Nov. 19, 2010— -- The U.S. Food and Drug Administration announced Friday that it is pulling off the U.S. market the prescription painkillers Darvon and Darvocet, which combines Darvon with the aspirin substitute acetaminophen, because of new scientific evidence they can damage the heart, even at recommended doses, or cause fatal cardiac abnormalities.
The manufacturer, Xanodyne Pharmaceuticals Inc. of Newport, Ky., agreed to withdraw the two brand-name drugs. The agency now is asking manufacturers of generic propoxyphene to do the same.
Propoxyphene-containing drugs have been banned in Great Britain since 2005. The European Medicines Agency in June 2009 recommended their gradual removal from the European Union market after concluding risks, including the risk of fatal overdose, outweighed pain-relieving benefits.
The FDA called upon the pharmaceutical companies to stop making propoxyphene (PPX) based upon a clinical trial in which electrocardiograms demonstrated that the drug altered the heart's electrical activity, potentially causing serious or life-threatening arrhythmias.
"These new heart data significantly alter propoxyphene's risk-benefit profile," Dr. John Jenkins, director of the Office of New Drugs at the FDA's Center for Drug Evaluation and Research (CDER), said in a statement. "The drug's effectiveness in reducing pain is no longer enough to outweigh the drug's serious potential heart risks."
Dr. Gerald J. Dal Pan, director of CDER's Office of Surveillance and Epidemiology, said that with the new results, "for the first time we now have data showing that the standard therapeutic dose of propoxyphene can be harmful to the heart."
Dal Pan said that the cardiac changes aren't cumulative and that "once patients stop taking propoxyphene, the risk will go away."
About 10 million Americans took a prescription containing propoxyphene for mild to moderate pain in 2009, the FDA said. That same year, the agency announced an ongoing safety review of the drug.
Darvon, developed by Eli Lilly and Co., received FDA approval in 1957 and has been a controlled drug since 1976.
According to an FDA memo from Dr. Bob A. Rapaport, director of the FDA's Division of Analgesia and Anesthesia Products, "there have long been concerns about PPX's safety. Reviews of the drug generated over the years have demonstrated PPX to be only mildly effective (although the studies are quite old and analgesic studies frequently demonstrate only limited efficacy.)"
With the newest data, he wrote, "it became apparent that the risk for the individual patient can change at any time, even after prolonged chronic use."
Consumer Group Sought Ban for Years
Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, which petitioned the agency in 1978 and again in 2006, called the delay "a serious indictment of the FDA's long-lasting unwillingness to protect people in this country from a deadly but barely effective painkiller."
Public Citizen contends that 1,000 to 2,000 Americans have died from the drug since the U.K. ban, based in part upon data from the state of Florida that found 395 deaths from 2005 to 2009 associated with propoxyphene.
On Jan. 30, 2009, an FDA advisory committee voted 14-12 against continued marketing of drugs containing propoxyphene. Those who voted to keep it on the market wanted more detailed labeling that warned about use in elderly patients, whose bodies take longer to break down and clear the drug from their systems, and about the risks of taking the drug along with other opioids or alcohol.
In July 2009, the FDA announced it would allow continued marketing of the drug with a new boxed warning that included the risk of fatal overdoses. Acting under new authority, the agency at that time asked Xanodyne to study the effects of the medication on heart rhythms.
The resulting 11-day study on healthy volunteers tested daily doses of 600 mg and 900 mg of the drug. Higher doses never were tested because of cardiac changes seen at the 600 mg and 900 mg levels.
In addition, the agency reviewed other large U.S. databases that collect information on side effects. It found a higher rate of deaths associated with the use of propoxyphene than the narcotic pain relievers tramadol (Ultram) and hydrocodone in five-year reviews of each drug. There were 16 drug-related deaths per 100,000 prescriptions for propoxyphene, compared with 10 per 100,000 prescriptions for tramadol and eight deaths per 100,000 prescriptions for hydrocodone.
As part of Friday's announcement, the FDA recommended that doctors stop prescribing the medication, advise patients using it to stop taking it and discuss other ways to manage pain, and be aware of the potential cardiac effects. Any patient who experiences an abnormal heart rate or heart rhythm, dizziness, lightheadedness, heart palpitations or fainting is advised to contact a doctor immediately.
FDA Lists Alternatives for Pain
Among alternative pain medications are the potentially addictive narcotic drugs oxycodone, hydrocodone and codeine; aspirin; non-aspirin pain relievers such as acetaminophen (Tylenol); and non-steroidal anti-inflammatory drugs such as ibuprofen (Advil, Motrin).
However, all have potential side effects. Codeine and other narcotics can cause constipation; aspirin can cause bleeding in the stomach and intestines; acetaminophen can damage the liver; ibuprofen can damage the kidneys; and some of the NSAIDs can cause blood clots dangerous to the heart.