Acetaminophen And Codeine and Fosphenytoin: 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
Fosphenytoin
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.
You're taking a pain medicine that contains acetaminophen (Tylenol) plus codeine, along with fosphenytoin, a medicine for seizures. Fosphenytoin turns into phenytoin in your body, and phenytoin can speed up how your liver breaks down acetaminophen. This can do two things: your acetaminophen may not relieve pain as long, and your liver ends up making more of a harmful byproduct, which can raise the risk of liver strain over time.
This matters most with large or daily, long-term acetaminophen use, not an occasional dose. The good news is your care team can manage this by keeping your acetaminophen amount sensible and watching your liver. Please talk with your pharmacist or doctor before making any changes.
Effect: Fosphenytoin (prodrug of phenytoin) induces CYP-mediated acetaminophen metabolism, reducing analgesic duration and increasing formation of the hepatotoxic metabolite NAPQI.
- Direction/magnitude: Phenytoin increases acetaminophen metabolism by >40% and shortens its half-life by ~25%.
- Onset: Delayed. Evidence: Probable. Severity: Moderate.
- Consequences: Reduced acetaminophen effect plus elevated hepatotoxicity risk, especially with large or chronic dosing.
- Management: Avoid large and/or chronic acetaminophen doses in patients on phenytoin/fosphenytoin. Monitor LFTs and for clinical signs of hepatotoxicity. The codeine component is not the primary driver here.
What happens
Decreased acetaminophen effectiveness and an increased risk of hepatotoxicity
Interaction Deep Dive
Phenytoin has been demonstrated to increase the metabolism of acetaminophen by greater than 40% and to decrease the acetaminophen half-life by about 25%. Because of the production of toxic acetaminophen metabolites, patients may be at a greater risk for acetaminophen toxicity when taking phenytoin concurrently. In addition, the duration of analgesia may be shorter3.
Why it happens (mechanism)
Induction of CYP3A4-mediated acetaminophen hepatic metabolism
How to manage this interaction
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise.
- Your team will likely want you to avoid large or long-term daily doses of acetaminophen while on fosphenytoin.
- Your acetaminophen amount may need to be adjusted and individualized by your prescriber.
- They may monitor your liver more closely with periodic blood tests.
- Watch for signs of liver trouble (yellowing skin or eyes, dark urine, belly pain on the right side, unusual tiredness, nausea) and report them promptly.
Ask your pharmacist before adding any other product that contains acetaminophen, since many combination products do.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
2 reports — tap to read
a) Acetaminophen undergoes hepatic metabolism through two distinct pathways in the liver. Roughly 80% to 90% of a given acetaminophen dose undergoes phase II conjugation to either glucuronic acid or sulfate, neither of which is toxic. The remaining fraction is processed through a phase I cytochrome P450 (CYP) reaction into a reactive, electrophilic intermediate known as N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is quickly conjugated with glutathione, yielding mercapturic acid and other nontoxic compounds that are excreted in the urine. When glutathione reserves become depleted or when NAPQI generation rises, the detoxification of NAPQI declines, allowing NAPQI to build up, bind to hepatic tissue macromolecules, and produce oxidative stress, tissue injury, or necrosis. When the CYP system is induced, the pace of drug metabolism rises, which also raises the rate at which NAPQI is generated. As a result, the quantity of NAPQI generated by a therapeutic acetaminophen dose in a patient taking a CYP-inducing drug may equal the quantity of NAPQI generated by a toxic acetaminophen dose in a person who is not induced 4.
b) A 55-year-old female smoker who had chronic obstructive pulmonary disease developed community-acquired pneumonia and was started on cefprozil 500 mg twice daily. Her other medications were phenytoin 400 mg alternating every other day with 300 mg, warfarin 6 mg daily, diltiazem 30 mg four times daily, cisapride 20 mg four times daily, famotidine 40 mg daily, and paroxetine 20 mg daily. When she was admitted to the hospital for placement of an inferior vena cava (IVC) filter, her hepatic transaminases, lactose dehydrogenase, and alkaline phosphatase were markedly elevated. A review of her medications revealed that three separate analgesics, each containing acetaminophen, had been prescribed and taken by the patient. Her daily acetaminophen intake ranged from 1300 mg to 6200 mg per day. Since phenytoin was also being administered, liver injury from acetaminophen due to enzyme induction was suspected. All products containing acetaminophen were stopped, and the patient's hepatic values were normal both two and six weeks afterward 4.
Common questions
Can I take Acetaminophen And Codeine and Fosphenytoin together?
Fosphenytoin can make acetaminophen wear off faster and raise the risk of liver harm, so avoid large or long-term acetaminophen doses and let your care team monitor your liver. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Fosphenytoin interaction?
It is rated moderate. Can be significant — usually manageable with 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 Fosphenytoin interaction managed?
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. Your team will likely want you to avoid large or long-term daily doses of acetaminophen while on fosphenytoin. Your acetaminophen amount may need to be adjusted and individualized by your prescriber. They may monitor your liver more closely with periodic blood tests. Watch for signs of liver trouble (yellow… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
Questions for your pharmacist
- Does my dose of Acetaminophen And Codeine or Fosphenytoin 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 (4)
- Product Information: Codeine sulfate oral solution, codeine sulfate oral solution. Hikma Pharmaceuticals USA Inc(per FDA), Berkeley Heights, NJ, 2023. DailyMed
- Product Information: Codeine sulfate oral tablets, codeine sulfate oral tablets. Hikma Pharmaceuticals USA Inc. (per FDA), Berkeley Heights, NJ, 2023. DailyMed
- Miners JO, Attwood J, & Birkett DJ: Determinants of acetaminophen metabolism: effect of inducers and inhibitors of drug metabolism on acetaminophen's metabolic pathways. Clin Pharmacol Ther 1984; 35:480-486. PubMed
- Brackett CC & Bloch JD: Phenytoin as a possible cause of acetaminophen hepatotoxicity: case report and review of the literature. Pharmacotherapy 2000; 20:229-233. PubMed
Keep reading about Acetaminophen And Codeine
Keep reading about Fosphenytoin
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