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 |
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 | 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 is excreted into breast milk. M/P ratio for codeine is not well established; however, its active metabolite morphine has an M/P ratio of approximately 2.5:1. Risk of infant sedation and respiratory depression, especially in CYP2D6 ultra-rapid metabolizers. Contraindicated during breastfeeding per FDA label due to risk of serious adverse reactions in infants. |
| Teratogenic Risk |
■ 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 or codeine; significant respiratory depression; acute or severe bronchial asthma; GI obstruction (including paralytic ileus); suspected surgical abdomen; concurrent use of MAOIs or within 14 days; post-operative pain management in children after tonsillectomy/adenoidectomy; use in children <12 years; use in patients with known CYP2D6 ultra-rapid metabolism; women who are breastfeeding (especially with ultra-rapid metabolism); severe hepatic impairment; chronic alcoholism; active liver disease.
| Precautions |
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| 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. |
| 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. |