Diphenhydramine and Zaleplon interaction
Diphenhydramine and Zaleplon: both prescribing labels flag this combination with the strongest language, such as a contraindication, a boxed warning, or an instruction to avoid it.
Do not combine without a prescriber's guidance. The label language below is the strongest FDA uses.
What the FDA labels say
From the Zaleplon label · effective 2025-10-08
The use of zaleplon with other sedative-hypnotics at bedtime or the middle of the night is not recommended (see ).
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.
Post-marketing reports have shown that complex sleep behaviors may occur with zaleplon alone at recommended dosages, with or without the concomitant use of alcohol or other central nervous system (CNS) depressants.
Coadministration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression.
Dosage adjustments of zaleplon and of other concomitant CNS depressants may be necessary when zaleplon is administered with such agents because of the potentially additive effects.
From the Diphenhydramine label · effective 2026-03-05
Drug Interactions Diphenhydramine hydrochloride has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc).
Taking more than these two? Interactions stack. Check your whole list at once; it stays in your browser.
Open in the checkerNot medical advice. Interaction Checker quotes FDA label text and NIH fact sheets. Whether an interaction matters for you depends on doses, timing, kidney and liver function, and other conditions. Confirm with a pharmacist or prescriber.