Acetaminophen And Codeine and Ranolazine: 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
Ranolazine
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, which your body turns into morphine to relieve pain. Ranolazine (Ranexa) can slow down the enzymes that handle codeine. That means codeine and morphine may build up more than expected, which can lead to stronger side effects like heavy drowsiness and, in serious cases, dangerously slow breathing.
This warning is based on how these drugs are expected to behave, not on lots of real-world reports, but because slowed breathing can be serious, it is worth taking seriously. The good news is your care team can manage this by adjusting your dose and watching you more closely. Please talk with your pharmacist or doctor before making any changes.
Effect: Increased codeine (and morphine) exposure via ranolazine inhibition of CYP3A4 and CYP2D6, the enzymes clearing and activating codeine.
Note on direction: Codeine is a prodrug activated by CYP2D6 to morphine, but the documented net effect here is increased opioid exposure (raised parent codeine plus reduced clearance), so treat as heightened opioid effect and respiratory depression risk.
- Evidence: Theoretical; onset unspecified.
- Severity: Major (potential fatal respiratory depression).
- Management: Monitor for sedation and respiratory depression, especially when adding ranolazine to stable codeine. Lower codeine doses may be needed. On ranolazine discontinuation, watch for withdrawal and titrate codeine to effect.
What happens
Increased codeine exposure
Interaction Deep Dive
Taking codeine (a substrate of both CYP3A4 and CYP2D6) together with ranolazine (which inhibits CYP3A4 and CYP2D6) can raise levels of codeine and morphine, potentially intensifying or extending adverse effects and possibly producing fatal respiratory depression. This risk is especially notable when the inhibitor is introduced once a patient has already reached a stable codeine dose. When the two agents must be used together, watch patients carefully for sedation and respiratory depression. Should ranolazine be stopped, observe patients for indications of opioid withdrawal and consider raising the codeine dose until consistent drug effects are seen12. Consequently, reduced codeine doses may be needed123.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated codeine metabolism; inhibition of CYP2D6-mediated metabolism of codeine
How to manage this interaction
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. This is something your team can manage.
- Your codeine dose may need to be adjusted and individualized by your care team, and lower doses may be used.
- Your team may monitor you more closely for heavy sleepiness or slow, shallow breathing, especially when ranolazine is first added.
- If ranolazine is stopped, tell your team so they can watch for withdrawal signs and adjust your codeine.
Get help right away if you notice extreme drowsiness, confusion, or trouble breathing. Raise any concerns with your pharmacist or prescriber.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) In a drug interaction study, giving ranolazine 750 mg twice daily together with a single dose of immediate release metoprolol (100 mg), a CYP2D6 substrate, produced an 80% rise in metoprolol exposure in extensive CYP2D6 metabolizers, with no requirement to adjust the metoprolol dose. Among extensive metabolizers of dextromethorphan, which is a CYP2D6 substrate, ranolazine partially inhibits the formation of the principal metabolite dextrorphan 3.
Common questions
Can I take Acetaminophen And Codeine and Ranolazine together?
Ranolazine can raise codeine and morphine levels, increasing the risk of heavy sedation and slowed breathing, so your care team may lower your codeine dose and monitor you closely. Keep taking both as prescribed and seek help for extreme drowsiness or trouble breathing. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Ranolazine 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 Ranolazine interaction managed?
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. This is something your team can manage. Your codeine dose may need to be adjusted and individualized by your care team, and lower doses may be used. Your team may monitor you more closely for heavy sleepiness or slow, shallow breathing, especially when ranolazine is first added. If ranolazine is stopped, te… 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 Ranolazine 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 (3)
- 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
- Product Information: RANOLAZINE oral extended-release tablets, ranolazine oral extended-release tablets. Viona Pharmaceuticals Inc. (per Dailymed), Cranford, NJ, 2023. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Ranolazine
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major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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