Drug Interaction Report

Diphenhydramine Topical and Clomipramine: Interaction Details

A pharmacist-reviewed analysis of the Diphenhydramine Topical and Clomipramine interaction: the documented clinical effects, severity rating, onset, mechanism, and management considerations, with cited references throughout.

AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature

Diphenhydramine Topical

Afterbite with Antihistamine Benadryl® Itch Stopping Gel Dermamycin
+

Clomipramine

Anafranil Calmera Caniquell Clomicalm
Dr. Brian Staiger, PharmD, BCPS
Medically reviewed by
Dr. Brian Staiger, PharmD, BCPS
Updated Aug 8, 2026
Editorial policy · Data sources
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Interaction severity
Major
Potentially serious — often needs a change or close monitoring.
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.

Of 123 documented Diphenhydramine Topical interactions, 102 are rated major — including this one.
Worried about symptoms right now? Contact your pharmacist or prescriber, or call Poison Control at 1-800-222-1222 (US). Call 911 for an emergency.
Onset
delayed
Evidence
theoretical
Severity
Major

What happens

Increased clomiPRAMINE exposure, an increased risk of CNS depression, increased anticholinergic effects (dry mouth, urinary retention)

Interaction Deep Dive

Exert caution with concomitant use of clomiPRAMINE with another CNS depressants, such as diphenhydrAMINE due to increased risk of additive CNS effects. Concomitant use of clomiPRAMINE with diphenhydrAMINE (CYP2D6 inhibitor) may increase the exposure of clomiPRAMINE and may require lower doses than usually prescribed for either clomiPRAMINE or diphenhydrAMINE. Furthermore, whenever one of these drugs is withdrawn from co-therapy, an increased dose of clomiPRAMINE may be required. It is desirable to monitor clomiPRAMINE exposure whenever is coadministered with diphenhydrAMINE. Concomitant administration of clomiPRAMINE with diphenhydrAMINE (anticholinergic agent) may also produce additive anticholinergic effects. Close supervision and careful adjustment of dosage are required when clomiPRAMINE is administered with diphenhydrAMINE2.

Why it happens (mechanism)

Inhibition of CYP2D6-mediated metabolism of clomiPRAMINE; additive CNS depression; additive anticholinergic effects

Literature reports

1 report — tap to read

a) Concomitant antidepressants with strong anticholinergic effects (eg, amitriptyline, amoxapine, clomiPRAMINE) and antihistamines may increase the possibility of adynamic ileus, urinary retention, or chronic glaucoma. This interaction may be more prominent in elderly patients 13.

Common questions

Can I take Diphenhydramine Topical and Clomipramine together?

Increased clomiPRAMINE exposure, an increased risk of CNS depression, increased anticholinergic effects (dry mouth, urinary retention) Always confirm with your pharmacist or prescriber before making any change.

How serious is the Diphenhydramine Topical and Clomipramine interaction?

It is rated major. Potentially serious — often needs a change or close monitoring.

How quickly could this interaction happen?

The documented onset is "delayed". Effects tend to build up gradually over days to weeks.

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 Diphenhydramine Topical or Clomipramine 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 (3)

  1. Blazer DG, Federspiel CF, Ray WA, et al: The risk of anticholinergic toxicity in the elderly: a study of prescribing practices in two populations. J Gerontol 1983; 38:31-35. DOI
  2. Product Information: ANAFRANIL(TM) oral capsules, clomipramine hydrochloride oral capsules. SpecGx LLC (per Dailymed), Webster Groves, MO, 2024. DailyMed
  3. Arnold SE, Kahn RJ, Faldetta LL, et al: Tricyclic antidepressants and peripheral anticholinergic activity. Psychopharmacology 1981; 74:325-328. PubMed
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Diphenhydramine Topical

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Clomipramine

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Beyond drug–drug

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Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:

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This information is for education, not a substitute for professional medical advice. Do not start, stop, or change any medication without talking to your pharmacist or prescriber.