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. |
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 | 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 | Codeine and acetaminophen are excreted into breast milk; M/P ratio for codeine is approximately 2.5; risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers; avoid use in breastfeeding due to potential CNS depression in infant; alternative analgesics preferred. |
| Teratogenic Risk |
■ 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 codeine, acetaminophen, or any component; significant respiratory depression; acute or severe bronchial asthma; hypercarbia; suspected or known gastrointestinal obstruction; use in children after tonsillectomy/adenoidectomy; diarrhea caused by poisoning or pseudomembranous colitis; severe hepatic impairment; concurrent use of MAOIs or within 14 days.
| Precautions | 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. |
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| 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). |