TYLENOL W/ CODEINE NO. 1
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 undergoes O-demethylation via CYP2D6 to morphine, which acts as a μ-opioid receptor agonist. Acetaminophen inhibits cyclooxygenase (COX) enzymes in the CNS, reducing prostaglandin synthesis and modulating pain perception.
| Metabolism | Acetaminophen is primarily metabolized via glucuronidation and sulfation in the liver, with a minor pathway via CYP2E1 to a toxic metabolite (NAPQI). Codeine is metabolized via CYP2D6 to morphine, via CYP3A4 to norcodeine, and via glucuronidation. |
| Excretion | Renal: ~70-80% of codeine as inactive metabolites (codeine-6-glucuronide, norcodeine, morphine) and ~5-10% as unchanged codeine; ~5-15% of acetaminophen as unchanged drug. Biliary/fecal: minimal (<5% for both). |
| Half-life | Acetaminophen: 2-3 hours; Codeine: 2.5-3.5 hours; Morphine (active metabolite): 2-4 hours. Terminal half-life prolonged in hepatic impairment or elderly. |
| Protein binding | Acetaminophen: 10-25% bound to plasma proteins; Codeine: ~25% bound to plasma proteins. |
| Volume of Distribution | Acetaminophen: ~0.9 L/kg (distributes throughout total body water); Codeine: ~3-6 L/kg (extensively distributed into tissues). |
| Bioavailability | Acetaminophen: oral bioavailability ~80-85%; Codeine: oral bioavailability ~60-90% (due to first-pass metabolism to morphine). |
| Onset of Action | Oral: acetaminophen onset 30-60 minutes; codeine onset 30-60 minutes for analgesia. |
| Duration of Action | Acetaminophen: 4-6 hours; Codeine: 4-6 hours (analgesia). Duration may be limited by hepatotoxicity risk with repeated acetaminophen dosing. |
| Molecular Weight | Acetaminophen: 151.16 Da; Codeine: 299.37 Da (codeine base) |
Adult: 1-2 tablets (acetaminophen 300 mg/codeine 8 mg per tablet) orally every 4-6 hours as needed; maximum 8 tablets per day. Route: oral. Frequency: every 4-6 hours.
| Dosage form | TABLET |
| Renal impairment | CrCl 30-50 mL/min: Administer every 6 hours; CrCl <30 mL/min: Avoid due to risk of codeine accumulation and toxicity; hemodialysis: Not recommended. |
| Liver impairment | Child-Pugh Class A (mild): No adjustment needed; Child-Pugh Class B (moderate): Reduce dose by 50% and extend interval to every 6-8 hours; Child-Pugh Class C (severe): Contraindicated. |
| Pediatric use | Weight-based: Codeine not recommended in pediatric patients <12 years due to risk of respiratory depression; for ages 12-18 years: 1 tablet (acetaminophen 300 mg/codeine 8 mg) orally every 4-6 hours as needed; maximum 4 tablets per day. |
| Geriatric use | Start at lowest effective dose (1 tablet) and monitor for respiratory depression and constipation; consider acetaminophen 300 mg/codeine 8 mg every 6 hours; maximum 4 tablets per day. |
| 1st trimester | Acetaminophen: Generally considered safe at therapeutic doses; codeine: Avoid due to risk of congenital malformations (case-control studies suggest increased risk of respiratory defects and oral clefts). Use only if benefit outweighs risk. |
| 2nd trimester | Acetaminophen: Safe at therapeutic doses; codeine: May be used with caution, but chronic use may lead to neonatal withdrawal. Consider alternative analgesics. |
| 3rd trimester | Acetaminophen: Safe at therapeutic doses; codeine: Avoid near term due to risk of neonatal respiratory depression and withdrawal. Chronic use may cause neonatal opioid 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. Acetaminophen: readily crosses; codeine: crosses with fetal concentrations about 50-100% of maternal levels. Codeine is metabolized to morphine in the fetus via CYP2D6 and CYP3A4. |
■ FDA Black Box Warning
WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; 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 or codeineSevere respiratory depressionAcute or severe bronchial asthmaParalytic ileusConcurrent use of MAO inhibitors or within 14 days
| Precautions | Risk of medication errors (confusion with other products), Addiction, abuse, and misuse, Life-threatening respiratory depression, Accidental ingestion (especially in children), Ultra-rapid metabolism of codeine (CYP2D6 ultra-rapid metabolizers), Neonatal opioid withdrawal syndrome with prolonged use during pregnancy, Hepatotoxicity (acetaminophen overdose), Severe hypotension, Seizures, Adrenal insufficiency, Serotonin syndrome with concomitant serotonergic drugs, Increased risk of severe skin reactions (e.g., SJS/TEN), Interaction with alcohol, Risks from concomitant use with benzodiazepines or other CNS depressants, Impaired mental/physical abilities, Use in children with respiratory conditions, Hepatic or renal impairment |
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| Breastfeeding | Acetaminophen is compatible with breastfeeding in usual doses. Codeine is excreted into breast milk in low levels; however, there is a risk of CNS depression in the infant, especially in mothers who are ultra-rapid metabolizers of codeine (CYP2D6). Use lowest effective dose for shortest duration. Monitor infant for drowsiness, poor feeding, or respiratory depression. The American Academy of Pediatrics considers codeine to be usually compatible with breastfeeding but cautious use is recommended. |
| Lactation Rating | L3 (Moderately Safe) - acetaminophen L1; codeine L3 |
| Teratogenic Risk | Acetaminophen: Low teratogenic risk; use at therapeutic doses not associated with increased major malformations. Codeine: First trimester: Risk of malformations unclear; some studies suggest small increased risk of respiratory defects and spina bifida. Third trimester: Prolonged use may cause neonatal opioid withdrawal syndrome (NOWS); high doses near term may cause neonatal respiratory depression. Avoid chronic high doses. |
| Fetal Monitoring | Maternal: Assess respiratory rate, sedation level, bowel function. Fetal: Ultrasound for growth restriction with prolonged use; neonatal monitoring for signs of opioid withdrawal after delivery if maternal use near term. |
| Fertility Effects | No significant effects reported for acetaminophen or codeine at therapeutic doses. Codeine may affect hormone levels with chronic high doses, potentially impacting ovulation. No conclusive data on fertility impairment. |
| Food/Dietary | Avoid alcohol; may increase risk of hepatotoxicity and CNS depression. No specific food restrictions. May be taken with food to reduce gastrointestinal upset. |
| Clinical Pearls | Contains 300 mg acetaminophen and 15 mg codeine per tablet. Maximum acetaminophen dose 4000 mg/day; avoid combination with other acetaminophen products. Codeine is a prodrug requiring CYP2D6 conversion to morphine; poor metabolizers have reduced analgesia, ultra-rapid metabolizers risk toxicity. Monitor for respiratory depression, especially in children, elderly, or obese. Not recommended in breastfeeding mothers due to risk of infant toxicity. |
| Patient Advice | Do not exceed 13 tablets per 24 hours due to acetaminophen limit. · Avoid alcohol while taking this medication. · Do not use with any other products containing acetaminophen or codeine. · May cause drowsiness; avoid driving or operating machinery. · Store out of reach of children and dispose of unused medication properly. · Seek medical help if you experience difficulty breathing, severe drowsiness, or signs of allergic reaction. |