Propoxyphene has been on the market since 1957. It is a widely prescribed member of a group of drugs known as opioids and is used as a treatment for mild to moderate pain. The most frequent side effects of propoxyphene include lightheadedness, dizziness, sedation, nausea, and vomiting.
Like certain other classes of pain medications, propoxyphene products can be addictive and have been linked to deaths in patients, especially when used with alcohol and other drugs. The drug labels' currently warn of those risks. In February, an FDA advisory panel had voted 14-to-12 to withdrawal drugs like Darvon from the market, citing its overdose risks. However, the FDA is not bound to follow the recommendations of its advisory panels.
In addition to the stronger label warnings, the FDA is requiring the manufacturers of these drugs to provide a medication guide to patients stressing the importance of using the drugs as directed.
Propoxyphene manufacturers are required to submit the requested safety labeling changes to the FDA within 30 days, or to provide a reason why they do not believe such changes are necessary. If they do not submit new language, or if the FDA disagrees with the language the companies propose, the Food, Drug, and Cosmetic Act provides strict timelines for discussions regarding the changes. At the end of these discussions, the FDA may issue an order directing the labeling changes as deemed appropriate to address the new safety information.
In addition, the FDA is requiring a new safety study assessing unanswered questions about the effects of propoxyphene on the heart at higher than recommended doses. Findings from this study, as well as other data, could lead to additional regulatory action. To further evaluate the safety of propoxyphene, the FDA plans to work with several groups including the Centers for Medicare & Medicaid Services and the Veterans Health Administration to study how often the elderly are prescribed propoxyphene instead of other pain relievers and the difference in the safety profiles of propoxyphene compared to other drugs.
However, the FDA also said today that it had rejected a petition from the advocacy group Public Citizen requesting a phased withdrawal of propoxyphene. The agency said in its response that despite serious concerns about propoxyphene, the benefits of using the medication for pain relief at recommended doses outweighs the safety risks at this time.
The Public Citizen petition was filed in 2006. In 2008, the group filed a federal lawsuit seeking to force the FDA to act on the petition.
Darvon, known generically as Propoxyphene Hydrochloride, is also prescribed as Darvocet, which contains the active ingredient in Tylenol, reported USA Today. At issue, is that consumer groups feel the drug does not provide effective pain relief and could, therefore, lead to overdose risks. Drug makers disagree, reported USA Today, and maintain that, when used as directed, Darvon is safe and effective.
And, while the panel voted that Darvon’s benefits don’t outweigh its risks, said the Wall Street Journal, the decision remains with the agency, which is known for agreeing with panel decisions, but not when the vote is this close.
Darvon has been on the market for over 50 years, since 1957. In 2007 alone, over 20 million prescriptions were written for propoxyphene medications, said the WSJ. Over 600 million prescriptions have been written for the drug since its introduction, said Dow Jones. Congressional hearings on the Darvon’s safety and efficacy began 30 years ago and critics have long claimed that the drug is responsible for accidental overdoses and suicides, said the Journal. Consumer advocacy group, Public Citizen, has been working to ban Darvon for decades and is responsible, with its petition and an ensuing lawsuit, for bringing about the recent FDA move.
Sidney Wolfe, a doctor at Public Citizen said of Darvon that, "Claims of its efficacy have been seriously undercut by the FDA's own analysis," adding that Darvon "possesses weak analgesic effects." Wolfe presented data last week revealing that over 500 deaths took place in 2007 in which propoxyphene was involved, reported the WSJ. "All drugs have risks," Dr. Wolfe said. "If they don't have benefits they need to come off the market," quoted the WSJ.
Today, the Darvon and Darvocet are manufactured and marketing by private, generic drug makers such as Xanodyne Pharmaceuticals Inc. of Newport, Kentucky and Qualitest/Vintage Pharmaceuticals, of Huntsville, Alabama, said Dow Jones. Approved for mild to moderate pain, the propoxyphene medications have been linked to death in patients—especially when used with alcohol and other drugs—and have also been found to be addictive. According to FiercePharma, it is because of the potential abuse that the FDA advisory committee was been called in to help determine if the drugs should or should not remain on the market.
The Public Citizen petition followed the United Kingdom ban of propoxyphene pain killers over concerns of abuse and fatalities linked to the drugs, said the WSJ. Dow Jones reported that an FDA review of its adverse-event reporting data base confirmed 3,028 serious and non-serious reports linked to propoxyphene from 1957 through September 24, 2008; 2,136 reports were considered serious and 1,452 ended in death. The FDA noted that much of the reports involved suicides, intentional and unintentional drug overdoses, and heart attacks.
Pubic Citizen petitioned the FDA two years ago to ban Propoxyphene saying it was not any more effective than other, safer painkillers and pointing to at least 2,110 accidental deaths between 1981 and 1999. Several hundred more accidental deaths have been linked to Darvon/Darvocet every year since, according to Public Citizen’s Health Research Group in its petition, which is planned for submission to FDA acting Commissioner Dr. Andrew von Eschenbach. Public Citizen first sought to ban Propoxyphene in 1978.
The lawsuit was filed in US District Court in Washington and argued that the FDA was in legal violation by not ruling on its petition within the required six months. The lawsuit states that Propoxyphen is an addictive narcotic that, even when used properly, can cause slowed heartbeat and other serious cardiac side effects. This February, Public Citizen’s Health Research Group asked the FDA to ban Darvon and Darvocet, two popular painkillers. Dr. Sidney Wolfe, the group’s director, said Propoxyphene, the drugs’ main active ingredient, is a relatively weak painkiller that presents an unacceptable toxic risk to millions of patients taking it annually. “This a black-and-white example of a drug where its risks far outweigh its benefits … there’s no excuse for this drug to be around” said Wolfe.
Prescriptions for the drug—which has been sold since 1957—have decreased, but 23 million prescriptions were still written for propoxyphene-containing drugs last year. Darvocet combines propoxyphene with acetaminophen and is the most popular of these types of painkillers.
An analysis of 26 studies comparing propoxyphene and acetaminophen with just acetaminophen or a placebo found the “narcotic combination offered little benefit over acetaminophen alone” in treating pain. “Thus, propoxyphene provides minimal if any additional analgesia to acetaminophen alone and is associated with significant adverse effects. It cannot be recommended for routine use,” Dr. Carolyn Sachs of the University of California, Los Angeles, wrote in her analysis, published in March 2005 in American Family Physician.
Wolfe said a “phase-out,” meant to wean users from the drug would be followed by a ban, similar to a move in 2005 by the United Kingdom over Co-proxamol, Britain’s most frequently used drug. Co-proxamol was banned over concerns about the high risk of accidental death from slight overdose and its frequent use in suicides. Co-proxamol, is sold under the brand names Distalgesic, Cosalgesic, and Dolgesic in the UK and under the names Darvocet and Darvon in the US.
The body transforms propoxyphene—or codeine—Into norpropoxyphene, which can build up in the body and is associated with a variety of heart problems, including arrhythmia. Propoxyphene is among the nation’s most widely abused painkillers, Substance Abuse and Mental Health Services Administration spokeswoman Leah Young said, adding that a 2004 survey found 21 million people had made “non-medical” use of products containing propoxyphene.
The petition to ban the popular pain reliever propoxyphene, known as Darvon, Darvocet and other generic versions, stems from the drug having ˘â‚¬Ĺ“been linked with more than two thousand accidental deaths ˘â‚¬ ť and because it ˘â‚¬Ĺ“is physically addictive and has not been shown to be any more effective than safer alternatives. ˘â‚¬ ť
The petition states that 5.6% of all drug related deaths during the past 19 years were related to propoxyphene, according to data from the Federal Drug Abuse Warning Network, which provides autopsy information from medical examiners in the US.
Yet despite this alarming rate of deaths, the drug remains widely prescribed, with 23 million prescriptions filled in 2004, making propoxyphene the 12th most commonly prescribed generic drug in the US.
According to Public Citizen, since 1981, propoxyphene has been associated with 2,110 reported accidental deaths in the US. Many of these deaths occur because most of the drug converts into a metabolite that is highly toxic to the heart and lasts longer in the body than the original compound, resulting in cardiac depression.
Negative heart problems associated with propoxyphene include an interruption of heart transmission of electrical impulses, slowed heartbeats and a disabling of the heart to contract properly.
"The number of deaths involving propoxyphene in the U.S. alone is striking," says the petition, filed by Public Citizen and two Swedish experts on propoxyphene, Drs. Ulf and Birgitta Jonasson.
Last year Britain announced a phased withdrawal of the drug because of the high risk of overdose and death and the drug's negligible effectiveness. "It has not been possible to identify any patient group in whom the risk-benefit [ratio] may be positive," the British government stated.
In addition to heart toxicity, popoxyphene is dangerous if prescribed to the elderly because the adverse events related to the central nervous system can increase the likelihood of falls and fall-related fractures in the elderly.
According to previous studies, propoxyphene prescribed widely in the institutionalized population, in emergency rooms and in community-dwelling older people. These populations are particularly vulnerable to the negative effects of propoxyphene.
"The Food the Drug Administration should immediately begin phasing out the use of propoxyphene," said Dr. Sidney Wolfe, director of Public Citizen's Health Research Group. "Millions of people, many of them elderly, are being put at risk when using this drug when there are safer, more effective alternatives available. We agree with the British government's conclusion that the efficacy of this product 'is poorly established and the risk of toxicity in overdose, both accidental and deliberate, is unacceptable.'"