FDA Adds Stronger Warnings to Propoxyphene

Kristina Rebelo

Disclosures

July 07, 2009

July 7, 2009 — The US Food and Drug Administration (FDA) is adding stronger warnings to pain medications that contain propoxyphene, such as Darvon and Darvocet, because of new data on fatal overdoses linked to propoxyphene products. The FDA is requiring the manufacturers of these drugs to strengthen the drug's boxed warning and to create a medication guide for patients.

The agency is stopping short of a phased withdrawal from the market as demanded by a Public Citizen petition filed in 2006.

To reduce the likelihood of overdose, the FDA will now require that manufacturers of propoxyphene-containing medications strengthen their label and include a boxed warning on the potential for overdose. Manufacturers will also be required to develop a medication guide for patients stressing that they use the medication as directed. Propoxyphene has been on the market since 1957.

Between 1969 and 2005, an FDA database has linked a total of 91 deaths in persons taking propoxyphene related to accidental overdoses and suicide attempts, although a direct link to propoxyphene is difficult to establish because multiple drugs and other conditions were involved, the agency said.

The FDA is currently working with several organizations, including the Centers for Medicare & Medicaid Services and the Veterans Health Administration, to collect data for a new safety study that will assess the cardiotoxic effects of propoxyphene at higher doses, particularly in elderly populations; findings from this study could lead to additional regulatory action. At this time, the FDA is looking at how Americans are using medications containing propoxyphene, and in which combinations.

Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, told reporters during a press briefing that propoxyphene is an accepted option for pain treatment at this time. "Pain is an important issue — it's the fifth vital sign. Millions of people suffer from pain; it is so prevalent that 1 in 10 people have chronic pain, and the FDA is committed to appropriate treatment of pain. At this time, propoxyphene is an acceptable choice for the treatment of mild to moderate pain when taken as directed."

Dr. Woodcock noted that after last week's advisory meeting on acetaminophen safety, the FDA heard from hundreds of patients concerned about the availability of their medications that contain acetaminophen.

"When it comes to acetaminophen or opioids, the FDA is constantly balancing benefit vs risk," she said.

The FDA said that in cases of overdose, propoxyphene can be a fatal medicine; however, most of the deaths connected to the drug in the FDA's database were in cases of ingestion of multiple drugs.

The consumer group Public Citizen petitioned the FDA in February 2006, asking that propoxyphene-containing products, sold primarily as a generic drug, be removed from the market. The FDA declined today to take action on the petition. The drug was withdrawn from the UK market in 2005, however, when the British government said it was unimpressed with the efficacy of the drug and that the risk of toxicity in cases of overdose — both intentional and accidental — were unacceptable.

The FDA defended its position in not removing the drug from the market, pointing out that there are not a lot of alternative drugs without similar adverse effects.

"In cases of mild to moderate pain, acetaminophen or [nonsteroidal anti-inflammatory drugs] may not be warranted, although it's common to proceed to opioid-acetaminophen combination drugs," said the FDA's Sharon H. Hertz, MD, deputy director, Division of Anesthesia, Analgesia and Rheumatology Products, Center for Drug Evaluation and Research.

"With codeine and hydrocodone, a number of patients, particularly older patients...have side effects[, such as constipation, that] can be limiting," she explained. "With hydrocodone, one needs to consider cognitive effects as well as other safety considerations."

She continued, "Nonsteroidal anti-inflammatory drugs can be used for the same type of pain, but they have other adverse events, such as gastrointestinal bleeding and fluid retention. There are recommendations to avoid [nonsteroidal anti-inflammatory drugs], in fact, in older patients. Within this group, Darvon has less constipation, and it tends to have fewer side effects with regard to sedation and confusion, so there are limited alternatives when treating mild to moderate pain."

Dr. Woodcock said, "We're trying to cover all the bases here at the FDA as far as pain medicine."

Adverse events related to use of propoxyphene should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.

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