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. |
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 | 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: Compatible; low levels in breast milk (M/P ratio ~0.91). Codeine: Excreted into breast milk; M/P ratio ~2.5. Risk of infant opioid toxicity, especially in ultra-rapid CYP2D6 metabolizers. Use lowest effective dose for shortest duration. Monitor infant for drowsiness, feeding difficulties, respiratory depression. |
| Teratogenic Risk |
■ 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 codeine, acetaminophen, or any component","Significant respiratory depression","Acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment","Known or suspected gastrointestinal obstruction, including paralytic ileus","Patients with severe hepatic impairment or acute liver disease","Postoperative pain management in children who have had tonsillectomy and/or adenoidectomy","Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of such therapy"]
| 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"] |
Loading safety data…
| 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. |