Acetaminophen And Codeine and Berotralstat: 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
Berotralstat
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.
These two medicines can interact. Your pain pill contains codeine, and berotralstat (Orladeyo) can slow down one of the liver enzymes that helps your body handle codeine. That can let more codeine, and the morphine it turns into, build up in your body. This may make you more sleepy or slow your breathing more than usual.
This concern is based mostly on how these drugs work in theory, not on a lot of real-world reports, so try not to worry. Watch for unusual drowsiness or slow, shallow breathing, and talk with your pharmacist or doctor before changing anything. Your care team can adjust your dose and check on you to keep you safe.
Mechanism: Berotralstat inhibits CYP3A4, reducing codeine clearance and increasing codeine and its active metabolite morphine exposure. Note codeine is a prodrug, but the primary safety concern here is accumulation of both parent and active opioid, raising sedation and respiratory depression risk.
- Direction: Increased opioid exposure/effect.
- Onset: Unspecified; risk highest when inhibitor added to a stable codeine dose.
- Evidence: Theoretical.
- Management: Monitor for respiratory depression and sedation; consider codeine dose reduction until stable effects observed. If berotralstat is discontinued, monitor for opioid withdrawal and consider increasing codeine dose.
What happens
Increased codeine and morphine exposure
Interaction Deep Dive
Concomitant use of codeine with CYP3A4 inhibitors 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.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both medicines as prescribed unless your care team tells you otherwise. Here is how this is usually handled:
- Your team may monitor you more closely for excess drowsiness and slow or shallow breathing, especially soon after starting or changing either drug.
- Your codeine dose may need to be adjusted and individualized by your care team until your response is steady.
- If berotralstat is ever stopped, your team may watch for signs your pain medicine is wearing off and adjust as needed.
Call your pharmacist or doctor if you feel unusually sleepy, confused, or notice trouble breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Berotralstat together?
Berotralstat can raise codeine and morphine levels, increasing the risk of heavy sedation and slowed breathing, so watch for these signs and let your care team adjust your dose and monitoring. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Berotralstat 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 Berotralstat interaction managed?
Keep taking both medicines as prescribed unless your care team tells you otherwise. Here is how this is usually handled: Your team may monitor you more closely for excess drowsiness and slow or shallow breathing, especially soon after starting or changing either drug. Your codeine dose may need to be adjusted and individualized by your care team until your response is steady. If berotralstat is ev… 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 Berotralstat 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
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