Drug Interaction Report

Tamoxifen and Diphenhydramine Injection: Interaction Details

A pharmacist-reviewed analysis of the Tamoxifen and Diphenhydramine Injection 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 Injection

Banophen Benadryl Calagel Reformulated Jun 2019 Compoz Dermamycin Diphedryl Diphenhist Dormin
+

Tamoxifen

Nolvadex® Soltamox Soltamox®
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
Moderate
Can be significant — usually manageable with 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 89 documented Tamoxifen interactions, 6 are rated moderate — including this one.
Onset
unspecified
Evidence
theoretical
Severity
Moderate

What happens

Decreased plasma concentrations of the active metabolites of tamoxifen

Interaction Deep Dive

Concomitant use of tamoxifen, a CYP2D6 substrate1, and a CYP2D6 inhibitor, such as diphenhydramine, may affect tamoxifen efficacy by inhibiting the formation of tamoxifen active metabolites. Therefore, concomitant use of diphenhydramine and tamoxifen should be avoided 2. If coadministration is required, monitoring for decreased tamoxifen efficacy with coadministration may be necessary.

Why it happens (mechanism)

Inhibition of CYP2D6-mediated tamoxifen metabolism

Literature reports

1 report — tap to read

a) In a retrospective study of premenopausal women diagnosed with stage I to III breast cancer in the Predictors of Breast Cancer Recurrence (ProBe CaRe) cohort (N=4493) using Bayesian joint modeling, patients concomitantly taking tamoxifen with a CYP2D6 inhibitor, including diphenhydramine, for more than half of the intended tamoxifen-treatment time had a higher recurrence rate of breast cancer compared with patients not taking a CYP2D6 inhibitor with tamoxifen (HR, 1.24; 95% CI, 0.96 to 1.58). This association was stronger with strong CYP2D6 inhibitors (HR, 1.25; 95% CI, 0.88 to 1.73) compared with weak CYP2D6 inhibitors (HR, 1.15; 95% CI, 0.57 to 1.53) 3.

Common questions

Can I take Tamoxifen and Diphenhydramine Injection together?

Decreased plasma concentrations of the active metabolites of tamoxifen Always confirm with your pharmacist or prescriber before making any change.

How serious is the Tamoxifen and Diphenhydramine Injection interaction?

It is rated moderate. Can be significant — usually manageable with 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 Tamoxifen or Diphenhydramine Injection 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 anything you'd monitor while I'm on both?

References (3)

  1. Product Information: tamoxifen citrate oral tablets, tamoxifen citrate oral tablets. Watson Laboratories (per manufacturer), Corona, CA, 2011. DailyMed
  2. Consortium on Breast Cancer Pharmacogenomics (COBRA): Drug-Interactions with Tamoxifen: a Guide for Breast Cancer Patients and Physicians. Consortium on Breast Cancer Pharmacogenomics (COBRA). Indianapolis, IN. 2008.
  3. Woolpert KM, Cronin-Fenton DP, Damkier P, et al: Drug interactions with tamoxifen and treatment effectiveness in premenopausal breast cancer patients: a Bayesian joint modeling approach. Pharmacoepidemiol Drug Saf 2025; 34(5):e70157-. PubMed
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