Clozapine 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
Clozapine
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 down your body in similar ways, so taking them together adds up. Codeine (an opioid pain reliever, combined here with acetaminophen) and clozapine (a medicine for certain mental health conditions) can each cause drowsiness, slowed breathing, and a very sluggish gut. Together, the risk of heavy sedation, slow breathing, and severe constipation (which can rarely lead to a blocked bowel) goes up.
This concern is based on how the drugs work rather than lots of hard data, but it is taken seriously. The good news is your care team can manage this by using the lowest helpful dose and watching you more closely. Please talk with your doctor or pharmacist before changing anything.
Effect: Additive CNS and respiratory depression, plus additive slowing of gastric motility raising the risk of severe constipation, urinary retention, and paralytic ileus.
Mechanism: Overlapping sedative/respiratory-depressant effects (opioid plus antipsychotic) and combined anticholinergic/opioid effects on gut motility. Pharmacodynamic, not primarily pharmacokinetic. Neither is a relevant prodrug concern here that reverses direction.
- Direction: Increased combined effect
- Onset: Unspecified
- Evidence: Theoretical
- Severity: Major
Management: Avoid where possible; reserve for inadequate alternatives. Use lowest dose and shortest duration; individualize dosing. Monitor for sedation, respiratory depression, reduced gastric motility, and urinary retention. Consider prescribing naloxone.
What happens
Increased risk of paralytic ileus and an increased risk of respiratory and CNS depression
Interaction Deep Dive
Avoid concomitant use of opioid cough medication formulations and CNS depressants2. Reserve the concomitant use of codeine and CNS depressants to patients for whom alternatives are inadequate. If concomitant use is necessary, use the lowest dose and shortest duration necessary to achieve treatment goals. Additionally, coadministration of codeine with anticholinergics may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Consider using a lower dose of codeine or the CNS depressant and closely monitor for urinary retention, reduced gastric motility, sedation, and respiratory depression. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose 134.
Why it happens (mechanism)
Additive effects on gastric motility; additive CNS depression
How to manage this interaction
Keep taking both exactly as prescribed unless your care team tells you otherwise. Because these medicines have overlapping effects, your team may take steps to keep you safe.
- Your team may use the lowest effective dose for the shortest time, and doses may be adjusted and individualized to you.
- They may monitor you more closely for heavy drowsiness, slow or shallow breathing, trouble urinating, and constipation.
- Your prescriber may consider providing naloxone for emergency use.
Tell your pharmacist or doctor right away about severe constipation, no bowel movements, belly swelling, trouble peeing, or unusual sleepiness or slow breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) In one study, 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. Drug overdose deaths attributable to prescribed and higher than prescribed doses of both drug classes likewise rose 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 the rate seen with 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 patients taking opioid analgesics who had no history of a benzodiazepine prescription. The risk of drug overdose deaths grew as the daily doses of benzodiazepines increased 2.
d) Observational studies have shown that using opioid analgesics and benzodiazepines together increases the risk of drug-related mortality relative to using opioid analgesics alone. Given their 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 Clozapine and Acetaminophen And Codeine together?
Combining codeine (with acetaminophen) and clozapine can add up to dangerous sedation, slowed breathing, and severe constipation or bowel blockage, so use only when needed at the lowest dose with close monitoring. Do not change either medicine on your own; talk with your doctor or pharmacist first. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Clozapine 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 Clozapine and Acetaminophen And Codeine interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. Because these medicines have overlapping effects, your team may take steps to keep you safe. Your team may use the lowest effective dose for the shortest time, and doses may be adjusted and individualized to you. They may monitor you more closely for heavy drowsiness, slow or shallow breathing, trouble urinating, and… 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 Clozapine 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
Keep reading about Clozapine
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