Ketoconazole and Acetaminophen And Codeine: 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
Ketoconazole
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 codeine, and ketoconazole can slow down one of the liver enzymes that helps process it. When that happens, more codeine and its active form (morphine) can build up in your body. That can make the medicine feel stronger and can raise the chance of side effects like heavy drowsiness or slowed breathing, which can be serious.
The good news is that this is very manageable. Please don't stop either medicine on your own. Just let your doctor or pharmacist know you take both so they can watch you more closely and adjust your codeine dose if needed to keep you safe.
Effect: Ketoconazole (potent CYP3A4 inhibitor) may increase exposure to codeine and its active metabolite morphine.
Mechanism/direction: Inhibition of CYP3A4-mediated codeine metabolism shifts codeine toward the CYP2D6 pathway and reduces clearance, raising codeine and morphine concentrations and increasing opioid effect. Codeine is a prodrug, but here the net effect is increased active opioid exposure.
- Risk: Enhanced/prolonged adverse effects, including potentially fatal respiratory depression and sedation.
- Onset: Unspecified; evidence: theoretical; severity: major.
- Management: Monitor for sedation/respiratory depression; consider codeine dose reduction. If ketoconazole is stopped, monitor for withdrawal and consider increasing codeine to prior effect.
What happens
Increased codeine and morphine exposure
Interaction Deep Dive
Taking codeine together with CYP3A4 inhibitors has led to elevated levels of both codeine and morphine, which may intensify or extend adverse effects and could produce respiratory depression that is potentially fatal, especially in cases where an inhibitor is introduced once a patient has reached a stable codeine dose. When the two must be used together, watch patients carefully for sedation and respiratory depression, and weigh reducing the codeine dose until steady drug effects are seen. Conversely, when a CYP3A4 inhibitor is being stopped, observe patients for indications of opioid withdrawal and consider raising the codeine dose until stable drug effects are apparent12.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both medicines as prescribed unless your care team tells you otherwise. This interaction is manageable with monitoring and dose tailoring.
- Your team may monitor you more closely for excess sleepiness or slowed, shallow breathing, especially soon after ketoconazole is added.
- Your codeine dose may be adjusted and individualized by your care team until they see a steady, safe effect.
- If ketoconazole is later stopped, tell your team, since your codeine may need to be re-adjusted to avoid a weaker effect or withdrawal.
Get emergency help for very slow breathing, extreme drowsiness, or trouble waking.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Ketoconazole and Acetaminophen And Codeine together?
Ketoconazole can raise codeine and morphine levels, increasing the risk of heavy sedation and dangerously slowed breathing. Keep taking both as prescribed and ask your doctor or pharmacist to monitor you and adjust your codeine dose as needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Ketoconazole 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 Ketoconazole and Acetaminophen And Codeine interaction managed?
Keep taking both medicines as prescribed unless your care team tells you otherwise. This interaction is manageable with monitoring and dose tailoring. Your team may monitor you more closely for excess sleepiness or slowed, shallow breathing, especially soon after ketoconazole is added. Your codeine dose may be adjusted and individualized by your care team until they see a steady, safe effect. If k… 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 Ketoconazole 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 Ketoconazole
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