TYLENOL W/ CODEINE 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.
Acetaminophen: Inhibits cyclooxygenase (COX) in the CNS, reducing prostaglandin synthesis, with weak peripheral COX inhibition. Codeine: Prodrug converted to morphine via CYP2D6; morphine acts as a mu-opioid receptor agonist, inhibiting ascending pain pathways and altering pain perception.
| Metabolism | Acetaminophen: Hepatic via conjugation (glucuronidation, sulfation, CYP2E1 minor). Codeine: Prodrug metabolized by CYP2D6 to morphine; also metabolized by CYP3A4 to norcodeine and by glucuronidation. |
| Excretion | Renal: 70-80% as glucuronide and sulfate conjugates of acetaminophen, 5-10% as unchanged acetaminophen, and 5-10% as unchanged codeine. Biliary/fecal: minor, <5%. |
| Half-life | Acetaminophen: 2-3 hours. Codeine: 2.5-3.5 hours. In hepatic impairment, half-life of codeine may be prolonged. |
| Protein binding | Acetaminophen: 10-25% (minimal). Codeine: 7-25%, primarily to albumin. |
| Volume of Distribution | Acetaminophen: 0.9-1.0 L/kg. Codeine: 2.2-3.5 L/kg (extensively distributed, including CNS). |
| Bioavailability | Oral: Acetaminophen: 85-95%; Codeine: 50-70% (first-pass metabolism to morphine). |
| Onset of Action | Oral: 30-45 minutes for analgesic effect (both components). Peak effect: 1-2 hours. |
| Duration of Action | Oral: 4-6 hours for analgesia. Note: Acetaminophen duration ~4 hours; codeine duration 4-6 hours (after metabolism to morphine). |
| Molecular Weight | 387.44 |
1 to 2 tablets (300 mg acetaminophen/15 mg codeine phosphate per tablet) orally every 4 hours as needed for pain; maximum 12 tablets per day.
| Dosage form | TABLET |
| Renal impairment | Not recommended for GFR < 30 mL/min; for GFR 30-59 mL/min, extend dosing interval to every 6 hours; avoid in severe renal impairment. |
| Liver impairment | Contraindicated in severe hepatic impairment; for Child-Pugh A or B, reduce dose by 50% and monitor; avoid in Child-Pugh C. |
| Pediatric use | Not recommended for children < 18 years due to risk of respiratory depression; for ages ≥18, same as adult dosing per body weight considerations. |
| Geriatric use | Initiate at half the adult dose (1 tablet every 4 hours as needed) due to increased sensitivity and renal/hepatic impairment; maximum 8 tablets per day. |
| 1st trimester | Avoid if possible; associated with increased risk of gastroschisis and cardiac defects. Use lowest effective dose for shortest duration. |
| 2nd trimester | Use with caution; may cause fetal respiratory depression and dependence with prolonged use. Avoid high doses or chronic use. |
| 3rd trimester | Avoid near term; risk of neonatal respiratory depression, withdrawal syndrome, and prolonged labor. Use only if clearly 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 | Both codeine and acetaminophen cross the placenta. Codeine is metabolized to morphine, which has been detected in fetal plasma and amniotic fluid. Acetaminophen readily crosses the placenta. Degree of transfer is significant. |
■ FDA Black Box Warning
Codeine is contraindicated in children younger than 12 years for postoperative management following tonsillectomy and/or adenoidectomy. Risk of respiratory depression and death in children with CYP2D6 ultra-rapid metabolizers. Avoid use in children 12–18 years with risk factors for respiratory depression.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to codeine or acetaminophenSignificant respiratory depressionAcute or severe bronchial asthma in an unmonitored setting or without resuscitative equipmentKnown or suspected gastrointestinal obstruction, including paralytic ileusConcurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of such therapyPostoperative pain management in children after tonsillectomy and/or adenoidectomy (due to risk of respiratory depression and death)Children under 12 years of age for pain (due to risk of respiratory depression from codeine)
| Precautions | Acetaminophen hepatotoxicity: Avoid exceeding 4 g/day in adults, risk of severe liver injury in alcoholism or pre-existing liver disease., Respiratory depression: Risk with codeine, especially in CYP2D6 ultra-rapid metabolizers, children, elderly, or patients with respiratory compromise., Addiction, abuse, and misuse: Opioid, risk of dependence., Neonatal opioid withdrawal syndrome with prolonged use during pregnancy., Adrenal insufficiency, serotonin syndrome, severe hypotension, and gastrointestinal obstruction. |
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| Breastfeeding | Codeine and acetaminophen are excreted into breast milk in low amounts. However, codeine can cause infant sedation and respiratory depression, especially in CYP2D6 ultra-rapid metabolizers. Use with caution; monitor infant for drowsiness and feeding difficulties. Consider lower doses and shortest duration. Acetaminophen is generally considered safe at recommended doses. |
| Lactation Rating | L3 - Moderately Safe |
| Teratogenic Risk | Acetaminophen and codeine combination: Codeine crosses placenta. Chronic use during pregnancy may lead to neonatal opioid withdrawal syndrome (NOWS). First trimester: Limited data, but acetaminophen not associated with major malformations; codeine weakly associated with neural tube defects in some studies. Third trimester: Prolonged use may cause respiratory depression and NOWS. Avoid high doses and prolonged use. |
| Fetal Monitoring | Monitor for neonatal respiratory depression and signs of withdrawal (e.g., irritability, feeding difficulty) in newborns after prolonged maternal use. Assess maternal liver function if high-dose acetaminophen used. Monitor maternal and fetal heart rate if codeine used near term. |
| Fertility Effects | No significant adverse effects on fertility reported with acetaminophen or codeine at therapeutic doses. Chronic high-dose opioid use may disrupt hypothalamic-pituitary-gonadal axis, potentially affecting ovulation and spermatogenesis. |
| Food/Dietary | Avoid alcohol; may increase hepatotoxicity (acetaminophen) and CNS depression (codeine). No specific food restrictions, but grapefruit juice may inhibit CYP2D6 (codeine metabolism) theoretically; consider limiting grapefruit intake. Maintain adequate hydration to prevent constipation. |
| Clinical Pearls | Tylenol with Codeine No. 2 contains 300 mg acetaminophen and 15 mg codeine phosphate per tablet. Avoid exceeding 4 g/day acetaminophen due to hepatotoxicity risk. Codeine is a prodrug metabolized by CYP2D6 to morphine; poor metabolizers (7-10% of population) have reduced efficacy, while ultra-rapid metabolizers risk toxicity. Monitor for respiratory depression, especially in children, obese, or sleep apnea patients. Use lowest effective dose for shortest duration. Contraindicated post-tonsillectomy/adenoidectomy in children <12 years. Naloxone should be available if opioid-naive. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency. · Do not combine with other acetaminophen-containing products (e.g., cold medicines, sleep aids) to avoid liver damage. · Avoid alcohol while taking this medication. · Do not drive or operate machinery until you know how this drug affects you. · Seek emergency care if you experience slow/shallow breathing, confusion, or severe drowsiness. · Store securely away from children; accidental overdose can be fatal. · Discontinue and contact doctor if signs of allergic reaction (rash, swelling, difficulty breathing) occur. · Do not crush or chew tablets; swallow whole with water. · Inform doctor of all medications, especially MAOIs, SSRIs, or other CNS depressants. · Codeine can cause constipation; increase fluid and fiber intake as preventive measure. |