Acetaminophen And Codeine and Bosentan: 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
Bosentan
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.
You've been prescribed codeine (with acetaminophen) for pain, and you're also taking bosentan. Here's what's worth knowing. Codeine is a prodrug, meaning your body has to convert it into morphine before it relieves pain. Bosentan can speed up the liver enzyme that handles codeine, so less of it turns into morphine. The likely result is that the codeine may not work as well for your pain, and if your body has gotten used to the opioid, you could notice mild withdrawal feelings like restlessness or aches.
The good news is this is very manageable. Your care team can watch how well your pain is controlled and adjust your dose to fit you. Don't change anything on your own, just talk with your pharmacist or doctor.
Effect: Bosentan is a CYP3A4 inducer. Codeine is a prodrug; induction of CYP3A4-mediated metabolism shifts codeine toward norcodeine, reducing the fraction available for CYP2D6 conversion to morphine. Net result: reduced codeine and morphine exposure, diminished analgesia, and possible opioid withdrawal in physically dependent patients.
- Direction: reduced active-metabolite (morphine) exposure, reduced opioid efficacy
- Evidence: theoretical; magnitude not quantified
- Onset: unspecified
Management: If used together, monitor for inadequate analgesia and withdrawal signs; codeine dose may be titrated upward as clinically indicated. If bosentan is discontinued, anticipate rising opioid effect, consider reducing codeine dose, and monitor for sedation/respiratory depression.
What happens
Reduced codeine and morphine exposure, reduced opioid efficacy and precipitation of opioid withdrawal
Interaction Deep Dive
Concomitant use of codeine with CYP3A4 inducers may result in reduced codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If concomitant use is needed, closely monitor patients for decreased efficacy or signs of opioid withdrawal syndrome, and consider increasing the dose of codeine as necessary. If a CYP3A4 inducer is being discontinued, consider codeine dose reduction and closely monitor patients for signs of respiratory depression or sedation12.
Why it happens (mechanism)
Induction of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both medications exactly as prescribed unless your care team tells you otherwise. Because bosentan can lower how much pain relief you get from codeine, here is how this is usually handled:
- Your team may monitor how well your pain is controlled and watch for signs of opioid withdrawal (restlessness, sweating, aches, stomach upset).
- Your codeine dose may need to be adjusted and individualized by your care team.
- If bosentan is ever stopped, your codeine effect could increase, so your team may lower the codeine dose and watch for excess drowsiness or slowed breathing.
Tell your pharmacist or prescriber if your pain isn't controlled or if you feel withdrawal symptoms.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Bosentan together?
Bosentan can speed up how your body handles codeine, so the codeine may relieve pain less well and could trigger withdrawal if you're dependent. Don't adjust anything yourself; your care team can monitor you and tailor the codeine dose. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Bosentan 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 Bosentan interaction managed?
Keep taking both medications exactly as prescribed unless your care team tells you otherwise. Because bosentan can lower how much pain relief you get from codeine, here is how this is usually handled: Your team may monitor how well your pain is controlled and watch for signs of opioid withdrawal (restlessness, sweating, aches, stomach upset). Your codeine dose may need to be adjusted and individua… 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 Bosentan 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 Bosentan
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