ACETAMINOPHEN 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: centrally acting analgesic and antipyretic, possibly via inhibition of cyclooxygenase (COX) and modulation of cannabinoid receptors. Codeine: prodrug converted to morphine; mu-opioid receptor agonist.
| Metabolism | Acetaminophen: primarily glucuronidation and sulfation in liver; minor CYP450 (CYP2E1) to toxic NAPQI. Codeine: CYP2D6 to morphine; CYP3A4 to norcodeine; glucuronidation. |
| Excretion | Acetaminophen: renal elimination of conjugated metabolites (glucuronide 60%, sulfate 30%, cysteine/mercapturate <5%), less than 5% unchanged. Codeine: renal elimination of codeine (5–15%), morphine (5–10%), norcodeine (10–20%), and conjugates; 90% excreted in urine within 24 hours. |
| Half-life | Acetaminophen: 2–3 hours (prolonged in hepatic impairment). Codeine: 2.5–3.5 hours; metabolites: morphine 1.5–2.5 hours, codeine-6-glucuronide 3–4 hours. Clinical context: dosing interval every 4–6 hours. |
| Protein binding | Acetaminophen: 10–25% (albumin). Codeine: 7–25% (primarily albumin). |
| Volume of Distribution | Acetaminophen: 0.9 L/kg. Codeine: 3–6 L/kg (extensive tissue distribution). |
| Bioavailability | Oral: acetaminophen 88% (variable first-pass); codeine 50–60% (first-pass metabolism to morphine, norcodeine, and conjugates). |
| Onset of Action | Oral: acetaminophen 30–60 minutes; codeine 30–60 minutes. |
| Duration of Action | Acetaminophen: 4–6 hours. Codeine: 4–6 hours. Clinical note: analgesic effect limited by codeine metabolism; peak effect at 1–2 hours. |
| Molecular Weight | 151.16 (acetaminophen) and 299.36 (codeine phosphate); combined product variable. |
One or two tablets (acetaminophen 300 mg/codeine 30 mg per tablet) orally every 4-6 hours as needed for pain; maximum 12 tablets daily.
| Dosage form | TABLET |
| Renal impairment | GFR 30-50 mL/min: administer every 6 hours; GFR 10-29 mL/min: administer every 8 hours; GFR <10 mL/min: administer every 12 hours; hemodialysis: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50% and extend interval to every 8 hours; Child-Pugh C: contraindicated. |
| Pediatric use | For children ≥12 years: acetaminophen 10-15 mg/kg/dose and codeine 0.5-1 mg/kg/dose orally every 4-6 hours; maximum acetaminophen 75 mg/kg/day, codeine 6 mg/kg/day. For children <12 years: not recommended due to codeine safety concerns. |
| Geriatric use | Start with lowest effective dose; acetaminophen component maximum 3 g/day; consider reduced codeine dose (e.g., 15 mg) due to increased sensitivity and risk of respiratory depression; extend dosing interval to every 6-8 hours. |
| 1st trimester | Use only if clearly needed; no teratogenicity in animal studies but risk of neural tube defects with codeine at high doses. Consider alternative analgesia. |
| 2nd trimester | Use with caution; no known teratogenicity but potential for fetal respiratory depression with high maternal doses. |
| 3rd trimester | Avoid use near term due to risk of neonatal respiratory depression and opioid withdrawal syndrome. Prolonged use may cause neonatal opioid withdrawal. |
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 | Both acetaminophen and codeine cross the placenta. Codeine is metabolized to morphine which readily crosses. Acetaminophen crosses but considered relatively safe in standard doses. |
■ FDA Black Box Warning
Risk of medication errors: confusion between milligram and milliliter doses, and between codeine and acetaminophen components. Contraindicated for postoperative pain management in children following tonsillectomy/adenoidectomy due to risk of respiratory depression and death.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to acetaminophen, codeine, or any componentAcute or severe bronchial asthmaHypercapniaRespiratory depression, especially in the presence of cyanosis and/or excessive bronchial secretionsParalytic ileusConcurrent use of MAOIs or within 14 days of such therapyPremature infants or neonates (especially in settings without resuscitation equipment)Breastfeeding in women known to be CYP2D6 ultra-rapid metabolizers
| Precautions | Hepatotoxicity (acetaminophen overdose); respiratory depression; drug dependence; ultra-rapid metabolizers of codeine (CYP2D6) leading to morphine toxicity; concomitant CNS depressants; use in pediatric patients; avoid alcohol. |
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| Breastfeeding | Codeine is excreted into breast milk; in some cases (CYP2D6 ultra-rapid metabolizers) can cause morphine overdose in infants. Risk of apnea and sedation. Use lowest effective dose for shortest duration. Monitor infant for drowsiness, feeding difficulties. Generally not recommended if maternal CYP2D6 status unknown. |
| Lactation Rating | L3 (Moderately Safe) - use with caution; avoid in mothers who are ultra-rapid metabolizers of codeine. |
| Teratogenic Risk | Acetaminophen is considered low risk in all trimesters at therapeutic doses; chronic high doses may be associated with adverse outcomes. Codeine is associated with risk of respiratory depression and neonatal withdrawal if used near term; may cause neural tube defects and other malformations with first-trimester exposure, but data are conflicting. Use lowest effective dose for shortest duration. |
| Fetal Monitoring | Monitor maternal liver function with prolonged acetaminophen use; monitor respiratory status and signs of sedation in both mother and fetus/neonate. For codeine, assess umbilical cord or neonatal blood for opioid levels if toxicity suspected. Perform fetal ultrasound if first-trimester exposure to codeine. |
| Fertility Effects | Acetaminophen at therapeutic doses has no known significant effect on fertility. Codeine may cause hormonal disturbances with chronic use, potentially affecting ovulation or spermatogenesis, but data are limited. Both should be used only when necessary in patients attempting conception. |
| Food/Dietary | Avoid alcohol; high-fat meals may delay absorption but not clinically significant. |
| Clinical Pearls | For acute pain, limit codeine to 3 days; avoid in children under 12 due to CYP2D6 ultra-rapid metabolizer risk of fatal respiratory depression; monitor for constipation; assess liver function for acetaminophen hepatotoxicity; use with caution in renal impairment. |
| Patient Advice | Take exactly as prescribed; do not exceed 4000 mg acetaminophen per day. · Avoid alcohol while taking this medication. · Do not use with other acetaminophen-containing products. · May cause dizziness or drowsiness; avoid driving until you know how you react. · Common side effects include constipation, nausea, and drowsiness. · Seek emergency if signs of allergic reaction or difficulty breathing occur. |