GAITHERSBURG, MD. — If the Food and Drug Administration agrees with an advisory panel's narrow recommendation to take Darvon and other products that contain propoxyphene off the market, the void may not make much difference to rheumatologists, who appear to be among the lowest prescribers of these products.
At a joint meeting of the FDA's Anesthetic and Life Support Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee last month, the panelists voted 14–12 that the risk-benefit profile on these products did not support their continued marketing for the treatment of patients with mild to moderate pain. The majority of panelists agreed that there was “marginal” or “modest” evidence at best indicating that propoxyphene, an opioid analgesic, was effective as monotherapy, or that propoxyphene plus acetaminophen was more effective than acetaminophen alone. Several panel members said they did not believe there was any evidence of efficacy for propoxyphene, either alone or in combination with acetaminophen.
The FDA held the meeting to review the safety of these products, first approved in 1957, in response to a Citizen's Petition filed by Public Citizen's Health Research Group in February 2006, calling for a phased withdrawal of all propoxyphene-containing products from the market.
Darvon and Darvocet (propoxyphene plus acetaminophen) are the branded versions of propoxyphene, which is a schedule IV drug. There are multiple generic formulations available. In the petition, the group maintained that the risks of these products outweigh their benefits, citing insufficient evidence that propoxyphene alone effectively alleviates pain and offers little, if any, added benefit when combined with acetaminophen. The petition states that propoxyphene and its main metabolite are cardiotoxic, and that it has a narrow therapeutic index and was associated with 2,110 reports of accidental deaths in the United States from 1981 through 1999.
Based on data from U.S. outpatient retail pharmacies presented by the FDA, rheumatologists wrote about 525,000 prescriptions for propoxyphene-acetaminophen in 2007 (2.4% of the total).
Propoxyphene “just simply is not a very good drug,” and has become less popular over the past few years, said Dr. Roy Altman, professor of rheumatology and immunology at the University of California, Los Angeles.
In an interview, Dr. Altman said that he has not used propoxyphene in more than a decade, “mostly because it's such a weak analgesic.” Moreover, because of the side effects associated with propoxyphene, a more potent analgesic effect would be needed to justify its use, he added. In fact, when he was at the University of Miami several years ago, these products were contraindicated in elderly patients because of the multiple central nervous system side effects—such as depression, depersonalization, drowsiness, and unsteadiness—in this population, so the outcome of the FDA panel meeting does not surprise him, nor would it surprise others in the geriatric community, he said, adding that the main reason these products remain in use now is because of the critical need for more analgesic options.
At the FDA meeting, Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, presented data from DAWN (Drug Abuse Warning Network), which received reports of 446 propoxyphene-related deaths from U.S. emergency departments in 2006, and 503 such reports in 2007. (DAWN, which collects data on drugs associated with emergency department visits or deaths, covers only a fraction of the U.S. population; during this time, the number of jurisdictions reporting to DAWN increased.)
Among the other data he presented were reports made to the medical examiner in Florida in 2007 (not included in the DAWN data), in which 314 deaths were related to propoxyphene; in 25% of the cases, the medical examiner concluded that the drug was the cause of death.
The panelists agreed there was no evidence that at therapeutic levels, propoxyphene has been associated with an increased risk for cardiotoxicity, largely because of an insufficient amount of data. However, the panel agreed that if propoxyphene remained on the market, the cardiotoxicity potential should be studied further—in studies that evaluate QT and EKG changes as well as in observational studies, including in elderly populations. The panel also recommended that the label should be changed to discourage chronic use, which has not been studied. The panel cited concerns over the lack of data on safety and efficacy in chronic use and use in the elderly.
Panelists were split on whether the lack of conclusive evidence on efficacy—most of which was from single-dose studies conducted in the 1970s—or on safety justified keeping these products available in the U.S. Sean Hennessy, Pharm.D., of the University of Pennsylvania, Philadelphia, said he voted no because in the “absence of benefit, no risk is acceptable.”