PROPOXYPHENE COMPOUND 65

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PROPOXYPHENE COMPOUND 65 (PROPOXYPHENE COMPOUND 65).

How it works

Propoxyphene is an opioid analgesic that binds to mu-opioid receptors in the central nervous system, resulting in inhibition of ascending pain pathways and alteration of pain perception. Acetaminophen component inhibits cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis.

What the body does with it

Metabolism	Propoxyphene is metabolized via hepatic CYP3A4 and CYP2D6 enzymes to norpropoxyphene, an active metabolite with cardiotoxic properties. Acetaminophen is metabolized primarily by glucuronidation and sulfation.
Excretion	Renal excretion of propoxyphene and its metabolites accounts for approximately 70-90% of an administered dose, with less than 5% excreted as unchanged drug. The remainder is eliminated via bile and feces. Minor amounts are excreted in breast milk.
Half-life	The terminal elimination half-life of propoxyphene is approximately 8-24 hours (mean 12 hours) in healthy adults. The half-life of its active metabolite, norpropoxyphene, is 30-36 hours, leading to prolonged effects and potential accumulation with repeated dosing, especially in renal impairment.
Protein binding	Propoxyphene is approximately 80% bound to plasma proteins, primarily albumin.
Volume of Distribution	The volume of distribution (Vd) of propoxyphene is approximately 10-16 L/kg (range 12 L/kg), indicating extensive tissue distribution. This large Vd reflects significant tissue binding and sequestration.
Bioavailability	Oral bioavailability is approximately 40-70% due to extensive first-pass hepatic metabolism. The formulation of propoxyphene napsylate may have slightly higher bioavailability than hydrochloride salts.
Onset of Action	Oral administration: Onset of analgesia occurs within 30-60 minutes.
Duration of Action	Oral administration: Duration of analgesia is 4-6 hours. However, due to the long half-life of norpropoxyphene, subjective effects may persist longer, and drug accumulation can occur with repeated dosing.

Classification & Brands

Dosing & administration

Adults: 1 capsule (65 mg propoxyphene HCl + 650 mg acetaminophen) orally every 4 hours as needed; maximum 6 capsules per day.

Dosage form	CAPSULE
Renal impairment	GFR 30-50 mL/min: 1 capsule every 6 hours; GFR <30 mL/min: 1 capsule every 8 hours; avoid if GFR <10 mL/min.
Liver impairment	Child-Pugh A: 1 capsule every 6 hours; Child-Pugh B: 1 capsule every 8 hours; Child-Pugh C: avoid use.
Pediatric use	Not recommended; safety and efficacy not established in children under 18 years.
Geriatric use	Elderly: 1 capsule every 6 hours; maximum 4 capsules per day; monitor for sedation and constipation.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PROPOXYPHENE COMPOUND 65 (PROPOXYPHENE COMPOUND 65).

Breastfeeding	Excreted in breast milk; M/P ratio approximately 0.15. Use with caution; monitor infant for sedation and respiratory depression.
Teratogenic Risk	First trimester: Inadequate human data; animal studies not conclusive. Avoid due to potential neural tube defects. Second/third trimester: Associated with neonatal respiratory depression and withdrawal syndrome if used near term; avoid prolonged use.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Risk of fatal overdose, especially when used with alcohol or other CNS depressants. QT interval prolongation and risk of torsades de pointes at therapeutic doses. Withdrawn from US market due to cardiac toxicity.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to propoxyphene or acetaminophen. Significant respiratory depression. Acute or severe bronchial asthma. QT prolongation or concurrent use of drugs that prolong QT interval. Use of MAO inhibitors within 14 days. Paralytic ileus. Known alcohol use disorder.

Clinical Precautions

Precautions

Risk of respiratory depression, especially in elderly or debilitated patients. QT prolongation, cardiac arrhythmias, and torsades de pointes. Avoid use with alcohol or other CNS depressants. Risk of dependence and abuse. Use with caution in patients with hepatic or renal impairment.

Clinical Tips & Counseling

Drug interactions

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PROPOXYPHENE COMPOUND 65

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PROPOXYPHENE COMPOUND 65 (PROPOXYPHENE COMPOUND 65).

How it works

What the body does with it

Metabolism	Propoxyphene is metabolized via hepatic CYP3A4 and CYP2D6 enzymes to norpropoxyphene, an active metabolite with cardiotoxic properties. Acetaminophen is metabolized primarily by glucuronidation and sulfation.
Excretion	Renal excretion of propoxyphene and its metabolites accounts for approximately 70-90% of an administered dose, with less than 5% excreted as unchanged drug. The remainder is eliminated via bile and feces. Minor amounts are excreted in breast milk.
Half-life	The terminal elimination half-life of propoxyphene is approximately 8-24 hours (mean 12 hours) in healthy adults. The half-life of its active metabolite, norpropoxyphene, is 30-36 hours, leading to prolonged effects and potential accumulation with repeated dosing, especially in renal impairment.
Protein binding	Propoxyphene is approximately 80% bound to plasma proteins, primarily albumin.
Volume of Distribution	The volume of distribution (Vd) of propoxyphene is approximately 10-16 L/kg (range 12 L/kg), indicating extensive tissue distribution. This large Vd reflects significant tissue binding and sequestration.
Bioavailability	Oral bioavailability is approximately 40-70% due to extensive first-pass hepatic metabolism. The formulation of propoxyphene napsylate may have slightly higher bioavailability than hydrochloride salts.
Onset of Action	Oral administration: Onset of analgesia occurs within 30-60 minutes.
Duration of Action	Oral administration: Duration of analgesia is 4-6 hours. However, due to the long half-life of norpropoxyphene, subjective effects may persist longer, and drug accumulation can occur with repeated dosing.

Classification & Brands

Dosing & administration

Adults: 1 capsule (65 mg propoxyphene HCl + 650 mg acetaminophen) orally every 4 hours as needed; maximum 6 capsules per day.

Dosage form	CAPSULE
Renal impairment	GFR 30-50 mL/min: 1 capsule every 6 hours; GFR <30 mL/min: 1 capsule every 8 hours; avoid if GFR <10 mL/min.
Liver impairment	Child-Pugh A: 1 capsule every 6 hours; Child-Pugh B: 1 capsule every 8 hours; Child-Pugh C: avoid use.
Pediatric use	Not recommended; safety and efficacy not established in children under 18 years.
Geriatric use	Elderly: 1 capsule every 6 hours; maximum 4 capsules per day; monitor for sedation and constipation.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PROPOXYPHENE COMPOUND 65 (PROPOXYPHENE COMPOUND 65).

Breastfeeding	Excreted in breast milk; M/P ratio approximately 0.15. Use with caution; monitor infant for sedation and respiratory depression.
Teratogenic Risk	First trimester: Inadequate human data; animal studies not conclusive. Avoid due to potential neural tube defects. Second/third trimester: Associated with neonatal respiratory depression and withdrawal syndrome if used near term; avoid prolonged use.
Fetal Monitoring