Can hydroxyzine (Vistaril) and diphenhydramine (Benadryl) be taken together?

Can You Take Hydroxyzine and Benadryl Together?

No, hydroxyzine and diphenhydramine (Benadryl) should not be taken together. Both are first-generation antihistamines with overlapping mechanisms of action and side effect profiles, making their combination both unnecessary and potentially dangerous due to additive central nervous system depression, anticholinergic effects, and increased risk of serious adverse events. 1, 2

Why This Combination Is Problematic

Overlapping Pharmacology Creates Redundancy

• Both hydroxyzine and diphenhydramine are first-generation H1-antihistamines that cross the blood-brain barrier and produce similar effects, making their combination therapeutically redundant. 1
• Combining these medications significantly increases the risk of antihistamine overdose, which can cause excessive sedation, seizures, cardiac arrhythmias, and central nervous system toxicity. 3

Additive Central Nervous System Depression

• The FDA explicitly warns that hydroxyzine potentiates the action of other CNS depressants, and when used concomitantly, their dosage should be reduced. 2
• Hydroxyzine causes sedation in approximately 80% of patients, compared to 50% with diphenhydramine, and combining them dramatically enhances performance impairment even when patients deny subjective drowsiness. 4
• Drivers taking hydroxyzine are 1.5 times more likely to be responsible for fatal automobile accidents, and concomitant use with other sedatives worsens this risk substantially. 4
• Both medications impair cognitive function, learning, work performance, and increase occupational accidents—effects that are compounded when used together. 1, 4

Compounded Anticholinergic Toxicity

• Both hydroxyzine and diphenhydramine have anticholinergic properties that cause dry mouth, constipation, urinary retention, visual disturbances, and confusion—particularly dangerous in elderly patients. 1, 4
• In older adults, the combined anticholinergic burden significantly increases the risk of delirium, falls, fractures, and cognitive impairment. 4
• Hydroxyzine is specifically listed among anticholinergic medications that should be avoided or deprescribed in older adults due to CNS impairment and fall risk. 4

Cardiovascular Risks

• Hydroxyzine carries an FDA black box warning for QT prolongation and Torsade de Pointes, particularly in patients with pre-existing heart disease, electrolyte imbalances, or concomitant use of other arrhythmogenic drugs. 2
• While diphenhydramine also carries cardiac risks, combining these agents may theoretically increase the risk of ventricular dysrhythmias, though hydroxyzine-poisoned patients actually show lower rates of ventricular dysrhythmias than diphenhydramine-poisoned patients in overdose scenarios. 5

What to Do Instead: Evidence-Based Alternatives

For Allergic Rhinitis or Urticaria

• Use a single second-generation antihistamine as first-line therapy (cetirizine, loratadine, fexofenadine, desloratadine, or levocetirizine) taken once daily in the morning. 1, 6
• Second-generation antihistamines have superior safety profiles with minimal sedation, no performance impairment, and proven efficacy. 1, 6
• If symptoms persist after 2-4 weeks, increase the dose of the second-generation antihistamine up to four-fold (e.g., cetirizine up to 40 mg daily) before considering any sedating agent. 7

For Persistent Nighttime Symptoms Only

• If nighttime itching and sleep disturbance persist despite optimized non-sedating antihistamine dosing, you may add either hydroxyzine 10-50 mg at bedtime or diphenhydramine at bedtime—but never both. 4, 7
• Hydroxyzine 50 mg at bedtime is the most commonly recommended regimen when a sedating antihistamine is needed, as it provides sustained effects into the next day due to its long half-life while minimizing daytime sedation. 4
• This approach uses the sedating antihistamine as an adjunct to—not a replacement for—the daytime non-sedating antihistamine. 4, 7

Avoid the AM/PM Split-Dosing Pitfall

• Do not use an AM/PM dosing strategy (non-sedating antihistamine in the morning plus hydroxyzine or diphenhydramine at night) as a cost-saving measure, because hydroxyzine's long half-life causes significant daytime impairment even with bedtime-only dosing. 4
• Performance impairment persists without subjective awareness of drowsiness, and tolerance may not develop. 4

Special Populations Requiring Extra Caution

Elderly Patients

• Older adults are at extremely high risk for adverse effects from first-generation antihistamines, particularly those with prostatic hypertrophy, elevated intraocular pressure, or cognitive impairment. 4
• If a sedating antihistamine is absolutely necessary in an elderly patient, start at the lowest dose (hydroxyzine 10 mg at bedtime) and avoid any combination with other sedating or anticholinergic agents. 4, 2
• Consider alternative anxiolytic options such as SSRIs rather than adding hydroxyzine to existing anticholinergic medications. 4

Patients with Renal or Hepatic Impairment

• In moderate renal impairment (creatinine clearance 10-20 mL/min), reduce the hydroxyzine dose by 50%; in severe renal impairment (creatinine clearance <10 mL/min), avoid hydroxyzine entirely. 7
• Hydroxyzine is absolutely contraindicated in severe hepatic disease due to excessive sedation risk and potential hepatic encephalopathy. 7
• Serum creatinine alone often overestimates renal function in older adults; calculate creatinine clearance using CKD-EPI or Cockcroft-Gault equations before initiating therapy. 4

Pregnancy

• Hydroxyzine is the only antihistamine explicitly contraindicated during the first trimester of pregnancy based on animal data, despite limited human evidence of teratogenicity. 1, 7
• If antihistamine therapy is necessary during pregnancy, chlorpheniramine or second-generation antihistamines (cetirizine, loratadine) are preferred due to their established safety records. 1, 7

Children

• The FDA explicitly recommends against using diphenhydramine (including topical formulations) in children under 6 years due to 33 deaths attributed to diphenhydramine in this age group between 1969-2006. 3
• Second-generation antihistamines like cetirizine are first-line treatment for pediatric allergic reactions and should be used as monotherapy without adding any other antihistamines. 3
• Both diphenhydramine and hydroxyzine cause significant CNS dysfunction in children, including impaired cognitive processing and increased somnolence. 8

Clinical Algorithm for Antihistamine Selection

1. Start with a second-generation antihistamine (cetirizine 10 mg, loratadine 10 mg, or fexofenadine 180 mg) once daily in the morning. 1, 6

2. If inadequate response after 2-4 weeks, increase the second-generation antihistamine dose up to four-fold (e.g., cetirizine 40 mg daily). 7

3. If nighttime symptoms persist despite optimized dosing, add one sedating antihistamine at bedtime (hydroxyzine 10-50 mg preferred over diphenhydramine due to longer duration of action). 4, 7

4. Never combine two first-generation antihistamines (hydroxyzine + diphenhydramine) due to additive toxicity without additional therapeutic benefit. 1, 2

5. Reassess after 1 week of combination therapy; if no improvement, consider alternative diagnoses or refer to an allergist for further evaluation. 1

Common Pitfalls to Avoid

• Never assume that combining antihistamines provides better symptom control—the evidence shows no improvement in overall urticaria control compared with higher-dose non-sedating antihistamines alone. 7
• Never use first-generation antihistamines as first-line monotherapy when second-generation agents are available, as their sedating properties and performance impairment outweigh any benefits. 1, 6
• Never combine multiple antihistamines without explicit direction from a physician, as this significantly increases overdose risk. 3
• Never use antihistamines "to make someone sleepy"—this is explicitly contraindicated per FDA labeling and represents inappropriate prescribing. 3
• Never ignore medication interactions—review the patient's complete medication list for other CNS depressants, QT-prolonging agents, and anticholinergic drugs before initiating hydroxyzine. 4, 2