid treatment may further hinge on whether the patient is genetically predisposed to be a rapid or slow acetylator. Caution is warranted when acetaminophen and isoniazid are given concurrently, since this combination may induce CYP2E1 and raise exposure to toxic metabolites of acetaminophen 1. Given the genetic differences in acetylator status, the variable influence of isoniazid on CYP2E1, the possibility of greater generation of toxic acetaminophen metabolites, and the additive hepatotoxicity risk, acetaminophen should be avoided or restricted in patients receiving isoniazid.
Why it happens (mechanism)
Initial inhibition of CYP2E1-mediated metabolism of acetaminophen by isoniazid; induction of CYP2E1-mediated metabolism of acetaminophen by isoniazid
How to manage this interaction
Keep taking both medicines as prescribed and don't make changes on your own, but bring this up with your pharmacist or prescriber soon.
- Because both drugs can stress the liver, acetaminophen should generally be avoided or limited while you're on isoniazid.
- Your care team may suggest a different pain option or set a safe acetaminophen limit tailored to you.
- They may monitor your liver more closely with blood tests.
- Watch for and report yellowing of the skin or eyes, dark urine, nausea, or right-upper-belly pain.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
3 reports — tap to read
a) The effect of isoniazid on CYP2E1 may vary, according to a pharmacokinetic study conducted in patients with tuberculosis (N=11). After 14 days of isoniazid treatment, CYP2E1 activity fell significantly in 8 patients, with a median decrease of 71.7%, whereas 3 patients showed a rise in CYP2E1 activity, with a median increase of 176% 2.
b) In a cohort of slow-acetylator volunteers who received isoniazid 300 mg daily for 7 days (N=10), giving acetaminophen 500 mg produced first a decrease and then an increase in acetaminophen metabolite formation. When acetaminophen was administered on day 1 or 3 of isoniazid, the levels of acetaminophen thioether metabolites were lower than those seen with acetaminophen alone. In contrast, when acetaminophen was given on day 8 or 10, the levels of acetaminophen thioether metabolites were higher than with acetaminophen monotherapy or with coadministration on days 1 or 3. Isoniazid may bind to CYP2E1 and lower enzyme activity through ligand stabilization, accompanied by a compensatory rise in CYP2E1 production. Over time, and particularly after isoniazid is stopped, the elevated levels of free CYP2E1 raised enzyme activity. The interaction may therefore be biphasic, beginning with a decrease in CYP2E1 activity and reduced formation of toxic acetaminophen metabolites, followed by an increase in CYP2E1 activity and greater formation of toxic acetaminophen metabolites 3.
c) One study described 3 patients who developed hepatotoxicity after self-medicating with acetaminophen taken together with antituberculosis drugs, including isoniazid and rifampin. Although the clinical signs and symptoms differed among the 3 patients, all showed markedly elevated serum levels of hepatic enzymes. All signs and symptoms of hepatotoxicity resolved once all medications were discontinued, and when antituberculosis treatment was restarted, no further adverse effects occurred 4.
Common questions
Can I take Acetaminophen And Codeine and Isoniazid together?
Combining acetaminophen (in your acetaminophen/codeine product) with isoniazid raises the risk of liver injury, so acetaminophen should be avoided or limited. Talk with your pharmacist or doctor before using it and don't stop either drug on your own. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Isoniazid interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Acetaminophen And Codeine and Isoniazid interaction managed?
Keep taking both medicines as prescribed and don't make changes on your own, but bring this up with your pharmacist or prescriber soon. Because both drugs can stress the liver, acetaminophen should generally be avoided or limited while you're on isoniazid. Your care team may suggest a different pain option or set a safe acetaminophen limit tailored to you. They may monitor your liver more closely… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
Questions for your pharmacist
- Does my dose of Acetaminophen And Codeine or Isoniazid need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (6)
- Product Information: isoniazid oral tablets, isoniazid oral tablets. West-ward Pharmaceutical Corp. (per DailyMed), Eatontown, NJ, 2011. DailyMed
- 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.
- 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
- 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. PubMed
- Murphy R, Swartz R, & Watkins PB: Severe acetaminophen toxicity in a patient receiving isoniazid. Ann Intern Med 1990; 113:799-802. PubMed
- Moulding TS, Redeker AG, & Kanel GC: Acetaminophen, isoniazid, and hepatic toxicity (letter). Ann Intern Med 1991; 114:431. PubMed
Keep reading about Acetaminophen And Codeine
Keep reading about Isoniazid
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist