Acetaminophen And Codeine and Itraconazole: 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
Itraconazole
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.
Here's what's going on. Itraconazole (Sporanox) slows down one of the liver enzymes (called CYP3A4) that helps your body handle codeine. When that pathway is blocked, more of the codeine and its active form (morphine) can build up in your body.
That means the usual dose of your acetaminophen and codeine may hit harder. You could feel more drowsy or sleepy, and in serious cases your breathing could slow down too much. This is most likely if the itraconazole is added after you've been doing fine on your codeine. Please don't change anything on your own. Let your pharmacist or doctor know you take both, so they can watch you closely and adjust your dose if needed.
Mechanism: Itraconazole is a potent CYP3A4 inhibitor. CYP3A4 mediates N-demethylation of codeine to norcodeine (a clearance route). Inhibition shunts more codeine toward CYP2D6-mediated O-demethylation to morphine and raises parent codeine exposure, increasing opioid effect.
- Direction: increased codeine and morphine concentrations (increased opioid effect).
- Risk: excess sedation and potentially fatal respiratory depression, especially when the inhibitor is added to a stable codeine regimen.
- Evidence: theoretical; severity rated major.
- Management: monitor for sedation and respiratory depression; consider codeine dose reduction until stable effects seen. On itraconazole discontinuation, watch for withdrawal and consider dose increase.
What happens
Increased codeine and morphine exposure
Interaction Deep Dive
When codeine is taken together with CYP3A4 inhibitors, elevated levels of both codeine and morphine have been observed. This can intensify or extend adverse effects and carries the risk of respiratory depression that may prove fatal, especially in cases where an inhibitor is introduced once a stable codeine dose has already been reached. When such combined therapy is required, patients should be watched carefully for sedation and respiratory depression, and reducing the codeine dose should be considered until the drug's effects have stabilized. Conversely, upon withdrawal of a CYP3A4 inhibitor, clinicians should observe patients for indications of opioid withdrawal and consider raising the codeine dose until stable drug effects are seen12.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination can be managed with the right monitoring and dose tailoring.
- Your team may monitor you more closely for excess drowsiness, confusion, or slowed breathing, especially soon after starting itraconazole.
- Your codeine dose may need to be adjusted and individualized by your care team until your response is stable.
- If itraconazole is later stopped, tell your team so they can watch for opioid withdrawal and adjust again.
Get urgent help for very slow or shallow breathing, extreme sleepiness, or trouble waking. Raise any new grogginess with your pharmacist or prescriber.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Itraconazole together?
Itraconazole can raise codeine and morphine levels, increasing sedation and the risk of dangerously slow breathing, so keep both as prescribed but tell your care team so they can monitor you and adjust the codeine dose. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Itraconazole interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Acetaminophen And Codeine and Itraconazole interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination can be managed with the right monitoring and dose tailoring. Your team may monitor you more closely for excess drowsiness, confusion, or slowed breathing, especially soon after starting itraconazole. Your codeine dose may need to be adjusted and individualized by your care team until your response is… 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.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Acetaminophen And Codeine or Itraconazole 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 (2)
- 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
Keep reading about Acetaminophen And Codeine
Keep reading about Itraconazole
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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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