Acetaminophen And Codeine and Enzalutamide: 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
Enzalutamide
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. Codeine only works as a painkiller after your body converts it into morphine. Enzalutamide (Xtandi) speeds up the liver enzyme that handles codeine, so more of your codeine gets broken down the wrong way and less becomes morphine. That can mean your pain isn't controlled as well, and if you've been on codeine a while, you could even feel withdrawal-type symptoms.
The good news: this is manageable. Don't stop or change either medicine on your own. Let your care team know if your pain relief seems weaker, and they can adjust your dose and keep a closer eye on you.
Mechanism: Enzalutamide is a strong CYP3A4 inducer. Codeine is a prodrug; induced CYP3A4 shunts more codeine to inactive norcodeine, leaving less available for CYP2D6 conversion to morphine (the active analgesic metabolite).
Direction/effect: Reduced codeine and morphine exposure, decreased opioid efficacy, and possible withdrawal in dependent patients.
- Onset: Unspecified; enzyme induction develops over days to weeks.
- Evidence: Theoretical.
- Management: Monitor for reduced analgesia and withdrawal signs; consider increasing codeine dose as needed. If enzalutamide is stopped, anticipate rising opioid levels, reduce codeine dose, and watch for sedation/respiratory depression.
What happens
Reduced codeine and morphine exposure, reduced opioid efficacy and precipitation of opioid withdrawal
Interaction Deep Dive
Concomitant use of codeine with CYP3A4 inducers may result in reduced codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If concomitant use is needed, closely monitor patients for decreased efficacy or signs of opioid withdrawal syndrome, and consider increasing the dose of codeine as necessary. If a CYP3A4 inducer is being discontinued, consider codeine dose reduction and closely monitor patients for signs of respiratory depression or sedation12.
Why it happens (mechanism)
Induction of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both medicines as prescribed unless your care team tells you otherwise. Because enzalutamide can lower how much pain relief you get from codeine, your team can manage this by tailoring your codeine dose and monitoring you more closely.
- Tell your pharmacist or doctor if your pain relief feels weaker than before.
- Report any withdrawal-type symptoms (restlessness, sweating, chills, stomach upset).
- Your codeine dose may need to be adjusted and individualized by your care team.
- If enzalutamide is ever stopped, your team may lower your codeine dose and watch for excess sedation or slowed breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Enzalutamide together?
Enzalutamide can speed up the breakdown of codeine, making your pain medicine less effective and possibly triggering withdrawal. Don't change anything on your own; tell your care team if your pain relief weakens so they can adjust and monitor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Enzalutamide 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 Enzalutamide interaction managed?
Keep taking both medicines as prescribed unless your care team tells you otherwise. Because enzalutamide can lower how much pain relief you get from codeine, your team can manage this by tailoring your codeine dose and monitoring you more closely. Tell your pharmacist or doctor if your pain relief feels weaker than before. Report any withdrawal-type symptoms (restlessness, sweating, chills, stomac… 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 Acetaminophen And Codeine or Enzalutamide 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 Enzalutamide
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