PROPOXYPHENE HYDROCHLORIDE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PROPOXYPHENE HYDROCHLORIDE (PROPOXYPHENE HYDROCHLORIDE).
Propoxyphene hydrochloride is a centrally acting opioid analgesic that binds to mu-opioid receptors in the central nervous system, inhibiting ascending pain pathways and altering perception of and response to pain.
| Metabolism | Hepatic via CYP3A4 mediated N-demethylation to norpropoxyphene, an active metabolite with similar analgesic but longer half-life; also undergoes O-demethylation and glucuronidation. |
| Excretion | Primarily renal (70-90% as unchanged drug and metabolites, including norpropoxyphene); biliary/fecal excretion accounts for less than 10%. |
| Half-life | 6–12 hours (parent drug); norpropoxyphene metabolite half-life 30–36 hours, accumulates with repeated dosing, increasing risk of toxicity, especially in elderly or renal impairment. |
| Protein binding | Approximately 80%, primarily to albumin. |
| Volume of Distribution | Approximately 16 L/kg (0.16 L/kg for parent drug; high for metabolite norpropoxyphene due to tissue binding). |
| Bioavailability | Oral: 30–70% due to extensive first-pass hepatic metabolism. |
| Onset of Action | Oral: 30–60 minutes. |
| Duration of Action | 4–6 hours after single oral dose; prolonged with repeated dosing due to metabolite accumulation. |
65 mg orally every 4 hours as needed for pain; maximum 390 mg per day.
| Dosage form | CAPSULE |
| Renal impairment | GFR 10-50 mL/min: Administer 65 mg every 6 hours; GFR <10 mL/min: Administer 65 mg every 8-12 hours. |
| Liver impairment | Child-Pugh Class A: No adjustment; Child-Pugh Class B: Reduce dose by 50% (e.g., 32.5 mg every 4 hours); Child-Pugh Class C: Avoid use. |
| Pediatric use | Not recommended for pediatric patients due to risk of respiratory depression and lack of safety data. |
| Geriatric use | Initiate at 65 mg every 6-8 hours; monitor for CNS effects and constipation; maximum 390 mg per day. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for PROPOXYPHENE HYDROCHLORIDE (PROPOXYPHENE HYDROCHLORIDE).
| Breastfeeding | Propoxyphene is excreted into human breast milk. M/P ratio: approximately 0.5–1.0 (low). In infants, estimated daily dose via milk is <2% of maternal weight-adjusted dose. American Academy of Pediatrics considers it compatible with breastfeeding but warn against prolonged use due to potential CNS depression in infant and risk of dependence. Monitor infant for sedation, poor feeding. |
| Teratogenic Risk | Propoxyphene hydrochloride crosses the placenta. First trimester: Limited human data; animal studies show no teratogenicity at clinically relevant doses, but risk cannot be excluded. Second and third trimesters: Chronic use may lead to fetal dependence and withdrawal (neonatal abstinence syndrome). Near term: Use may cause neonatal respiratory depression if administered shortly before delivery. |
■ FDA Black Box Warning
WARNING: RISK OF SERIOUS CARDIOVASCULAR EVENTS AND DEATH. Propoxyphene has been associated with QT interval prolongation and serious cardiac toxicity, including fatal arrhythmias, especially at higher doses. The drug is contraindicated in patients with a history of QT prolongation, electrolyte abnormalities, or concurrent use of QT-prolonging drugs. Because of its cardiac toxicity, propoxyphene should be reserved for patients for whom alternative analgesics are ineffective or not tolerated. FDA has withdrawn propoxyphene from the market (2010); however, this warning applies to historical use.
| Serious Effects |
Hypersensitivity to propoxyphene or any component; significant respiratory depression; acute or severe bronchial asthma; known or suspected paralytic ileus; concomitant use with MAO inhibitors; QT prolongation or concomitant QT-prolonging drugs; electrolyte abnormalities (hypokalemia, hypomagnesemia); use during or within 14 days following MAOI therapy
| Precautions | Risk of QT prolongation and fatal arrhythmias; opioid-induced respiratory depression; abuse potential; dependence and withdrawal; CNS depression; hepatic impairment; renal impairment; concurrent use of alcohol or other CNS depressants; elderly patients; use in pregnancy and lactation. |
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| Fetal Monitoring | Monitor maternal vital signs (BP, HR, respiratory rate) and pain scores. Fetal: assess growth and amniotic fluid volume if used chronically; near term, monitor fetal heart rate patterns. Neonatal: observe for signs of withdrawal (irritability, hypertonia, feeding difficulties) for 24–48 hours if used in late pregnancy. |
| Fertility Effects | Propoxyphene may affect fertility in males and females by altering hormone levels or gonadal function based on animal data. In humans, chronic opioid use can disrupt hypothalamic-pituitary-gonadal axis, leading to menstrual irregularities, anovulation, reduced sperm quality. Reversible upon discontinuation. |