DIPHEN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DIPHEN (DIPHEN).
Diphenhydramine is a first-generation antihistamine that competitively antagonizes histamine at H1 receptors. It also exhibits anticholinergic, sedative, antiemetic, and local anesthetic effects.
| Metabolism | Primarily metabolized by CYP2D6 to diphenylmethoxyacetic acid and other metabolites. Undergoes first-pass metabolism. Metabolites are excreted in urine. |
| Excretion | Primarily hepatic metabolism; renal excretion of inactive metabolites accounts for ~70% of eliminated drug; biliary/fecal excretion accounts for ~30%. |
| Half-life | Terminal elimination half-life is 22–72 hours (mean 30–40 hours); increases with hepatic disease or enzyme inhibitors. |
| Protein binding | 85–90%, primarily to albumin. |
| Volume of Distribution | 0.5–1.0 L/kg; distributes into CSF and brain. |
| Bioavailability | Oral: 70–80% (tablets/capsules). |
| Onset of Action | Oral: 30–60 minutes; intravenous: <5 minutes. |
| Duration of Action | Oral: 6–8 hours; intravenous: 4–6 hours. Titrated based on seizure control. |
| Molecular Weight | 255.36 |
50 mg IV/IM every 4 hours as needed for nausea/vomiting; 25-50 mg PO every 4-6 hours as needed for nausea/vomiting or motion sickness; 25 mg PO 3-4 times daily for vertigo; 15.6-25 mg IM/IV for antiemetic in surgery; maximum 300 mg/day.
| Dosage form | SYRUP |
| Renal impairment | CrCl <10 mL/min: dose reduction to 50% of usual dose recommended; monitor for CNS effects. |
| Liver impairment | Child-Pugh Class C: avoid use; Class A or B: dose reduction to 50% of usual dose; monitor for sedation. |
| Pediatric use | Children >2 years: 5 mg/kg/day PO/IM/IV in 3-4 divided doses, maximum 15 mg/kg/day; <2 years: not recommended due to risk of respiratory depression. |
| Geriatric use | Elderly: initiate at 25 mg PO once daily or 12.5 mg IM/IV; increase cautiously; avoid prolonged use due to anticholinergic effects and sedation. |
| 1st trimester | Avoid; associated with cardiovascular defects and oral clefts. Use only if benefit outweighs risk. |
| 2nd trimester | Avoid; risk of fetal hydantoin syndrome including growth retardation, dysmorphic features, and cognitive impairment. |
| 3rd trimester | Avoid; risk of neonatal hemorrhage, withdrawal, and sedation. Consider vitamin K supplementation if used. |
Clinical note
Comprehensive clinical and safety monograph for DIPHEN (DIPHEN).
| Placental transfer | Crosses placenta readily; cord blood levels approximate maternal levels. Associated with neonatal withdrawal and adverse effects. |
| Breastfeeding | Diphenhydramine is excreted into breast milk in small amounts. In infants, potential for sedation, irritability, and paradoxical excitement. Use with caution, especially in premature neonates or those with apnea risk. Monitor infant for drowsiness. |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to diphenhydramine or any componentNeonates (especially premature) due to risk of apneaBreastfeeding infants at risk of apneaConcurrent use with MAO inhibitors
| Precautions | Anticholinergic effects (e.g., confusion, urinary retention, blurred vision) especially in elderly, Sedation and impairment of cognitive/motor function, Risk of falls in elderly, Extrapyramidal symptoms with high doses, Respiratory depression in young children or with overdose, Interference with skin tests for allergies |
| Food/Dietary | Grapefruit and grapefruit juice may increase diphenhydramine blood levels by inhibiting hepatic metabolism (CYP2D6). Avoid concurrent use of alcohol or sedatives as they potentiate CNS depression. High-fat meals may delay absorption; take on an empty stomach for faster onset when needed for acute symptoms. |
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| Lactation Rating | L3 - 'Moderately Safe'. Use only if clearly needed. |
| Teratogenic Risk | Fetal risk cannot be ruled out. First trimester: Limited human data; animal studies show no teratogenicity. Second/Third trimester: Potential for fetal respiratory depression and hypotonia if used near term. |
| Fetal Monitoring | Monitor maternal vital signs, respiratory rate, and sedation level. In term pregnancy, assess neonatal respiratory status at delivery. |
| Fertility Effects | No known effect on fertility; limited evidence suggests potential for menstrual irregularities at high doses. |
| Clinical Pearls | Diphenhydramine is a first-generation antihistamine with strong anticholinergic properties; use with caution in elderly due to risk of confusion, falls, and urinary retention. It is effective for acute allergic reactions but not first-line for chronic urticaria. Avoid in patients with narrow-angle glaucoma, prostatic hyperplasia, or asthma. QT prolongation risk exists at high doses. Onset of sedation is rapid (15-30 min) making it useful for insomnia but not for daily use due to tolerance and anticholinergic burden. Intravenous administration can cause hypotension and extravasation injury. May interfere with allergy skin testing; discontinue 48-72 hours prior. |
| Patient Advice | May cause drowsiness; do not drive or operate machinery until you know how you respond. · Avoid alcohol and other CNS depressants while taking this medication. · Take exactly as prescribed; do not exceed recommended dose to reduce risk of side effects. · Report symptoms of confusion, blurred vision, difficulty urinating, or rapid heartbeat to your healthcare provider. · Store at room temperature away from moisture and heat. |