Clinical safety rating: caution
Animal studies have demonstrated safety
Inverse agonist at histamine H1 receptors, blocking histamine-mediated effects in blood vessels, respiratory smooth muscle, and GI tract; also anticholinergic by blocking muscarinic receptors and sedative via central H1 receptor antagonism.
| Metabolism | Primarily hepatic via CYP2D6, with minor contributions from CYP1A2, CYP2C9, and CYP2C19; undergoes N-demethylation and N-oxidation; first-pass metabolism is extensive. |
| Excretion | Primarily renal (90-95% as metabolites, <5% unchanged). Minor biliary/fecal elimination (<5%). |
| Half-life | Terminal elimination half-life 4-8 hours in adults; prolonged in hepatic impairment (up to 20 hours) and elderly. |
| Protein binding | 98-99% bound, primarily to albumin. |
| Volume of Distribution | Vd 3-5 L/kg (wide distribution, high tissue binding). |
| Bioavailability | Oral: 50-70% (first-pass metabolism). IM: 100% (assumed). IV: 100%. |
| Onset of Action | Oral: 15-30 min; IM: 20-30 min; IV: immediate to 5 min; Topical: 20-30 min. |
| Duration of Action | Oral/IM: 4-6 hours; IV: 3-5 hours; Topical: 2-4 hours. Duration may be shorter with chronic use due to tolerance. |
| Molecular Weight | 255.36 |
| Action Class | First-generation antihistamine (H1-receptor antagonist) |
25-50 mg orally or intramuscularly every 4-6 hours; maximum 300 mg/day. Intravenous administration: 10-50 mg slow IV push (max 25 mg/min).
| Renal impairment | No specific dose adjustment for GFR. Use with caution in severe renal impairment (CrCl <10 mL/min) due to potential accumulation; consider reducing dose or extending interval. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: use with caution, consider 25% of usual dose or avoid. |
| Pediatric use | Children 2-5 years: 6.25 mg orally every 4-6 hours (max 37.5 mg/day). Children 6-11 years: 12.5-25 mg orally every 4-6 hours (max 150 mg/day). Children ≥12 years: 25-50 mg orally every 4-6 hours (max 300 mg/day). |
| Geriatric use | Elderly patients (>65 years): initially 25 mg orally at bedtime, increase if needed; maximum 50 mg/day. Avoid as first-line antihistamine due to anticholinergic adverse effects (confusion, falls). |
| 1st trimester | Avoid use in first trimester due to potential teratogenic effects; limited human studies suggest possible increased risk of cleft palate. |
| 2nd trimester | Use with caution; no evidence of major teratogenicity, but may cause uterine contractions at high doses. |
| 3rd trimester | Avoid near term due to risk of neonatal respiratory depression, irritability, and withdrawal symptoms. |
Clinical note
First-generation sedating antihistamine used for allergic conditions, sleep, and NVP. More sedating than second-generation agents. No established teratogenicity in humans but limited near-term use recommended. When used very close to delivery, associated with neonatal CNS depression, jitteriness, and respiratory issues. Prefer second-generation antihistamines (cetirizine, loratadine) for routine use.
| Placental transfer | Diphenhydramine crosses the placenta readily; fetal concentrations may reach similar levels to maternal serum. |
| Breastfeeding |
■ FDA Black Box Warning
Not recommended for use in neonates or premature infants due to potential association with sudden infant death syndrome (SIDS) and paradoxical CNS excitation.
| Common Effects | Drowsiness, Dizziness, Dry mouth, Blurred vision, Urinary retention, Constipation, Thickened bronchial secretions |
| Serious Effects | Respiratory depression (especially in overdose or with CNS depressants), Seizures, Cardiac arrhythmias (QT prolongation, torsades de pointes), Severe hypotension, Acute dystonic reactions, Anticholinergic toxicity (delirium, hyperthermia, ileus) |
Hypersensitivity to diphenhydramine or other antihistaminesPremature neonates and newbornsBreastfeeding in preterm infantsAcute asthma attackUse with MAOIs (within 14 days)Narrow-angle glaucomaUrinary retention (e.g., prostatic hypertrophy)Steroid-dependent patients (risk of kernicterus in neonates)
| Precautions | Causes significant sedation, impairing ability to drive or operate machinery; anticholinergic effects may exacerbate narrow-angle glaucoma, urinary retention, hyperthyroidism, hypertension, and prostatic hypertrophy; avoid concurrent use with alcohol or other CNS depressants. |
Loading safety data…
| Diphenhydramine is excreted into breast milk in low amounts. However, due to its anticholinergic and sedative effects, it may cause drowsiness, irritability, or paradoxical excitation in breastfed infants. Avoid use in breastfeeding mothers, especially in preterm or neonates. If necessary, use lowest effective dose. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: No increased risk of major congenital anomalies based on large cohort studies, though a weak association with oral clefts has been reported (RR ~1.3-1.5). Second trimester: No known risk. Third trimester: Near term, high doses may cause oxytocin-like effects; once-daily antihistamine effect with minimal fetal risk. Avoid use during late third trimester due to potential for uterine hyperstimulation. |
| Fetal Monitoring | No specific mandatory monitoring. Clinical monitoring for maternal sedation, hypotension, and paradoxical CNS stimulation. Fetal heart rate monitoring may be considered if used intravenously during labor due to risk of uterine hyperstimulation and fetal distress. |
| Fertility Effects | Animal studies show no impairment of fertility at clinically relevant doses. Human data limited; no adverse effects on fertility reported. Anticholinergic effects may theoretically impact cervical mucus, but no clinical evidence of reduced fertility. |
| Food/Dietary | No significant food interactions. Grapefruit juice may theoretically inhibit CYP2D6 metabolism, but clinical relevance is minimal. Avoid alcohol due to additive CNS depression. |
| Clinical Pearls | Diphenhydramine is a first-generation antihistamine with strong anticholinergic effects; avoid in elderly due to increased risk of confusion, falls, and urinary retention. Rapid IV administration can cause hypotension and arrhythmias; give slow IV push. Use with caution in patients with glaucoma, prostate hypertrophy, or asthma. Onset of sedation within 30-60 minutes; useful for acute dystonias (e.g., from antipsychotics) at 25-50 mg IM/IV. Not recommended for children <2 years due to risk of respiratory depression. |
| Patient Advice | Do not drive or operate heavy machinery until you know how this drug affects you, as it causes drowsiness. · Avoid alcohol and other CNS depressants (e.g., benzodiazepines, opioids) as they increase sedation and fall risk. · Dry mouth, blurred vision, and constipation are common; drink water and use sugar-free gum for dry mouth. · If you have difficulty urinating or eye pain, stop the medication and seek medical help. · Do not exceed recommended dose; overdose can cause seizures, hallucinations, or serious heart problems. · Take with food if stomach upset occurs, but avoid grapefruit juice as it may affect drug metabolism. |