Diphenhydramine and Zaleplon Interaction
Drug interaction information between Diphenhydramine and Zaleplon.
Diphenhydramine and Zaleplon have a documented minor interaction in FDA labeling.
FDA drug labeling documents a minor-severity interaction between Diphenhydramine and Zaleplon. Major interactions are generally avoided, moderate ones may need monitoring or a dose adjustment, and minor ones are usually low-risk. This page shows the documented mechanism and guidance. Label-documented interactions are not a complete safety review, so always confirm your own medications with a pharmacist or doctor. Educational information, not medical advice.
How They Interact
Diphenhydramine might weakly block a liver enzyme, but studies show it does not change how the body processes zaleplon. There is no evidence that these drugs interfere with each other's levels in the blood.
What To Do
No dose adjustments are usually needed when taking these two drugs together. Always inform your doctor about all medications you are using.
FDA Label Information
Diphenhydramine: Diphenhydramine is reported to be a weak inhibitor of aldehyde oxidase in rat liver, but its inhibitory effects in human liver are not known. There is no pharmacokinetic interaction between zaleplon and diphenhydramine following the administration of a single dose (10 mg and 50 mg, respectively) of each drug.
Zaleplon Also Interacts With
- Ibuprofen minor
- Venlafaxine minor
- Paroxetine minor
- Warfarin minor
- Ketoconazole minor
Frequently Asked Questions
Can I take Diphenhydramine and Zaleplon together?
This is a minor interaction. No dose adjustments are usually needed when taking these two drugs together. Always inform your doctor about all medications you are using.
How serious is the interaction between Diphenhydramine and Zaleplon?
This interaction is classified as "minor" severity by the FDA. Minor interactions are unlikely to cause significant problems but should still be mentioned to your healthcare provider.
Why do Diphenhydramine and Zaleplon interact?
Diphenhydramine might weakly block a liver enzyme, but studies show it does not change how the body processes zaleplon. There is no evidence that these drugs interfere with each other's levels in the blood.
Understanding the Diphenhydramine and Zaleplon Interaction
FDA-approved prescribing information for these two drugs flags their combination as a minor-severity interaction. Diphenhydramine belongs to the First-Generation Antihistamine class and Zaleplon belongs to the Non-Benzodiazepine Hypnotic (Z-Drug) class - two categories that can collide when co-prescribed. The mechanism described in FDA labeling is: Diphenhydramine might weakly block a liver enzyme, but studies show it does not change how the body processes zaleplon. Severity tiers matter: major flags generally advise avoidance, moderate flags often require monitoring or dose adjustment, and minor flags may only call for awareness.
Context around a specific patient determines real-world impact. Diphenhydramine has 2 total documented interactions on file in this dataset, and Zaleplon has 16. Each additional medication compounds the interaction surface, which is why pharmacists run full-profile checks rather than evaluating one pair at a time. FDA-derived guidance for this pair is: No dose adjustments are usually needed when taking these two drugs together. Timing of doses, renal and hepatic function, age, and other concurrent prescriptions all shape whether a labeled interaction matters clinically.
An interaction flag is not a verdict. A large share of labeled interactions are managed routinely in clinical practice, the fix may be as simple as spacing doses or adding a monitoring test. Others require the prescriber to choose a different medication entirely. This page surfaces FDA-sourced labeling and openFDA data for educational purposes only; it is not medical advice and cannot account for your full clinical picture. Never start, stop, or adjust either Diphenhydramine or Zaleplon based on a web page, speak with your prescriber or pharmacist before making any change.
Sources: FDA Drug Labels (SPL) via openFDA (2026). This is for informational purposes only and is not medical advice. Always consult your healthcare provider about drug interactions.
Read our methodology - how this data is sourced, computed, and verified.