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). |
| Molecular Weight | 417.5 |
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 | Avoid use due to risk of congenital malformations; limited data show potential association with respiratory defects. |
| 2nd trimester | Use with caution; may cause fetal respiratory depression if used near term. |
| 3rd trimester | Avoid prolonged use or high doses; risk of neonatal respiratory depression and withdrawal syndrome. |
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; codeine achieves fetal serum concentrations up to 50% of maternal levels. |
| Breastfeeding |
■ 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 codeineSevere respiratory depressionAcute or severe bronchial asthmaParalytic ileusConcurrent use of MAOIs or within 14 days
| 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. |
| Food/Dietary |
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| Codeine and acetaminophen are excreted into breast milk. Codeine metabolism varies; ultrarapid metabolizers may risk infant toxicity. Use lowest effective dose for shortest duration; monitor infant for sedation or respiratory depression. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | 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. |
| Avoid alcohol due to increased hepatotoxicity risk and CNS depression. High-fat meals may delay absorption but not significantly alter clinical effect. No specific food restrictions otherwise. |
| Clinical Pearls | Tylenol with Codeine contains acetaminophen 300 mg and codeine 30 mg per tablet. Codeine is a prodrug metabolized by CYP2D6 to morphine; poor metabolizers (7-10% of population) may have reduced analgesia, while ultra-rapid metabolizers risk toxicity. Maximum acetaminophen dose is 4 g/day; hepatotoxicity risk with alcohol use. Avoid in children under 12 years due to risk of respiratory depression; FDA boxed warning for children post-tonsillectomy/adenoidectomy. Constipation common; prescribe stool softeners proactively. |
| Patient Advice | Do not exceed 12 tablets in 24 hours due to acetaminophen content; liver damage risk with overdose. · Avoid alcohol while taking this medication. · May cause drowsiness; do not drive or operate machinery until you know how you react. · Take with food to reduce nausea. · Do not take with other products containing acetaminophen (e.g., Tylenol, cold medications). · Report signs of allergic reaction (rash, itching) or breathing difficulties immediately. · Codeine can be habit-forming; use only as prescribed. |