Diphenhydramine (Benadryl)

Emergency & Prehospital

• Anaphylaxis, adjunct only: it treats the hives and itch after IM epinephrine. The FDA label calls it an adjunct to epinephrine and other standard measures, once acute symptoms are controlled
• Acute allergic reactions without anaphylaxis: urticaria and pruritus. Use it when oral therapy is impractical
• Acute dystonic reaction: torticollis, oculogyric crisis, jaw or tongue spasm or laryngeal dystonia, usually shows up within 96 hr of starting or raising a dopamine blocker such as haloperidol, metoclopramide or prochlorperazine (off-label; not a listed indication on current injection labels)

ED / ICU / Transport

• Allergic reactions to blood or plasma: urticarial transfusion reactions (FDA-labeled)
• Infusion-reaction premedication: some chemotherapy and monoclonal-antibody protocols; also given with metoclopramide or prochlorperazine to prevent dystonia (off-label)

Other Uses

• Motion sickness: prevention and treatment by mouth (OTC monograph). The injection is labeled only for active treatment, and only when oral therapy is impractical
• Parkinsonism: FDA-labeled but rarely used
• Insomnia: don't use it as a sleep aid. The Beers Criteria say to avoid it in older adults

These are the E3 house doses. Where the label differs, the table says so.

Available Forms

• Injection: 50 mg/mL in 1 mL (50 mg) vial, for IV or deep IM use only. It's the form EMS and emergency departments stock
• Oral: 25 mg and 50 mg tablets and capsules; 12.5 mg chewable tablets; 12.5 mg/5 mL liquid

Adult Dosing

Pediatric Dosing

Pediatric doses come from three sources, in this order. AHA/AAP 2025 comes first, where it states a dose. The NASEMSO National Model EMS Clinical Guidelines v3.0 (2022) come next, then the US label. If none of them gives a dose, the table shows none. A pediatric maximum never goes above the adult maximum (NASEMSO Universal Care Guideline, p. 13). Unless a dose is marked labeled, treat it as off-label.

Check the dose against the child's weight with weight-based dosing. At 50 mg/mL, 1 mg/kg is 0.02 mL/kg. A 20 kg child needs 20 mg, or 0.4 mL.

Preparation & Administration

• Push rate: IV, no faster than 25 mg/min. A 50 mg dose takes at least 2 min.
• IM: deep IM into a large muscle.
• Never subcut or intradermal: tissue necrosis has been reported. The label contraindicates it as a local anesthetic.
• Dilution: none required by the label; follow institutional practice.
• Light: keep vials in the carton until use.

Older adults, renal and hepatic impairment: see Special Populations.

Contraindications

• Neonates and premature infants
• Breastfeeding (labeled contraindication; see Special Populations)
• Use as a local anesthetic (tissue necrosis)
• Hypersensitivity to diphenhydramine or structurally similar antihistamines

Precautions

• Narrow-angle glaucoma or raised intraocular pressure
• Prostatic hypertrophy, bladder-neck or pyloroduodenal obstruction, stenosing peptic ulcer: retention and obstruction worsen.
• Asthma and lower respiratory disease: thickens bronchial secretions.
• Cardiovascular disease, hypertension, hyperthyroidism: atropine-like tachycardia.
• Older adults (about 60 years and older): more dizziness, sedation, hypotension, delirium and falls.
• Young children: they get excited instead of sleepy. In overdose, expect hallucinations, seizures and death.

Hold / Reassess If

• Stridor, wheeze, hypotension or poor perfusion. That is anaphylaxis. Give IM epinephrine, not more diphenhydramine
• New confusion, agitation or hallucinations: stop further doses
• Blood pressure falls after an IV dose: slow or stop the push, give fluids
• Unable to void or bladder distended: bladder scan, catheter
• Hard to rouse or breathing slows: support the airway, hold other sedatives

Common

• Sedation and sleepiness (most frequent)
• Dizziness and disturbed coordination
• Epigastric distress
• Thickened bronchial secretions
• Antimuscarinic effects: dry mouth, nose and throat; blurred vision; urinary retention; constipation
• Hypotension, palpitations, tachycardia
• Paradoxical excitation: restlessness, nervousness, insomnia, mostly in young children

Serious / Life-Threatening

Overdose & Toxicity Management

• Referral thresholds (poison centers): ingestion of at least 7.5 mg/kg in a child under 6 years, or at least 7.5 mg/kg or 300 mg (whichever is less) at 6 years and older, or any intentional ingestion or suspected abuse or neglect. Whatever the dose, refer any patient with more than mild drowsiness or mild stimulation (agitation, hallucinations, abnormal movements, seizures, decreased consciousness, respiratory depression). Consider ambulance transport. No symptoms more than 4 hr after ingestion means no ED referral is needed.
• Picture: anticholinergic delirium plus sodium-channel blockade. Watch for these red flags of severe toxicity: QRS >120 ms, QTc >500 ms, metabolic acidosis with a high anion gap, coma.
• Immediate management: airway, ECG, glucose, temperature. Benzodiazepines for agitation or seizures. Sodium bicarbonate for QRS >100 ms, seizures, ventricular dysrhythmia or non-hypovolemic hypotension; vasopressors for hypotension. Do not use stimulants.
• Co-ingestants: check acetaminophen and salicylate levels in every intentional ingestion. Many OTC "PM" products pair diphenhydramine with acetaminophen or ibuprofen. Early acetaminophen poisoning causes no symptoms.
• Physostigmine: agitated anticholinergic delirium only, with toxicology input and atropine at the bedside: adult 0.5–1 mg slow IV over a full 5 min; may repeat 1 mg after 10–15 min. Stop if heart rate falls below 70 or cholinergic signs appear. Not if QRS >100–120 ms, PR >200 ms or higher-degree AV block, heart rate below 60–80, GI or urinary obstruction, coma with an unprotected airway, a proconvulsant co-ingestant, or suspected tricyclic co-ingestion. Pediatric dose per toxicology.
• Decontamination: no activated charcoal en route; in hospital, consider it once the airway is protected.

Clinically Significant Interactions

IV Compatibility

• The injection label has no diluent or Y-site compatibility data. Don't assume compatibility.
• Flush the line before and after the dose when sharing a line.
• Verify with an institutional compatibility resource.

• Pediatrics: see the Pediatric Dosing table. Young children may get excited instead of sedated. Overdose can bring hallucinations, seizures and death.
• Neonates: contraindicated in neonates and premature infants.
• Pregnancy: It crosses the placenta. Animal studies at up to 5 times the human dose showed no fetal harm. There are no adequate human studies, though. Never delay epinephrine for anaphylaxis in pregnancy. Give diphenhydramine as an adjunct when it's needed.
• Lactation: the injection label lists breastfeeding as a contraindication. Higher or repeated doses can sedate the infant, make it irritable and lower milk supply. For ongoing treatment, prefer a non-sedating antihistamine.
• Older Adults: AGS Beers Criteria 2023 says avoid it. It is strongly anticholinergic, bringing delirium, falls, constipation and urinary retention. For an acute severe allergic reaction, use may be appropriate. Start at the low end of the dose range.
• Renal Impairment: the label makes no adjustment. Some renal-dosing references stretch the dosing interval in moderate to severe impairment. Others change nothing, so follow pharmacy guidance. Use caution in end-stage kidney disease. Urinary retention can cause post-renal acute kidney injury.
• Hepatic Impairment: no labeled adjustment. The liver clears it mainly through CYP2D6 metabolism. Use the lowest effective dose.
• Obesity / Dosing Weight: adult doses stay fixed. Pediatric weight-based doses cap at 50 mg per dose (NASEMSO v3.0 pp. 67 and 90). Never go above the adult maximum.

• Scope: IV/IM diphenhydramine is usually a paramedic, RN and critical-care transport drug (Paramedic/RN/CCT). EMT use, if any, follows local protocol. It varies by state and agency protocol.
• Anaphylaxis Sequence: epinephrine goes IM first, and you repeat it as needed. En route, diphenhydramine is for hives and itch only. Never delay transport or epinephrine to give it.
• Storage & Stability: 20–25 °C (68–77 °F). Excursions to 15–30 °C (59–86 °F) are acceptable. Keep it in the carton, away from light, until use.
• Carried Concentration: 50 mg/mL. One 1 mL vial is 50 mg, the top of the usual adult dose. Draw children's doses in a 1 mL syringe at 0.02 mL/kg.
• Overdose in the Field: no activated charcoal en route. Benzodiazepines for agitation or seizures. Sodium bicarbonate for QRS >100 ms. Both per medical direction. Physostigmine is a hospital drug.
• Handoff Essentials: trigger or offending drug; time, dose and route of each epinephrine and diphenhydramine dose; response; for overdose, product name (e.g., a "PM" combination), amount, time, co-ingestants and latest QRS.

Mechanism of Action

• Peripheral H1 inverse agonist → reverses histamine-driven capillary leak and vasodilation → less urticaria, itch and flushing.
• Central H1 blockade (crosses the blood–brain barrier) → sedation and cough suppression.
• Muscarinic antagonist → restores the dopamine–acetylcholine balance in drug-induced dystonia. It also dries secretions and causes anticholinergic effects.
• Sodium- and potassium-channel blockade → local anesthetic effect. In overdose, it widens the QRS and prolongs the QT.

Pharmacokinetics

• Half-life: about 9 hr in adults and 5.4 hr in children. The reported range is 3–17 hr, and it runs longer with age.
• Metabolism: extensive hepatic first-pass, mainly CYP2D6. Oral bioavailability is about 72%.
• Elimination: urine, about 2% unchanged.
• Distribution: volume of distribution about 17 L/kg. It enters the CNS readily. In overdose, absorption can be delayed, because gut motility slows.

Generic Name

Diphenhydramine hydrochloride

Brand Names

Benadryl (over-the-counter oral and topical); the injection is generic. Also in OTC combination products with pain relievers and decongestants

Pharmacologic Class

First-generation H1 antihistamine (inverse agonist) with antimuscarinic and sodium-channel-blocking activity

Therapeutic Class

Antihistamine; anticholinergic antiparkinson agent (acute dystonia); motion-sickness agent

Controlled Substance

Not controlled

ISMP High-Alert

No

Look-Alike / Sound-Alike

diphenhydrAMINE / dimenhyDRINATE