TYLENOL W/ CODEINE NO. 4
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 by CYP2D6 to morphine, which acts as a μ-opioid receptor agonist, inhibiting adenylate cyclase and modulating neurotransmitter release in the CNS. Acetaminophen inhibits cyclooxygenase (COX) enzymes, primarily in the CNS, reducing prostaglandin synthesis and modulating pain perception.
| Metabolism | Codeine: metabolized by CYP2D6 to morphine (active), CYP3A4 to norcodeine, and glucuronidation. Acetaminophen: extensively metabolized in the liver via conjugation (glucuronidation, sulfation) and minor oxidation by CYP2E1 to N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified by glutathione. |
| Excretion | Codeine and its metabolites (including morphine, morphine-6-glucuronide, and norcodeine) are primarily excreted renally. Approximately 90% of a codeine dose is excreted in urine within 24 hours, with 5-15% as free codeine, 5-13% as free morphine, 40-60% as codeine conjugates, and 5-10% as morphine conjugates. Fecal excretion accounts for less than 5%. Acetaminophen is primarily metabolized in the liver to glucuronide and sulfate conjugates; about 85% of a dose is excreted renally as conjugates within 24 hours, with 2-4% excreted unchanged. Minor biliary/fecal elimination occurs for both drugs. |
| Half-life | Codeine: Terminal half-life of 2.5-3.5 hours; however, its active metabolite morphine has a half-life of 1.5-2 hours, and morphine-6-glucuronide (M6G) has a half-life of 2-4 hours. Acetaminophen: Terminal half-life of 2-3 hours in adults; prolonged in hepatic impairment (up to 4-5 hours) or overdose (4-12 hours). Clinically, duration of analgesic effect is approximately 4-6 hours. |
| Protein binding | Codeine: Approximately 20-40% bound to plasma proteins (primarily albumin). Morphine: 20-35% bound. Acetaminophen: 10-25% bound to albumin. Binding is minimal and generally not clinically significant. |
| Volume of Distribution | Codeine: Vd approximately 3-4 L/kg (range 2.5-5 L/kg). Acetaminophen: Vd approximately 0.9 L/kg (range 0.7-1.0 L/kg). Codeine's larger Vd indicates extensive tissue distribution; acetaminophen distributes evenly throughout body fluids. |
| Bioavailability | Oral: Codeine bioavailability is approximately 50-60% (first-pass metabolism). Acetaminophen bioavailability is 70-90% (absorbed rapidly from GI tract; first-pass metabolism minimal). Rectal bioavailability of acetaminophen is approximately 80-90% of oral. |
| Onset of Action | Oral: Onset of analgesia for codeine occurs within 30-60 minutes, with peak effect at 1-2 hours. Acetaminophen onset within 30-60 minutes, peak at 1-2 hours. Both are absorbed from the GI tract; food may delay absorption. |
| Duration of Action | Oral: Duration of analgesia is 4-6 hours. Codeine's effect is limited by its conversion to morphine; the duration of respiratory depression may outlast analgesia. Acetaminophen's antipyretic effect lasts 4-6 hours. |
One or 2 tablets (acetaminophen 300 mg-codeine 60 mg per tablet) orally every 4 hours as needed for pain; maximum 12 tablets per day.
| Dosage form | CAPSULE |
| Renal impairment | eGFR 30-50 mL/min: use with caution, reduce dose by 25%. eGFR <30 mL/min: not recommended due to risk of accumulation and respiratory depression. |
| Liver impairment | Child-Pugh class A: caution, maximum 2 tablets per dose; class B or C: contraindicated. |
| Pediatric use | Not recommended for children under 12 years. For ages 12-18: weight-based codeine dosing 0.5-1 mg/kg/dose every 4-6 hours (max 60 mg/dose); acetaminophen 15 mg/kg/dose every 4-6 hours (max 75 mg/kg/day). Use lowest effective dose. |
| Geriatric use | Initiate at half the adult dose (1 tablet) every 4 hours due to increased sensitivity to opioids and acetaminophen hepatotoxicity; maximum 8 tablets per day. Monitor renal and hepatic function closely. |
| 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 is compatible (low levels in milk). Codeine is present in milk; M/P ratio approximately 2:1 (morphine). Caution: ultra-rapid CYP2D6 metabolizers may produce high morphine levels leading to infant toxicity. Use lowest effective dose for shortest duration; monitor infant for drowsiness, difficulty breathing. |
| Teratogenic Risk |
■ FDA Black Box Warning
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; HEPATOTOXICITY; INTERACTION WITH ALCOHOL; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS.
| 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","Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days","Children <12 years of age","Children <18 years of age after tonsillectomy/adenoidectomy"]
| Precautions | ["Risk of addiction, abuse, and misuse","Life-threatening respiratory depression, especially in patients with compromised respiratory function","Accidental ingestion of even one dose, especially by children, can be fatal","Ultra-rapid metabolism of codeine to morphine due to CYP2D6 polymorphism leading to toxicity","Neonatal opioid withdrawal syndrome with prolonged use during pregnancy","Hepatotoxicity due to acetaminophen, especially with doses >4000 mg/day or with concurrent alcohol use","Interaction with alcohol and other CNS depressants","Concomitant use with MAOIs or within 14 days is contraindicated","Avoid use in children <12 years of age and in children <18 years after tonsillectomy/adenoidectomy"] |
Loading safety data…
| Pregnancy Category C prior to 2015; current data insufficient for definitive risk. Acetaminophen: no consistent evidence of major malformations; codeine: opioid use in first trimester associated with small increased risk of neural tube defects (OR 1.1-1.3); third trimester use may cause neonatal opioid withdrawal syndrome (NOWS) and respiratory depression at delivery. |
| Fetal Monitoring | Maternal: liver function tests (acetaminophen), signs of opioid toxicity (respiratory depression, constipation). Fetal/neonatal: growth ultrasound if chronic use; monitor for NOWS if used >30 days in third trimester; assess infant Apgar scores and respiratory status at delivery. |
| Fertility Effects | Acetaminophen may impair fertility by interfering with prostaglandin synthesis; codeine may disrupt menstrual cycle via opioid receptor modulation. No data on long-term human fertility outcomes. |