PAPA-DEINE #4
Clinical safety rating
cautionComprehensive 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. |
| Molecular Weight | 325 mg acetaminophen (MW 151.2 Da) + 60 mg codeine phosphate (MW 406.4 Da). Combined: 2271.2 Da total. |
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 | Avoid due to risk of neural tube defects and other malformations with high-dose codeine; acetaminophen is generally considered safe but limit dose. Use only if clearly needed and no alternative. |
| 2nd trimester | Use with caution; acetaminophen is considered safe, but codeine associated with neonatal opioid withdrawal and limited data. May cause fetal dependence if used chronically near term. |
| 3rd trimester | Avoid prolonged use due to risk of neonatal opioid withdrawal syndrome and respiratory depression. Acetaminophen at recommended doses is safe. Short-term use only if benefits outweigh risks. |
Clinical note
Comprehensive clinical and safety monograph for PAPA-DEINE #4 (PAPA-DEINE #4).
| Placental transfer | Both acetaminophen and codeine cross the placenta. Codeine achieves fetal concentrations approximately 50-60% of maternal levels, with active metabolite morphine also crossing. Acetaminophen crosses readily with fetal levels similar to maternal. |
| Breastfeeding | Codeine is excreted into breast milk; risk of opioid effects in breastfed infant, especially with ultrarapid CYP2D6 metabolism. Acetaminophen is considered compatible. Use lowest effective dose for shortest duration. Monitor infant for drowsiness, feeding difficulties, or respiratory depression. Genetic testing for CYP2D6 activity may be considered. |
| Lactation Rating | L3: Moderately Safe (codeine); L1: Safest (acetaminophen). Combined product: generally caution advised. |
| 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. |
| 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. |
■ 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, codeine, or any componentAcute or severe bronchial asthma, hypercapnia, respiratory depressionParalytic ileus, suspected or known gastrointestinal obstructionConcurrent use of MAO inhibitors or within 14 daysSevere hepatic impairment or active liver diseaseHead injury or increased intracranial pressureStatus asthmaticusChildren <12 years for opioid-containing product (FDA warning due to risk of respiratory depression)
| 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. |
| Food/Dietary | Avoid excessive intake of caffeine-containing foods or beverages as papaverine may increase caffeine effects. No specific food interactions known, but take with food if gastrointestinal upset occurs. |
| Clinical Pearls | Papa-Deine #4 contains papaverine, a phosphodiesterase inhibitor, and may cause hypotension; monitor blood pressure closely when used with antihypertensives. Avoid in patients with glaucoma due to anticholinergic effects. Papaverine can cause hepatotoxicity; liver function tests should be monitored. |
| Patient Advice | Take this medication exactly as prescribed; do not crush or chew tablets. · Dizziness, drowsiness, or flushed skin may occur; avoid driving until you know how the medication affects you. · Alcohol can increase drowsiness; limit alcohol intake. · Report any vision changes, eye pain, or jaundice to your healthcare provider immediately. · Store at room temperature away from moisture and heat. |
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