Acetaminophen And Codeine and Rilzabrutinib: 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
Rilzabrutinib
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, which your liver turns into its active form using several enzymes. Rilzabrutinib (Wayrilz) can slow down one of those liver enzymes, called CYP3A. When that enzyme is slowed, codeine and its byproducts can linger in your body longer than usual.
In plain terms, this means you might feel more of codeine's effects, like extra drowsiness, dizziness, constipation, or slowed breathing. This concern is based mostly on how these drugs behave in theory, not on lots of real-world reports. The good news is your care team can manage this easily by watching you a bit more closely and adjusting your dose if needed. Please don't stop either medicine on your own.
Mechanism: Rilzabrutinib is a moderate CYP3A inhibitor. Codeine and, to a lesser extent, acetaminophen undergo CYP3A-mediated metabolism, so co-administration may increase substrate exposure and the risk of substrate-related adverse effects.
- Direction: Increased opioid effect (sedation, respiratory depression, constipation) from higher codeine/metabolite exposure.
- Magnitude: Rilzabrutinib raised midazolam Cmax/AUC ~2.2-fold (single dose); AUC predicted up to 3.0-fold at 400 mg BID. Effect on codeine is extrapolated.
- Onset: Unspecified. Evidence: Theoretical.
Management: Monitor more frequently for opioid-related adverse reactions and individualize/adjust the acetaminophen-codeine dose as clinically indicated.
What happens
Increased CYP3A substrate exposure and an increased risk of CYP3A substrate-related adverse reactions
Interaction Deep Dive
When rilzabrutinib, a moderate inhibitor of CYP3A, is given together with substrates of CYP3A, exposure to those substrates may rise, thereby heightening the likelihood of adverse reactions associated with them. It is advisable to watch more closely for adverse reactions from the co-administered CYP3A substrate and to weigh a corresponding change in dosage. In a drug interaction study conducted in healthy participants, giving a single 400 mg dose of rilzabrutinib alongside midazolam (a sensitive CYP3A substrate) raised the Cmax and AUC of midazolam by 2.2-fold. In patients with immune thrombocytopenia, midazolam AUC is projected to rise by as much as 3.0-fold when combined with rilzabrutinib 400 mg twice daily1.
Why it happens (mechanism)
Inhibition of CYP3A-substrate metabolism by rilzabrutinib
How to manage this interaction
This interaction is manageable, and you should keep taking both medicines exactly as prescribed unless your clinician tells you otherwise.
- Your care team may monitor you more closely for opioid side effects such as unusual drowsiness, dizziness, confusion, constipation, or slowed breathing.
- Your codeine dose may be adjusted and individualized by your care team if needed.
- Tell your pharmacist or prescriber about any new or stronger sedation, especially early in treatment.
Ask your pharmacist before adding any other medicine that causes drowsiness, and reach out to your prescriber with questions about your dose.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) In a drug interaction study involving healthy volunteers, taking a single 400 mg dose of rilzabrutinib together with midazolam (a sensitive CYP3A substrate) raised the Cmax and AUC of midazolam by 2.2-fold. In patients with immune thrombocytopenia, the AUC of midazolam is projected to rise as much as 3.0-fold when given alongside 400 mg rilzabrutinib twice daily 1.
Common questions
Can I take Acetaminophen And Codeine and Rilzabrutinib together?
Rilzabrutinib can slow the breakdown of codeine, so watch for stronger opioid effects like drowsiness or slowed breathing, and let your care team monitor you and adjust your dose if needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Rilzabrutinib interaction?
It is rated moderate. Can be significant — usually manageable with 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 Rilzabrutinib interaction managed?
This interaction is manageable, and you should keep taking both medicines exactly as prescribed unless your clinician tells you otherwise. Your care team may monitor you more closely for opioid side effects such as unusual drowsiness, dizziness, confusion, constipation, or slowed breathing. Your codeine dose may be adjusted and individualized by your care team if needed. Tell your pharmacist or pr… 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 Rilzabrutinib 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 anything you'd monitor while I'm on both?
References (1)
- Product Information: WAYRILZ™ oral tablets, rilzabrutinib oral tablets. Genzyme Corporation (per FDA), Cambridge, MA, 2025. DailyMed
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