Promethazine 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
Promethazine
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. Codeine (in your acetaminophen and codeine pill) is an opioid that can make you sleepy and slow your breathing. Promethazine (Phenergan) also causes drowsiness and has drying, anticholinergic effects that slow your gut and bladder.
Taken together, they can add up. That means more sedation, slower breathing, and a higher chance of severe constipation or even a stopped-up bowel and trouble urinating. This is based on how the drugs work rather than large studies, but it is taken seriously. The good news: your care team can manage this safely by adjusting doses and watching you closely. Please talk with your pharmacist or doctor before combining them.
Additive CNS and GI/anticholinergic effects. Codeine (an opioid; note it is a prodrug activated by CYP2D6 to morphine) plus promethazine produce overlapping pharmacodynamic depression rather than a metabolic interaction.
- Direction: increased sedation, respiratory depression, and reduced gastric motility.
- Mechanism: additive CNS depression; additive/anticholinergic slowing of gut and bladder, raising risk of urinary retention, severe constipation, and paralytic ileus.
- Evidence: theoretical; severity major; onset unspecified.
Management: reserve for patients lacking adequate alternatives; use lowest effective dose and shortest duration. Consider reducing codeine or the CNS depressant dose. Monitor sedation, respiratory rate, bowel/bladder function. Consider prescribing naloxone.
What happens
Increased risk of paralytic ileus and an increased risk of respiratory and CNS depression
Interaction Deep Dive
Do not combine opioid-containing cough medication products with CNS depressants2. The joint use of codeine alongside CNS depressants should be limited to patients for whom other options are insufficient. When such combined use cannot be avoided, employ the smallest dose and the briefest duration required to meet therapeutic objectives. Furthermore, giving codeine together with anticholinergics can heighten the likelihood of urinary retention and/or severe constipation, potentially progressing to paralytic ileus. A reduced dose of either codeine or the CNS depressant should be considered, along with vigilant monitoring for urinary retention, decreased gastric motility, sedation, and respiratory depression. Should concurrent administration be justified, prescribing naloxone for the emergency management of opioid overdose may be appropriate 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. This combination can be used when needed, but it is watched carefully.
- Your team may choose the lowest dose for the shortest time that works, and may lower the dose of the codeine product or the promethazine.
- They may monitor you more closely for excess drowsiness, slow or shallow breathing, constipation, and trouble urinating.
- Your doctor may prescribe naloxone as a safety measure.
Call your pharmacist or prescriber right away if you notice heavy sedation, very slow breathing, no bowel movements, belly pain, or difficulty passing urine.
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. Deaths from drug overdose attributable to prescribed doses and doses exceeding those prescribed 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 the dispensing of both opioid analgesics and benzodiazepines was 10 times greater than that seen with the dispensing of opioid analgesics alone (7 versus 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 among patients receiving opioid analgesics who had a prior benzodiazepine prescription, and rose by 3.86 fold among those with an active benzodiazepine prescription, compared with patients taking opioid analgesics who had no history of a benzodiazepine prescription. The risk of 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 death compared with using opioid analgesics on their own. Given their comparable pharmacological characteristics, it is reasonable to anticipate a similar risk when other CNS depressant drugs are used alongside opioid analgesics 34.
Common questions
Can I take Promethazine and Acetaminophen And Codeine together?
Combining acetaminophen with codeine and promethazine can add up to dangerous drowsiness, slowed breathing, and severe constipation or urinary retention, so use it only when necessary at the lowest dose and let your care team monitor you closely. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Promethazine 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 Promethazine and Acetaminophen And Codeine interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination can be used when needed, but it is watched carefully. Your team may choose the lowest dose for the shortest time that works, and may lower the dose of the codeine product or the promethazine. They may monitor you more closely for excess drowsiness, slow or shallow breathing, constipation, and trouble… 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.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Promethazine 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 Promethazine
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