Asenapine and Acetaminophen And Codeine: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 1, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Asenapine
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.
Both of these medicines can slow you down. The codeine in your pain medicine and asenapine (Saphris or Secuado) are both able to calm the brain and nervous system. When you take them together, that calming effect can add up. That can mean feeling very sleepy or dizzy, having low blood pressure, or in serious cases breathing that becomes too slow or shallow.
The good news is that your care team can manage this. They may use the lowest dose for the shortest time and keep a closer eye on you. Please don't stop or change either medicine on your own. Just talk with your pharmacist or doctor, and get help right away if you feel very drowsy or hard to wake.
Interaction: Additive CNS and respiratory depression from combining codeine (an opioid analgesic) with asenapine (a second-generation antipsychotic with sedating properties).
- Direction: Increased risk of hypotension, profound sedation, respiratory depression, coma, and death (pharmacodynamic, not PK-driven).
- Mechanism: Additive CNS depression at overlapping receptor systems.
- Evidence: Theoretical; severity rated major.
- Management: Reserve concurrent use for patients lacking adequate alternatives. Use the lowest effective doses and shortest duration; consider reducing the dose of codeine or asenapine. Monitor closely for sedation and respiratory depression. Consider prescribing naloxone.
What happens
An increased risk of respiratory and CNS depression
Interaction Deep Dive
Avoid concomitant use of opioid cough medication formulations and CNS depressants. Concomitant use of opioid analgesics with benzodiazepines has been associated with increased rates of emergency department visits and fatal overdose2. Concomitant use of codeine with CNS depressants can increase the risk of hypotension, respiratory depression, profound sedation, coma and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose 341.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. This combination is used only when other options aren't a good fit, so it's worth a conversation.
- Your team may prescribe the lowest dose for the shortest time and may lower the dose of the codeine product or the asenapine.
- Expect closer monitoring for sedation and slowed breathing.
- Ask whether having naloxone on hand makes sense for you.
- Seek help right away for severe drowsiness, confusion, very slow or shallow breathing, or trouble waking.
Check with your pharmacist or prescriber before making any changes.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) In one study, the frequency of emergency department visits related to nonmedical use between 2004 and 2011 that involved opioid analgesics and benzodiazepines rose significantly from 11 to 34.2 per 100,000. Drug overdose fatalities attributable to prescribed and higher than prescribed doses of both drug classes likewise increased significantly from 0.6 to 1.7 per 100,000, and overdose deaths attributable to benzodiazepines rose significantly from 18% to 31% 2.
b) In a prospective cohort study, the rate of overdose deaths involving the dispensing of both opioid analgesics and benzodiazepines was 10 times greater than that with the dispensing of opioid analgesics alone (7 vs 0.7 per 10,000 person years) 2.
c) In a cohort study using data from 2004 to 2009, the risk of fatal overdose rose significantly by 2.33 fold in patients taking opioid analgesics who had a history of a benzodiazepine prescription and rose by 3.86 fold in those with a current benzodiazepine prescription, compared with those taking opioid analgesics without any history of a benzodiazepine prescription. The risk of drug overdose deaths grew as daily benzodiazepine doses increased 2.
d) Observational studies have shown that concurrent use of opioid analgesics and benzodiazepines raises the risk of drug-related mortality relative to use of opioid analgesics alone. Owing to comparable pharmacological properties, it is reasonable to anticipate a similar risk when other CNS depressant drugs are used together with opioid analgesics 34.
Common questions
Can I take Asenapine and Acetaminophen And Codeine together?
Taking codeine-containing pain medicine with asenapine adds up their sedating effects and can slow your breathing, so use only under close medical supervision and get emergency help if you become very drowsy or hard to wake. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Asenapine 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 Asenapine and Acetaminophen And Codeine interaction managed?
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. This combination is used only when other options aren't a good fit, so it's worth a conversation. Your team may prescribe the lowest dose for the shortest time and may lower the dose of the codeine product or the asenapine. Expect closer monitoring for sedation and slowed breathing. Ask whether having nalox… 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 Asenapine 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: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
- US Food and Drug Administration (FDA): Drug Safety Communications: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. US Food and Drug Administration (FDA). Silver Spring, MD. 2016.
- 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
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