Erythromycin 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
Erythromycin
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 here is codeine (combined with acetaminophen), and erythromycin is an antibiotic. Your body normally breaks codeine down using a liver enzyme called CYP3A4. Erythromycin can slow that enzyme down, so more codeine (and the morphine your body makes from it) can build up. That can mean stronger drowsiness, and in serious cases, slowed or shallow breathing.
This concern is based mostly on how these drugs work rather than lots of real-world reports, but breathing problems are serious enough to take seriously. Don't stop or change either medicine on your own. Just let your pharmacist or doctor know you take both so they can watch you closely and adjust things if needed.
Effect: Erythromycin (CYP3A4 inhibitor) may reduce CYP3A4-mediated codeine metabolism, increasing codeine and morphine exposure and raising the risk of sedation and respiratory depression.
- Direction: Increased opioid effect (codeine is largely inactivated via CYP3A4; blocking that pathway raises parent codeine and shunts more toward morphine).
- Evidence: Theoretical; magnitude not quantified.
- Onset: Unspecified; risk notable when inhibitor is added to a stable codeine dose.
- Management: Monitor for respiratory depression and sedation; consider codeine dose reduction until stable effects seen. If erythromycin is stopped, monitor for withdrawal and consider increasing codeine dose to stable effect.
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
The good news is that your care team can manage this by tailoring your dose and keeping a closer eye on you.
- Keep taking both as prescribed unless your prescriber tells you otherwise.
- Your team may monitor you more closely for excess drowsiness or slowed breathing, especially when erythromycin is first added.
- Your codeine dose may be adjusted and individualized until steady, predictable effects are seen.
- When erythromycin is stopped, they may watch for withdrawal and may adjust the codeine dose again.
Call for help right away if you notice heavy sedation, confusion, or slow/shallow breathing. Ask your pharmacist any questions.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Erythromycin and Acetaminophen And Codeine together?
Erythromycin can raise codeine and morphine levels and increase sedation or breathing risk, so tell your care team you take both and watch for excess drowsiness or slowed breathing. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Erythromycin 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 Erythromycin and Acetaminophen And Codeine interaction managed?
The good news is that your care team can manage this by tailoring your dose and keeping a closer eye on you. Keep taking both as prescribed unless your prescriber tells you otherwise. Your team may monitor you more closely for excess drowsiness or slowed breathing, especially when erythromycin is first added. Your codeine dose may be adjusted and individualized until steady, predictable effects ar… 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 Erythromycin 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 Erythromycin
These medications also interact with supplements
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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