Cimetidine 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
Cimetidine
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," meaning your body has to convert it into morphine to actually relieve pain. Cimetidine (Tagamet) can slow down the enzymes that both break down codeine and turn it into morphine. Because of that, this combo can go two ways: it may raise codeine levels and cause more drowsiness, slowed breathing, or heavy sedation, or it may lower the morphine you make so your pain relief drops off.
The good news is this is a theoretical concern, and your care team can manage it easily. If you take both, keep taking them as prescribed and let your pharmacist or doctor know so they can watch how you're doing.
Mechanism: Cimetidine inhibits both CYP3A4 and CYP2D6. Codeine is a prodrug requiring CYP2D6-mediated O-demethylation to morphine (active metabolite); CYP3A4 handles N-demethylation to inactive norcodeine.
- Direction: Variable. Reduced clearance raises parent codeine exposure (sedation, respiratory depression risk), while CYP2D6 inhibition can lower morphine formation (reduced analgesia, possible withdrawal).
- Evidence: Theoretical; magnitude/onset not established.
- Severity: Major (opioid-related respiratory depression).
- Management: If co-use is necessary, monitor for sedation, respiratory depression, and inadequate analgesia/withdrawal. Adjust codeine dose as clinically indicated.
What happens
Increased codeine exposure and increased or reduced active metabolite (morphine) exposure
Interaction Deep Dive
Concomitant use of codeine with a CYP3A4 inhibitor that is also a CYP2D6 inhibitor may either increase the codeine exposure and may either increase or reduce plasma concentrations of morphine, the active metabolite of codeine, thus potentially leading to reduced efficacy and withdrawal symptoms or an increased risk of adverse effects such as respiratory depression and sedation. If concomitant use is necessary, monitor patients for withdrawal symptoms, respiratory depression and sedation, and consider adjusting the codeine dose as needed123.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated codeine metabolism; inhibition of CYP2D6-mediated codeine metabolism
How to manage this interaction
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This is a theoretical interaction that your care team can manage with monitoring and, if needed, individualized dose changes.
- Watch for too much effect: unusual drowsiness, confusion, or slow or shallow breathing.
- Also watch for too little effect: pain not controlled, or withdrawal-like feelings.
- Your codeine dose may need to be adjusted and individualized by your care team, and they may monitor you more closely while you use both.
- Tell your pharmacist or doctor you take both so they can factor this in.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Cimetidine and Acetaminophen And Codeine together?
Cimetidine can change how your body handles codeine, either building it up (more sedation and slowed breathing) or lowering pain relief. Keep taking both as prescribed and ask your pharmacist or doctor to help watch and adjust as needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Cimetidine 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 Cimetidine and Acetaminophen And Codeine interaction managed?
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This is a theoretical interaction that your care team can manage with monitoring and, if needed, individualized dose changes. Watch for too much effect: unusual drowsiness, confusion, or slow or shallow breathing. Also watch for too little effect: pain not controlled, or withdrawal-like feelings. Your codeine dose… 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 Cimetidine 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 (3)
- Product Information: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
- 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 Cimetidine
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