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. |
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 | 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 | Acetaminophen: low levels in breast milk, M/P ratio 0.9-1.0, considered compatible. Codeine: M/P ratio 0.20-0.25, but metabolite morphine can accumulate; risk of neonatal CNS depression, especially in mothers who are CYP2D6 ultra-rapid metabolizers. Use with caution; lowest effective dose. Discontinue if infant shows drowsiness or difficulty feeding. |
| Teratogenic Risk |
■ 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 codeine, significant respiratory depression, acute or severe bronchial asthma, GI obstruction, known CYP2D6 ultrarapid metabolizer, children <12y (post-tonsillectomy/adenoidectomy), concomitant MAOIs or within 14 days, pregnancy (prolonged use leading to neonatal opioid withdrawal syndrome), breastfeeding (increased risk in infants).
| 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. |
Loading safety data…
| 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. |