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Last Updated: February 17, 2025

CLINICAL TRIALS PROFILE FOR PROPOXYPHENE HYDROCHLORIDE 65


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505(b)(2) Clinical Trials for Propoxyphene Hydrochloride 65

This table shows clinical trials for potential 505(b)(2) applications. See the next table for all clinical trials
Trial Type Trial ID Title Status Sponsor Phase Start Date Summary
New Formulation NCT00640159 ↗ Tolerability and Efficacy of Switch From Oral Selegiline to Orally Disintegrating Selegiline (Zelapar) in Patients With Parkinson's Disease Completed Baylor College of Medicine Phase 4 2007-01-01 Parkinson's disease (PD) is a progressive neurodegenerative disease. Symptomatic therapy is primarily aimed at restoring dopamine function in the brain. Oral selegiline in conjunction with L-dopa has been a mainstay of therapy for PD patients experiencing motor fluctuations for many years. The mechanisms accounting for selegiline's beneficial adjunctive action in the treatment of PD are not fully understood. Inhibition of monoamine oxidase (MAO) type B (MAO-B) activity is generally considered to be of primary importance. Oral selegiline has low bio-availability and is typically dosed BID, for a total of 5-10 mg daily. Recently, the FDA approved a new orally disintegration tablet (ODT) formulation of selegiline, called ZelaparTM. This new formulation utilizes Zydis technology to dissolve in the mouth, with absorption through the oral mucosa, thereby largely bypassing the gut and avoiding first pass hepatic metabolism. This allows more active drug to be delivered at a lower dose. Consequently, Zelapar is dosed once-daily, up to 2.5 mg per day. There are no empirical data indicating whether the use of the new approved formulation of selegiline ODT (Zelapar) is superior or preferred by patients compared to traditional oral selegiline. It is believed that clinical efficacy will be preserved or enhanced, by delivering more active drug, with improved patient preference for the ODT formulation due to the once-daily dosing . The effectiveness of orally disintegrating selegiline as an adjunct to carbidopa/levodopa in the treatment of PD was established in a multicenter randomized placebo-controlled trial (n=140; 94 received orally disintegrating selegiline, 46 received placebo) of three months' duration. Patients randomized to orally disintegrating selegiline received a daily dose of 1.25 mg for the first 6 weeks and a daily dose of 2.5 mg for the last 6 weeks. Patients were all treated with levodopa and could additionally have been on dopamine agonists, anticholinergics, amantadine, or any combination of these during the trial. At 12 weeks, orally disintegrating selegiline-treated patients had an average of 2.2 hours per day less "OFF" time compared to baseline. Placebo treated patients had 0.6 hours per day less "OFF" time compared to baseline. These differences were significant (p < 0.001). Adverse events were very similar between drug and placebo.
>Trial Type >Trial ID >Title >Status >Phase >Start Date >Summary

All Clinical Trials for Propoxyphene Hydrochloride 65

Trial ID Title Status Sponsor Phase Start Date Summary
NCT00240786 ↗ An Effectiveness and Safety Study of Two Doses of Acetaminophen Extended Release Caplets in the Treatment of Osteoarthritis of the Hip or Knee Completed Johnson & Johnson Consumer and Personal Products Worldwide Phase 3 2002-04-01 The purpose of this study is to determine the safety and effectiveness of 650 mg and 1300 mg acetaminophen extended release given three times a day for the relief of signs and symptoms of osteoarthritis of the hip or knee for a period of 12 weeks.
NCT00240799 ↗ An Effectiveness and Safety Study of Acetaminophen Extended Release Caplets in the Treatment of Osteoarthritis of the Hip or Knee. Completed McNeil Consumer & Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc. Phase 3 1969-12-31 The purpose of this study is to evaluate acetaminophen extended release (3900 mg/day) compared to placebo for safety and effectiveness in the relief of signs and symptoms of osteoarthritis of the hip or knee over 12 weeks
NCT00240799 ↗ An Effectiveness and Safety Study of Acetaminophen Extended Release Caplets in the Treatment of Osteoarthritis of the Hip or Knee. Completed Johnson & Johnson Consumer and Personal Products Worldwide Phase 3 1969-12-31 The purpose of this study is to evaluate acetaminophen extended release (3900 mg/day) compared to placebo for safety and effectiveness in the relief of signs and symptoms of osteoarthritis of the hip or knee over 12 weeks
>Trial ID >Title >Status >Phase >Start Date >Summary

Clinical Trial Conditions for Propoxyphene Hydrochloride 65

Condition Name

Condition Name for Propoxyphene Hydrochloride 65
Intervention Trials
Osteoarthritis 2
Bariatric Surgery Candidate 1
Healthy 1
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Condition MeSH

Condition MeSH for Propoxyphene Hydrochloride 65
Intervention Trials
Osteoarthritis, Hip 2
Osteoarthritis 2
Constriction, Pathologic 1
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Clinical Trial Locations for Propoxyphene Hydrochloride 65

Trials by Country

Trials by Country for Propoxyphene Hydrochloride 65
Location Trials
United States 6
Egypt 1
Brazil 1
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Trials by US State

Trials by US State for Propoxyphene Hydrochloride 65
Location Trials
California 2
Utah 1
New York 1
Texas 1
Florida 1
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Clinical Trial Progress for Propoxyphene Hydrochloride 65

Clinical Trial Phase

Clinical Trial Phase for Propoxyphene Hydrochloride 65
Clinical Trial Phase Trials
Phase 4 4
Phase 3 3
Phase 1/Phase 2 1
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Clinical Trial Status

Clinical Trial Status for Propoxyphene Hydrochloride 65
Clinical Trial Phase Trials
Completed 5
Terminated 2
Suspended 1
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Clinical Trial Sponsors for Propoxyphene Hydrochloride 65

Sponsor Name

Sponsor Name for Propoxyphene Hydrochloride 65
Sponsor Trials
Johnson & Johnson Consumer and Personal Products Worldwide 2
Baylor College of Medicine 1
Endo Pharmaceuticals 1
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Sponsor Type

Sponsor Type for Propoxyphene Hydrochloride 65
Sponsor Trials
Other 6
Industry 5
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Propoxyphene Hydrochloride: A Comprehensive Review of Clinical Trials, Market Analysis, and Projections

Introduction

Propoxyphene hydrochloride, a synthetic opioid analgesic, was widely used for the treatment of mild to moderate pain. However, its use has been significantly impacted by safety concerns, leading to its withdrawal from the market in several countries. Here, we delve into the clinical trials, market analysis, and projections for this drug.

Clinical Trials and Safety Concerns

The MAD Study and Thorough QT Study

A pivotal study that led to the withdrawal of propoxyphene was the Multiple-Ascending Dose (MAD) study, a randomized, double-blind, placebo-controlled trial. This study evaluated the effects of increasing doses of propoxyphene on the heart in healthy volunteers. The results showed significant prolongations of the QTc interval, PR interval, and QRS complex, even at therapeutic doses, indicating a substantial risk of serious abnormal heart rhythms[1].

Cardiac Toxicity

The FDA's thorough QT study further substantiated these findings, revealing that propoxyphene caused significant QTc interval prolongations. For instance, at a 600 mg daily dose, the largest mean change in QTcF was 29.8 milliseconds, and at a 900 mg dose, it was 38.2 milliseconds. These changes are associated with a substantially increased likelihood of being proarrhythmic[1].

Market Analysis

Withdrawal from the Market

Due to the compelling evidence of cardiac toxicity, the FDA recommended against the continued use of propoxyphene in November 2010. The manufacturer voluntarily withdrew the drug from the U.S. market. This decision was supported by an FDA Advisory Committee, which voted narrowly against the continued marketing of propoxyphene products[1][2].

Impact on Pain Management

The withdrawal of propoxyphene left a gap in pain management options, particularly for patients who were dependent on this medication. Alternative opioid and non-opioid pain relievers had to be considered, and healthcare providers had to adjust treatment plans accordingly. For example, patients could be switched to other opioids like hydrocodone or to non-opioid analgesics, depending on the patient's condition and medical history[3].

Projections and Future Outlook

No Future Market Presence

Given the severe safety concerns and the FDA's definitive stance against its use, propoxyphene hydrochloride is not expected to return to the market. The focus has shifted to safer alternatives that provide effective pain relief without the associated cardiac risks.

Lessons Learned

The case of propoxyphene highlights the importance of rigorous post-marketing surveillance and the need for continuous safety evaluations of pharmaceuticals. It also underscores the critical role of regulatory bodies in protecting public health by making informed decisions based on emerging data.

Pharmacokinetics and Pharmacodynamics

Mechanism of Action

Propoxyphene acts as a weak agonist at opioid receptors (OP1, OP2, and OP3) in the central nervous system, primarily affecting OP3 receptors. This action inhibits the release of nociceptive neurotransmitters, thereby providing pain relief[5].

Metabolism and Excretion

Propoxyphene undergoes extensive first-pass metabolism by intestinal and hepatic enzymes, primarily through CYP3A4-mediated N-demethylation to norpropoxyphene. The drug and its metabolite are excreted by the kidneys, with a renal clearance rate of 2.6 L/min. In elderly patients and those with renal insufficiency, the clearance of propoxyphene and norpropoxyphene is reduced, leading to higher plasma concentrations and increased risk of adverse effects[4].

Special Populations

Geriatric Patients

Elderly patients are particularly susceptible to the adverse cardiac effects of propoxyphene due to reduced clearance and longer half-lives of the drug and its metabolite. This population requires careful monitoring and potentially adjusted dosing, although the drug is no longer recommended for use[4].

Pediatric and Hepatic Impairment

Propoxyphene has not been studied in pediatric patients, and there is insufficient information to make dosing recommendations for patients with hepatic or renal impairment. In patients with cirrhosis, the drug's first-pass metabolism is decreased, leading to higher plasma concentrations and potential toxicity[4].

Adverse Effects and Abuse Potential

Cardiac and Other Adverse Effects

The most significant adverse effect of propoxyphene is its potential to cause serious cardiac arrhythmias. Other adverse effects include respiratory depression, circulatory collapse, and seizures. The drug also has a potential for abuse and dependence, classified as a Schedule IV narcotic under the U.S. Controlled Substances Act[5].

Key Takeaways

  • Safety Concerns: Propoxyphene hydrochloride was withdrawn from the market due to significant cardiac toxicity, including QTc interval prolongation and increased risk of arrhythmias.
  • Market Impact: The withdrawal left a gap in pain management options, necessitating the use of alternative analgesics.
  • Pharmacokinetics: The drug undergoes extensive first-pass metabolism and is excreted by the kidneys, with reduced clearance in elderly and renally impaired patients.
  • Special Populations: Elderly patients are at higher risk due to reduced clearance and longer half-lives.
  • Adverse Effects: Serious cardiac arrhythmias, respiratory depression, and potential for abuse and dependence.

FAQs

Q: Why was propoxyphene hydrochloride withdrawn from the market?

A: Propoxyphene was withdrawn due to new data showing that it can cause serious cardiac toxicity, including prolonged QTc intervals and increased risk of arrhythmias, even at therapeutic doses[1].

Q: What were the key findings of the MAD study?

A: The MAD study showed significant prolongations of the QTc interval, PR interval, and QRS complex, indicating a substantial risk of serious abnormal heart rhythms[1].

Q: How does propoxyphene act in the body?

A: Propoxyphene acts as a weak agonist at opioid receptors in the central nervous system, primarily affecting OP3 receptors, which inhibits the release of nociceptive neurotransmitters[5].

Q: What populations are particularly susceptible to the adverse effects of propoxyphene?

A: Elderly patients and those with renal insufficiency are particularly susceptible due to reduced clearance and longer half-lives of the drug and its metabolite[4].

Q: Is propoxyphene still available for use in any form?

A: No, propoxyphene hydrochloride is no longer available for use in the U.S. or several other countries due to its withdrawal from the market[1][2].

Sources

  1. FDA Drug Safety Communication: FDA recommends against the continued use of propoxyphene[1].
  2. Drugs.com: Propoxyphene Dosage Guide + Max Dose, Adjustments[2].
  3. U.S. District Court Document: Case 1:14-cv-11689-RWZ Document 1 Filed 04/07/14[3].
  4. FDA Label: DarvonĀ® (propoxyphene hydrochloride capsules, USP) Pulvules[4].
  5. DrugBank: Dextropropoxyphene: Uses, Interactions, Mechanism of Action[5].

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