TYLENOL W/ CODEINE
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 that is metabolized to morphine, which acts as a mu-opioid receptor agonist; acetaminophen inhibits cyclooxygenase (COX) and modulates descending serotonergic pathways.
| Metabolism | Acetaminophen is primarily metabolized via glucuronidation and sulfation; codeine is metabolized via CYP2D6 to morphine, CYP3A4 to norcodeine, and glucuronidation. |
| Excretion | Renal: ~90% as glucuronide conjugates (acetaminophen 50-70%, codeine 10-15%), 10-15% as free acetaminophen, <5% free codeine; biliary/fecal: <5%. |
| Half-life | Acetaminophen: 2-3 hours (prolonged in hepatic impairment). Codeine: 2.5-4 hours (slower in CYP2D6 poor metabolizers). |
| Protein binding | Acetaminophen: 10-25% (albumin). Codeine: 7-25% (albumin). |
| Volume of Distribution | Acetaminophen: 0.8-1.0 L/kg (distributes evenly in body water). Codeine: 3-6 L/kg (extensive tissue distribution). |
| Bioavailability | Oral: acetaminophen: 85-98%; codeine: ~90% (first-pass metabolism to morphine via CYP2D6 reduces systemic bioavailability of active metabolite). |
| Onset of Action | Oral: acetaminophen: 30-60 min; codeine: 30-60 min (analgesic peak effect 1-2 hours). |
| Duration of Action | Analgesia: 4-6 hours (shorter with hepatic impairment or CYP2D6 ultrarapid metabolizers). |
1-2 tablets (300-600 mg acetaminophen / 30-60 mg codeine) every 4-6 hours as needed; maximum 12 tablets/day (codeine max 360 mg, acetaminophen max 3600 mg). Route: oral.
| Dosage form | TABLET |
| Renal impairment | GFR > 50 mL/min: no adjustment; GFR 10-50 mL/min: extend interval to 6-8 hours; avoid if GFR < 10 mL/min. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50% or extend interval; Child-Pugh C: contraindicated. |
| Pediatric use | Based on codeine component: 0.5-1 mg codeine/kg/dose every 4-6 hours. Note: codeine contraindicated in children <12 years due to FDA boxed warning. |
| Geriatric use | Start at lower end of dosing (e.g., 1 tablet every 6 hours); monitor for respiratory depression and CNS effects; consider reducing acetaminophen max if hepatic impairment. |
| 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 | Codeine is excreted into breast milk. M/P ratio approximately 2.1 (codeine and metabolites). Low levels generally considered compatible with breastfeeding; but ultra-rapid metabolizers may transfer higher morphine levels. Monitor infant for sedation, respiratory depression, poor feeding. American Academy of Pediatrics recommends caution. |
| Teratogenic Risk |
■ FDA Black Box Warning
Risk of respiratory depression, addiction, abuse, and misuse; life-threatening respiratory depression can occur; accidental ingestion can be fatal; risks from concomitant use with benzodiazepines or other CNS depressants; neonatal opioid withdrawal syndrome with prolonged use; ultra-rapid metabolizers of codeine can convert to morphine faster, leading to fatal respiratory depression.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to acetaminophen or codeine, significant respiratory depression, acute or severe bronchial asthma, gastrointestinal obstruction, use of MAO inhibitors within 14 days, post-operative pain in children after tonsillectomy/adenoidectomy.
| Precautions | Respiratory depression, drug dependence, interactions with CNS depressants, hepatotoxicity from acetaminophen, ultra-rapid metabolizer risk, elderly or debilitated patients, renal impairment, head injury, acute abdominal conditions. |
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| FDA Pregnancy Category C prior to 2015; current data insufficient to rule out risk. First trimester: association with oral clefts in some studies, but confounding by maternal condition. Second/third trimester: respiratory depression in neonate if used near term; chronic use may lead to neonatal opioid withdrawal syndrome. Avoid prolonged use or high doses. |
| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, and bowel function. Fetal: ultrasound for growth restriction if chronic use. Neonatal: observe for signs of opioid withdrawal (irritability, poor feeding, respiratory depression) after delivery if used near term. |
| Fertility Effects | No known direct effect on fertility. Opioid use may disrupt menstrual cycle and reduce libido; chronic use can lead to hypogonadism and potential reversible fertility impairment. |