EMPRACET W/ CODEINE PHOSPHATE #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 converted to morphine by CYP2D6, acting as a mu-opioid receptor agonist. Acetaminophen inhibits cyclooxygenase (COX) and modulates descending serotonergic pathways, reducing pain and fever.
| Metabolism | Codeine: O-demethylation by CYP2D6 to morphine (active), N-demethylation by CYP3A4 to norcodeine. Acetaminophen: primarily conjugated via glucuronidation and sulfation, with minor oxidation by CYP2E1 and CYP3A4 to N-acetyl-p-benzoquinone imine (NAPQI). |
| Excretion | Renal: ~90% as unchanged acetaminophen and metabolites (glucuronide 60%, sulfate 30%, cysteine/mercapturate <5%), 5% unchanged; codeine: ~90% renal as metabolites (codeine-6-glucuronide, norcodeine, morphine, morphine-3-glucuronide, morphine-6-glucuronide), <15% unchanged. |
| Half-life | Acetaminophen: 2-3 hours (prolonged in hepatic insufficiency). Codeine: 2.5-3.5 hours; morphine (active metabolite): 1.5-4.5 hours. |
| Protein binding | Acetaminophen: 10-25% (albumin). Codeine: 7-25% (primarily albumin). |
| Volume of Distribution | Acetaminophen: 0.95-1.0 L/kg. Codeine: 3-6 L/kg (extensive tissue distribution). |
| Bioavailability | Acetaminophen: ~88% oral. Codeine: ~90% oral (first-pass metabolism to morphine ~5-15% yields variable analgesia). |
| Onset of Action | Oral: 30-45 minutes (acetaminophen analgesia), 30-60 minutes (codeine analgesia). |
| Duration of Action | Acetaminophen: 4-6 hours. Codeine: 4-6 hours. Sustained with hepatic impairment. |
| Molecular Weight | Codeine phosphate: 397.36 Da; Acetaminophen: 151.17 Da; Combination product: not applicable |
1-2 tablets (acetaminophen 300 mg / codeine phosphate 60 mg per tablet) orally every 4-6 hours as needed for pain; maximum 12 tablets per day.
| Dosage form | TABLET |
| Renal impairment | GFR 10-50 mL/min: administer every 6 hours; GFR <10 mL/min: administer every 8-12 hours; avoid use in severe renal impairment due to risk of accumulation of codeine metabolites. |
| Liver impairment | Child-Pugh Class A: no adjustment necessary; Child-Pugh Class B: reduce dose by 50% and extend dosing interval to every 8 hours; Child-Pugh Class C: avoid use; contraindicated in severe hepatic impairment. |
| Pediatric use | Not recommended for children <12 years; for children ≥12 years: weight-based dosing 0.5-1 mg/kg codeine plus 10-15 mg/kg acetaminophen per dose, max every 4-6 hours, not to exceed 60 mg codeine or 3000 mg acetaminophen per day. |
| Geriatric use | Initiate at low end of dosing range (1 tablet every 6 hours), titrate cautiously; monitor for respiratory depression, constipation, and falls; consider renal and hepatic function; avoid in frail elderly. |
| 1st trimester | Codeine is generally avoided in first trimester due to risk of congenital malformations; acetaminophen is considered safe at therapeutic doses. |
| 2nd trimester | Codeine may be used if necessary but risk of fetal dependence; acetaminophen is safe. |
| 3rd trimester | Codeine may cause neonatal respiratory depression, withdrawal; acetaminophen is safe. Avoid prolonged use. |
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 | Codeine and acetaminophen both cross the placenta. Codeine is metabolized to morphine, which achieves fetal concentrations similar to maternal. |
■ FDA Black Box Warning
Risk of medication errors due to confusion between different strengths of EMPRACET W/ CODEINE PHOSPHATE; addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; cytochrome P450 2D6 ultra-rapid metabolizer risk; risks from concomitant use with benzodiazepines or other CNS depressants.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to codeine or acetaminophenAcute or severe bronchial asthmaRespiratory depressionParalytic ileusCYP2D6 ultrarapid metabolizers (risk of morphine toxicity)Concurrent MAOIs or within 14 days
| Precautions | Respiratory depression, especially in elderly, cachectic, or debilitated; risk of opioid-induced hyperalgesia; severe hypotension; seizures; adrenal insufficiency; hepatotoxicity from acetaminophen overdose; serotonin syndrome; interactions with MAOIs and other CNS depressants. |
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| Breastfeeding |
| Codeine is excreted in breast milk; risk of infant CNS depression especially in CYP2D6 ultrarapid metabolizers. Acetaminophen is safe. Use lowest effective dose for shortest duration. |
| Lactation Rating | L3 (Moderately Safe) - codeine; L1 (Safe) - acetaminophen |
| Teratogenic Risk | First trimester: Limited data, but acetaminophen is generally considered low risk; codeine is associated with neural tube defects in some studies, but causal relationship not established. Second trimester: No specific risks identified. Third trimester: Prolonged use may lead to neonatal opioid withdrawal syndrome; high doses near term may cause respiratory depression in neonate. Avoid codeine in pregnancy if possible due to CYP2D6 variability and potential ultrarapid metabolism leading to toxic morphine levels. |
| Fetal Monitoring | Maternal: periodic liver function tests if prolonged acetaminophen use; signs of opioid adverse effects (respiratory depression, sedation). Fetal/neonatal: ultrasound for growth restriction with chronic use; at delivery, assess for neonatal opioid withdrawal syndrome using Finnegan score; monitor respiratory status in neonate if used near term. |
| Fertility Effects | Acetaminophen: no known effect on fertility. Codeine: chronic use may affect ovulation via prolactin increase; no definitive data on human fertility impact. |
| Food/Dietary |
| Avoid alcohol and grapefruit juice (grapefruit can inhibit CYP3A4, increasing codeine levels). High-fat meals may delay absorption; take consistently with or without food. |
| Clinical Pearls | Monitor respiratory depression, especially in elderly or opioid-naïve patients. Use with caution in renal impairment (accumulation of codeine metabolites). Avoid in children post-tonsillectomy/adenoidectomy (risk of fatal respiratory depression due to CYP2D6 ultra-rapid metabolizers). Coadministration with CYP3A4 inhibitors (e.g., ketoconazole) or CYP2D6 inhibitors (e.g., fluoxetine) may increase toxicity. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · This drug contains codeine, which can be habit-forming; avoid abrupt discontinuation to prevent withdrawal. · Do not drive or operate heavy machinery until you know how this medication affects you. · Avoid alcohol and other CNS depressants (sleeping pills, tranquilizers) while taking this medication. · Store securely out of reach of children; accidental ingestion can be fatal. · Seek emergency medical attention if you have severe drowsiness, slow/shallow breathing, or difficulty waking up. |