Netupitant and Acetaminophen And Codeine: 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
Netupitant
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.
What's going on: Codeine has to be broken down in your body, and one of the pathways that helps clear it is an enzyme called CYP3A4. Netupitant (used to prevent nausea from chemotherapy) slows that enzyme down. When it's slowed, more codeine and its active form (morphine) can build up in your body.
That extra buildup can mean more sleepiness and, in some cases, dangerously slow or shallow breathing. This is especially a concern if netupitant is added after you've already been stable on codeine. The good news is your care team can manage this by watching you closely and adjusting your dose if needed. Don't change anything on your own, just talk with your pharmacist or doctor.
Mechanism: Netupitant is a moderate CYP3A4 inhibitor. Codeine is partly metabolized via CYP3A4 (and bioactivated to morphine via CYP2D6). Inhibiting CYP3A4 reduces codeine clearance, increasing codeine and morphine exposure.
Direction/effect: Increased opioid exposure, raising risk of sedation and potentially fatal respiratory depression, particularly when the inhibitor is added to a stable codeine regimen.
- Evidence: Theoretical; severity major.
- Management: Avoid co-use for 1 week after netupitant. If unavoidable, consider reducing codeine dose and monitor closely for sedation/respiratory depression.
- On inhibitor discontinuation, monitor for opioid withdrawal and consider dose increase.
What happens
Increased codeine and morphine exposure
Interaction Deep Dive
Taking codeine together with CYP3A4 inhibitors such as netupitant has been shown to raise the concentrations of both codeine and morphine. This elevation can intensify or extend adverse effects and carries the risk of respiratory depression that may prove fatal, especially in cases where the inhibitor is introduced after the patient has already reached a stable codeine dose. When such combined use is necessary, monitor the patient carefully for sedation and respiratory depression, and consider lowering the codeine dose until stable drug effects are seen. Conversely, when a CYP3A4 inhibitor is being withdrawn, watch the patient for indications of opioid withdrawal, and consider raising the codeine dose until stable drug effects are seen12. Concurrent administration of CYP3A4 substrates with netupitant (which is a moderate CYP3A4 inhibitor) should be avoided for a period of 1 week. Should a CYP3A4 substrate need to be given within 1 week of netupitant, consider decreasing the dose of that CYP3A4 substrate3.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both exactly as prescribed unless your care team tells you otherwise. Here's how teams typically handle this:
- They may space these medicines apart, since netupitant's effect can last about a week.
- Your codeine dose may need to be adjusted and individualized by your care team, and they may monitor you more closely for heavy sedation or slow, shallow breathing.
- When netupitant wears off, they may watch for signs of opioid withdrawal and readjust your dose.
Call your prescriber or pharmacist if you feel unusually drowsy, confused, or short of breath. Seek emergency care for very slow or stopped breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Netupitant and Acetaminophen And Codeine together?
Netupitant can slow the breakdown of codeine, letting codeine and morphine build up and raising the risk of excessive sedation and dangerously slow breathing. Take both only as directed, watch for heavy drowsiness or breathing trouble, and let your care team adjust and monitor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Netupitant 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 Netupitant and Acetaminophen And Codeine interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. Here's how teams typically handle this: They may space these medicines apart, since netupitant's effect can last about a week. Your codeine dose may need to be adjusted and individualized by your care team, and they may monitor you more closely for heavy sedation or slow, shallow breathing. When netupitant wears off,… 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 Netupitant 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: 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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