Acetaminophen And Codeine and Ondansetron: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 1, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Ondansetron
No brand names on record
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.
You've been given two medicines that can each nudge up a brain chemical called serotonin. The codeine in your acetaminophen-codeine pain pills and the ondansetron (an anti-nausea drug) can add together. In rare cases, having too much serotonin can cause something called serotonin syndrome.
Signs to watch for include feeling agitated or restless, a fast heartbeat, sweating, shivering, shaky muscles, or a fever. This is mostly a theoretical concern, so please don't panic. Keep taking both as prescribed, and your care team can manage this by watching you closely, especially when you first start or change doses. If you ever feel those symptoms, contact your doctor right away.
Effect: Additive serotonergic activity, theoretically increasing the risk of serotonin syndrome. Codeine has weak serotonergic properties; ondansetron is a 5-HT3 antagonist also implicated in serotonergic toxicity reports.
- Direction/mechanism: Pharmacodynamic (additive), not a PK/CYP interaction.
- Severity: Major on file, though evidence is theoretical.
- Onset: Unspecified; highest vigilance at initiation and dose escalation.
- Monitoring: Watch for agitation, autonomic instability (tachycardia, hyperthermia, diaphoresis), neuromuscular signs (clonus, hyperreflexia, tremor).
- Management: Concomitant use may proceed with close observation; discontinue codeine if serotonin syndrome is suspected.
What happens
Increased risk of serotonin syndrome
Interaction Deep Dive
Serotonin syndrome has been reported when opioids like codeine are taken together with serotonergic agents. When such combined use cannot be avoided, monitor the patient closely, especially when therapy is being started and when doses are being changed. Should serotonin syndrome be suspected, stop codeine123.
Why it happens (mechanism)
Additive serotonergic effects
How to manage this interaction
Good news: this combination can usually be used safely with a little extra attention from your care team.
- Keep taking both as prescribed unless your doctor or pharmacist tells you otherwise.
- Your team may monitor you more closely, especially when you first start or when a dose is changed.
- Watch for warning signs: restlessness or agitation, fast heartbeat, sweating, shivering, muscle twitching or stiffness, or fever.
- If any of those happen, contact your prescriber right away, since they may stop the codeine if serotonin syndrome is suspected.
Ask your pharmacist to review any other serotonin-affecting medicines you take.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
Common questions
Can I take Acetaminophen And Codeine and Ondansetron together?
Taking acetaminophen-codeine with ondansetron carries a theoretical, additive risk of serotonin syndrome. Keep taking both as prescribed, watch for symptoms like agitation, fast heartbeat, sweating or muscle twitching, and contact your care team if they appear. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Ondansetron 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 Ondansetron interaction managed?
Good news: this combination can usually be used safely with a little extra attention from your care team. Keep taking both as prescribed unless your doctor or pharmacist tells you otherwise. Your team may monitor you more closely, especially when you first start or when a dose is changed. Watch for warning signs: restlessness or agitation, fast heartbeat, sweating, shivering, muscle twitching or s… 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 Acetaminophen And Codeine or Ondansetron 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 tablets, codeine sulfate oral tablets. West-Ward Pharmaceuticals Corp (per DailyMed), Eatontown, NJ, 2016. 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 Ondansetron
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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