Timing Between Benadryl and Atarax Administration
You should wait at least 7-10 days between administering diphenhydramine (Benadryl) and hydroxyzine (Atarax) when discontinuing one before starting the other, based on hydroxyzine's longer elimination half-life and the need to avoid additive anticholinergic and sedative toxicity. 1
Rationale for Extended Washout Period
The 7-10 day washout period for hydroxyzine reflects its prolonged elimination kinetics and the serious risks of combining two first-generation antihistamines with overlapping mechanisms 1:
Hydroxyzine requires 7-10 days for complete elimination before oral food challenge testing, indicating this is the minimum time needed to clear the drug from the system and avoid interference with subsequent antihistamine effects 1
Diphenhydramine requires only 3 days for elimination, demonstrating its shorter half-life, but this does not mean you can safely give hydroxyzine immediately after—you must wait for the first drug to clear 1
The longer elimination time of hydroxyzine (7-10 days) should guide your decision when switching between these medications in either direction 1
Risks of Concurrent or Overlapping Use
Combining diphenhydramine and hydroxyzine creates dangerous additive effects that justify the extended washout period 2:
Severe anticholinergic toxicity including urinary retention, dry mouth, blurred vision, constipation, confusion, and delirium—particularly dangerous in elderly patients 3, 2, 4
Excessive sedation and cognitive impairment that can lead to falls, accidents, and respiratory depression 3, 2, 5
Cardiovascular effects including hypotension and potential cardiac complications, with case reports of cardiac arrest following intravenous diphenhydramine 3, 6
Paradoxical agitation can occur unpredictably, especially in children and adolescents 3
Clinical Context Considerations
If you need continuous antihistamine coverage (switching from one to the other for ongoing treatment):
- Wait the full 7-10 days after stopping hydroxyzine before starting diphenhydramine 1
- Wait 3 days after stopping diphenhydramine before starting hydroxyzine 1
- Consider using a second-generation antihistamine (cetirizine, loratadine, fexofenadine) instead, which have superior safety profiles and lack significant anticholinergic effects 5
If treating acute allergic reactions or anaphylaxis:
- Use only ONE first-generation antihistamine as adjunctive therapy to epinephrine 1
- Diphenhydramine 1-2 mg/kg (maximum 50 mg) every 6 hours for 2-3 days is the standard recommendation 1
- Never use antihistamines as monotherapy for anaphylaxis—epinephrine is first-line 1
High-Risk Populations Requiring Extra Caution
Elderly patients (especially >85 years) face dramatically increased risks 4:
- Higher sensitivity to anticholinergic effects leading to confusion and delirium 4
- Increased fall risk from sedation 4
- Consider avoiding first-generation antihistamines entirely in this population 5
Patients with specific conditions should avoid overlapping use 2:
- Urinary retention or benign prostatic hyperplasia 3, 2
- Narrow-angle glaucoma 2
- Cardiovascular disease 3, 2
- Cognitive impairment or dementia 4
Preferred Alternative Approach
Second-generation antihistamines are safer and should be first-line for most indications 5:
- Cetirizine, loratadine, or fexofenadine have minimal sedation and anticholinergic effects 5
- No washout period needed when switching between second-generation agents 1
- Superior safety profile with proven efficacy for allergic rhinitis and urticaria 5
Critical Pitfall to Avoid
Do not assume you can give these medications close together simply because they are both "just antihistamines"—the combination creates a high-risk scenario for anticholinergic crisis, severe sedation, and cardiovascular complications that can be life-threatening, particularly in vulnerable populations 3, 2, 6, 5.