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). |
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 | 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 (M/P ratio ~0.91-1.42), considered compatible at therapeutic doses. Codeine enters milk (M/P ratio ~2.5) and may cause infant sedation; avoid in breastfeeding mothers who are ultra-rapid metabolizers of CYP2D6 due to risk of morphine accumulation. Use lowest effective dose for shortest duration. |
| Teratogenic Risk |
■ 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 acetaminophen, codeine, or any component.","Significant respiratory depression.","Acute or severe bronchial asthma in an unmonitored setting.","Paralytic ileus or known gastrointestinal obstruction.","Children younger than 12 years for postoperative pain management following tonsillectomy/adenoidectomy.","Use in children 12–18 years with risk factors for respiratory depression."]
| 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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| 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. |