IBUPROFEN AND DIPHENHYDRAMINE HYDROCHLORIDE
Clinical safety rating: avoid
ACE inhibitors and ARBs may have diminished antihypertensive effect Increases risk of serious cardiovascular thrombotic events and GI bleeding.
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX-1 and COX-2) enzymes, reducing prostaglandin synthesis. Diphenhydramine is an antihistamine that antagonizes histamine H1 receptors.
| Metabolism | Ibuprofen is primarily metabolized by CYP2C9. Diphenhydramine undergoes extensive first-pass metabolism via CYP2D6. |
| Excretion | Ibuprofen: Renal (90% as glucuronide conjugates, <10% unchanged). Diphenhydramine: Renal (primarily as metabolites, <10% unchanged). Both undergo hepatic metabolism with renal excretion of metabolites. |
| Half-life | Ibuprofen: 2-4 hours (immediate-release). Diphenhydramine: 8-12 hours (prolonged in hepatic impairment). |
| Protein binding | Ibuprofen: >99% bound to albumin; Diphenhydramine: 78-85% bound to plasma proteins. |
| Volume of Distribution | Ibuprofen: 0.1-0.2 L/kg (confined to plasma and interstitial fluid). Diphenhydramine: 3-8 L/kg (extensive tissue distribution). |
| Bioavailability | Ibuprofen: 80-100% (oral immediate-release). Diphenhydramine: 50-75% (oral, first-pass metabolism). |
| Onset of Action | Oral: Ibuprofen 30-60 min; Diphenhydramine 30-60 min. Onset may be slower with food. |
| Duration of Action | Ibuprofen: 4-6 hours; Diphenhydramine: 4-6 hours (up to 12 hours for sedation). |
1-2 tablets (200 mg ibuprofen/25 mg diphenhydramine HCl each) orally every 4-6 hours as needed; maximum 6 tablets in 24 hours.
| Dosage form | CAPSULE |
| Renal impairment | GFR 30-89 mL/min: No adjustment needed. GFR 15-29 mL/min: Avoid use due to diphenhydramine accumulation and ibuprofen nephrotoxicity. GFR <15 mL/min: Contraindicated. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Use with caution; reduce dose by 50% or avoid due to increased diphenhydramine sedation. Child-Pugh C: Contraindicated. |
| Pediatric use | Age ≥12 years: Same as adult dose (1-2 tablets). Age 6-11 years: Not recommended. Age <6 years: Contraindicated. |
| Geriatric use | Reduce dose to 1 tablet every 6-8 hours; maximum 3 tablets in 24 hours due to increased risk of anticholinergic effects, sedation, and renal impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
ACE inhibitors and ARBs may have diminished antihypertensive effect Increases risk of serious cardiovascular thrombotic events and GI bleeding.
| FDA category | Positive |
| Breastfeeding | Ibuprofen is excreted into breast milk in very low concentrations (M/P ratio ~0.01) and is considered compatible with breastfeeding. Diphenhydramine is excreted into breast milk (M/P ratio ~0.5-1.0) and may cause irritability, drowsiness, or respiratory depression in the infant, especially with high maternal doses. Caution is advised; use lowest effective dose for shortest duration. |
| Teratogenic Risk |
■ FDA Black Box Warning
NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. Risk may increase with duration of use. NSAIDs are contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
| Common Effects | fever |
| Serious Effects |
["Known hypersensitivity to ibuprofen, diphenhydramine, or any component of the formulation","History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs","Active peptic ulcer disease","History of gastrointestinal bleeding or perforation","Severe renal impairment","Advanced hepatic impairment","In setting of CABG surgery"]
| Precautions | ["Risk of serious cardiovascular events","Risk of serious gastrointestinal bleeding, ulceration, and perforation","Avoid use in patients with known hypersensitivity to NSAIDs or diphenhydramine","May cause drowsiness and impair mental alertness","Not for use in children under 12 years of age"] |
Loading safety data…
| First trimester: Ibuprofen is associated with an increased risk of spontaneous abortion and congenital malformations (cardiac defects, gastroschisis) in some studies. Diphenhydramine is generally considered low risk, but some data suggest a possible increased risk of cleft palate. Second trimester: Ibuprofen is relatively low risk for major malformations; diphenhydramine is low risk. Third trimester: Ibuprofen is contraindicated due to risk of premature closure of the ductus arteriosus, oligohydramnios, and neonatal renal impairment; diphenhydramine may cause neonatal respiratory depression and withdrawal symptoms if used near term. |
| Fetal Monitoring | Monitor for oligohydramnios (via ultrasound) and ductus arteriosus constriction (via fetal echocardiography) if ibuprofen is used in third trimester. Monitor neonatal respiratory status and sedation if diphenhydramine is used near delivery. In all trimesters, assess maternal renal function and bleeding risk. |
| Fertility Effects | Ibuprofen may reversibly impair female fertility by interfering with ovulation (prostaglandin synthesis inhibition); effect resolves upon discontinuation. Diphenhydramine has no known direct effect on fertility. |