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. |
| Molecular Weight | 423.46 |
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 | Avoid use during first trimester due to risk of congenital malformations associated with codeine; acetaminophen is generally considered safe but use lowest effective dose. |
| 2nd trimester | Use with caution; acetaminophen is safe, but codeine may cause fetal respiratory depression and withdrawal if used chronically or in high doses near term. |
| 3rd trimester | Avoid prolonged use or high doses due to risk of neonatal respiratory depression, withdrawal syndrome, and premature closure of ductus arteriosus (codeine). |
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 is metabolized to morphine which readily crosses; acetaminophen crosses but with limited fetal exposure at therapeutic doses. |
■ 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 acetaminophen, codeine, or any componentRespiratory depression (especially in absence of resuscitative equipment)Acute or severe bronchial asthma or hypercarbiaParalytic ileusConcurrent use of MAO inhibitors or within 14 daysSignificant respiratory depressionPostoperative pain management in children after tonsillectomy/adenoidectomy (codeine)
| 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 |
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| Breastfeeding | Codeine is excreted into breast milk in low amounts; however, there is a risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers who produce higher levels of morphine. Acetaminophen is considered safe. Benefit-risk assessment recommended; monitor infant for sedation, respiratory depression, and poor feeding. |
| Lactation Rating | L3 - Moderately Safe (codeine); Acetaminophen L1 - Safest |
| Teratogenic Risk | 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. |
| Food/Dietary | Avoid alcohol and foods containing alcohol (e.g., desserts, sauces) due to increased risk of hepatotoxicity and CNS depression. No specific food restrictions otherwise. |
| Clinical Pearls | Each tablet contains acetaminophen 300 mg and codeine phosphate 60 mg. Maximum acetaminophen dose: 4 g/day; avoid other acetaminophen-containing products. Codeine is a prodrug; CYP2D6 poor metabolizers may have reduced efficacy, while ultra-rapid metabolizers risk toxicity. Monitor for respiratory depression, especially in opioid-naive patients. Use with caution in patients with liver impairment or G6PD deficiency. |
| Patient Advice | Do not exceed 12 tablets in 24 hours due to acetaminophen content. · Avoid alcohol while taking this medication. · This drug may cause drowsiness; do not drive or operate machinery until you know how it affects you. · Contact your doctor if you experience signs of allergic reaction (rash, difficulty breathing) or liver injury (yellowing of skin/eyes, dark urine). · Do not take with other products containing acetaminophen (e.g., Tylenol, cold medicines). · Codeine can be habit-forming; use only as prescribed. · Women who are breastfeeding should consult their doctor; codeine can pass into breast milk. |