Diphenhydramine
Diphenhydramine HCl
Also known as: Benadryl · Banophen · Genahist · AllerMax · Diphenhist · Dytan · Siladryl · Tusstat · Nytol · chloranautine · dimenhydrinatum · diphenhydramine teoclate · diphenhydramine theoclate · Diphenhydramine hydrochloride · DPH
Reviewed by the VetSheet Veterinary TeamUpdated Apr 5, 2026Evidence-based veterinary reference
Audited v13 dosing evidence
Structured calculator evidencePrevaccination (extra-label)
Verified clinician required
- once · vaccination
NA
Governing clinical context (1)
- ■ This medicine can be given either with or without food, but if an animal vomits or drools after receiving the medication on an empty stomach, try giving it with food. If vomiting continues, contact your veterinarian.
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Overview
Diphenhydramine is a first-generation ethanolamine-derivative antihistamine widely used in veterinary medicine.
- Primary Indications: Management of allergic reactions (urticaria, angioedema, atopy), pruritus, and anaphylaxis.
- Secondary Indications: Prevention of motion sickness, mild sedation, and as an antiemetic.
Clinical Pearls:
- Because it readily crosses the blood-brain barrier, it causes more pronounced CNS depression (sedation) compared to second-generation antihistamines (e.g., cetirizine, loratadine).
- In cats, histamine is not considered a primary mediator of emesis. Therefore, NK-1 antagonists (like maropitant) or M1-cholinergic antagonists are generally preferred over diphenhydramine for treating feline motion sickness or vomiting.
- It is sometimes used as an adjunctive treatment for aseptic laminitis in cattle and feline pancreatitis.
Mechanism of action
Diphenhydramine exerts its effects through multiple pathways:
- H1-Receptor Antagonism: Competitively binds to and blocks H1 receptors on effector cells → prevents histamine-mediated capillary permeability, vasodilation, and smooth muscle spasms (bronchoconstriction).
- Central Effects: Readily crosses the blood-brain barrier → blocks central H1 receptors → produces sedation and antiemetic effects.
- Anticholinergic Activity: Non-selectively binds to muscarinic receptors → decreases exocrine secretions (drying effect) and can cause urinary retention or tachycardia.
- Additional Effects: Possesses mild antitussive properties.
Safety & warnings
Contraindications
- Hypersensitivity to diphenhydramine or other antihistamines in its class
- Angle closure glaucoma
- Pyloroduodenal or bladder neck obstruction
- COPD (if mucosal secretions are a problem)
- Hyperthyroidism (use with caution)
- Cardiovascular disease or hypertension (use with caution)
- Seizure disorders (use with caution)
- Known hypersensitivity to diphenhydramine
- Glaucoma (due to anticholinergic effects)
- Prostatic hypertrophy or urinary retention
- Gastrointestinal obstruction
- Use with caution in working dogs due to sedation
Adverse effects
- CNS depression (lethargy, somnolence)
- Anticholinergic effects (dry mouth, urinary retention)
- GI effects (diarrhea, vomiting, anorexia)
- Paradoxical excitement (especially in cats)
- Sedation/lethargy
- Dry mouth (xerostomia)
- Tachycardia
- Gastrointestinal disturbances (diarrhea, vomiting, anorexia)
Precautions
Important Warning: May mask clinical signs of ototoxicity. The sedative effects of antihistamines may adversely affect the performance of working dogs. Use with caution in pregnant or nursing animals, particularly in neonates, as the drug is excreted in milk. Liquid formulations are very distasteful to cats and may cause hypersalivation.
Drug interactions
May potentiate anticholinergic effects
Increased sedation can occur
Additive sedation and central nervous system depression
Additive anticholinergic effects (dry mouth, tachycardia, urinary retention)
May prolong and intensify the anticholinergic effects of antihistamines
Additive CNS depression and sedation
Additive anticholinergic effects (tachycardia, dry mouth, ileus)
Increased risk of anticholinergic toxicity and sedation
Monitoring
- Clinical efficacy (reduction in pruritus, allergic signs, or vomiting)
- Adverse effects (excessive sedation, anticholinergic signs)
- Resolution of allergic signs or pruritus
- Degree of sedation
- Heart rate (monitor for tachycardia)
- Urination frequency (monitor for retention)
Pharmacokinetics
Half-life
Absorption
Well absorbed after oral administration, but undergoes a relatively high first-pass effect. In humans, only about 40-60% reaches systemic circulation.
Distribution
Reaches highest levels in the spleen, lungs, and brain. Crosses the placenta and is distributed into milk. Approximately 80% bound to plasma proteins in humans.
Metabolism
Metabolized in the liver.
Elimination
The majority of the drug is excreted as metabolites into the urine.
Overdose
Overdosage can cause CNS stimulation (ranging from excitement to seizures) or CNS depression (lethargy to coma), severe anticholinergic effects, respiratory depression, and death.
Treatment:
- Empty the gut after oral ingestion using standard protocols.
- Induce emesis if the patient is alert and CNS status is stable.
- Administer a saline cathartic and/or activated charcoal after emesis or gastric lavage.
- Provide symptomatic and supportive therapies.
- Seizure management: Phenytoin (IV) is recommended in humans for seizures caused by antihistamine overdose; barbiturates and diazepam should be avoided.
Available products
Formulations
- Capsules
- Chewable tablets
- Orally disintegrating tablets
- Orally disintegrating strips
- Oral liquid/syrup/elixir
- Injection
- Topical shampoo
- Topical spray
- Topical liquid
- 25 mg tablet (Oral)
- 2 mg/ml solution (Oral)
Veterinary
- Topical shampoo
- Topical spray
- Topical liquid
Human-labeled
- Diphenhydramine HCl Capsules and Tablets: 12.5 mg, 25 mg, 50 mg
- Diphenhydramine HCl Orally Disintegrating Tablets: 12.5 mg
- Diphenhydramine Orally Disintegrating Strips: 12.5 mg, 25 mg
- Diphenhydramine HCl Oral Liquid, Solution, Suspension, Elixir or Syrup: 12.5 mg/5 mL, 25 mg/5 mL
- Diphenhydramine Injection: 50 mg/mL
- Benadryl (various strengths)
- Nytol (various strengths)
Regulatory status
Often used under the cascade system.
Classified as a 'P' (Pharmacy) medicine in the UK, meaning it can be purchased from a pharmacy under the supervision of a pharmacist.
No regulatory data for: 🇺🇸 US · 🇭🇰 HK · 🇹🇼 TW · 🇯🇵 JP · 🇰🇷 KR · 🇦🇺 AU
Storage & stability
Store at room temperature (15-30°C). Solutions should be protected from freezing. Tablets and oral solutions should be kept in well-closed containers. Capsules and elixir should be stored in tight containers. Protect from light.
Client information
Important: Do not use human combination cold or allergy products (which may contain toxic ingredients like xylitol, decongestants, or pain relievers) without consulting your veterinarian.
- What to expect: The most common side effect is sleepiness or lethargy. However, some pets (especially cats) may experience paradoxical excitement and become hyperactive or agitated.
- Administration: The liquid form tastes very bitter to cats; they may drool excessively if given the liquid. Tablets or capsules hidden in a treat are usually preferred.
- Side Effects: May cause dry mouth (you might notice your pet smacking their lips or drinking more water) and occasionally vomiting or diarrhea.
- Testing: If your pet is scheduled for allergy skin testing, this medication usually needs to be stopped several days in advance. Ask your veterinarian for specific instructions.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturer’s current label.