EMPRACET W/ CODEINE PHOSPHATE #3
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 metabolized to morphine, which acts as a mu-opioid receptor agonist. Acetaminophen inhibits cyclooxygenase (COX) and modulates descending serotonergic pathways, providing analgesia and antipyresis.
| Metabolism | Codeine: primarily via CYP2D6 to morphine and CYP3A4 to norcodeine; acetaminophen: primarily via glucuronidation (UGT1A1, UGT1A6, UGT1A9) and sulfation (SULT1A1), with minor CYP2E1 oxidation to toxic NAPQI. |
| Excretion | Acetaminophen is excreted renally as conjugates (glucuronide 60%, sulfate 30%, cysteine/mercapturate 8%), with <5% unchanged; codeine is metabolized to codeine-6-glucuronide (70%), norcodeine (10%), morphine (10%, via CYP2D6), and conjugates; renal excretion of metabolites; <15% of codeine excreted unchanged; fecal elimination minor. |
| Half-life | Acetaminophen: 2-3 hours; codeine: 2.5-3 hours; both prolonged in hepatic impairment; clinical context: dosing every 4-6 hours for acute pain. |
| Protein binding | Acetaminophen: 10-25% (albumin); codeine: 7-25% (primarily albumin). |
| Volume of Distribution | Acetaminophen: 0.9-1.0 L/kg; codeine: 3-6 L/kg; clinical meaning: codeine widely distributed, crosses placenta and blood-brain barrier. |
| Bioavailability | Oral: acetaminophen 85-98%; codeine 90% (first-pass metabolism reduces to ~70% active morphine equivalents). |
| Onset of Action | Oral: 30-60 min (acetaminophen); codeine requires hepatic conversion to morphine, onset 30-60 min; peak effect 1-2 hours. |
| Duration of Action | 4-6 hours; clinical note: analgesic effect limited by codeine metabolism; CYP2D6 poor metabolizers may have reduced efficacy. |
| Molecular Weight | 303.35 |
One or two tablets (300 mg acetaminophen / 30 mg codeine phosphate per tablet) orally every 4 hours as needed for pain, not to exceed 12 tablets per day.
| Dosage form | TABLET |
| Renal impairment | GFR 50-89 mL/min: No adjustment. GFR 10-49 mL/min: Administer every 6 hours. GFR <10 mL/min: Not recommended due to risk of codeine toxicity. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce dose by 50% or extend interval. Child-Pugh Class C: Contraindicated. |
| Pediatric use | Weight-based dose: Acetaminophen 10-15 mg/kg/dose and codeine 0.5-1 mg/kg/dose every 4-6 hours as needed, maximum 5 doses/day. Not recommended for children <12 years due to risk of respiratory depression. |
| Geriatric use | Initiate at lowest effective dose (e.g., one tablet every 4-6 hours). Monitor for respiratory depression and constipation. Avoid in patients with renal or hepatic impairment. |
| 1st trimester | Avoid; risk of congenital malformations with codeine (especially in first trimester) and acetaminophen use has been associated with possible risk; use only if clearly needed. |
| 2nd trimester | Use with caution; prolonged use may lead to fetal dependence and neonatal withdrawal; avoid near term. |
| 3rd trimester | Avoid; codeine can cause neonatal respiratory depression and withdrawal syndrome; acetaminophen is generally safe but combination not recommended. |
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. Degree: extensive for codeine and morphine. |
■ FDA Black Box Warning
Risk of medication errors: confusion between acetaminophen-codeine products with different strengths can lead to overdose; respiratory depression: life-threatening respiratory depression can occur, especially in children; neonatal opioid withdrawal syndrome: prolonged use during pregnancy can result in neonatal opioid withdrawal; CYP2D6 ultra-rapid metabolizers: codeine can be rapidly converted to morphine in some individuals, leading to fatal respiratory depression; hepatotoxicity: acetaminophen overdose can cause severe liver damage.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to acetaminophen, codeine, or any componentRespiratory depression (especially in absence of resuscitative equipment)Acute or severe bronchial asthmaPulmonary edemaParalytic ileusMAO inhibitor use within 14 daysPostoperative pain management in children undergoing tonsillectomy/adenoidectomy (due to risk of fatal respiratory depression in CYP2D6 ultra-rapid metabolizers)Breastfeeding in CYP2D6 ultra-rapid metabolizersSevere hepatic impairment (acetaminophen component)
| Precautions |
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| Breastfeeding | Codeine is excreted into breast milk; ultra-rapid metabolizers of CYP2D6 can produce dangerous levels of morphine, leading to infant toxicity. Acetaminophen is considered compatible. Use lowest effective dose for shortest duration; monitor infant for sedation, respiratory depression, and poor feeding. Avoid in breastfeeding mothers who are ultra-rapid metabolizers or if infant is <1 month old or has respiratory compromise. |
| Lactation Rating | L3 (Moderately Safe) with caution; L4 if ultra-rapid metabolizer or high dose/prolonged use. |
| Teratogenic Risk | First trimester: Limited human data, but animal studies suggest increased risk of neural tube defects at high doses; second/third trimester: Prolonged use may cause fetal opioid dependence, respiratory depression, and growth restriction; third trimester: Risk of neonatal opioid withdrawal syndrome (NOWS) with chronic use near term. |
| Fetal Monitoring | Maternal: Respiratory rate, sedation status, bowel function, signs of opioid dependence; Fetal: Ultrasound for growth restriction with chronic use; Neonatal: Monitor for signs of NOWS (irritability, poor feeding, respiratory distress) for 72 hours after birth if maternal use in third trimester. |
| Fertility Effects | Possible reversible impairment of female fertility (anovulation, menstrual irregularities) with chronic opioid use due to suppression of hypothalamic-pituitary-gonadal axis; male fertility may be reduced (sperm motility, morphology). |
| Respiratory depression: risk increases with higher doses and in elderly/debilitated patients; CYP2D6 ultra-rapid metabolizers: increased risk of morphine toxicity; acetaminophen hepatotoxicity: avoid exceeding 4000 mg/day; risks of opioid use disorder, abuse, and addiction; central nervous system depression: additive effects with alcohol and other CNS depressants; increased intracranial pressure: use with caution in head injury; severe hypotension: risk in hypovolemic patients; gastrointestinal obstruction: avoid in known or suspected obstruction; withdrawal: abrupt discontinuation may cause withdrawal symptoms. |
| Food/Dietary | Avoid alcohol; may increase hepatotoxicity risk. No known significant food interactions. Grapefruit juice may alter codeine metabolism. High-fat meals may delay absorption but do not significantly alter effects. |
| Clinical Pearls | APAP/Codeine #3 contains 300 mg acetaminophen and 30 mg codeine phosphate 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. Max acetaminophen dose from all sources is 4 g/day (3 g in elderly or hepatic impairment). Contraindicated in children <12 years old, post-tonsillectomy/adenoidectomy in children <18, and in breastfeeding mothers due to risk of respiratory depression in infants. Avoid concurrent use with other CNS depressants. |
| Patient Advice | Do not exceed 12 tablets in 24 hours due to acetaminophen content. · Avoid alcohol while taking this medication to prevent liver damage. · Do not take with other products containing acetaminophen (e.g., Tylenol, cold medicines). · May cause drowsiness or dizziness; avoid driving or operating machinery until effects are known. · Limit caffeine intake as it may increase side effects like nervousness and insomnia. · If pregnant, breastfeeding, or planning to become pregnant, consult healthcare provider. · Seek emergency care for signs of allergic reaction: rash, difficulty breathing, swelling of face or throat. |