Calcium Oxybate and Acetaminophen And Codeine: 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
Calcium Oxybate
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 two medicines both slow down the brain and body. Codeine (the pain reliever combined with acetaminophen) is an opioid, and Xywav (calcium oxybate) is a strong sleep medicine. When taken together, their calming effects stack up. This can lead to heavy sedation, dangerously slow or shallow breathing, low blood pressure, fainting, and in serious cases it can be life threatening.
The good news is that your care team can manage this safely. Please do not stop or change either medicine on your own. Instead, let your pharmacist or doctor know you take both, so they can decide the safest plan for you.
Mechanism: additive CNS depression between an opioid (codeine, with acetaminophen) and calcium oxybate (Xywav). Both are pharmacodynamic CNS depressants; effect is additive, not PK-driven. Neither is a prodrug concern here that reverses direction (codeine is a prodrug for morphine, but the sedative additive risk stands regardless).
- Direction: increased CNS/respiratory depression
- Risk: profound sedation, respiratory depression, hypotension, syncope, death
- Evidence: theoretical; severity major; onset unspecified
- Management: combination not recommended; if required, reduce dose or discontinue one agent, or interrupt oxybate for short-term opioid use; monitor mental status and respiration; strongly consider prescribing naloxone.
What happens
An increased risk of CNS depression and clinically significant respiratory depression, obtundation, hypotension, profound sedation, syncope, and death
Interaction Deep Dive
Concomitant use of sodium oxybate or mixed oxybate salts and other CNS depressants increases the risk for additive CNS depression and clinically significant respiratory depression, obtundation, hypotension, profound sedation, syncope, and death. However, if use of these CNS depressants in combination with an oxybate is required, dose reduction or discontinuation of one or more CNS depressant(s) (including oxybates) should be considered. In addition, if short-term use of an opioid (e.g., post-or perioperative) is required, interruption of treatment with the oxybate should be considered123. If concomitant use is necessary, monitor for mental status changes and respiratory depression and manage cautiously and strongly consider prescribing naloxone for the emergency treatment of opioid overdose 4.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
This combination is generally not recommended because both drugs deepen sedation and can slow breathing. Keep taking both exactly as prescribed until you speak with your care team. Bring this up with your pharmacist or prescriber, who may:
- Lower the dose of one medicine or pause one of them
- Interrupt the Xywav if you need a short course of the opioid (for example, after surgery)
- Monitor you more closely for excess drowsiness or breathing changes
- Prescribe naloxone as an emergency rescue in case of opioid overdose
Get emergency help right away for very slow breathing, extreme drowsiness, or fainting.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Calcium Oxybate and Acetaminophen And Codeine together?
Combining codeine/acetaminophen with calcium oxybate (Xywav) can dangerously deepen sedation and slow breathing, so it is generally not recommended. Talk to your pharmacist or doctor before using both, and ask about a naloxone rescue kit. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Calcium Oxybate 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 Calcium Oxybate and Acetaminophen And Codeine interaction managed?
This combination is generally not recommended because both drugs deepen sedation and can slow breathing. Keep taking both exactly as prescribed until you speak with your care team. Bring this up with your pharmacist or prescriber, who may: Lower the dose of one medicine or pause one of them Interrupt the Xywav if you need a short course of the opioid (for example, after surgery) Monitor you more c… 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 Calcium Oxybate 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 (4)
- Product Information: XYWAV(R) oral solution, calcium, magnesium, potassium, sodium oxybates oral solution. Jazz Pharmaceuticals Inc (per manufacturer), Palo Alto, CA, 2023. DailyMed
- Product Information: XYREM(R) oral solution, sodium oxybate oral solution. Jazz Pharmaceuticals Inc (per manufacturer), Palo Alto, CA, 2023. DailyMed
- Product Information: LUMRYZ(TM) oral extended-release suspension, sodium oxybate extended-release suspension. Avadel CNS Phamaceuticals LLC (per FDA), Chesterfield, MO, 2024. DailyMed
- Product Information: SUBUTEX(R) sublingual tablets, buprenorphine sublingual tablets. Indivior Inc (per FDA), North Chesterfield, VA, 2021. DailyMed
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