Acetaminophen And Codeine and Fosnetupitant: 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
Fosnetupitant
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.
Your pain medicine contains codeine, and fosnetupitant (which turns into netupitant in your body) can slow down one of the liver pathways that breaks codeine down. That means more codeine, and more of its active form morphine, can build up. This could make you feel extra sleepy or slow your breathing, which is the effect we watch most closely with opioids.
The good news is this is very manageable. Your care team may lower your codeine dose for a while and keep a closer eye on how sleepy or short of breath you feel. Please don't stop either medicine on your own. Just let your pharmacist or doctor know you're taking both so they can tailor things safely.
Effect: Netupitant (active moiety of fosnetupitant) is a moderate CYP3A4 inhibitor. Inhibition of CYP3A4-mediated codeine metabolism increases codeine and morphine exposure, raising risk of sedation and potentially fatal respiratory depression.
- Direction: Increased opioid effect (codeine is metabolized via CYP3A4 and CYP2D6; reduced clearance raises parent and active metabolite levels).
- Onset: Unspecified; risk is highest when inhibitor is added to a stable codeine dose.
- Evidence: Theoretical, but severity rated major.
- Management: Monitor for respiratory depression/sedation; consider codeine dose reduction. Avoid CYP3A4 substrates for ~1 week around netupitant; if unavoidable, reduce substrate dose. On inhibitor discontinuation, monitor for withdrawal and consider dose increase.
What happens
Increased codeine and morphine exposure
Interaction Deep Dive
Concomitant use of codeine with CYP3A4 inhibitors (netupitant) 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. Avoid concomitant use of CYP3A4 substrates with netupitant (a moderate inhibitor of CYP3A4) for 1 week. If a CYP3A4 substrate must be administered within 1 week of netupitant, consider reducing the dose of the CYP3A4 substrate 3.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. Here is what teams typically do:
- Closer monitoring for excessive drowsiness and slow or shallow breathing, especially soon after fosnetupitant is given.
- Dose adjustment: your codeine dose may be lowered and individualized until your response is stable, and may be adjusted again once the inhibitor effect wears off (about a week).
- Timing: your team may separate these medicines when possible.
Call your pharmacist or prescriber right away if you feel unusually sleepy, confused, or have trouble breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Fosnetupitant together?
Fosnetupitant can raise codeine and morphine levels, increasing the risk of oversedation and slowed breathing, so your care team may lower your codeine dose and watch you more closely. Keep taking both as prescribed and report any unusual drowsiness or breathing trouble. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Fosnetupitant 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 Fosnetupitant interaction managed?
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. Here is what teams typically do: Closer monitoring for excessive drowsiness and slow or shallow breathing, especially soon after fosnetupitant is given. Dose adjustment: your codeine dose may be lowered and individualized until your response is stable, and may be adjusted again once the inhibitor effect wea… 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 Fosnetupitant 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: AKYNZEO(R) oral capsules, netupitant palonosetron oral capsules. Helsinn Therapeutics (US), Inc (per FDA), Iselin, NJ, 2018. DailyMed
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