What are the dosing guidelines for injectable antihistamines, such as diphenhydramine (Benadryl) and promethazine (Phenergan), in acute, severe allergic reactions?

Injectable Antihistamines in Acute Severe Allergic Reactions

Injectable antihistamines are second-line adjunctive therapy to epinephrine in anaphylaxis, with diphenhydramine dosed at 1-2 mg/kg (maximum 50 mg) parenterally, and promethazine at 12.5-25 mg (maximum 25 mg) for adults, though promethazine carries significant tissue injury risks and should be avoided when diphenhydramine is available. 1, 2, 3

Critical Context: Antihistamines Are NOT First-Line Treatment

• H1 antihistamines are considered second-line therapy to epinephrine and should never be administered alone in the treatment of anaphylaxis. 1
• Antihistamines only relieve itching and urticaria—they do not relieve stridor, shortness of breath, wheezing, gastrointestinal symptoms, or shock. 1
• Epinephrine must always be administered first in anaphylaxis, as it is the only medication that addresses the life-threatening cardiovascular and respiratory manifestations. 1

Diphenhydramine (Benadryl) Dosing

Pediatric Dosing

• 1-2 mg/kg per dose, maximum 50 mg administered IV or IM 1
• FDA labeling specifies: 5 mg/kg/24 hours or 150 mg/m²/24 hours, divided into four doses, with maximum daily dosage of 300 mg 3
• When administered IV, rate should generally not exceed 25 mg/min 3

Adult Dosing

• 25-50 mg per dose administered parenterally (IV or IM) 1
• FDA labeling allows 10-50 mg IV at a rate not exceeding 25 mg/min, or deep IM, with 100 mg if required; maximum daily dosage is 400 mg 3

Route Considerations

• Deep intramuscular injection is preferred over IV administration to minimize risk of rapid infusion-related adverse effects 3
• Oral liquid formulations are more readily absorbed than tablets when oral route is appropriate 1

Promethazine (Phenergan) Dosing and Safety Concerns

Adult Dosing for Allergic Reactions

• 25 mg per dose for allergic reactions to blood or plasma 1
• For nausea/vomiting: 12.5-25 mg, not repeated more frequently than every 4 hours 2

Critical Safety Warnings

• Promethazine carries severe tissue injury risks including gangrene with improper administration 2
• Under no circumstances should promethazine be given intra-arterially due to likelihood of severe arteriospasm and possible gangrene 2
• Subcutaneous injection is contraindicated as it may result in tissue necrosis 2
• When given IV, concentration should not exceed 25 mg/mL and rate should not exceed 25 mg/minute 2
• Promethazine is contraindicated in pediatric patients less than 2 years of age 2

Pediatric Considerations (≥2 years)

• Dosage should not exceed half the suggested adult dose 2
• As premedication adjunct: 1.1 mg/kg body weight in combination with appropriately reduced narcotic/barbiturate doses 2

Combination H1/H2 Antihistamine Therapy

The combination of diphenhydramine (H1) and ranitidine (H2) is superior to diphenhydramine alone in managing anaphylaxis. 1

Ranitidine (H2 Blocker) Dosing

• Adults: 50 mg 1
• Pediatrics: 1-2 mg/kg per dose (12.5-50 mg range), maximum 75-150 mg 1
• Dilute in 5% dextrose to total volume of 20 mL and inject IV over 5 minutes 1

Alternative H2 Blocker

• Cimetidine 4 mg/kg can be administered IV to adults, but no pediatric dosage in anaphylaxis has been established 1

Common Pitfalls to Avoid

Timing and Sequence Errors

• Never delay or substitute antihistamines for epinephrine—antihistamines have a much slower onset of action than epinephrine 1
• Do not wait to see if antihistamines work before giving epinephrine in true anaphylaxis 1

Administration Route Mistakes

• Avoid rapid IV push of diphenhydramine, which can cause hypotension and sedation 3
• Never give promethazine intra-arterially or subcutaneously 2
• If patient complains of pain during IV promethazine injection, stop immediately to evaluate for arterial injection or extravasation 2

Dosing Errors

• Do not exceed maximum single doses: diphenhydramine 50 mg in children, promethazine 25 mg 1, 2, 3
• Remember that sedation from first-generation antihistamines may mask progression of anaphylaxis symptoms 1

Alternative Considerations

• Second-generation antihistamines (cetirizine, fexofenadine) may be considered as alternatives with less sedation, though they have slower onset than diphenhydramine 1
• Cetirizine has the fastest onset among newer antihistamines but still causes more sedation than fexofenadine 4
• The marginal speed advantage of diphenhydramine over fexofenadine may not justify the sedation risk in all clinical scenarios 5, 4