CODEINE, ASPIRIN, APAP FORMULA NO. 2
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.
Codeine is a prodrug that is metabolized to morphine, which acts as an agonist at mu-opioid receptors in the central nervous system, producing analgesia. Aspirin irreversibly inhibits cyclooxygenase-1 and -2, reducing prostaglandin synthesis and providing analgesic, anti-inflammatory, and antipyretic effects. Acetaminophen (APAP) inhibits cyclooxygenase centrally, with weak peripheral activity, producing analgesia and antipyresis.
| Metabolism | Codeine is metabolized primarily by CYP2D6 to morphine (active) and by CYP3A4 to norcodeine. Aspirin is hydrolyzed to salicylic acid, which is further metabolized by conjugation and oxidation. Acetaminophen is metabolized primarily by glucuronidation and sulfation; a minor pathway via CYP2E1 produces N-acetyl-p-benzoquinone imine (NAPQI), a toxic metabolite. |
| Excretion | Codeine: Renal 90% (10% unchanged, 80% as conjugates). Aspirin: Renal 80-100% (dose-dependent, as salicylate and metabolites). Acetaminophen (APAP): Predominantly renal (90-100% as conjugates, <5% unchanged). |
| Half-life | Codeine: 2.5-4 hours. Aspirin (as salicylate): 2-3 hours (low dose), up to 15-30 hours (high dose due to saturable metabolism). Acetaminophen: 2-3 hours (therapeutic doses), prolonged in overdose or hepatic impairment. |
| Protein binding | Codeine: ~7-25% (primarily albumin). Aspirin (salicylate): 80-90% (albumin), concentration-dependent. Acetaminophen: 10-25% (albumin), minimal at therapeutic levels. |
| Volume of Distribution | Codeine: 3-6 L/kg. Aspirin (salicylate): 0.15-0.2 L/kg (low dose), higher at toxic levels. Acetaminophen: 0.9-1.2 L/kg. |
| Bioavailability | Oral: Codeine ~90% (extensive first-pass, variable due to CYP2D6). Aspirin ~40-50% (hydrolyzed in gut and liver). Acetaminophen ~85-95% (rapidly absorbed). |
| Onset of Action | Oral: Codeine 30-60 min; Aspirin 30 min; Acetaminophen 30-60 min. Peak analgesic effects: 1-2 hours for all. |
| Duration of Action | Analgesia: 4-6 hours for all components. Antipyretic effect of aspirin and acetaminophen: 4-6 hours. Antiplatelet effect of aspirin: irreversible, lasting 7-10 days. |
| Molecular Weight | Codeine: 299.36 Da; Aspirin: 180.16 Da; Acetaminophen: 151.16 Da |
1 to 2 tablets orally every 4 to 6 hours as needed for pain; maximum 12 tablets per day. Each tablet contains codeine 30 mg, aspirin 325 mg, and acetaminophen 325 mg.
| Dosage form | CAPSULE |
| Renal impairment | GFR 30-50 mL/min: avoid codeine; consider alternative therapy. GFR <30 mL/min: avoid aspirin and codeine; use acetaminophen alone with dose adjustment (maximum 2 g/day). |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce codeine dose by 50% and avoid aspirin; monitor acetaminophen (maximum 2 g/day). Child-Pugh C: contraindicated due to risk of hepatotoxicity and encephalopathy. |
| Pediatric use | Not recommended for children <12 years due to risk of respiratory depression; for children ≥12 years: 1 tablet orally every 4-6 hours as needed; maximum 6 tablets per day. Weight-based: codeine 0.5-1 mg/kg/dose every 4-6 hours; aspirin 10-15 mg/kg/dose every 4-6 hours; acetaminophen 10-15 mg/kg/dose every 4-6 hours; avoid in patients with viral illness due to Reye syndrome risk. |
| Geriatric use | Start at lower end of dosing (1 tablet every 6 hours); maximum 6 tablets per day. Caution with renal impairment and increased sensitivity to codeine; avoid in patients with GFR <30 mL/min. |
| 1st trimester | Avoid. Aspirin and codeine are associated with increased risk of congenital malformations, particularly cardiac defects and gastroschisis with aspirin; codeine may cause respiratory depression and dependence. APAP is considered safe at low doses but combination products are discouraged. |
| 2nd trimester | Avoid. Aspirin may cause premature closure of ductus arteriosus and oligohydramnios; codeine may cause fetal dependence and respiratory depression. APAP is safer alone. |
| 3rd trimester | Contraindicated. Aspirin at high doses increases risk of intracranial hemorrhage in neonate and premature closure of ductus arteriosus; codeine may cause neonatal respiratory depression and withdrawal. APAP is preferred if needed. |
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 |
| Placental transfer |
■ FDA Black Box Warning
WARNING: RISK OF MEDICATION ERRORS, ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 2D6 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE; RISK OF SERIOUS GASTROINTESTINAL ADVERSE EVENTS WITH ASPIRIN; RISK OF SEVERE LIVER INJURY WITH ACETAMINOPHEN.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to any componentSevere hepatic impairmentAsthma, nasal polyps, or urticaria with aspirin or NSAIDsActive peptic ulcer disease or GI bleedingSevere renal impairmentThird trimester of pregnancyChildren with viral infection (Reye's syndrome risk with aspirin)Concurrent use of MAOIs or within 14 daysBreastfeeding while infant has G6PD deficiency (aspirin risk)CYP2D6 ultra-rapid metabolizer (codeine risk)
| Precautions | Risk of opioid addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; interaction with CYP2D6 inhibitors; risks with concomitant use of CNS depressants; ultra-rapid metabolism of codeine (CYP2D6 poor or ultra-rapid metabolizers); aspirin increases risk of GI bleeding; Reye's syndrome with aspirin in children; acetaminophen hepatotoxicity; avoid exceeding 4 g/day acetaminophen; renal impairment; pregnancy and breastfeeding. |
Loading safety data…
| All components cross placenta. Aspirin: extensive transfer (protein-bound, active transport). Codeine: crosses freely, reaches fetal levels similar to maternal. APAP: readily crosses placenta via passive diffusion. |
| Breastfeeding | Use with caution. Codeine is excreted into breast milk and may cause infant sedation, respiratory depression, or dependence, especially in CYP2D6 ultra-rapid metabolizers. Aspirin and APAP are excreted in low amounts; aspirin may cause Reye's syndrome risk if infant has viral illness. Avoid combination if possible; lowest effective dose for shortest duration if necessary. |
| Lactation Rating | L3 (Moderately Safe) - Caution advised |
| Teratogenic Risk | First trimester: Codeine is associated with a slightly increased risk of congenital malformations, particularly cardiac defects, based on observational studies. Aspirin (high dose) is associated with increased risk of neural tube defects and gastroschisis; low-dose aspirin is generally not linked to major malformations. APAP (acetaminophen) is generally considered low risk, though some studies suggest a possible association with neurodevelopmental outcomes. Second trimester: Aspirin (high dose) may impair fetal renal function and lead to oligohydramnios; codeine may cause fetal dependence; APAP is generally safe. Third trimester: Aspirin (high dose) increases risk of premature closure of ductus arteriosus, pulmonary hypertension, and intracranial hemorrhage in the neonate; codeine use may lead to neonatal opioid withdrawal syndrome; APAP is generally safe but high doses may be associated with necrotizing enterocolitis. |
| Fetal Monitoring | Monitor maternal liver function (aspartate aminotransferase, alanine aminotransferase) and renal function (serum creatinine, blood urea nitrogen) due to APAP and aspirin components. Assess fetal growth and amniotic fluid volume with ultrasound, especially with chronic aspirin use. Monitor for signs of neonatal opioid withdrawal (e.g., tremors, irritability, poor feeding) if codeine used near term. Also monitor for maternal and fetal bleeding (coagulation parameters, platelet count) due to aspirin. |
| Fertility Effects | Codeine: No established effect on human fertility. Aspirin: High doses may inhibit ovulation by affecting prostaglandin synthesis; low doses are not known to impair fertility. APAP: No significant effect on fertility. Overall, combination use is unlikely to cause clinically significant fertility impairment. |
| Food/Dietary | Avoid alcohol; increases risk of hepatotoxicity (APAP) and GI bleeding (aspirin). Take with food or milk to minimize GI irritation. Avoid grapefruit juice? Not significant for this combination. No specific dietary restrictions beyond avoiding alcohol. |
| Clinical Pearls | Codeine is a prodrug requiring CYP2D6 conversion to morphine; poor metabolizers may have reduced efficacy, while ultra-rapid metabolizers risk toxicity. Aspirin is contraindicated in children with viral illness due to Reye's syndrome risk. APAP hepatotoxicity risk increases with alcohol use or pre-existing liver disease. Maximum APAP dose: 4 g/day from all sources. Codeine and APAP combination limits titration flexibility; monitor for opioid-induced constipation and respiratory depression. |
| Patient Advice | Take with food or milk to reduce stomach upset from aspirin. · Do not exceed recommended dose; APAP overdose can cause severe liver damage. · Avoid alcohol while taking this medication; increases risk of liver damage and stomach bleeding. · Do not take with other products containing acetaminophen (APAP). · Stop use and seek medical attention if allergic reaction (rash, swelling, trouble breathing) or signs of bleeding (black stools, vomiting blood) occur. · Avoid driving or operating heavy machinery until you know how this medication affects you. · Inform your doctor if you have asthma, liver disease, kidney disease, or history of stomach ulcers. · Do not use in children younger than 12 years without doctor approval. · This medication may be habit-forming; use only as prescribed. |