Acetaminophen And Codeine and Zotepine: 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
Zotepine
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.
Your pain medicine contains codeine, an opioid, and it also has acetaminophen (like Tylenol). Zotepine is an antipsychotic that calms the brain. Both of these can slow down your brain and your breathing. When you take them together, those calming effects can add up, which may make you very drowsy, lightheaded, or cause your breathing to become dangerously slow.
This is why the two are usually avoided together. But the good news is that your care team can manage this safely by using the lowest doses that work and watching you closely. Please talk with your doctor or pharmacist before combining them so they can make the safest plan for you.
Effect: Additive CNS and respiratory depression from combining codeine (opioid) plus acetaminophen with zotepine (sedating atypical antipsychotic).
- Mechanism: Pharmacodynamic additive CNS depression; risk of hypotension, profound sedation, respiratory depression, coma, death.
- Direction: Increased depressant effect (both agents sedating; not a prodrug-activation concern here).
- Evidence: Theoretical, but severity rated major; opioid plus CNS depressant combinations are linked to increased ED visits and fatal overdose.
- Management: Avoid if possible. If required, use lowest effective dose and shortest duration, consider reducing either agent, monitor sedation and respiratory status, and consider prescribing naloxone.
What happens
An increased risk of respiratory and CNS depression
Interaction Deep Dive
Opioid-containing cough preparations should not be taken together with CNS depressants. When opioid analgesics are combined with benzodiazepines, higher rates of emergency department visits and fatal overdose have been observed2. Taking codeine alongside CNS depressants can heighten the likelihood of hypotension, respiratory depression, profound sedation, coma and death. Prescribing these agents together should be limited to patients for whom other treatment approaches are insufficient. Keep both the doses and the treatment durations to the smallest amount necessary. Monitor patients carefully for indications of sedation and respiratory depression. Should combined use be justified, consider prescribing naloxone to allow emergency management of opioid overdose341.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Keep taking both exactly as prescribed unless your doctor or pharmacist tells you otherwise. This combination is generally avoided, but when it is needed your care team has clear ways to keep you safe:
- They may use the lowest dose and shortest duration of the codeine product, the zotepine, or both.
- They may monitor you more closely for heavy drowsiness or slowed breathing.
- They may consider prescribing naloxone as an emergency rescue medicine.
Tell your care team right away if you feel very sleepy, confused, faint, or notice slow or shallow breathing. Ask before adding any other sedating medicines or alcohol.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) One study found that emergency department visits related to nonmedical use that took place between 2004 and 2011 and involved both opioid analgesics and benzodiazepines rose significantly from 11 to 34.2 per 100,000. Deaths from drug overdose attributable to prescribed and above-prescribed doses of both drug classes likewise rose significantly from 0.6 to 1.7 per 100,000, while overdose deaths attributable to benzodiazepines rose significantly from 18% to 31% 2.
b) In a prospective cohort study, the rate of overdose deaths involving dispensing of both opioid analgesics and benzodiazepines was 10 times greater than that involving dispensing of opioid analgesics alone (7 versus 0.7 per 10,000 person years) 2.
c) In a cohort study drawing on 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 patients taking opioid analgesics who had no history of a benzodiazepine prescription. The risk of drug overdose deaths grew as daily benzodiazepine doses increased 2.
d) Observational studies have shown that using opioid analgesics together with benzodiazepines raises the risk of drug-related mortality relative to using 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 Acetaminophen And Codeine and Zotepine together?
Codeine (an opioid) and zotepine both depress the brain and breathing, so combining them can be dangerous; use them together only under your care team's guidance with the lowest doses and close monitoring. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Zotepine 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 Zotepine interaction managed?
Keep taking both exactly as prescribed unless your doctor or pharmacist tells you otherwise. This combination is generally avoided, but when it is needed your care team has clear ways to keep you safe: They may use the lowest dose and shortest duration of the codeine product, the zotepine, or both. They may monitor you more closely for heavy drowsiness or slowed breathing. They may consider prescr… 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 Zotepine 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
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