PROPOXYPHENE HYDROCHLORIDE 65
Clinical safety rating
cautionComprehensive clinical and safety monograph for PROPOXYPHENE HYDROCHLORIDE 65 (PROPOXYPHENE HYDROCHLORIDE 65).
Propoxyphene is a centrally acting opioid agonist that binds to mu-opioid receptors in the central nervous system, inhibiting pain signal transmission and altering pain perception. It also has local anesthetic effects.
| Metabolism | Primarily hepatic via N-demethylation (CYP3A4) to norpropoxyphene, an active metabolite with longer half-life and potential for toxicity. |
| Excretion | Renal excretion of unchanged drug (approximately 20-30%) and metabolites; approximately 40-60% as conjugated metabolites; minor biliary/fecal elimination. |
| Half-life | 6-12 hours (mean ~8 hours); prolonged in hepatic impairment and elderly; accumulation possible with repeated dosing. |
| Protein binding | 40-50% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | 8-16 L/kg; extensive tissue distribution, including CNS. |
| Bioavailability | Oral: 30-70% due to first-pass metabolism. |
| Onset of Action | Oral: 30-60 minutes. |
| Duration of Action | 4-6 hours; longer with hepatic impairment or in elderly patients. |
| Molecular Weight | 375.9 |
65 mg orally every 4 hours as needed for pain; maximum 390 mg/day.
| Dosage form | CAPSULE |
| Renal impairment | GFR 10-50 mL/min: administer 50% of normal dose every 6 hours. GFR <10 mL/min: administer 50% of normal dose every 6-8 hours or avoid use; increase risk of accumulation of toxic metabolite norpropoxyphene. |
| Liver impairment | Child-Pugh Class A and B: reduce dose by 50% and extend dosing interval to every 6-8 hours. Child-Pugh Class C: contraindicated due to risk of accumulation and toxicity; alternative therapy recommended. |
| Pediatric use | Not recommended for use in children due to risk of respiratory depression and toxicity. No established weight-based dosing guidelines. |
| Geriatric use | Initiate at 50% of adult dose (e.g., 32.5 mg) every 6 hours as needed; cautiously titrate due to prolonged half-life, increased CNS sensitivity, and risk of falls. Avoid use if possible; alternative safer analgesics recommended. |
| 1st trimester | Avoid in first trimester due to risk of neural tube defects and congenital heart defects from case-control studies. Use only if benefit outweighs risk. |
| 2nd trimester | Avoid unless no alternative; may cause maternal physical dependence and neonatal withdrawal syndrome. Consider shorter duration and lowest effective dose. |
| 3rd trimester | Avoid near term due to risk of respiratory depression in the neonate; prolonged use may lead to neonatal opioid withdrawal syndrome. Use only if maternal benefit clearly outweighs neonatal risk. |
Clinical note
Comprehensive clinical and safety monograph for PROPOXYPHENE HYDROCHLORIDE 65 (PROPOXYPHENE HYDROCHLORIDE 65).
| Placental transfer | Crosses the placenta readily; umbilical cord serum levels approximately equal to maternal serum levels. Norpropoxyphene also crosses and may accumulate in fetal tissues. |
| Breastfeeding | Propoxyphene passes minimally into breast milk; however, reports of infant sedation and respiratory depression exist. Use with caution, monitor infant for drowsiness, poor feeding, and respiratory rate. The active metabolite norpropoxyphene has a long half-life and may accumulate. Avoid or use lowest effective dose for shortest duration. |
| Lactation Rating | L3 (Moderately Safe) — limited data suggest risk, but use may be acceptable with close infant monitoring. Avoid in breastfeeding mothers of premature or medically compromised infants. |
| Teratogenic Risk | First trimester: Limited human data; animal studies show no teratogenicity at therapeutic doses. Second and third trimesters: Associated with neonatal respiratory depression, withdrawal syndrome if chronic use near term. Avoid prolonged use. |
| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, bowel function; fetal heart rate monitoring if near term; neonatal assessment for withdrawal (irritability, poor feeding) after birth. |
| Fertility Effects | No direct reproductive toxicity in animal studies; chronic use may cause menstrual irregularities or reduced libido in humans. |
■ FDA Black Box Warning
Propoxyphene is associated with a risk of fatal respiratory depression, especially when used in higher doses, in elderly patients, or in combination with other CNS depressants. It increases the risk of QT prolongation and fatal arrhythmias, leading to its withdrawal from the market in some countries.
| Serious Effects |
Hypersensitivity to propoxyphene or any componentSignificant respiratory depression (unmonitored or in absence of resuscitative equipment)Acute or severe bronchial asthma in an unmonitored settingConcurrent use of benzodiazepines or other CNS depressants (including alcohol) that may lead to profound sedation, respiratory depression, coma, or deathSuspected or known gastrointestinal obstruction, including paralytic ileusSuicidal ideation or history of suicide attempt due to risk of fatal overdoseKnown CYP2D6 ultra-rapid metabolizers (increased risk of toxicity from active metabolite norpropoxyphene)
| Precautions | Risk of respiratory depression, especially in elderly, debilitated, or opioid-naive patients, QT prolongation and risk of torsade de pointes, particularly with doses >400 mg/day, Dependence, abuse, and tolerance potential, Concomitant use with alcohol or CNS depressants increases toxicity risk, Use in hepatic or renal impairment requires dose adjustment |
| Food/Dietary | Avoid alcohol and grapefruit juice. Alcohol increases CNS depression and hepatotoxicity risk; grapefruit juice may inhibit metabolism and increase propoxyphene levels. |
| Clinical Pearls | Propoxyphene is a weak opioid with efficacy similar to aspirin but carries a high risk of QT prolongation and cardiotoxicity, especially in overdose or with renal impairment. Avoid in patients with history of QT prolongation, electrolyte disturbances, or concurrent use of other QT-prolonging drugs. Due to its narrow therapeutic index and risk of fatal arrhythmias, it has been withdrawn from many markets. Use with extreme caution in elderly and those with hepatic/renal dysfunction. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency. · Do not consume alcohol or other CNS depressants while taking this medication. · Do not drive or operate heavy machinery until you know how this drug affects you. · Seek immediate medical attention if you experience fainting, irregular heartbeat, or seizures. · Do not stop abruptly without consulting your doctor; withdrawal symptoms may occur. · Keep out of reach of children; accidental overdose can be fatal. |
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