TYLENOL W/ CODEINE NO. 3
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 converted to morphine, which acts as a mu-opioid receptor agonist; acetaminophen inhibits cyclooxygenase (COX) and modulates cannabinoid and serotonergic pathways, with central analgesic effect.
| Metabolism | Codeine: primarily metabolized by CYP2D6 to morphine (active), and via CYP3A4 to norcodeine; acetaminophen: primarily metabolized by conjugation (glucuronidation, sulfation) and minimally by CYP2E1 and CYP1A2. |
| Excretion | Acetaminophen: primarily renal (hepatic metabolism followed by renal excretion of metabolites; <5% unchanged). Codeine: renal (primarily as codeine and its metabolites, including morphine, norcodeine, and conjugated forms; 90% excreted in urine, 10% in feces). |
| Half-life | Acetaminophen: 2-3 hours (prolonged in hepatic or renal impairment, overdose). Codeine: 2.5-3.5 hours; morphine from codeine: approx 2 hours; prolonged in hepatic or renal impairment. |
| Protein binding | Acetaminophen: 10-25% (albumin). Codeine: 7-25% (albumin); morphine: 30-40%. |
| Volume of Distribution | Acetaminophen: 0.9-1.0 L/kg (distributes throughout total body water). Codeine: 3-6 L/kg (highly tissue-bound, extensive distribution). |
| Bioavailability | Acetaminophen: oral 88-100% (therapeutic doses). Codeine: oral 50-60% (first-pass metabolism; extensive variability due to CYP2D6 metabolism). |
| Onset of Action | Oral: acetaminophen 30-60 minutes; codeine 30-60 minutes; peak effect 1-2 hours. |
| Duration of Action | Acetaminophen: 4-6 hours. Codeine: 4-6 hours (analgesic); prolonged with higher doses or in slow metabolizers (CYP2D6 poor metabolizers have reduced efficacy). |
1-2 tablets (300 mg acetaminophen/30 mg codeine per tablet) orally every 4 hours as needed for pain; maximum 12 tablets per day.
| Dosage form | TABLET |
| Renal impairment | GFR 10-50 mL/min: administer 75% of normal dose every 6 hours; GFR <10 mL/min: administer 50% of normal dose every 6 hours. Codeine is not recommended in severe renal impairment due to risk of toxicity. |
| Liver impairment | Child-Pugh Class A (mild): no adjustment; Class B (moderate): reduce dose by 50% or extend dosing interval to every 6 hours; Class C (severe): avoid use due to risk of acetaminophen toxicity and altered codeine metabolism. |
| Pediatric use | Based on codeine component: weight-based dosing of 0.5-1 mg codeine/kg/dose every 4-6 hours as needed; maximum daily dose: 6 mg/kg/day of codeine. Use lowest effective dose. Contraindicated in children <12 years due to risk of respiratory depression. |
| Geriatric use | Starting dose: 1 tablet every 6 hours as needed; maximum 8 tablets per day. Use with caution due to increased sensitivity, reduced hepatic and renal function, and risk of falls. Monitor for constipation and respiratory depression. |
| 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: Enters breast milk in low amounts (M/P ratio ~0.2-0.5); considered compatible. Codeine: Excreted into breast milk (M/P ratio ~2.4); variable due to CYP2D6 polymorphisms. Risk of opioid toxicity in nursing infants, especially in ultrarapid metabolizers; caution advised. American Academy of Pediatrics recommends avoiding if possible. |
| Teratogenic Risk |
■ FDA Black Box Warning
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; HEPATOTOXICITY.
| Common Effects | cough |
| Serious Effects |
["Hypersensitivity to codeine, acetaminophen, or any component of the formulation","Significant respiratory depression","Acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment","Paralytic ileus (known or suspected)","Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of such therapy","COPD, cor pulmonale, or other chronic respiratory conditions","Children younger than 12 years","Children younger than 18 years following tonsillectomy and/or adenoidectomy","Patients with severe hepatic impairment"]
| Precautions | ["Addiction, abuse, and misuse","Life-threatening respiratory depression","Accidental ingestion","Ultra-rapid metabolism of codeine and risk factors for respiratory depression in children","Neonatal opioid withdrawal syndrome","Interaction with alcohol and CNS depressants","Hepatotoxicity (acetaminophen)","Risks from concomitant use with benzodiazepines or other CNS depressants","Adrenal insufficiency","Severe hypotension","Gastrointestinal adverse reactions (e.g., constipation)","Seizures","Opioid-induced hyperalgesia","Risk of serotonin syndrome"] |
Loading safety data…
| Acetaminophen: Generally considered low risk; no consistent evidence of major malformations. Codeine: First trimester: risk of neural tube defects, cleft palate; second trimester: no specific major risks; third trimester: risk of neonatal respiratory depression, withdrawal syndrome if chronic use. Codeine is metabolized to morphine, which may cause fetal dependence. |
| Fetal Monitoring | Maternal: Assess pain severity, respiratory status, bowel function, signs of opioid tolerance/dependence. Fetal: Ultrasound for anomalies if first-trimester exposure; monitor for intrauterine growth restriction with chronic use. Neonatal: Observe for respiratory depression, sedation, and withdrawal symptoms (irritability, poor feeding) if codeine used near term. |
| Fertility Effects | Acetaminophen: No known adverse effects on fertility at therapeutic doses. Codeine: Opioids may affect hormone levels; chronic use can lead to menstrual irregularities, reduced libido, and potential hypothalamic-pituitary-gonadal axis suppression, but evidence limited at typical analgesic doses. |