At the meeting, the FDA presented efficacy data from seven acute-pain, single-dose trials that compared propoxyphene alone with acetaminophen alone, with propoxyphene plus acetaminophen, and with placebo, as well as a review of the medical literature through December 2008. Based on a review of these data, the agency concluded that propoxy-phene had a weak analgesic effect in some of the acute-pain trials, and that the contribution of propoxyphene to the analgesic effects of acetaminophen was “variable across acute pain trials,” said Dr. Jin Chen, a medical officer in the FDA's Division of Anesthesia, Analgesia, and Rheumatology Products. There were no data on chronic pain submitted to the FDA, and there is insufficient information in the literature to make any conclusions about its analgesic effects with chronic use, he said.
Other data presented by FDA reviewers indicated that there are possible drug-drug interactions with CYP3A4 inhibitors, and that the pharmacokinetics of the drug are altered with hepatic and renal impairment and in the elderly. Animal data indicate that propoxyphene may affect cardiac conduction and toxicity, possibly through its effects on sodium and potassium channels. There also have been case reports of cardiac effects in humans, such as prolonged PR interval and QRS widening associated with drug concentrations that exceed the clinical therapeutic level.
But it is unclear whether the cardiac effects seen in nonclinical studies would be a risk in people who are taking therapeutic doses of propoxyphene-containing drugs, according to the FDA reviewers.
Of the 65 unduplicated adverse event reports associated with propoxyphene-containing products that were submitted to the FDA's Adverse Event Reporting System between 2006 and 2007, 17% (11 cases) were cardiac-related events—including 4 cases of bradycardia, 2 cases of cardiorespiratory arrest, and 2 cases of tachycardia—but 82% of the cardiac cases were confounded by other factors that made it difficult to attribute the report to the drug, according to the FDA. The other cases included accidental multiple drug overdoses in 14% (nine cases) and 18% that were psychiatry related, such as hallucinations or changes in mental status; 40% of the reports overall were in the elderly, and 18% overall were fatal accidental overdoses.
Panelist Dr. William Hiatt, professor of medicine at the University of Colorado, Denver, said that based on these efficacy data, it appears that acetaminophen and propoxyphene alone are more effective than placebo, but that the combination did not clearly exceed pain relief with either component alone in studies of a single dose in people with acute postoperative or postpartum pain.
He also cited preclinical evidence of possible cardiotoxicity, particularly its effect on sodium channels, and recommended that if the products remained on the market, clinical studies should be conducted to evaluate QT changes associated with the drug, and whether the drug increases the background risk of cardiac events in an elderly population.
The FDA usually follows the recommendations of its advisory panels, which are not binding.