PROPOXYPHENE HYDROCHLORIDE AND ACETAMINOPHEN
Clinical safety rating
cautionComprehensive clinical and safety monograph for PROPOXYPHENE HYDROCHLORIDE AND ACETAMINOPHEN (PROPOXYPHENE HYDROCHLORIDE AND ACETAMINOPHEN).
Propoxyphene is a mu-opioid receptor agonist; acetaminophen inhibits cyclooxygenase (COX) and modulates central pain pathways.
| Metabolism | Propoxyphene: hepatic via CYP3A4 and CYP2D6 to norpropoxyphene (active); acetaminophen: hepatic via conjugation (glucuronidation, sulfation) and CYP2E1. |
| Excretion | Renal: Propoxyphene ~20-25% as unchanged drug and metabolites; Acetaminophen ~85-90% as glucuronide and sulfate conjugates, <5% unchanged. Fecal: Minimal for both. |
| Half-life | Propoxyphene: 6-12 h (prolonged in hepatic disease); Norpropoxyphene (active metabolite): 30-36 h (accumulation risk). Acetaminophen: 2-3 h (prolonged in hepatic disease). |
| Protein binding | Propoxyphene: ~80% bound to albumin; Acetaminophen: 10-25% bound to albumin at therapeutic concentrations. |
| Volume of Distribution | Propoxyphene: 12-26 L/kg (large, extensive tissue distribution; clinical meaning: high CNS penetration). Acetaminophen: 0.9-1.0 L/kg (clinical meaning: uniform distribution, limited tissue binding). |
| Bioavailability | Oral: Propoxyphene ~30-70% due to extensive first-pass metabolism; Acetaminophen ~85-90%. |
| Onset of Action | Oral: Propoxyphene effect within 30-60 min; Acetaminophen antipyretic effect within 30 min. |
| Duration of Action | Propoxyphene: 4-6 h (analgesic); Acetaminophen: 4-6 h (antipyretic/analgesic). Note: Norpropoxyphene may prolong toxicity risk. |
| Molecular Weight | 375.9 |
One tablet (propoxyphene HCl 65 mg/acetaminophen 650 mg) orally every 4 hours as needed for pain; maximum: 6 tablets per day.
| Dosage form | TABLET |
| Renal impairment | Not recommended in severe renal impairment (CrCl <30 mL/min). For moderate impairment (CrCl 30-50 mL/min), reduce frequency to every 6-8 hours; use with caution. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh C). For Child-Pugh A or B, reduce dose by 50% and monitor hepatic function; maximum duration limited. |
| Pediatric use | Not recommended for pediatric use due to risk of respiratory depression and propoxyphene toxicity; safety and efficacy not established. |
| Geriatric use | Initiate with lower doses (e.g., half tablet) and increase cautiously; avoid in elderly with renal or hepatic impairment; monitor for CNS and respiratory effects. |
| 1st trimester | Avoid. Associated with increased risk of cardiovascular malformations and neural tube defects. Prolonged use may cause neonatal withdrawal syndrome. |
| 2nd trimester | Avoid. Use only if potential benefit outweighs risk. Risk of fetal dependence and withdrawal. May cause premature closure of ductus arteriosus if used near term. |
| 3rd trimester | Avoid. Prolonged use may result in neonatal opioid withdrawal syndrome. Acetaminophen component generally considered safe at therapeutic doses, but propoxyphene is contraindicated. |
Clinical note
Comprehensive clinical and safety monograph for PROPOXYPHENE HYDROCHLORIDE AND ACETAMINOPHEN (PROPOXYPHENE HYDROCHLORIDE AND ACETAMINOPHEN).
| Placental transfer | Propoxyphene and its metabolite norpropoxyphene cross the placenta, achieving fetal plasma levels approximately 50-60% of maternal levels. Acetaminophen also crosses readily. |
| Breastfeeding | Propoxyphene is excreted into breast milk in small amounts. The relative infant dose is low, but prolonged use may cause neonatal sedation or withdrawal. Acetaminophen is considered compatible. However, given propoxyphene's potential for CNS depression and its withdrawal from many markets due to toxicity, alternative analgesics are preferred. Caution is advised. |
| Lactation Rating | L3 - Moderately Safe |
| Teratogenic Risk | Propoxyphene is contraindicated in pregnancy due to risk of neonatal opioid withdrawal syndrome and respiratory depression. Acetaminophen is generally considered safe in pregnancy at therapeutic doses. First trimester: Propoxyphene may increase risk of congenital malformations, though data are limited. Second/third trimester: Prolonged use may cause neonatal opioid withdrawal; high doses near term may cause respiratory depression in the neonate. |
| Fetal Monitoring | Monitor maternal respiratory status, sedation level, and signs of opioid toxicity. For the fetus, monitor for growth restrictions, preterm labor, and non-stress testing in cases of prolonged use. Neonates exposed in utero require monitoring for opioid withdrawal (e.g., Finnegan scoring). |
| Fertility Effects | Propoxyphene may impair fertility in both males and females by disrupting hormonal regulation and affecting sperm or ovum function. Acetaminophen at high doses may also impact fertility; data are limited. Discontinuation may restore fertility. |
■ FDA Black Box Warning
Risk of respiratory depression, addiction, abuse, and misuse; concomitant use with benzodiazepines or CNS depressants may cause profound sedation, respiratory depression, coma, and death.
| Serious Effects |
History of hypersensitivity to propoxyphene or acetaminophenSevere respiratory depressionAcute or severe bronchial asthmaParalytic ileusKnown or suspected gastrointestinal obstructionConcurrent use of MAOIs or within 14 daysSuicidal ideation or history of substance abuseProlonged QT interval
| Precautions | Respiratory depression risk, Abuse and dependence potential, CNS depression with alcohol or other drugs, Hepatotoxicity from acetaminophen overdose, QT prolongation with high doses, Neonatal opioid withdrawal syndrome with prolonged use during pregnancy |
| Food/Dietary | Avoid alcohol; may increase risk of hepatotoxicity and CNS depression. High-fat meals may delay absorption but not clinically significant. |
| Clinical Pearls | Propoxyphene is a weak opioid with a narrow therapeutic index; acetaminophen component limits daily dose due to hepatotoxicity risk. Propoxyphene has been withdrawn in many countries due to cardiotoxicity (QT prolongation, arrhythmias) and overdose risks. Avoid in elderly due to accumulation of norpropoxyphene metabolite. Use with caution in renal impairment. Monitor for CNS depression when combined with other depressants. |
| Patient Advice | Do not exceed recommended dose; acetaminophen overdose can cause severe liver damage. · Propoxyphene may cause dizziness, drowsiness, or confusion; avoid driving or operating machinery. · Avoid alcohol and other CNS depressants during therapy. · Inform your doctor if you have a history of heart rhythm problems, as propoxyphene can affect heart rhythm. · Do not stop abruptly after prolonged use; withdrawal may occur. |
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