Acetaminophen And Codeine and Omaveloxolone: 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
Omaveloxolone
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 is a "prodrug," which means your body has to break it down into morphine before it can relieve pain. Omaveloxolone (Skyclarys) can speed up one of the liver enzymes that handles codeine. When codeine is cleared faster, less of it turns into morphine, so the pain relief may be weaker than expected.
If you've been taking codeine regularly, you might even feel early withdrawal signs like aches, chills, or restlessness. This is based mostly on how the drugs work rather than lots of patient studies, so don't worry. Your care team can watch how you're doing and adjust things safely. Just talk with your pharmacist or doctor before making any changes.
Mechanism: Omaveloxolone is a CYP3A4 inducer. Codeine is a prodrug requiring CYP2D6-mediated O-demethylation to morphine (its active metabolite). Enhanced CYP3A4 shunts codeine toward norcodeine, lowering codeine exposure and reducing morphine formation.
Direction/effect: Reduced opioid efficacy and possible precipitation of withdrawal in physically dependent patients.
- Onset: unspecified
- Evidence: theoretical
- Management: Monitor for decreased analgesia or withdrawal; codeine dose may be increased and individualized if needed. If omaveloxolone is discontinued, consider codeine dose reduction and monitor for sedation/respiratory depression as induction resolves.
What happens
Reduced codeine and morphine exposure, reduced opioid efficacy and precipitation of opioid withdrawal
Interaction Deep Dive
When codeine is taken alongside CYP3A4 inducers, codeine concentrations may drop while norcodeine concentrations rise, and CYP2D6-mediated metabolism may decrease, producing lower morphine levels. This can diminish therapeutic effect or trigger a withdrawal syndrome in patients who have become physically dependent. Should combined use be required, patients should be watched closely for reduced efficacy or indications of opioid withdrawal syndrome, and raising the codeine dose as needed should be considered. When a CYP3A4 inducer is stopped, consider lowering the codeine dose and monitor patients carefully for signs of sedation or respiratory depression12.
Why it happens (mechanism)
Induction of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both medications as prescribed unless your care team tells you otherwise. Because omaveloxolone can lower how much pain relief you get from codeine, your team can manage this by tailoring your treatment.
- Watch for weaker pain control, or withdrawal-like symptoms (aches, sweating, chills, restlessness) if you take codeine regularly.
- Your codeine dose may need to be adjusted and individualized by your care team, and they may monitor you more closely.
- If omaveloxolone is ever stopped, tell your prescriber, since your codeine dose may need to come down to avoid too much sedation.
Report any changes to your pharmacist or doctor.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Omaveloxolone together?
Omaveloxolone can speed up codeine's breakdown, which may reduce pain relief or trigger withdrawal if you take codeine regularly; keep taking both and let your care team adjust and monitor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Omaveloxolone 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 Omaveloxolone interaction managed?
Keep taking both medications as prescribed unless your care team tells you otherwise. Because omaveloxolone can lower how much pain relief you get from codeine, your team can manage this by tailoring your treatment. Watch for weaker pain control, or withdrawal-like symptoms (aches, sweating, chills, restlessness) if you take codeine regularly. Your codeine dose may need to be adjusted and individu… 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 Omaveloxolone 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 Omaveloxolone
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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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