DIPHENHYDRAMINE HYDROCHLORIDE
Clinical safety rating: safe
CNS depressants may enhance sedative effects May cause marked drowsiness and impair mental and physical abilities.
Competitive antagonist of histamine H1 receptors, reducing allergic symptoms; also exerts anticholinergic, sedative, and antiemetic effects via central and peripheral receptor blockade.
| Metabolism | Primarily hepatic via CYP2D6; also via CYP1A2, CYP2C9, and CYP3A4. |
| Excretion | Renal elimination of metabolites accounts for ~60% of the dose; <5% excreted unchanged. Fecal excretion ~40% via bile. |
| Half-life | Terminal elimination half-life 4–10 hours (mean ~7 hours); prolonged in elderly, hepatic impairment, and with CYP2D6 poor metabolizers. |
| Protein binding | 78–85%, primarily to albumin. |
| Volume of Distribution | 3–7 L/kg; indicates extensive tissue distribution, including CNS. |
| Bioavailability | Oral: 40–60% (first-pass metabolism); IM: ~100%; IV: 100%. |
| Onset of Action | Oral: 15–30 minutes; IM: 10–20 minutes; IV: 5–10 minutes. Topical: 20–30 minutes. |
| Duration of Action | 4–6 hours for antihistaminic effect; up to 12 hours for sedation. Duration shorter with rapid tolerance to sedation. |
| Molecular Weight | 291.8 |
| Action Class | First-generation antihistamine (H1 receptor antagonist) |
25-50 mg orally or intramuscularly every 4-6 hours as needed; maximum 300 mg per day.
| Dosage form | CAPSULE |
| Renal impairment | eGFR 10-50 mL/min: administer every 6-8 hours; eGFR <10 mL/min: administer every 8-12 hours. |
| Liver impairment | Child-Pugh Class A and B: no adjustment; Child-Pugh Class C: use with caution, reduce dose by 50%. |
| Pediatric use | 1 mg/kg orally or intramuscularly every 4-6 hours as needed; maximum 300 mg per day. |
| Geriatric use | Initiate at 25 mg orally or intramuscularly every 8 hours as needed; maximum 100 mg per day due to increased risk of confusion, sedation, and anticholinergic effects. |
| 1st trimester | Limited human data; animal studies show increased risk of cleft palate and embryonic mortality at high doses. Use only if potential benefit outweighs risk. |
| 2nd trimester | Avoid due to possible association with preterm labor and low birth weight when used near term. |
| 3rd trimester | Avoid during third trimester; may cause uterine irritability, premature contractions, and neonatal respiratory depression or withdrawal symptoms. |
Clinical note
CNS depressants may enhance sedative effects May cause marked drowsiness and impair mental and physical abilities.
| FDA category | Animal |
| Placental transfer | Diphenhydramine crosses the placenta readily, with cord blood concentrations approximately equal to maternal serum levels. Fetal exposure is significant. |
■ FDA Black Box Warning
None.
| Common Effects | insomnia |
| Serious Effects | Sedation and drowsiness (impairing cognitive and motor function), Anticholinergic effects: dry mouth, urinary retention, blurred vision, constipation, Paradoxical CNS stimulation (especially in children): restlessness, insomnia, irritability, QT prolongation and risk of torsades de pointes (especially with overdose or in patients with risk factors), Hypotension, palpitations, tachycardia, Seizures (with overdose or in susceptible patients), Acute dystonic reactions (rare), Anaphylaxis (rare) |
Hypersensitivity to diphenhydramine or any component of the formulationNeonates and premature infants (due to risk of paradoxical CNS excitation and apnea)Acute asthma attack (due to anticholinergic drying of secretions)Monoamine oxidase inhibitor (MAOI) therapy (concurrent or within 14 days, due to risk of hypertensive crisis)Narrow-angle glaucoma (due to anticholinergic exacerbation)Symptomatic prostatic hyperplasia (due to risk of urinary retention)Obstructive bladder neck disordersStenosing peptic ulcerPyloroduodenal obstruction
| Precautions |
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| Breastfeeding |
| Diphenhydramine is excreted into breast milk in small amounts (estimated infant dose <1% maternal weight-adjusted dose). However, due to its anticholinergic and sedative effects, it may cause drowsiness, irritability, or paradoxical excitation in nursing infants. Use with caution and monitor infant for adverse effects. The American Academy of Pediatrics considers it compatible with breastfeeding, but lowest effective dose for shortest duration is recommended. |
| Lactation Rating | L2 (Safer) |
| Teratogenic Risk | FDA Pregnancy Category B. Animal studies show no fetal harm; no adequate human studies in first trimester. In third trimester, use near term may cause neonatal withdrawal symptoms (jitteriness, irritability) or respiratory depression. No established teratogenicity in first or second trimester. |
| Fetal Monitoring | Monitor maternal blood pressure and heart rate; fetal heart rate if used intravenously in labor. Assess neonatal respiratory status and neurobehavior if used near term. |
| Fertility Effects | No known adverse effects on human fertility. In animal studies, no impairment of fertility at clinically relevant doses. |
| Avoid use in infants and neonates due to risk of paradoxical excitation and apnea., Caution in elderly due to increased risk of confusion, falls, and anticholinergic effects., May cause significant drowsiness; avoid driving or operating machinery., Avoid concurrent use with alcohol or other CNS depressants., Use with caution in patients with asthma, COPD, or urinary retention. |
| Food/Dietary | Avoid alcohol, which increases sedation. No significant food interactions. |
| Clinical Pearls | First-generation antihistamine; anticholinergic effects cause sedation and dry mouth; paradoxical excitation in children; contraindicated in acute asthma attacks; use with caution in BPH, urinary retention, glaucoma, and elderly due to fall risk; IV formulation can cause local irritation and phlebitis; avoid in breastfeeding due to reduced milk supply. |
| Patient Advice | Take exactly as prescribed; do not exceed recommended dose. · May cause drowsiness; avoid driving or operating machinery until you know how it affects you. · Avoid alcohol and other CNS depressants. · Do not use with other diphenhydramine-containing products (e.g., Tylenol PM, Advil PM). · Notify your doctor if you have glaucoma, enlarged prostate, or difficulty urinating. · Store at room temperature away from moisture and heat. |