Head-to-head clinical analysis & difference comparison: details on mechanism of action, dosing, half-life, interactions, and maternal-fetal safety.
ADVIL PM vs ACETAMINOPHEN, ASPIRIN, AND CODEINE PHOSPHATE
Clinician-reviewed, head-to-head comparison of mechanism, dosing, pharmacokinetics, and safety profiles.
Last clinically reviewed: July 2026 · OpiCalc Medical Review Team
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis. Diphenhydramine is a first-generation antihistamine that antagonizes histamine H1 receptors, causing sedation.
Acetaminophen: cyclooxygenase (COX) inhibitor, primarily central, analgesic and antipyretic. Aspirin: irreversible COX-1 and COX-2 inhibitor, analgesic, anti-inflammatory, antipyretic, antiplatelet. Codeine: prodrug converted to morphine; mu-opioid receptor agonist.
Temporary relief of occasional sleeplessness associated with minor aches and pains
Mild to moderate pain,Fever (acetaminophen and aspirin),Inflammatory conditions (aspirin)
Two caplets (ibuprofen 200 mg, diphenhydramine citrate 38 mg) orally at bedtime as needed for insomnia. Maximum: 2 caplets in 24 hours.
1-2 tablets (each containing acetaminophen 300 mg, aspirin 300 mg, codeine phosphate 30 mg) orally every 4-6 hours as needed for pain; maximum 8 tablets/day.
Ibuprofen: 2-4 hours (terminal); clinical context: steady state achieved in 1 day, not affected by renal impairment. Diphenhydramine: 4-8 hours (terminal); clinical context: prolonged in hepatic impairment.
Acetaminophen: 2-3 hours (terminal). Aspirin: 15-30 minutes (parent drug); salicylate: 2-3 hours at low doses, 15-30 hours at high doses due to saturable metabolism. Codeine: 2.5-4 hours. Clinical context: Prolonged half-life of salicylate at high doses increases risk of toxicity; hepatic impairment prolongs acetaminophen and codeine half-lives.
Ibuprofen is primarily metabolized via hepatic oxidation by CYP2C9. Diphenhydramine is metabolized via hepatic N-demethylation and oxidation, primarily by CYP2D6.
Acetaminophen: hepatic via CYP2E1, CYP1A2, CYP3A4; glucuronidation and sulfation; NAPQI formation. Aspirin: hepatic hydrolysis to salicylate; conjugation with glycine and glucuronic acid. Codeine: hepatic via CYP2D6 to morphine (active); also via CYP3A4 to norcodeine.
Ibuprofen: Renal (90% as metabolites and conjugates, <10% unchanged); Diphenhydramine: Renal (primarily as metabolites, ~1% unchanged). Fecal excretion is negligible for both.
Acetaminophen: renal excretion of metabolites (glucuronide and sulfate conjugates, ~85-90%), minor parent drug (<5%). Aspirin: renal excretion of salicylate and its metabolites (salicyluric acid, glucuronides, gentisic acid), dose-dependent; at therapeutic doses, ~50-80% as free salicylate and conjugates. Codeine: renal excretion of free and conjugated codeine (about 90%) and metabolites (morphine, norcodeine).
Ibuprofen: >99% bound to albumin; Diphenhydramine: 78-85% bound to albumin.
Acetaminophen: 10-25% (albumin). Aspirin: 50-80% (albumin), dose-dependent; salicylate: 75-90% (albumin). Codeine: ~7% (albumin).
Ibuprofen: 0.1-0.2 L/kg; small Vd consistent with high protein binding. Diphenhydramine: 4.5-8.5 L/kg; large Vd indicating extensive tissue distribution.
Acetaminophen: 0.9-1.0 L/kg (large distribution including liver). Aspirin: 0.15-0.2 L/kg (low Vd, confined to plasma and extracellular fluid); salicylate: 0.2-0.3 L/kg. Codeine: 3-6 L/kg (extensive tissue distribution). Clinical meaning: Large Vd for codeine suggests extensive tissue binding; aspirin Vd is small, consistent with limited extravascular distribution.
Ibuprofen: 80-100% (oral); Diphenhydramine: 50-70% (oral) due to first-pass metabolism.
Oral: Acetaminophen: 85-95%. Aspirin: 40-60% (due to first-pass hydrolysis to salicylate). Codeine: ~50% due to first-pass metabolism.
Avoid use in GFR <30 m L/min. For GFR 30-59 m L/min, limit to single dose and avoid chronic use. No adjustment needed for GFR ≥60 m L/min.
GFR 30-59 m L/min: Administer every 6 hours; maximum 6 tablets/day. GFR 15-29 m L/min: Administer every 12 hours; maximum 4 tablets/day. GFR <15 m L/min: Not recommended due to accumulation of codeine metabolites.
Contraindicated in Child-Pugh Class C. In Child-Pugh Class B, reduce dose by 50% (max 1 caplet) and monitor for toxicity. No adjustment for Child-Pugh Class A.
Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce dose by 50% and extend interval to every 6 hours; maximum 4 tablets/day. Child-Pugh Class C: Contraindicated.
Not recommended for children under 12 years. For age ≥12 years, same adult dose: 2 caplets at bedtime.
Not recommended for children <12 years due to aspirin risk of Reye syndrome. For children ≥12 years: Dose based on codeine component (0.5-1 mg/kg/dose) with maximum acetaminophen 75 mg/kg/day and aspirin 100 mg/kg/day. Typical: 1 tablet (acetaminophen 300 mg/aspirin 300 mg/codeine 30 mg) every 4-6 hours as needed; max 4 tablets/day.
Start with lowest effective dose (1 caplet) at bedtime to minimize anticholinergic and GI adverse effects. Avoid in elderly with cognitive impairment or high fall risk.
Start with lowest effective dose (e.g., 1 tablet every 6 hours); monitor renal and hepatic function; maximum 6 tablets/day due to increased sensitivity and risk of adverse effects.
NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. NSAIDs are contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
Risk of medication errors: confusion between different strengths and concentrations of acetaminophen can result in accidental overdose and fatal hepatotoxicity. Aspirin use in children and teenagers with viral infections is associated with Reye's syndrome.
Cardiovascular thrombotic events,Gastrointestinal bleeding, ulceration, and perforation,Renal toxicity,Sedation and impaired cognitive function,Anticholinergic effects,Avoid use with other NSAIDs or antihistamines,Use caution in elderly, renal impairment, hepatic impairment, and pregnancy
Hepatotoxicity (acetaminophen dose >4 g/day), Reye's syndrome (aspirin in children), respiratory depression (codeine), tolerance/dependence, bleeding risk (aspirin), GI toxicity, renal impairment, hypersensitivity reactions.
Hypersensitivity to ibuprofen, diphenhydramine, or any component of the formulation,History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs,Perioperative pain in the setting of coronary artery bypass graft (CABG) surgery,Neonates and premature infants (due to diphenhydramine),Concurrent use with other diphenhydramine products or sedatives
Hypersensitivity to any component, active peptic ulcer disease, bleeding disorders, severe hepatic impairment, severe respiratory depression, children with viral illness (aspirin), pregnancy (third trimester for aspirin, codeine cautious).
Take with food or milk to reduce GI upset. Avoid alcohol and grapefruit juice. Caffeine may enhance CNS stimulation and should be limited.
Avoid alcohol due to increased risk of acetaminophen hepatotoxicity and aspirin-induced GI bleeding. Avoid large amounts of caffeine or high-tyramine foods (e.g., aged cheeses, cured meats) as they may affect CYP2D6 metabolism of codeine.
Pregnancy Category C/D (after 30 weeks). First trimester: Potential risk of miscarriage and cardiac defects (limited data with NSAIDs). Second trimester: Avoid unless clearly needed; possible oligohydramnios, premature closure of ductus arteriosus, and fetal renal impairment. Third trimester: Contraindicated after 30 weeks due to risk of premature ductus arteriosus closure and persistent pulmonary hypertension.
Acetaminophen: Generally considered low risk; association with ASD and ADHD with prolonged use not fully established. Aspirin: First trimester: possible increased risk of gastroschisis; second trimester: relatively safe; third trimester: risk of premature closure of ductus arteriosus, oligohydramnios, and increased peripartum hemorrhage. Codeine: First trimester: possible neural tube defects; second and third trimesters: risk of respiratory depression, withdrawal in neonate with chronic use; neonatal opioid withdrawal syndrome (NOWS) possible.
Diphenhydramine and ibuprofen are excreted into breast milk. M/P ratio not established. Both drugs are considered compatible with breastfeeding in low doses, but theoretical risk of infant sedation (diphenhydramine) and gastrointestinal effects (ibuprofen). Max daily dose for mother should not exceed recommended limits. Monitor infant for drowsiness and poor feeding.
Acetaminophen: M/P ratio approximately 0.91-1.42; considered safe. Aspirin: M/P ratio 0.08-0.15; high doses may cause Reye's syndrome; avoid or use low doses. Codeine: M/P ratio about 2.5; variable metabolism; risk of CNS depression in infant; avoid due to potential for toxicity in CYP2D6 ultrarapid metabolizers.
No specific dose adjustment recommended for ibuprofen or diphenhydramine in pregnancy. However, due to altered pharmacokinetics (increased volume of distribution, renal clearance), standard doses may be less effective. Avoid use if possible, especially after 30 weeks. Use lowest effective dose for shortest duration.
Acetaminophen: No dose adjustment needed. Aspirin: Avoid in third trimester; use lowest effective dose if necessary. Codeine: Avoid in pregnancy; if used, lowest effective dose for shortest duration; caution for CYP2D6 polymorphism. Pharmacokinetic changes: Increased clearance of codeine during pregnancy may require higher doses but risk outweighs benefit.
Advil PM combines ibuprofen (NSAID) and diphenhydramine (antihistamine). Avoid concomitant use with other NSAIDs or CNS depressants (including alcohol). Use lowest effective dose for shortest duration. Contraindicated in severe hepatic/renal impairment, active GI bleeding, or during third trimester of pregnancy. May cause morning drowsiness due to antihistamine.
Combination analgesic with acetaminophen (hepatotoxic at high doses), aspirin (antiplatelet, GI irritant, contraindicated in children <12 due to Reye's syndrome), and codeine (prodrug to morphine via CYP2D6; efficacy depends on CYP2D6 phenotype; risk of CNS/respiratory depression). Avoid in severe hepatic/renal impairment, active peptic ulcer, bleeding disorders, or concomitant use of other CNS depressants. Maximum acetaminophen dose from all sources: 4 g/day.
Take only one tablet before bedtime; do not exceed recommended dose.,Avoid alcohol and other sedatives while using this medication.,Do not use for more than 10 days for pain or 3 days for fever unless directed by a doctor.,May cause drowsiness; avoid driving or operating machinery until you know how the drug affects you.,Not for use in children under 12 years of age or during pregnancy/breastfeeding without consulting a healthcare provider.,Report signs of stomach bleeding (e.g., black/tarry stools, vomiting blood) or allergic reactions (e.g., facial swelling, difficulty breathing).
Do not exceed recommended dose; acetaminophen overdosage can cause serious liver damage.,Do not take with other products containing acetaminophen or aspirin.,Avoid alcohol while taking this medication to reduce risk of liver toxicity and GI bleeding.,This product contains aspirin; do not give to children/teenagers with chickenpox or flu-like symptoms to avoid Reye's syndrome.,May cause drowsiness; do not drive or operate machinery until you know how you react.,Codeine is a narcotic pain reliever with abuse potential; use exactly as prescribed.,Seek medical attention if you experience signs of allergic reaction (rash, difficulty breathing) or bleeding (black/tarry stools, unusual bruising).
No interactions on record
"Pirenzepine, a selective M1 muscarinic antagonist, reduces gastrointestinal motility and secretions, while codeine, an opioid agonist, also decreases gastrointestinal motility via mu-opioid receptors. Concurrent use leads to additive anticholinergic and opioid effects, resulting in enhanced risk of severe constipation, paralytic ileus, and central nervous system depression. Clinically, patients may experience exacerbated sedation, respiratory depression, and urinary retention."
"Ropinirole, a non-ergoline dopamine agonist used in Parkinson's disease and restless legs syndrome, may reduce the analgesic efficacy of codeine. This is likely due to pharmacodynamic antagonism at central dopamine and opioid receptors, as well as potential pharmacokinetic interactions that decrease the conversion of codeine to its active metabolite morphine via CYP2D6 inhibition by ropinirole. The resultant blunted opioid response can lead to inadequate pain control, necessitating dose adjustment or alternative therapy."
"Vemurafenib induces CYP3A4, significantly reducing the plasma concentrations of codeine, which is metabolized via CYP3A4 to its active metabolite morphine. This may diminish codeine's analgesic efficacy, potentially leading to inadequate pain control. Additionally, reduced formation of morphine may lower the risk of opioid-related adverse effects."
Explore head-to-head clinical comparisons of other medications in the same therapeutic classes.
Common clinical questions about ADVIL PM vs ACETAMINOPHEN, ASPIRIN, AND CODEINE PHOSPHATE, answered by our medical review team.
ADVIL PM is a NSAID/Sedative Combination that works by Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis. Diphenhydramine is a first-generation antihistamine that antagonizes histamine H1 receptors, causing sedation.. ACETAMINOPHEN, ASPIRIN, AND CODEINE PHOSPHATE is a Opioid Agonist that works by Acetaminophen: cyclooxygenase (COX) inhibitor, primarily central, analgesic and antipyretic. Aspirin: irreversible COX-1 and COX-2 inhibitor, analgesic, anti-inflammatory, antipyretic, antiplatelet. Codeine: prodrug converted to morphine; mu-opioid receptor agonist.. They differ in pharmacokinetic profiles, FDA-approved indications, and side effect profiles.
Potency comparisons between ADVIL PM and ACETAMINOPHEN, ASPIRIN, AND CODEINE PHOSPHATE depend on the specific clinical indication. These are agents from distinct pharmacological classes and are not directly interchangeable by dose. A physician or clinical pharmacist should guide any therapeutic switching decisions.
The standard adult dose of ADVIL PM is: Two caplets (ibuprofen 200 mg, diphenhydramine citrate 38 mg) orally at bedtime as needed for insomnia. Maximum: 2 caplets in 24 hours.. The standard adult dose of ACETAMINOPHEN, ASPIRIN, AND CODEINE PHOSPHATE is: 1-2 tablets (each containing acetaminophen 300 mg, aspirin 300 mg, codeine phosphate 30 mg) orally every 4-6 hours as needed for pain; maximum 8 tablets/day.. Dosing should always be individualized based on indication, renal and hepatic function, age, and other patient factors.
No direct drug-drug interaction has been formally documented between ADVIL PM and ACETAMINOPHEN, ASPIRIN, AND CODEINE PHOSPHATE in current clinical databases. However, individual patient risk factors including other medications, organ function, and comorbidities should always be evaluated by a qualified healthcare provider.
The maternal-fetal safety profiles differ. ADVIL PM is classified as Category C. Pregnancy Category C/D (after 30 weeks). First trimester: Potential risk of miscarriage and cardiac defects (limited data with NSAIDs). Second trimester: Avoid unless clearly neede. ACETAMINOPHEN, ASPIRIN, AND CODEINE PHOSPHATE is classified as Category D/X. Acetaminophen: Generally considered low risk; association with ASD and ADHD with prolonged use not fully established. Aspirin: First trimester: possible increased risk of gastrosch. Always consult a maternal-fetal medicine specialist before taking either drug during pregnancy or lactation.