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). |
| Molecular Weight | 397.52 |
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 | Acetaminophen is generally considered safe; codeine is associated with rare congenital malformations, especially with first-trimester exposure. Use only if clearly needed. |
| 2nd trimester | No specific major teratogenic risk identified, but chronic use may lead to neonatal withdrawal; use lowest effective dose for shortest duration. |
| 3rd trimester | Prolonged use may cause neonatal respiratory depression, withdrawal syndrome, and premature birth. Avoid near term. |
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. Acetaminophen crosses rapidly; codeine crosses and may accumulate in fetal tissues. |
■ 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 acetaminophen, codeine, or any componentAcute or severe bronchial asthmaRespiratory depressionParalytic ileusMonoamine oxidase inhibitor (MAOI) use within 14 daysChildren <12 years with post-tonsillectomy/adenoidectomy obstructive sleep apneaKnown CYP2D6 ultrarapid metabolizer
| 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 |
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| Breastfeeding | Acetaminophen is excreted in low amounts; codeine is excreted in variable amounts. Some infants may experience sedation, poor feeding, or apnea. Avoid in mothers who are ultrarapid metabolizers of CYP2D6. Consider monitoring infant for drowsiness and respiratory rate. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | 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. |
| Food/Dietary | Avoid alcohol; concurrent use increases hepatotoxicity risk. Grapefruit juice may inhibit CYP3A4 metabolism, potentially altering codeine effectiveness (limited significance). High-fat meals may delay codeine absorption but do not require dose adjustment. Maintain adequate hydration and fiber intake to mitigate constipation. |
| Clinical Pearls | Tylenol with Codeine No. 3 contains 300 mg acetaminophen and 30 mg codeine phosphate. Codeine is a prodrug requiring CYP2D6 conversion to morphine; poor metabolizers have reduced efficacy, while ultrarapid metabolizers risk toxicity. Avoid exceeding 4 g acetaminophen daily due to hepatotoxicity. Use with caution in patients with respiratory compromise, as codeine can cause respiratory depression. Monitor for constipation; prescribe stool softeners prophylactically. Not recommended in children under 12 and contraindicated in post-tonsillectomy/adenoidectomy pain in children due to risk of fatal respiratory depression. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · Do not take other acetaminophen-containing products simultaneously; total daily acetaminophen from all sources should not exceed 4000 mg. · Avoid alcohol while taking this medication to prevent liver damage. · This drug may cause drowsiness or dizziness; do not drive or operate machinery until you know how it affects you. · Constipation is common; increase fluid and fiber intake, and consider a stool softener. · Discontinue and seek medical help if you experience signs of serotonin syndrome (e.g., agitation, hallucinations, rapid heart rate) or allergic reaction (e.g., rash, difficulty breathing). · Do not stop abruptly after long-term use; taper under medical supervision to avoid withdrawal symptoms. · Keep out of reach of children; accidental overdose of acetaminophen can be fatal. |