PAPA-DEINE #4
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PAPA-DEINE #4 (PAPA-DEINE #4).
Acetaminophen: centrally acting analgesic and antipyretic, inhibits cyclooxygenase (COX) enzymes, primarily in the CNS, reducing prostaglandin synthesis. Codeine: opioid agonist, binds to mu-opioid receptors in the CNS, altering pain perception and emotional response to pain.
| Metabolism | Acetaminophen: Primarily metabolized in the liver via glucuronidation (UGT1A1, UGT1A6, UGT1A9) and sulfation (SULT1A1, SULT1A3); a minor pathway via CYP2E1 yields toxic NAPQI, which is detoxified by glutathione. Codeine: Metabolized by CYP2D6 to morphine (active), and by CYP3A4 to norcodeine. |
| Excretion | Renal: ~90% (70% as glucuronide conjugates, 10% as morphine, 10% as normorphine). Biliary/fecal: ~10%. |
| Half-life | 2-4 hours. In hepatic or renal impairment, half-life may increase to 4-6 hours, requiring dose adjustment. |
| Protein binding | 35% bound to albumin. |
| Volume of Distribution | 3-5 L/kg. Large Vd indicates extensive tissue distribution. |
| Bioavailability | Oral: 40-50% (first-pass effect). IV: 100%. |
| Onset of Action | Oral: 30-60 min. IV: 5-10 min. IM: 10-30 min. |
| Duration of Action | Oral: 4-6 hours. IV/IM: 3-5 hours. |
1-2 tablets orally every 4-6 hours as needed for pain, not to exceed 8 tablets per day.
| Dosage form | TABLET |
| Renal impairment | CrCl 30-50 mL/min: extend dosing interval to every 6-8 hours; CrCl <30 mL/min: not recommended due to risk of acetaminophen accumulation and codeine toxicity. |
| 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 | Weight-based: acetaminophen 10-15 mg/kg/dose and codeine 0.5-1 mg/kg/dose orally every 4-6 hours as needed; maximum acetaminophen 75 mg/kg/day, codeine limited due to CYP2D6 variability and risk of respiratory depression. |
| Geriatric use | Initiate with lowest effective dose (e.g., 1 tablet every 6 hours), monitor for respiratory depression, constipation, and falls; avoid in frail elderly or those with impaired renal/hepatic function; use with caution due to increased sensitivity and slower metabolism. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for PAPA-DEINE #4 (PAPA-DEINE #4).
| Breastfeeding | Acetaminophen enters breast milk in low amounts (M/P ratio ~0.91), considered compatible. Codeine is present in breast milk; M/P ratio ~2.3. In mothers who are CYP2D6 ultrarapid metabolizers, codeine can produce toxic morphine levels in infant, leading to risk of neonatal opioid toxicity (CNS depression, apnea). Contraindicated in lactation unless benefits outweigh risks; prefer non-opioid alternatives. |
| Teratogenic Risk | PAPA-DEINE #4 (acetaminophen 300 mg + codeine phosphate 30 mg). Acetaminophen is generally considered low risk in pregnancy; codeine is associated with increased risk of congenital malformations, particularly respiratory and cardiac defects, in first trimester. Chronic use in third trimester may lead to neonatal opioid withdrawal syndrome (NOWS). Use only if clearly needed and at lowest effective dose for shortest duration. |
■ FDA Black Box Warning
Acetaminophen: Risk of severe liver injury (hepatotoxicity) with doses exceeding 4000 mg per day or in patients with hepatic impairment. Codeine: Risk of respiratory depression, especially in children, and risk of opioid addiction, abuse, and misuse.
| Serious Effects |
Hypersensitivity to acetaminophen or codeine, severe hepatic impairment, acute or severe bronchial asthma, respiratory depression, paralytic ileus, suspected or known gastrointestinal obstruction, use of MAO inhibitors within 14 days.
| Precautions | Hepatotoxicity (acetaminophen), respiratory depression (codeine), opioid-induced hyperalgesia, tolerance, dependence, withdrawal, risk of serotonin syndrome with serotonergic drugs, risk of adrenal insufficiency, severe hypotension, seizure, and increased intracranial pressure. |
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| Fetal Monitoring | Monitor maternal: pain scores, respiratory rate, sedation, bowel function. Fetal: uterine activity and fetal heart rate if used during labor. Neonatal: observe for signs of opioid withdrawal (irritability, hypertonia, feeding difficulties) if used chronically near term. |
| Fertility Effects | Acetaminophen has minimal known effect on fertility. Chronic opioid use may disrupt hypothalamic-pituitary-gonadal axis, potentially causing menstrual irregularities and reduced fertility. Effect is reversible upon discontinuation. |