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. |
| Molecular Weight | Acetaminophen: 151.17 Da; Codeine: 299.36 Da; Codeine phosphate: 397.37 Da (salt). |
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 | Avoid due to risk of neural tube defects and congenital anomalies associated with codeine use; acetaminophen is generally considered safe at therapeutic doses. |
| 2nd trimester | Use with caution; codeine may cause fetal respiratory depression and acetaminophen is safe at therapeutic doses. |
| 3rd trimester | Avoid; prolonged use may lead to neonatal opioid withdrawal syndrome, respiratory depression, and premature closure of ductus arteriosus. |
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 freely crosses; acetaminophen crosses readily. |
■ 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 acetaminophen, codeine, or any componentRespiratory depressionAcute or severe bronchial asthmaKnown glucose-6-phosphate dehydrogenase deficiency (with acetaminophen)Concomitant use of MAOIs or within 14 daysObstructive bowel disorderSevere 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…
| Breastfeeding | Codeine is excreted into breast milk in low levels; however, ultra-rapid metabolizers of codeine may produce high levels of morphine, posing risk of infant respiratory depression. Acetaminophen is considered safe. Use lowest effective dose for shortest duration and monitor infant for sedation and respiratory depression. |
| Lactation Rating | L3 (Moderately Safe) for codeine; acetaminophen is L1 (Safe). Overall rating L3. |
| Teratogenic Risk | 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. |
| Food/Dietary | Avoid ethanol; may increase risk of hepatotoxicity. Grapefruit juice may inhibit CYP2D6 and alter codeine metabolism, but clinical significance is unclear. High-fat meals may delay absorption. |
| Clinical Pearls | Phenaphen w/ Codeine No. 3 contains acetaminophen 325 mg and codeine phosphate 30 mg. Codeine is a prodrug metabolized to morphine via CYP2D6; poor metabolizers may have reduced analgesia, while ultrarapid metabolizers risk toxicity. Avoid exceeding 4000 mg/day acetaminophen due to hepatotoxicity risk. Use cautiously in patients with respiratory compromise, head injury, or history of substance abuse. May cause constipation; consider prophylactic laxatives. |
| Patient Advice | Do not exceed 12 tablets in 24 hours due to acetaminophen content. · Avoid alcohol while taking this medication. · This drug may cause drowsiness; avoid driving or operating machinery. · Take with food if nausea occurs. · Do not use with other products containing acetaminophen. · Report difficulty breathing or signs of allergic reaction immediately. |