Fluconazole 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
Fluconazole
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. Your pain medicine contains codeine, and codeine is normally broken down by an enzyme in your liver called CYP3A4. Fluconazole (Diflucan) slows that enzyme down. This means more of your codeine, and the morphine your body makes from it, can build up in your blood.
More opioid in your system can mean stronger drowsiness, and in serious cases, slowed or dangerously shallow breathing. This is more of a concern if the fluconazole is added after you've been stable on your codeine dose. The good news is your care team can manage this by watching you more closely and adjusting your codeine dose if needed. Please don't change anything on your own. Just check in with your pharmacist or doctor.
Mechanism: Fluconazole is a moderate CYP3A4 inhibitor. Codeine undergoes CYP3A4-mediated metabolism (and CYP2D6-mediated conversion to morphine, its active opioid). Inhibiting the CYP3A4 clearance pathway shifts codeine toward increased parent and morphine exposure.
- Direction: increased codeine and morphine concentrations, enhanced/prolonged opioid effect.
- Evidence: theoretical; magnitude not quantified.
- Onset: unspecified; highest risk when inhibitor added to a stable codeine regimen.
- Management: monitor for respiratory depression and sedation; consider codeine dose reduction until stable effects observed. On fluconazole discontinuation, monitor for opioid withdrawal and consider dose increase.
What happens
Increased codeine and morphine exposure
Interaction Deep Dive
Concomitant use of codeine with CYP3A4 inhibitors has resulted in increased codeine and morphine concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of codeine is achieved. If concomitant use is needed, closely monitor patients for respiratory depression and sedation, and consider dose reduction of codeine until stable drug effects have been observed. If a CYP3A4 inhibitor is being discontinued, monitor patients for signs of opioid withdrawal, and consider increasing dose of codeine until stable drug effects have been observed12.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both as prescribed unless your care team tells you otherwise. This interaction is manageable.
- Your team may monitor you more closely for excess sleepiness or slowed breathing, especially in the first days after fluconazole is started.
- Your codeine dose may need to be adjusted and individualized by your care team until your response is stable.
- If fluconazole is later stopped, your team may watch for withdrawal-type symptoms and adjust again.
- Get urgent help for very slow or shallow breathing, extreme drowsiness, or trouble staying awake.
- Tell your pharmacist or prescriber you take both so they can plan monitoring.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Fluconazole and Acetaminophen And Codeine together?
Fluconazole can raise codeine and morphine levels, increasing sedation and, rarely, dangerous breathing problems; keep taking both as prescribed but ask your pharmacist or doctor about monitoring and possible dose adjustment. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Fluconazole and Acetaminophen And Codeine 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 Fluconazole and Acetaminophen And Codeine interaction managed?
Keep taking both as prescribed unless your care team tells you otherwise. This interaction is manageable. Your team may monitor you more closely for excess sleepiness or slowed breathing, especially in the first days after fluconazole is started. Your codeine dose may need to be adjusted and individualized by your care team until your response is stable. If fluconazole is later stopped, your team… 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 Fluconazole 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 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 Fluconazole
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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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