On November 19, 2010, the U.S. Food and Drug Administration (FDA) announced that it intends to withdraw propoxyphene from the United States market, because new data indicate this drug may cause serious toxicity to the heart, even when used at therapeutic doses.
Q1. What is propoxyphene?
Propoxyphene is an opioid pain reliever used to treat mild to moderate pain. It is sold under various names as a single-ingredient product (e.g., Darvon) and as part of a combination product with acetaminophen (e.g., Darvocet). Propoxyphene is also marketed under such names as Dolene, Propacet 100, Wygesic, SK-65, SK-65 APAP, Trycet, Genagesic, E-Lor, and Balacet.
Q2. FDA stated that Xanodyne agreed to withdraw propoxyphene from the United States market. What are other generic propoxyphene manufacturers doing?
FDA has informed the generic manufacturers of Xanodyne’s decision and requested that they withdraw their propoxyphene-containing products as well. FDA expects that the generic companies will stop marketing propoxyphene immediately.
The companies will ask pharmacies and other retail establishments where propoxyphene is sold to return the product to the companies.
Q3. Why has FDA asked manufacturers of propoxyphene to remove propoxyphene containing drugs off the market?
Data from a new study have become available that shows that propoxyphene can cause significant changes to the electrical activity of the heart, even when the drug is used at therapeutic doses. These changes, prolonged PR interval, widened QRS complex and prolonged QT interval, which can be seen on an electrocardiogram (ECG), can increase the risk for serious abnormal heart rhythms.
A patient’s risk for these cardiac effects while taking propoxyphene can change at any time, even if the patient has been taking propoxyphene for many years. A change in the patient’s disease state, intake of other medications, or a decrease in kidney function can greatly increase their risk for cardiac effects with propoxyphene.
Based on this new information, FDA believes this action is necessary to ensure patient safety.
Q4. FDA previously announced in July 2009 that it was not proposing removal of propoxyphene products from the United States market. Why does FDA now want to withdraw propoxyphene?
Based on all evidence available to the Agency in July 2009, FDA concluded that the benefits of propoxyphene for pain relief at recommended doses outweighed the safety risks known at the time.
However, new data now show that propoxyphene can cause significant changes to the electrical activity of the heart, including prolonged PR interval, widened QRS complex and prolonged QT interval, even when the drug is used at therapeutic doses. These changes, which can be seen on an ECG, can increase the risk for serious abnormal heart rhythms.
These new data indicate that the risks associated with propoxyphene now outweigh any potential benefit.
Q5. Why was the new study conducted? What did the results show?
In January 2009, an Advisory Committee meeting (see Question 13) was held to discuss the efficacy and safety of propoxyphene after a Citizen’s Petition requesting withdrawal of propoxyphene was received by FDA. After consideration of the efficacy and safety data from the propoxyphene drug applications, the literature and postmarketing safety databases, the Committee voted by a narrow margin (14-to-12) against the continued marketing of propoxyphene products, noting that additional information about the cardiac effects of propoxyphene would be useful in further weighing the risk and benefit. FDA recognized that there were unanswered questions about the safety of propoxyphene, including its effects on the heart in overdose. In July 2009, FDA announced an ongoing safety review of propoxyphene and required the manufacturer to conduct a safety study of the effects of this drug on the heart, at higher than recommended doses. The Food and Drug Administration Amendments Act (FDAAA) gives FDA new authority to require such studies once a drug is on the market and a potential safety issue emerges or needs further evaluation.
Before proceeding with the cardiac safety study, the company first conducted a study on healthy volunteers to determine a safe dose for use in the cardiac safety study. In this study, one group of healthy volunteers was given a total daily dose of 600 mg of propoxyphene (the maximum approved dose) and the second group was given a total daily dose of 900 mg (a dose higher than recommended in the drug’s labeling).
The results showed that there were significant changes to the electrical activity of the heart (prolonged PR interval, widened QRS complex and prolonged QT interval), at both the 600 and 900 mg doses. These changes, which can be seen on an ECG, can increase the risk for serious abnormal heart rhythms.
Q6. Are there any populations who are more susceptible to these safety risks when taking propoxyphene?
Yes. Patients with impaired kidney function may be more susceptible to these safety risks because they cannot eliminate propoxyphene from the body as well as patients with healthy kidneys; this can lead to accumulation of the drug in the body. Patients taking other medicines that can affect the heart or the break down (metabolism) of propoxyphene are also at higher risk.
Q7. What should patients do if they are currently taking propoxyphene?
Patients who are currently taking propoxyphene should contact their healthcare professional as soon as possible to discuss switching to an alternate pain medicine.
Q8. What should patients do with their unused propoxyphene after switching to an alternate pain medicine?
Patients can dispose of unused propoxyphene in their household trash by following the recommendations outlined in the Federal Drug Disposal Guidelines
- Take the propoxyphene out of its original container and mix it with an undesirable substance, such as used coffee grounds or kitty litter. The medication will be less appealing to children and pets, and unrecognizable to people who may intentionally go through your trash.
- Put the medication in a sealable bag, empty can, or other container to prevent it from breaking out of a garbage bag.
Q9. Are there any side effects from stopping propoxyphene?
Patients who have used propoxyphene on a regular basis for more than a few weeks may experience withdrawal symptoms (nausea, vomiting, diarrhea, anxiety, and shivering) if regular use of propoxyphene is stopped suddenly.
FDA encourages patients to talk to their healthcare professionals about how to discontinue propoxyphene and switch to an alternate pain medicine.
Q10. What alternative pain medicines are available for patients?
There are a number of other pain medicines that patients can use to manage their pain. These include other narcotic-based drugs (e.g., oxycodone, hydrocodone, codeine), aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, and other drugs.
All pain medicines have risks and side effects. Aspirin can cause bleeding of the stomach and intestines and other serious problems. Acetaminophen, the main ingredient in Tylenol and other drugs, can cause liver damage. Codeine, one of the most widely used opioids, can cause severe constipation.
It is important that healthcare professionals and patients be aware of all the risks associated with pain medicines when making decisions on how to treat pain.
Q11. Did FDA review other data as part of its ongoing safety review?
Yes. FDA also reviewed data from three large databases in the United States that collect information on drug use and adverse health outcomes: The Drug Abuse Warning Network Emergency Department (DAWN-ED), The Drug Abuse Warning Network Medical Examiner (DAWN-ME), and the Florida Department of Law Enforcement database.
FDA’s review of these databases showed that propoxyphene was associated with a higher frequency of deaths compared to the pain relievers tramadol and hydrocodone. Over a five-year period, the number of drug-related deaths was approximately 16 deaths per 100,000 prescriptions for propoxyphene, 10 deaths per 100,000 prescriptions for tramadol and 8 deaths per 100,000 prescriptions for hydrocodone.
Q12. Was FDA aware of any potential safety concerns with propoxyphene when the drug was approved?
No. This safety information was not available at the time of drug approval.
Yes. An FDA Advisory Committee meeting was convened on January 30, 2009 to discuss the continued marketing of propoxyphene in the United States. There was one voting question posed to the committee:
Based on the data presented, does the balance of risk and benefit support continued marketing of propoxyphene-containing products for the management of mild to moderate pain?
The Committee voted by a narrow margin (14-to-12) against the continued marketing of propoxyphene products. Committee members who voted for propoxyphene to remain on the market advised FDA to revise the propoxyphene label to add warnings about use of the drug in elderly patients and about use with concomitant opioids or alcohol. There was general agreement among the Committee members that additional information about the cardiac effects of propoxyphene would be useful in further weighing the drug’s risk and benefit.
Q14. Were any label changes put into effect to try and manage the risks associated with propoxyphene?
Yes. Following the Advisory Committee meeting in 2009, FDA revised the physician labeling for propoxyphene-containing products to strengthen the boxed warning to address the risk of overdose with these products. FDA also required the drug manufacturers to develop a Medication Guide to inform patients about the risks of propoxyphene and the importance of using propoxyphene as directed. Medication Guides are required to be given to patients with each prescription or refill.
Q15. What actions have other regulatory groups, such as the European Medicines Agency, taken regarding propoxyphene?
In June 2009, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) concluded that the risks of propoxyphene, particularly the risk of potentially fatal overdose, are greater than the benefits and recommended the withdrawal of these medicines across the European Union.
Propoxyphene-Containing Products FDA recommends against the continued use of propoxyphene FDA Drug Safety Communication: FDA recommends against the continued use of propoxyphene
Xanodyne agrees to withdraw propoxyphene from the U.S. market[ARCHIVED]