ACETAMINOPHEN, ASPIRIN, AND CODEINE PHOSPHATE
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
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.
| Metabolism | 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. |
| Excretion | 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). |
| Half-life | 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. |
| Protein binding | Acetaminophen: 10-25% (albumin). Aspirin: 50-80% (albumin), dose-dependent; salicylate: 75-90% (albumin). Codeine: ~7% (albumin). |
| Volume of 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. |
| Bioavailability | Oral: Acetaminophen: 85-95%. Aspirin: 40-60% (due to first-pass hydrolysis to salicylate). Codeine: ~50% due to first-pass metabolism. |
| Onset of Action | Oral: Acetaminophen and aspirin: 30-60 minutes; codeine: 30-60 minutes. Onset for combination analgesia is within 1 hour. |
| Duration of Action | Acetaminophen: 4-6 hours. Aspirin: 4-6 hours. Codeine: 4-6 hours. Combination duration: 4-6 hours. Clinical notes: Duration may be shorter with immediate-release formulations; sustained-release not available for this combination. |
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.
| Dosage form | CAPSULE |
| Renal impairment | GFR 30-59 mL/min: Administer every 6 hours; maximum 6 tablets/day. GFR 15-29 mL/min: Administer every 12 hours; maximum 4 tablets/day. GFR <15 mL/min: Not recommended due to accumulation of codeine metabolites. |
| Liver impairment | 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. |
| Pediatric use | 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. |
| Geriatric use | 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. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
| FDA category | Positive |
| Breastfeeding | 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. |
| Teratogenic Risk |
■ FDA Black Box Warning
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.
| Common Effects | cough |
| Serious Effects |
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).
| Precautions | 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. |
| Food/Dietary |
Loading safety data…
| 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. |
| Fetal Monitoring | Monitor maternal bleeding time, platelet function, renal function, and liver function. Fetal ultrasound for ductus arteriosus and amniotic fluid index in third trimester. Neonatal monitoring for respiratory depression, withdrawal symptoms, and bleeding disorders. |
| Fertility Effects | Acetaminophen: No known negative effects on fertility. Aspirin: High doses may impair fertility by inhibiting prostaglandin synthesis affecting ovulation; low-dose ASA may improve fertility in some conditions (e.g., antiphospholipid syndrome). Codeine: Chronic use may cause menstrual irregularities and decreased libido due to hyperprolactinemia. |
| 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. |
| Clinical Pearls | 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. |
| Patient Advice | 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). |