Diphenhydramine Topical and Promethazine: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Diphenhydramine Topical
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.
What happens
Increased risk of paralytic ileus and an increased risk of respiratory, profound sedation, hypotension, coma and death
Interaction Deep Dive
Concomitant use of promethazine and a CNS depressant may increase the risk of respiratory depression, profound sedation, hypotension, coma and opioid overdose. Additionally, concomitant use of promethazine with anticholinergics may increase the risk of urinary retention and/or severe constipation, which can lead to paralytic ileus. Reserve the concomitant use of promethazine 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. In patients already receiving promethazine, prescribe a lower initial dose of the other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If promethazine is initiated in a patient already taking other CNS depressant, prescribe a lower initial dose of promethazine, and titrate based on clinical response. Closely monitor patients for sedation, respiratory depression, signs of urinary retention or reduced gastric motility1.
Why it happens (mechanism)
Additive effects on gastric motility; additive CNS depression
Common questions
Can I take Diphenhydramine Topical and Promethazine together?
Increased risk of paralytic ileus and an increased risk of respiratory, profound sedation, hypotension, coma and death Always confirm with your pharmacist or prescriber before making any change.
How serious is the Diphenhydramine Topical and Promethazine 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 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 Diphenhydramine Topical or Promethazine 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 (1)
- Product Information: MEPERGAN intramuscular, intravenous injection, meperidine HCl, promethazine HCl intramuscular, intravenous injection. West-Ward Pharmaceuticals Corp (per FDA), Eatontown, NJ, 2023.
Keep reading about Diphenhydramine Topical
Keep reading about Promethazine
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist