PHENAPHEN W/ CODEINE NO. 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.
Phenaphen w/ Codeine No. 4 contains acetaminophen and codeine. Acetaminophen inhibits prostaglandin synthesis in the CNS, reducing pain and fever. Codeine, an opioid prodrug, is converted to morphine via CYP2D6 and binds to mu-opioid receptors, inhibiting ascending pain pathways.
| Metabolism | Acetaminophen is primarily metabolized via conjugation (glucuronidation, sulfation) and CYP2E1-mediated oxidation to NAPQI (toxic metabolite). Codeine is metabolized by CYP2D6 to morphine (active) and CYP3A4 to norcodeine. |
| Excretion | Renal: 90-100% as codeine and metabolites (codeine: 5-15%, morphine: 10%, norcodeine: 10%, morphine-3-glucuronide: 50%, morphine-6-glucuronide: <5%); biliary/fecal: minimal (<5%) |
| Half-life | Codeine: 2.5-3.5 h; morphine: 2-4 h; clinically, analgesia correlates with morphine levels |
| Protein binding | Codeine: ~7% bound to albumin; morphine: ~35% bound to albumin and alpha1-acid glycoprotein |
| Volume of Distribution | Codeine: 3-6 L/kg; morphine: 1-6 L/kg; large Vd indicates extensive tissue distribution |
| Bioavailability | Codeine: 40-70% (oral, due to first-pass metabolism to morphine) |
| Onset of Action | Oral: 30-60 min for analgesia; peak effect 1-2 h |
| Duration of Action | Oral: 4-6 h; analgesia may persist longer with hepatic impairment |
| Molecular Weight | Acetaminophen: 151.16 Da; Codeine: 299.36 Da |
1-2 tablets (300-600 mg acetaminophen / 30-60 mg codeine phosphate) orally every 4 hours as needed for pain; maximum 12 tablets per day.
| Dosage form | CAPSULE |
| Renal impairment | GFR 30-50 mL/min: administer 75% of normal dose every 6 hours; GFR 10-29 mL/min: administer 50% of normal dose every 8 hours; GFR <10 mL/min: not recommended due to risk of metabolite accumulation. |
| Liver impairment | Child-Pugh class A: no adjustment; Child-Pugh class B: reduce dose by 50% or extend interval; Child-Pugh class C: contraindicated. |
| Pediatric use | Weight-based dosing: codeine 0.5-1 mg/kg/dose every 4-6 hours (max 60 mg/dose); acetaminophen 10-15 mg/kg/dose every 4-6 hours (max 5 doses/day). Note: codeine is contraindicated in children <12 years due to risk of respiratory depression. |
| Geriatric use | Initiate with 1 tablet every 6 hours due to increased sensitivity and risk of respiratory depression. Titrate cautiously; maximum 8 tablets per day. |
| 1st trimester | Contraindicated. Risk of teratogenicity (neural tube defects, gastroschisis) and neonatal withdrawal. |
| 2nd trimester | Use only if necessary; risk of miscarriage, IUGR, and preterm labor. |
| 3rd trimester | Contraindicated. Risk of neonatal respiratory depression, withdrawal, and persistent pulmonary hypertension. |
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 crosses readily. Acetaminophen placental transfer is rapid and complete. |
| Breastfeeding |
■ FDA Black Box Warning
Risk of medication errors: Misuse of different strengths can lead to fatal overdose. Addiction, abuse, and misuse: Can lead to addiction and fatal overdose. Life-threatening respiratory depression: Especially in elderly, cachectic, or debilitated patients. Neonatal opioid withdrawal syndrome: Prolonged use during pregnancy can result in withdrawal. CYP2D6 ultra-rapid metabolizers: May experience life-threatening respiratory depression or death from codeine. Accidental ingestion: Especially in children, can be fatal.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to acetaminophen, codeine, or any componentSevere asthma, acute or severe bronchospasmKnown or suspected gastrointestinal obstructionConcurrent use of MAOIs or within 14 daysPostoperative pain management in children after tonsillectomy/adenoidectomySignificant respiratory depressionAcute alcoholism, delirium tremensSevere hepatic impairmentAcute or chronic diarrhea with pseudomembranous colitisCYP2D6 ultra-rapid metabolizers
| Precautions | Respiratory depression; drug dependence; renal/hepatic impairment; hepatotoxicity (acetaminophen); opioid-induced hyperalgesia; serotonin syndrome; severe hypotension; adrenal insufficiency; seizures; use in elderly, cachectic, or debilitated patients; pediatric use; mastocytosis; inflammatory bowel disease; acute abdominal conditions; interactions with CNS depressants, MAOIs, and other drugs. |
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| Codeine and acetaminophen pass into breast milk. Codeine is metabolized to morphine; risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers. Use lowest dose for shortest duration; monitor infant for sedation, respiratory depression. Consider non-opioid alternatives. |
| Lactation Rating | L3 - Moderately Safe |
| Teratogenic Risk | First trimester: Limited human data; animal studies show increased risk of neural tube defects and other malformations at high doses. Risk of respiratory depression in neonates if used near term. Second and third trimesters: Prolonged use may lead to neonatal opioid withdrawal syndrome. Avoid in first and third trimesters unless benefit outweighs risk. |
| Fetal Monitoring | Monitor maternal respiratory status, sedation level, and bowel function. For fetus/nonate: monitor for signs of neonatal opioid withdrawal syndrome (NOWs) including irritability, hypertonia, tremors, respiratory distress, and poor feeding. Perform umbilical cord blood gas analysis at delivery if opioid use near term. |
| Fertility Effects | Opioids may impair fertility by affecting hypothalamic-pituitary-gonadal axis, leading to decreased libido, anovulation, and menstrual irregularities in women. Reversible upon discontinuation. |
| Food/Dietary | Avoid alcohol due to increased hepatotoxicity risk. Grapefruit juice may inhibit CYP3A4-mediated metabolism of codeine, potentially increasing toxicity. High-fat meals may delay absorption but not significantly alter overall exposure. No specific dietary restrictions, but maintain adequate hydration to prevent constipation. |
| Clinical Pearls | Acetaminophen (325 mg) + Codeine (60 mg) per tablet. Maximum acetaminophen dose from all sources ≤4000 mg/day. Codeine is a prodrug requiring CYP2D6 metabolism; poor metabolizers have reduced efficacy, ultrarapid metabolizers risk toxicity. Use with caution in children undergoing tonsillectomy/adenoidectomy for OSA due to fatal respiratory depression. Half-life: codeine 2.5-3h, acetaminophen 1.5-2.5h. Onset: 30-60 min. Duration: 4-6h. |
| Patient Advice | Do not exceed 12 tablets in 24 hours due to risk of liver damage from acetaminophen. · Avoid alcohol while taking this medication. · Do not take with other products containing acetaminophen or codeine. · May cause drowsiness; avoid driving or operating machinery until you know how you react. · Take with food or milk to reduce stomach upset. · Store securely; keep out of reach of children, as accidental overdose can be fatal. · Contact your doctor if pain does not improve after 5 days. · Do not stop suddenly after long-term use; taper under medical supervision to avoid withdrawal. |