PHENAPHEN-650 W/ CODEINE
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.
Acetaminophen: Weak COX-1 and COX-2 inhibitor in CNS, antipyretic via hypothalamic heat-regulating center. Codeine: Prodrug converted to morphine; mu-opioid receptor agonist.
| Metabolism | Acetaminophen: Hepatic via glucuronidation (UGT1A1, UGT1A6, UGT1A9), sulfation (SULT1A1), and CYP2E1 (minor). Codeine: CYP2D6 (to morphine), UGT2B7 (to codeine-6-glucuronide), CYP3A4 (to norcodeine). |
| Excretion | Acetaminophen: renal excretion of conjugates (glucuronide ~55%, sulfate ~30%, cysteine/mercapturate ~4%), with <5% unchanged. Codeine: renal excretion as codeine (~10%), norcodeine (~10%), morphine (~10%), and their conjugates; total 70-90% in urine as glucuronide conjugates. |
| Half-life | Acetaminophen: 2-3 hours (normal liver function); prolonged in liver disease (up to 5-10 hours) or overdose. Codeine: 2.5-3.5 hours; active metabolite morphine ~2 hours. Clinical context: half-life affects dosing interval; accumulation in hepatic or renal impairment. |
| Protein binding | Acetaminophen: 10-20% bound to plasma proteins. Codeine: 7-25% bound, primarily to albumin. |
| Volume of Distribution | Acetaminophen: 0.9-1.0 L/kg; codeine: 3-6 L/kg (mean ~3.5 L/kg). Clinical meaning: extensive tissue distribution for codeine, minimal for acetaminophen. |
| Bioavailability | Acetaminophen: oral bioavailability ~85-95% (first-pass metabolism minimal). Codeine: oral bioavailability ~50-60% (extensive first-pass metabolism via CYP2D6 and CYP3A4). |
| Onset of Action | Oral: acetaminophen onset 30-60 minutes (analgesic/antipyretic); codeine onset 30-60 minutes (analgesic). |
| Duration of Action | Acetaminophen: analgesic effect 4-6 hours; antipyretic effect 4-6 hours. Codeine: analgesic effect 4-6 hours. Clinical note: duration may be shorter in rapid metabolizers of codeine (CYP2D6 ultrarapid metabolizers) leading to morphine toxicity. |
| Molecular Weight | Acetaminophen: 151.16 Da; Codeine: 299.36 Da (as base). |
Acetaminophen 650 mg and codeine 60 mg orally every 4 hours as needed for pain; maximum acetaminophen 3 g/day.
| Dosage form | TABLET |
| Renal impairment | GFR 10-50 mL/min: administer every 6 hours; GFR <10 mL/min: administer every 8 hours; avoid in severe renal impairment due to accumulation of codeine metabolites. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce total daily dose by 50% or extend dosing interval; Child-Pugh C: contraindicated. |
| Pediatric use | Weight-based dosing: Acetaminophen 10-15 mg/kg/dose and codeine 0.5-1 mg/kg/dose orally every 4-6 hours; maximum acetaminophen 75 mg/kg/day; codeine not recommended in children under 12 years due to risk of respiratory depression. |
| Geriatric use | Initiate at lowest effective dose (e.g., acetaminophen 325 mg with codeine 30 mg) and titrate carefully; monitor for respiratory depression, sedation, and constipation; consider alternative analgesics if possible. |
| 1st trimester | Associated with cardiovascular malformations and gastroschisis with first trimester use. Avoid unless no alternative. |
| 2nd trimester | May be used if benefits outweigh risks, but avoid prolonged use. Possible risk of miscarriage. |
| 3rd trimester | Avoid in third trimester due to risk of premature closure of ductus arteriosus, oligohydramnios, and neonatal complications including respiratory depression and withdrawal. |
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 can cause neonatal respiratory depression. |
■ FDA Black Box Warning
Acetaminophen may cause severe hepatic injury with overdose; codeine for children post-tonsillectomy/adenoidectomy: risk of respiratory depression (UGT2B7 poor metabolizers).
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to acetaminophen or codeineSevere hepatic impairmentSevere respiratory depressionAcute or severe bronchial asthmaGI obstruction including paralytic ileusConcurrent use of MAO inhibitors or within 14 daysPostoperative pain management in children after tonsillectomy/adenoidectomy (due to CYP2D6 ultra-rapid metabolizer risk)
| Precautions | Hepatotoxicity (acetaminophen overdose), respiratory depression, opioid-induced hyperalgesia, tolerance/dependence, serotonin syndrome (if combined with serotonergic drugs), adrenal insufficiency, hypotension, seizure risk, severe hypotension, impaired mental/physical abilities, not for children <12y, risk in CYP2D6 ultrarapid metabolizers. |
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| Breastfeeding |
| Excreted into breast milk in small amounts. With typical doses, risk to infant is low, but monitor for sedation and poor feeding. Avoid in breastfeeding mothers with infants under 2 months or with compromised renal function. |
| Lactation Rating | L2 (Safer) |
| Teratogenic Risk | First trimester: Acetaminophen considered low risk; codeine associated with neural tube defects, cleft palate, and congenital heart defects in retrospective studies, but absolute risk is small. Second and third trimesters: Chronic high-dose acetaminophen may cause fetal hepatotoxicity; codeine may produce neonatal respiratory depression and withdrawal if used near term. Avoid in third trimester due to risk of premature closure of ductus arteriosus with codeine. |
| Fetal Monitoring | Maternal: liver function tests if high-dose acetaminophen; monitor for respiratory depression, sedation, and constipation. Fetal: ultrasound for congenital anomalies if first-trimester exposure; fetal heart rate monitoring if codeine near term. Neonatal: observe for withdrawal symptoms (irritability, hypertonia) and respiratory depression for 48 hours after birth. |
| Fertility Effects | Acetaminophen: limited data; high-dose chronic use may impair ovulation via prostaglandin inhibition. Codeine: may reduce libido and cause sexual dysfunction in males; no direct evidence of fertility impairment in females. Overall, minimal impact on fertility with short-term use. |
| Food/Dietary |
| Avoid alcohol; may increase hepatotoxicity risk. No specific food restrictions, but maintain adequate hydration. Codeine absorption may be affected by high-fat meals; take consistently with or without food. |
| Clinical Pearls | Phenaphen-650 w/ Codeine contains acetaminophen 650 mg and codeine phosphate (30 mg or 60 mg). Monitor for acetaminophen hepatotoxicity; do not exceed 4 g/day from all sources. Codeine is a prodrug metabolized by CYP2D6 to morphine; ultrarapid metabolizers may experience toxicity and are at risk for respiratory depression. Use lowest effective dose for shortest duration. Avoid in patients with known G6PD deficiency due to potential hemolysis from acetaminophen. |
| Patient Advice | Do not take more than directed; overdose of acetaminophen can cause severe liver damage. · Avoid alcohol while taking this medication. · Do not take with other products containing acetaminophen without consulting a healthcare provider. · This medication may cause drowsiness or dizziness; avoid driving or operating machinery until you know how it affects you. · Seek emergency medical attention if you have shallow breathing, slow heartbeat, or severe drowsiness. · Do not use if you have a history of breathing problems or a head injury. · Keep out of reach of children. · Consult a doctor if you are pregnant, planning to become pregnant, or breastfeeding. |