Comparative Pharmacology
Head-to-head clinical analysis: ALEVE PM versus ALEVE D SINUS COLD.
Peer-Reviewed Evidence
Head-to-head clinical analysis: ALEVE PM versus ALEVE D SINUS COLD.
ALEVE PM vs ALEVE-D SINUS & COLD
Head-to-head clinical comparison of therapeutic indices and safety profiles.
Diphenhydramine is a histamine H1 receptor antagonist that competes with histamine for binding at H1 receptor sites, reducing symptoms of allergic reactions and causing sedation. Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX) enzymes, decreasing synthesis of prostaglandins, which reduces pain and inflammation.
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX-1 and COX-2), reducing prostaglandin synthesis. Pseudoephedrine is a sympathomimetic amine that acts as a decongestant via alpha-adrenergic receptor agonism in the nasal mucosa.
Temporary relief of minor aches and pains (e.g., headache, backache, menstrual cramps, toothache, muscle aches)Temporary relief of pain from arthritisTemporary relief from difficulty falling asleep (insomnia) associated with minor aches and pains
Temporary relief of nasal congestionSinus pressureHeadacheFeverMinor aches and pains associated with the common cold or flu
1 tablet (220 mg naproxen sodium / 25 mg diphenhydramine HCl) orally at bedtime as needed. Maximum: 2 tablets in 24 hours.
Naproxen 220 mg (as naproxen sodium) and pseudoephedrine HCl 120 mg orally every 12 hours; maximum 2 doses per 24 hours.
None Documented
None Documented
Naproxen: 12-17 hours (mean 13.6 hours); sufficient for twice-daily dosing; prolonged in renal impairment. Diphenhydramine: 2.4-9.3 hours (mean 5.5 hours); longer in elderly, hepatic impairment.
Naproxen: 12-17 hours (clinical: twice daily dosing); pseudoephedrine: 4-6 hours (clinical: every 4-6 hours).
Naproxen is extensively metabolized in the liver via CYP1A2 and CYP2C9 enzymes, primarily to 6-desmethylnaproxen. Diphenhydramine is metabolized in the liver via CYP2D6 to diphenylmethoxyacetic acid and other metabolites; undergoes extensive first-pass metabolism.
Naproxen is primarily metabolized by CYP2C9 and to a lesser extent by CYP1A2. Pseudoephedrine is partially metabolized by CYP450 enzymes (likely CYP2D6) and is primarily excreted unchanged in urine.
Naproxen: renal (95% as unchanged drug and metabolites, primarily as naproxen and 6-O-desmethyl naproxen). Diphenhydramine: renal (50-60% as unchanged drug and metabolites, primarily as diphenhydramine and nor diphenhydramine); small amounts in feces.
Renal elimination: naproxen ~95% (mostly as unconjugated naproxen and 6-O-desmethyl naproxen), pseudoephedrine ~70-90% unchanged. Biliary/fecal: minor (<5% for each).
Naproxen: >99% bound to albumin. Diphenhydramine: 80-85% bound to albumin, alpha-1-acid glycoprotein.
Naproxen: >99% bound to albumin; pseudoephedrine: negligible binding (<20%).
Naproxen: 0.16 L/kg (low, indicates limited tissue distribution). Diphenhydramine: 3-5 L/kg (large, extensive tissue binding).
Naproxen: 0.16 L/kg (low, indicates plasma/tissue distribution); pseudoephedrine: 2.6-3.3 L/kg (extensive tissue distribution).
Naproxen: ~95% (oral). Diphenhydramine: 40-60% (oral, first-pass metabolism).
Naproxen: oral ~95%; pseudoephedrine: oral ~100%.
Contraindicated if CrCl <30 mL/min. For CrCl 30-59 mL/min, reduce naproxen dose or avoid use. No specific dose adjustment for diphenhydramine, but use with caution.
GFR 30-59 mL/min: not recommended; GFR <30 mL/min: contraindicated.
Child-Pugh Class A: No adjustment needed. Child-Pugh Class B or C: Avoid use of naproxen. Diphenhydramine: Use with caution and consider dose reduction.
Child-Pugh Class A: no adjustment; Child-Pugh Class B or C: contraindicated due to naproxen component.
Not recommended for children under 12 years. For ages 12-17: Limit to 1 tablet at bedtime, not to exceed 1 tablet in 24 hours. Use under medical supervision.
Not recommended for children under 12 years of age. For ages 12-17: same as adult dose (naproxen 220 mg/pseudoephedrine 120 mg) every 12 hours, maximum 2 doses in 24 hours.
Initiate at the lowest effective dose (1 tablet at bedtime). Monitor for gastrointestinal bleeding, renal function, hypotension, and anticholinergic effects. Avoid in patients with significant renal impairment or dementia.
Avoid use in elderly due to increased risk of gastrointestinal bleeding, renal impairment, and cardiovascular events; use lowest effective dose for shortest duration if necessary, with monitoring.
NSAIDs may increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. Risk may increase with duration of use and in patients with cardiovascular risk factors. NSAIDs are contraindicated for treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.
Naproxen carries a black box warning for increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. Risk increases with duration of use and in patients with cardiovascular risk factors. Also, naproxen is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.
["Cardiovascular risk: increased risk of thrombotic events, MI, stroke, particularly with prolonged use and in patients with risk factors","Gastrointestinal risk: increased risk of GI bleeding, ulceration, and perforation; caution in patients with history of GI disease","Renal toxicity: NSAIDs may cause renal impairment; avoid in patients with advanced renal disease","Hepatic effects: elevated liver enzymes; discontinue if liver disease develops","Sedation: diphenhydramine may cause marked drowsiness; avoid driving or operating machinery","Anticholinergic effects: caution in patients with glaucoma, prostatic hypertrophy, or urinary retention"]
Cardiovascular risk (increased risk of thrombosis, MI, stroke, hypertension exacerbation), gastrointestinal risk (bleeding, ulceration, perforation), renal toxicity, hepatic effects, anaphylactoid reactions, asthma exacerbation, and use in pregnancy (avoid in third trimester).
["Hypersensitivity to naproxen, diphenhydramine, or any component","History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs","Perioperative pain in the setting of CABG surgery","Advanced renal disease","Concurrent use with other NSAIDs or aspirin","Pregnancy (especially third trimester) as it may cause premature closure of ductus arteriosus"]
Hypersensitivity to naproxen, pseudoephedrine, or any component; history of asthma, urticaria, or allergic-type reaction after taking aspirin or other NSAIDs; perioperative pain in CABG surgery; severe hypertension or coronary artery disease; concurrent use of MAO inhibitors or within 14 days of stopping them.
Data Pending Review
Data Pending Review
Avoid alcohol. Taking with food may decrease GI irritation. Avoid grapefruit juice? No known interaction; however, naproxen is metabolized by CYP2C9 and CYP1A2, and grapefruit affects CYP3A4, so interaction unlikely. Still, caution with high-fat meals may delay absorption but not clinically significant.
Avoid high-tyramine foods (aged cheeses, cured meats, fermented products) due to risk of hypertensive crisis with pseudoephedrine. Take naproxen with food or milk to reduce GI upset. Avoid excessive caffeine.
First trimester: NSAID use associated with increased risk of spontaneous abortion and congenital malformations (e.g., cardiac defects). Avoid. Second trimester: Use only if clearly needed; potential for decreased fetal renal function and oligohydramnios. Third trimester: Contraindicated due to risk of premature closure of ductus arteriosus, oligohydramnios, and fetal renal impairment.
First trimester: NSAIDs (naproxen) associated with increased risk of cardiac defects and gastroschisis; pseudoephedrine may be associated with gastroschisis and small intestinal atresia. Second trimester: NSAIDs risk of fetal renal impairment and oligohydramnios; pseudoephedrine may cause fetal tachycardia. Third trimester: NSAIDs risk of premature closure of ductus arteriosus, pulmonary hypertension, oligohydramnios, and fetal/neonatal renal dysfunction; pseudoephedrine may cause neonatal irritability and tachycardia.
Naproxen and diphenhydramine are excreted into breast milk. Naproxen M/P ratio ~0.01; low oral bioavailability to infant. Diphenhydramine M/P ratio ~0.80; may cause drowsiness or fussiness in infant. Use with caution, especially in premature or high-risk infants.
Naproxen is excreted into breast milk in low amounts (M/P ratio 0.01-0.1); pseudoephedrine is excreted into breast milk (M/P ratio 2.5-3.5) and may cause irritability in nursing infants. Use is generally not recommended due to potential adverse effects on infant cardiovascular and renal function.
No specific dose adjustments recommended; however, use lowest effective dose for shortest duration. Avoid in third trimester due to fetal risks. Pharmacokinetic changes in pregnancy (increased Vd, clearance) may necessitate higher doses but are not routinely recommended.
No specific dosing adjustments are recommended due to pregnancy, but use of this combination is contraindicated in third trimester due to NSAID risks. Avoid use in pregnancy unless clearly needed; use lowest effective dose for shortest duration.
Category C
Category C
ALEVE PM contains naproxen (NSAID) and diphenhydramine (antihistamine/sedative). Avoid concurrent use of other NSAIDs, anticoagulants, or CNS depressants. Use with caution in elderly, renal impairment, or history of GI bleeding. Max naproxen dose 440 mg/day; diphenhydramine may cause anticholinergic effects.
Aleve-D Sinus & Cold contains naproxen 220 mg (NSAID) and pseudoephedrine 120 mg (sympathomimetic). Avoid in patients with uncontrolled hypertension, CAD, or MAOI use within 14 days. Naproxen increases bleeding risk; caution with anticoagulants. Pseudoephedrine can cause urinary retention in BPH. Limit caffeine intake to reduce additive CNS stimulation.
Take with food or milk to reduce stomach upset.Do not exceed 2 tablets in 24 hours.Do not use with other NSAIDs or pain relievers.May cause drowsiness; avoid driving or operating machinery.Avoid alcohol while taking this medication.Do not use for more than 10 days for pain or 3 days for fever.Stop and consult doctor if allergic reaction, chest pain, or bleeding occurs.
Do not take with other products containing NSAIDs or pseudoephedrine.Avoid alcohol to reduce risk of GI bleeding.Use with caution if you have high blood pressure, heart disease, or glaucoma.Do not use for more than 7 days for cold symptoms.Discontinue and seek medical attention if symptoms worsen or new symptoms occur.