DIPHENHYDRAMINE HYDROCHLORIDE PRESERVATIVE FREE
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; centrally acting anticholinergic agent that inhibits acetylcholine muscarinic receptors.
| Metabolism | Primarily hepatic via CYP2D6, minor via CYP1A2, CYP2C9, and CYP2C19; forms diphenylmethoxyacetic acid and nor-diphenhydramine. |
| Excretion | Primarily renal as inactive metabolites; ~60% of a dose appears in urine as metabolites, with <5% unchanged. Minor biliary/fecal elimination (<10%). |
| Half-life | Terminal elimination half-life: 4-10 hours (mean ~8 hours); prolonged in hepatic impairment or elderly (up to 20 hours). |
| Protein binding | ~78-80% bound to albumin. |
| Volume of Distribution | 3-10 L/kg; large due to extensive tissue distribution, crossing blood-brain barrier. |
| Bioavailability | Oral: 50-70% due to first-pass metabolism; IM: near 100%. |
| Onset of Action | IM: 15-30 minutes; IV: immediate (2-5 minutes); oral: 15-45 minutes. |
| Duration of Action | IM/IV: 4-6 hours; oral: 4-6 hours; suppressed wheal-and-flare response up to 12 hours. |
| Molecular Weight | 291.82 |
| Action Class | First-generation antihistamine (ethanolamine class) |
25 to 50 mg intravenously or intramuscularly every 4 to 6 hours as needed; maximum 400 mg per day.
| Dosage form | INJECTABLE |
| Renal impairment | For GFR 10-50 mL/min: administer 25 mg every 6 hours; for GFR <10 mL/min: administer 25 mg every 12 hours. |
| Liver impairment | Child-Pugh class A: no adjustment; Child-Pugh class B or C: reduce dose by 50% and administer every 12 hours. |
| Pediatric use | 1 to 2 mg/kg intravenously or intramuscularly every 4 to 6 hours as needed; maximum 300 mg per day. |
| Geriatric use | Initiate at 25 mg intravenously or intramuscularly every 6 hours; monitor for anticholinergic effects and cognitive impairment; avoid routine use due to Beers Criteria recommendation. |
| 1st trimester | Diphenhydramine crosses the placenta. Case-control studies have not found an increased risk of major malformations with occasional use, but avoid routine use due to limited data. Use only if clearly needed. |
| 2nd trimester | Similar to T1. Avoid routine use. May be used for acute allergic reactions or severe nausea if benefit outweighs risk. Monitor for maternal anticholinergic effects. |
| 3rd trimester | Avoid use near term as diphenhydramine may cause uterine irritability or neonatal withdrawal symptoms (irritability, tremors) if used chronically. Single doses for labor are not recommended due to potential neonatal respiratory depression. |
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 via passive diffusion. Fetal serum concentrations are about 60-90% of maternal concentrations after intravenous administration. |
■ FDA Black Box Warning
Not recommended for use in children younger than 2 years due to risk of respiratory depression and death.
| Common Effects | insomnia |
| Serious Effects | Respiratory depression (especially in overdose or with CNS depressants), Seizures, Acute dystonic reactions, Cardiac arrhythmias (e.g., QT prolongation, torsades de pointes), Severe hypotension, Anaphylaxis, Acute urinary retention (in patients with prostatic hypertrophy), Angle-closure glaucoma exacerbation |
Hypersensitivity to diphenhydramine or any componentNeonates (especially premature infants) due to risk of paradoxical CNS excitation and anticholinergic toxicityBreastfeeding mothers of premature or sensitive infants (chronic use contraindicated; low-dose occasional use considered compatible per lactation rating)Acute asthma attacks (due to drying of respiratory secretions and anticholinergic effects)Porphyria (may exacerbate symptoms)Concurrent use with monoamine oxidase inhibitors (MAOIs) due to potentiated anticholinergic effects
| Precautions | Avoid in patients with asthma, COPD, glaucoma, prostatic hyperplasia, urinary retention, and elderly patients due to increased risk of anticholinergic effects, sedation, and confusion. |
Loading safety data…
| Breastfeeding | Diphenhydramine is excreted into breast milk in small amounts. The relative infant dose is low (approximately 0.5-1% of maternal weight-adjusted dose). However, due to its anticholinergic properties, it may theoretically reduce milk production, especially with high doses or prolonged use. Occasional single doses are considered compatible; chronic use should be avoided. Monitor infant for drowsiness, irritability, or paradoxical excitation. |
| Lactation Rating | L2 (SafER - limited data suggest low risk) |
| Teratogenic Risk | FDA Pregnancy Category B. First trimester: No evidence of increased risk of major malformations in human studies; however, animal studies are inadequate. Second and third trimesters: Use not associated with teratogenicity; risk of uterine contractions with high doses near term. Avoid in late pregnancy due to potential for oxytocic effects. |
| Fetal Monitoring | Monitor maternal blood pressure, heart rate, and sedation level. Fetal heart rate monitoring recommended if used during labor due to potential uterine hyperstimulation. Assess for anticholinergic effects (dry mouth, urinary retention, blurred vision) in the mother. |
| Fertility Effects | Limited human data. Animal studies suggest no significant effects on fertility. Anticholinergic properties may theoretically affect cervical mucus or sperm motility, but not clinically relevant. |
| Food/Dietary | No specific food interactions. Alcohol must be avoided due to additive CNS depressant effects. |
| Clinical Pearls | Preservative-free formulation indicated for single-dose use to avoid benzyl alcohol toxicity in neonates. Use with caution in elderly due to anticholinergic effects (confusion, urinary retention). Avoid in patients with narrow-angle glaucoma, prostatic hyperplasia, or asthma. Monitor for paradoxical excitation in children. Onset of sedation occurs within 15-30 minutes; duration 4-6 hours. |
| Patient Advice | Avoid alcohol and other CNS depressants (sedatives, tranquilizers) as they increase drowsiness. · Do not drive or operate heavy machinery until you know how this drug affects you. · Take exactly as prescribed; do not exceed recommended dose. · Notify your doctor if you experience difficulty urinating, blurred vision, or rapid heartbeat. · Store at room temperature; discard any unused portion after single use as this product contains no preservatives. |