Is it safe to administer hydroxyzine (antihistamine) 50 mg and Benadryl (diphenhydramine) 50 mg concurrently to an adult patient with no known medical history or allergies?

Concurrent Administration of Hydroxyzine 50 mg and Diphenhydramine 50 mg

No, you should not give hydroxyzine 50 mg and diphenhydramine (Benadryl) 50 mg together—both are first-generation antihistamines with overlapping mechanisms and additive CNS depressant effects, creating unnecessary risk of severe sedation, anticholinergic toxicity, and performance impairment without additional therapeutic benefit. 1, 2

Why This Combination Is Problematic

Redundant Mechanism of Action

• Both hydroxyzine and diphenhydramine are first-generation H1-antihistamines that work through the same receptor mechanism 1
• Combining them provides no additional antihistamine effect beyond what a single agent at an appropriate dose would achieve, as the H1 receptor becomes saturated 1
• The FDA label for hydroxyzine explicitly warns that "THE POTENTIATING ACTION OF HYDROXYZINE MUST BE CONSIDERED WHEN THE DRUG IS USED IN CONJUNCTION WITH CENTRAL NERVOUS SYSTEM DEPRESSANTS" and mandates dose reduction when combining CNS depressants 2

Additive CNS Depression and Safety Risks

• Hydroxyzine causes sedation in 80% of patients, while diphenhydramine causes sedation in 50% of patients 1
• When first-generation antihistamines are combined, their CNS depressant effects are additive, significantly increasing the risk of severe drowsiness, cognitive impairment, and dangerous performance degradation 1, 2
• Studies demonstrate that hydroxyzine 25 mg twice daily significantly prolongs both simple and choice reaction times (p ≤ 0.0001), with no development of tolerance over 5 days 3
• Patients may experience performance impairment without subjective awareness of drowsiness, making this combination particularly dangerous for activities requiring alertness 1

Anticholinergic Toxicity Risk

• Both medications have significant anticholinergic properties that can cause dry mouth, constipation, urinary retention, and increased risk of narrow-angle glaucoma 1
• Older adults are at particularly high risk for anticholinergic side effects, including cognitive impairment and confusion 1
• The FDA label specifically warns that "sedating drugs may cause confusion and over sedation in the elderly" 2

Cardiac Considerations

• Hydroxyzine carries FDA warnings about QT prolongation and Torsade de Pointes, particularly in patients with risk factors for arrhythmias 2
• While diphenhydramine has less documented cardiac risk, combining two first-generation antihistamines unnecessarily increases the overall risk profile 2

What to Do Instead

For Allergic Conditions

• Use a single first-generation antihistamine at the appropriate dose (hydroxyzine 25 mg four times daily OR diphenhydramine 25-50 mg four times daily), not both 1
• Better option: Switch to a second-generation antihistamine (cetirizine, loratadine, fexofenadine) which have significantly lower sedation rates (1.3-14% vs 50-80%) and no anticholinergic effects 1
• If inadequate response to standard dosing, increase the dose of a single second-generation antihistamine up to fourfold (e.g., cetirizine 40 mg daily) rather than combining first-generation agents 1, 4

For Refractory Urticaria

• Add an H2-antihistamine (ranitidine 50 mg or famotidine 20 mg) to an H1-antihistamine for better control, rather than combining two H1-antihistamines 1, 5
• This combination (H1 + H2) provides superior symptom control compared to H1 alone, with a different mechanism of action 5

For Nighttime Sedation Plus Daytime Coverage

• If sedation is desired at night, use hydroxyzine 10-50 mg at bedtime PLUS a non-sedating second-generation antihistamine during the day (not another first-generation agent) 1
• Bedtime dosing of hydroxyzine 50 mg maintains H1-receptor antagonism the following morning while mitigating daytime reaction time degradation 6
• This strategy provides 24-hour coverage without the dangerous additive CNS depression of combining two first-generation antihistamines 1

Critical Pitfalls to Avoid

• Never combine two first-generation antihistamines concurrently—this violates basic pharmacologic principles and FDA warnings 2
• Do not assume patients are tolerant to sedation—objective performance impairment occurs even when patients deny subjective drowsiness 1, 3
• Avoid first-generation antihistamines entirely in elderly patients, those with prostatic hypertrophy, elevated intraocular pressure, or cognitive impairment 1
• Do not use this combination in patients taking other CNS depressants (alcohol, benzodiazepines, opioids) or medications that prolong QT interval 2