PAPA-DEINE #3
Clinical safety rating
cautionComprehensive clinical and safety monograph for PAPA-DEINE #3 (PAPA-DEINE #3).
Acetaminophen produces analgesia and antipyresis via central COX-2 inhibition and activation of descending serotonergic pathways. Codeine is a prodrug converted to morphine, a mu-opioid receptor agonist, which inhibits ascending pain pathways and alters pain perception.
| Metabolism | Acetaminophen is primarily metabolized via glucuronidation and sulfation, with a minor pathway via CYP2E1 to NAPQI (toxic metabolite). Codeine is metabolized by CYP2D6 to morphine (active), by CYP3A4 to norcodeine, and by glucuronidation. |
| Excretion | Primarily renal (90% as glucuronide conjugates, 10% as morphine, codeine, and norcodeine). Biliary/fecal elimination accounts for <5%. |
| Half-life | Codeine: 2.5-3 hours; Acetaminophen: 2-3 hours; Morphine (active metabolite): 2-3 hours. In hepatic impairment, codeine half-life may extend to 4-6 hours. |
| Protein binding | Codeine: ~25% bound to albumin; Acetaminophen: 10-25% bound; Morphine: 30-35% bound to albumin. |
| Volume of Distribution | Codeine: 3-6 L/kg; Acetaminophen: 0.9-1.0 L/kg; Morphine: 3-4 L/kg. Codeine's high Vd indicates extensive tissue distribution. |
| Bioavailability | Codeine: 53% (oral) due to first-pass metabolism; Acetaminophen: 85-90% (oral); Morphine (from codeine): 0.05-10% depending on CYP2D6 phenotype. |
| Onset of Action | Oral: 30-45 minutes for analgesia. |
| Duration of Action | Analgesia: 4-6 hours. Clinical note: Duration may be prolonged in CYP2D6 poor metabolizers due to reduced morphine formation. |
| Molecular Weight | 330.36 |
1-2 tablets orally every 4-6 hours as needed for pain, not to exceed 12 tablets in 24 hours. Each tablet contains acetaminophen 300 mg, codeine phosphate 30 mg.
| Dosage form | TABLET |
| Renal impairment | GFR 30-50 mL/min: administer every 6 hours; GFR 10-29 mL/min: administer every 8 hours; GFR <10 mL/min: administer every 12 hours. Avoid in severe renal impairment due to acetaminophen accumulation. |
| Liver impairment | Child-Pugh class A: no adjustment; Child-Pugh class B: reduce dose by 50% or extend interval to every 8 hours; Child-Pugh class C: contraindicated. |
| Pediatric use | Not recommended for children under 12 years. For adolescents 12-18 years: 1 tablet orally every 4-6 hours as needed, max 6 tablets/day. Weight-based dosing not established. |
| Geriatric use | Initiate at lowest dose, 1 tablet every 6 hours, and titrate cautiously due to increased sensitivity and risk of acetaminophen hepatotoxicity. Monitor renal and hepatic function. |
| 1st trimester | Avoid; associated with neural tube defects and cardiovascular malformations due to folate antagonism. |
| 2nd trimester | Use with caution; risk of oligohydramnios and fetal renal impairment, especially with chronic use. |
| 3rd trimester | Avoid; risk of premature closure of ductus arteriosus, oligohydramnios, and neonatal renal impairment. |
Clinical note
Comprehensive clinical and safety monograph for PAPA-DEINE #3 (PAPA-DEINE #3).
| Placental transfer | Readily crosses the placenta; fetal levels reach 50-100% of maternal concentrations. |
| Breastfeeding | Excreted in breast milk in small amounts; potential for kernicterus in neonates, especially those with G6PD deficiency. Use only if benefit outweighs risk; monitor infant for jaundice. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Pregnancy Category C prior to FDA pregnancy labeling rule. First trimester: Risk of neural tube defects and oral clefts with codeine component; limited data on papaverine. Second trimester: Potential for fetal growth restriction with chronic use; codeine associated with respiratory depression. Third trimester: Risk of neonatal opioid withdrawal syndrome (NOWS) and respiratory depression at delivery; papaverine may cause fetal bradycardia. |
| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, and bowel function. Fetal monitoring: Assess fetal movement and heart rate; non-stress test and biophysical profile for chronic use. Neonatal monitoring for NOWS if used beyond 30 weeks gestation. |
| Fertility Effects | Codeine: May increase prolactin and disrupt ovulatory cycles; reduced libido. Papaverine: Vasodilatory effects may theoretically improve uterine blood flow; limited data on fertility. No specific studies on combination product. |
■ FDA Black Box Warning
Risk of medication errors: Confusion between different concentrations and dosage forms can lead to accidental overdose and death. Respiratory depression: Life-threatening respiratory depression may occur, especially in elderly, cachectic, or debilitated patients. Neonatal opioid withdrawal syndrome: Prolonged use during pregnancy can result in neonatal withdrawal. CYP2D6 metabolism: Ultra-rapid metabolizers of codeine convert codeine to morphine faster, leading to higher morphine levels and risk of fatal respiratory depression. Accidental exposure: Ingesting even one dose by a child can be fatal.
| Serious Effects |
Hypersensitivity to papa-deine or any componentSevere hepatic impairmentSevere renal impairment (CrCl <30 mL/min)Active peptic ulcer diseaseBleeding disordersHistory of asthma or allergic-type reactions after taking aspirin or NSAIDsCoronary artery bypass graft surgery (perioperative pain)Third trimester of pregnancy (risk of premature ductus arteriosus closure)
| Precautions | Acetaminophen hepatotoxicity: Severe liver injury, including acute liver failure, may occur with doses exceeding 4 g/day or with pre-existing liver disease. Respiratory depression: Use with caution in patients with respiratory compromise. Drug dependence and abuse: Codeine has addiction potential and may cause physical and psychological dependence. Serotonin syndrome: Concomitant use with serotonergic drugs may cause serotonin syndrome. CYP2D6 ultra-rapid metabolizers: Increased risk of morphine toxicity. Use in children: Not recommended for children under 12 years; for those 12-18 years, avoid if at risk of respiratory depression. Avoid alcohol and other CNS depressants. |
| Food/Dietary | Grapefruit and grapefruit juice may inhibit CYP2D6, reducing codeine efficacy. Avoid excessive alcohol; increases acetaminophen hepatotoxicity. |
| Clinical Pearls | Contains codeine (prodrug converted to morphine via CYP2D6) and acetaminophen. Avoid in children <12 years due to risk of respiratory depression. Check CYP2D6 status if ultra-rapid metabolizer. Never exceed 4g/day acetaminophen. Monitor for constipation, abuse potential. |
| Patient Advice | Take only as prescribed; do not exceed 4 grams of acetaminophen per day. · Avoid alcohol; risk of liver damage. · May cause drowsiness; avoid driving or operating machinery. · Do not use with other acetaminophen-containing products. · Report signs of liver injury: yellow skin/eyes, dark urine, abdominal pain. |
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