PHENAPHEN W/ CODEINE NO. 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 an opioid agonist that binds to mu-opioid receptors, inhibiting adenylate cyclase and reducing cAMP production, leading to decreased neurotransmitter release and modulation of pain perception. Acetaminophen produces analgesia through central cyclooxygenase (COX) inhibition and activation of descending serotonergic pathways.
| Metabolism | Codeine undergoes hepatic metabolism via CYP2D6 to active metabolite morphine, via CYP3A4 to norcodeine, and via glucuronidation. Acetaminophen is primarily metabolized by glucuronidation and sulfation, with minor CYP2E1 oxidation producing NAPQI. |
| Excretion | Renal excretion of codeine and its metabolites (morphine, norcodeine, codeine-6-glucuronide, morphine-3-glucuronide, morphine-6-glucuronide). Approximately 80-90% of the dose is eliminated in urine within 24 hours, with about 10% as unchanged codeine, 10% as norcodeine, 10% as free and conjugated morphine, and the remainder as conjugated codeine and other metabolites. Fecal excretion accounts for less than 10%. |
| Half-life | Codeine: terminal elimination half-life is 2.5–3.5 hours in healthy adults; morphine: 1.5–4.5 hours; morphine-6-glucuronide: 2.5–4.5 hours. Half-life is prolonged in hepatic or renal impairment; in end-stage renal disease, half-life of codeine and metabolites may exceed 24 hours. |
| Protein binding | Codeine: approximately 25% bound to albumin and alpha-1-acid glycoprotein. Morphine: 30–35% bound, mainly to albumin. |
| Volume of Distribution | Codeine: Vd approximately 3–6 L/kg; morphine: Vd 1–4 L/kg. Large Vd indicates extensive tissue distribution; crosses placenta and enters breast milk. |
| Bioavailability | Oral bioavailability of codeine is 40–70% due to first-pass metabolism (O-demethylation by CYP2D6 to morphine and glucuronidation). Bioavailability varies with CYP2D6 phenotype; poor metabolizers have 30% lower morphine production. |
| Onset of Action | Oral: codeine onset of analgesia is 30–60 minutes; peak effect at 1–2 hours. Onset of antitussive effect is similar. |
| Duration of Action | Analgesia: 4–6 hours. Duration is shorter with repeated dosing due to tolerance; effect may be prolonged in hepatic or renal impairment. |
One to two tablets (30-60 mg codeine phosphate/300-600 mg acetaminophen) orally every 4 hours as needed for pain, maximum 12 tablets per day.
| Dosage form | CAPSULE |
| Renal impairment | CrCl 10-50 mL/min: administer 75% of usual dose every 4 hours; CrCl <10 mL/min: administer 50% of usual dose every 6 hours. Avoid use or reduce dose due to risk of codeine accumulation. |
| Liver impairment | Child-Pugh Class A: no adjustment; Child-Pugh Class B: reduce dose by 50% and extend interval to every 6 hours; Child-Pugh Class C: contraindicated due to acetaminophen hepatotoxicity and impaired codeine metabolism. |
| Pediatric use | Weight-based dosing for children ≥2 years: codeine 0.5-1 mg/kg/dose, acetaminophen 10-15 mg/kg/dose orally every 4-6 hours as needed, maximum 5 doses/24 hours. Maximum daily acetaminophen 75 mg/kg/day. Contraindicated in children <12 years due to risk of respiratory depression. |
| Geriatric use | Initiate with lowest effective dose (e.g., one tablet every 6 hours) due to increased sensitivity, reduced clearance, and higher risk of respiratory depression, falls, and acetaminophen hepatotoxicity. Maximum 6 tablets daily. |
| 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: Present in breast milk; M/P ratio approximately 2.5. Risk of infant sedation and respiratory depression, especially in CYP2D6 ultrarapid metabolizers. Use with caution; lowest effective dose for shortest duration. Phenacetin: Contraindicated in lactation due to risk of methemoglobinemia and hemolysis in infant. |
| Teratogenic Risk |
■ FDA Black Box Warning
Addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; interactions with drugs affecting CYP3A4, CYP2D6 metabolism; hepatotoxicity (acetaminophen); ultra-rapid metabolism of codeine to morphine in CYP2D6 ultrarapid metabolizers (especially children), leading to fatal respiratory depression.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to codeine, acetaminophen, or any component; significant respiratory depression; acute or severe bronchial asthma; known or suspected gastrointestinal obstruction (e.g., paralytic ileus); use in children under 12 years; post-operative management in children after tonsillectomy/adenoidectomy; concurrent use of MAOIs or within 14 days; use in patients with severe hepatic impairment.
| Precautions | Respiratory depression risks; use in elderly, cachectic, or debilitated patients; risk of opioid-induced hyperalgesia; severe hypotension; risk of serotonin syndrome with serotonergic drugs; adrenal insufficiency; hepatotoxicity from acetaminophen overdose; risks of use in patients with gastrointestinal obstruction, head injury, impaired consciousness; risks of driving and operating machinery. |
Loading safety data…
| Codeine: First trimester: Risk of congenital malformations not clearly established; may be associated with respiratory malformations. Second/third trimesters: Chronic use may lead to fetal dependence and neonatal opioid withdrawal syndrome. Use near term: Respiratory depression in neonate. Phenacetin: Withdrawn from market due to nephrotoxicity and carcinogenicity; historical data suggest possible teratogenicity, but not applicable to modern formulations. |
| Fetal Monitoring | Maternal: Pain control, respiratory rate, sedation level, bowel function. Fetal/neonatal: Ultrasound for growth restriction if chronic use; monitor for neonatal withdrawal symptoms after delivery (e.g., irritability, poor feeding, respiratory distress). |
| Fertility Effects | Codeine: No known direct effect on fertility. Phenacetin: Chronic use may impair fertility due to renal toxicity. Overall, limited data suggest no significant impact from therapeutic use. |