What is the treatment for an allergy to Benadryl (diphenhydramine)?

Treatment of Allergy to Benadryl (Diphenhydramine)

If a patient has a documented allergy to diphenhydramine, immediately discontinue the drug and substitute with a second-generation antihistamine such as cetirizine, loratadine, desloratadine, or fexofenadine for ongoing allergic symptom management. 1, 2

Acute Management of Diphenhydramine Allergic Reaction

Immediate Actions

• Stop diphenhydramine administration immediately and maintain intravenous access if the drug was given parenterally 3
• Assess airway, breathing, circulation (ABCs) and level of consciousness 3
• Position the patient appropriately: Trendelenburg for hypotension, sitting upright for respiratory distress, or recovery position if unconscious 3

For Anaphylaxis to Diphenhydramine

If the patient meets anaphylaxis criteria (acute onset with skin/mucosal involvement plus respiratory compromise or hypotension):

• Administer epinephrine 0.01 mg/kg intramuscularly (1:1000 dilution, maximum 0.5 mg) into the lateral thigh immediately 3
• Repeat epinephrine every 5-15 minutes as needed 3
• Provide rapid fluid resuscitation with 1-2 liters normal saline at 5-10 mL/kg in first 5 minutes 3
• Do NOT use diphenhydramine or any other H1-antihistamine that cross-reacts 3, 1
• Consider H2-antihistamine (ranitidine 50 mg IV or famotidine) which does not cross-react with diphenhydramine 3
• Administer corticosteroids (methylprednisolone 1-2 mg/kg IV every 6 hours) to prevent biphasic reactions 3

For Mild-to-Moderate Reactions

• Use a second-generation antihistamine (cetirizine, loratadine, fexofenadine) as these have different chemical structures and do not cross-react with diphenhydramine 2, 4
• Monitor closely for 24 hours after severe reactions 3

Long-Term Management and Alternative Antihistamines

Preferred Alternatives

Second-generation antihistamines are the definitive replacement for diphenhydramine due to superior safety profiles, lack of sedation, and no cross-reactivity 2, 4:

• Cetirizine
• Loratadine
• Desloratadine
• Fexofenadine

These agents are widely available, affordable, and provide equivalent or superior efficacy without the sedation, impairment, and cardiac toxicity risks associated with diphenhydramine 2, 4

Critical Pitfalls to Avoid

• Never substitute with other first-generation antihistamines (chlorpheniramine, brompheniramine) as they may have structural similarities and cross-reactivity potential 1, 2
• Never use antihistamines as monotherapy for anaphylaxis—epinephrine is the only first-line treatment and delays increase mortality 5
• Avoid assuming all antihistamines are safe alternatives; document the specific drug allergy and cross-reactivity patterns 1

Documentation Requirements

• Document the specific reaction type (urticaria, anaphylaxis, other), severity grade, timing, and management provided 3
• Clearly label the allergy in the medical record to prevent future diphenhydramine administration 1
• Provide patient education on avoiding over-the-counter products containing diphenhydramine 1