Diflunisal and Acetaminophen And Codeine: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jun 30, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Diflunisal
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.
One of your medicines, Diflunisal (a pain and anti-inflammatory drug), can raise the level of acetaminophen (the Tylenol part of your acetaminophen with codeine) in your blood, by about half again as much. Higher acetaminophen levels can be harder on your liver.
This is based on theory and lab data rather than a lot of real-world reports, so try not to worry. The bigger thing is to never go over your daily acetaminophen limit, and to be extra careful if you already have liver concerns or drink alcohol. Please check with your pharmacist or doctor before changing anything. Your care team can watch this and keep you safe.
Effect: Diflunisal reportedly increases plasma acetaminophen concentrations by ~50%, raising theoretical hepatotoxicity risk. Neither agent is metabolically activated in a way that reverses this direction; the concern is increased acetaminophen exposure (AUC).
- Mechanism: unknown; possibly altered acetaminophen clearance/glucuronidation.
- Direction: increased acetaminophen effect/toxicity potential.
- Onset: rapid.
- Evidence: theoretical.
- Severity: moderate.
Management: Use with caution, especially with predisposition to hepatic dysfunction. Monitor liver function (LFTs). Reinforce staying within maximum daily acetaminophen dosing. Codeine component is not implicated in this specific interaction.
What happens
An increased risk of acetaminophen toxicity (hepatotoxicity)
Interaction Deep Dive
Concomitant diflunisal and acetaminophen administration results in a 50% increase in plasma concentrations of acetaminophen2. Since significantly elevated acetaminophen plasma levels have been associated with hepatotoxicity, the combination should be used with caution.
Why it happens (mechanism)
Unknown
How to manage this interaction
Keep taking both medicines as prescribed unless your care team tells you otherwise. Here is what usually helps:
- Stay within your daily acetaminophen limit, and watch for hidden acetaminophen in other over-the-counter products.
- Your team may check your liver function with blood tests, especially if you have existing liver problems or drink alcohol.
- Doses may need to be individualized by your care team, and they may monitor you a bit more closely.
Tell your pharmacist or doctor if you notice yellowing skin or eyes, dark urine, upper right belly pain, nausea, or unusual tiredness.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) When acetaminophen was given together with diflunisal, acetaminophen plasma concentrations rose by roughly 50% in normal volunteers 1. The simultaneous use of acetaminophen produced no changes in diflunisal concentrations.
Common questions
Can I take Diflunisal and Acetaminophen And Codeine together?
Diflunisal can raise acetaminophen levels by about 50%, which could stress the liver, so stay within your daily acetaminophen limit and let your care team monitor your liver function. This is a theoretical concern, so keep taking both as prescribed and ask your pharmacist or doctor before making changes. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Diflunisal and Acetaminophen And Codeine interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "rapid". Effects can appear quickly, often within about 24 hours of combining the drugs.
How is the Diflunisal and Acetaminophen And Codeine interaction managed?
Keep taking both medicines as prescribed unless your care team tells you otherwise. Here is what usually helps: Stay within your daily acetaminophen limit, and watch for hidden acetaminophen in other over-the-counter products. Your team may check your liver function with blood tests, especially if you have existing liver problems or drink alcohol. Doses may need to be individualized by your care t… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
Questions for your pharmacist
- Does my dose of Diflunisal or Acetaminophen And Codeine 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 anything you'd monitor while I'm on both?
References (2)
Keep reading about Acetaminophen And Codeine
Keep reading about Diflunisal
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.
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