Acetaminophen And Codeine and Tucatinib: 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
Tucatinib
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: Your pain pill contains codeine. Codeine is a "prodrug," meaning your body has to change it into active pain relievers, including morphine. Tucatinib (Tukysa) slows down one of the pathways (an enzyme called CYP3A4) that normally breaks codeine down. That can let codeine and morphine build up higher than usual.
When opioid levels climb, you may feel more drowsy, dizzy, or, in a serious case, your breathing can slow down too much. This matters most if the tucatinib is added after you've been on a steady codeine dose. The good news is your care team can manage this by watching you closely and adjusting your dose if needed. Don't stop either medicine on your own, just talk with your pharmacist or doctor.
Mechanism: Tucatinib is a CYP3A4 inhibitor. Codeine undergoes CYP3A4-mediated metabolism (and CYP2D6 activation to morphine); reduced CYP3A4 clearance increases codeine and morphine exposure.
- Direction: Increased opioid exposure and effect (enhanced/prolonged adverse reactions).
- Risk: Sedation and potentially fatal respiratory depression, especially when inhibitor is added to a stable codeine regimen.
- Evidence: Theoretical; severity rated major.
- Onset: Unspecified.
Management: Monitor for respiratory depression and sedation; consider codeine dose reduction until stable effects observed. If tucatinib is discontinued, monitor for opioid withdrawal and consider increasing codeine dose to re-stabilize.
What happens
Increased codeine and morphine exposure
Interaction Deep Dive
Taking codeine together with CYP3A4 inhibitors has led to elevated levels of both codeine and morphine, which may intensify or extend adverse effects and carries the risk of respiratory depression that could be fatal, especially when the inhibitor is introduced after a patient has already reached a stable codeine dose. When these agents must be used together, watch patients carefully for sedation and respiratory depression, and consider lowering the codeine dose until steady drug effects are seen. Conversely, when a CYP3A4 inhibitor is being withdrawn, observe patients for indications of opioid withdrawal and consider raising the codeine dose until stable drug effects have been established12.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both as prescribed unless your care team tells you otherwise. Because tucatinib can raise codeine and morphine levels, here's how a team typically handles it:
- They may watch you more closely for excess sleepiness or slowed breathing, especially right after tucatinib is started.
- Your codeine dose may be adjusted and individualized until your response is steady.
- If tucatinib is later stopped, they may watch for opioid withdrawal and adjust codeine again.
Call your prescriber or pharmacist promptly if you notice unusual drowsiness, confusion, or slow or shallow breathing. This is manageable with the right monitoring.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Tucatinib together?
Tucatinib can raise codeine and morphine levels, increasing sedation and the risk of dangerously slow breathing. Keep taking both as prescribed, watch for excess drowsiness or slowed breathing, and let your care team adjust and monitor your codeine dose. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Tucatinib 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 Tucatinib interaction managed?
Keep taking both as prescribed unless your care team tells you otherwise. Because tucatinib can raise codeine and morphine levels, here's how a team typically handles it: They may watch you more closely for excess sleepiness or slowed breathing, especially right after tucatinib is started. Your codeine dose may be adjusted and individualized until your response is steady. If tucatinib is later sto… 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 Tucatinib 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 Tucatinib
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