Xanodyne agrees to withdraw propoxyphene from the U.S. market

Xanodyne Pharmaceuticals Inc. which makes Darvon and Darvocet, the brand version of the prescription pain medication propoxyphene, has agreed to withdraw the medication from the U.S. market at the request of the U.S. Food and Drug Administration. The FDA has also informed the generic manufacturers of propoxyphene-containing products of Xanodyne’s decision and requested that they voluntarily remove their products as well.

The FDA sought market withdrawal of propoxyphene after receiving new clinical data showing that the drug puts patients at risk of potentially serious or even fatal heart rhythm abnormalities. As a result of these data, combined with other information, including new epidemiological data, the agency concluded that the risks of the medication outweigh the benefits.

“The FDA is pleased by Xanodyne’s decision to voluntarily remove its products from the U.S. market,” said John Jenkins, M.D., director of the Office of New Drugs in the FDA’s Center for Drug Evaluation and Research (CDER). “These new heart data significantly alter propoxyphene’s risk-benefit profile. The drug’s effectiveness in reducing pain is no longer enough to outweigh the drug’s serious potential heart risks.”

The FDA is advising health care professionals to stop prescribing propoxyphene to their patients, and patients who are currently taking the drug should contact their health care professional as soon as possible to discuss switching to another pain management therapy.

Propoxyphene is an opioid used to treat mild to moderate pain. First approved by the FDA in 1957, propoxophene is sold by prescription under various names both alone (e.g., Darvon) or in combination with acetaminophen (e.g., Darvocet).

Since 1978, the FDA has received two requests to remove propoxyphene from the market. Until now, the FDA had concluded that the benefits of propoxyphene for pain relief at recommended doses outweighed the safety risks of the drug.

In January 2009, the FDA held an advisory committee meeting to address the efficacy and safety of propoxyphene. After considering the data submitted with the original drug applications for propoxyphene, as well as subsequent medical literature and postmarketing safety databases, the committee voted 14 to 12 against the continued marketing of propoxyphene products. In making this recommendation, the committee noted that additional information about the drug’s cardiac effects would be relevant in weighing its risks and benefits.

In June 2009, the European Medicines Agency (EMEA) recommended that the marketing authorizations for propoxyphene be withdrawn across the European Union. A phased withdrawal of propoxyphene is underway.

In July 2009, the FDA decided to permit continued marketing, but required that a new boxed warning be added to the drug label alerting patients and health care professionals to the risk of a fatal overdose. In addition, the agency required Xanodyne to conduct a new safety study assessing unanswered questions about the effects of propoxyphene on the heart.

The agency now has reviewed the data from that study, which show that, even when taken at recommended doses, propoxyphene causes significant changes to the electrical activity of the heart. These changes, which can be seen on an electrocardiogram (EKG), can increase the risk for serious abnormal heart rhythms that have been linked to serious adverse effects, including sudden death. The available data also indicate that the risk of adverse events for any particular patient (even patients who have taken the drug for many years) is subject to change based on small changes in the health status of the patient, such as dehydration, a change in medications, or decreased kidney function.

“With the new study results, for the first time we now have data showing that the standard therapeutic dose of propoxyphene can be harmful to the heart,” said Gerald Dal Pan, M.D., M.H.S., director of the Office of Surveillance and Epidemiology, CDER. “However, long-time users of the drug need to know that these changes to the heart’s electrical activity are not cumulative. Once patients stop taking propoxyphene, the risk will go away.”

Xanodyne is based in Newport, Ky.

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FDA: Pfizer Voluntarily Withdraws Cancer Treatment Mylotarg from U.S. Market

Pfizer Inc. today announced the voluntary withdrawal from the U.S. market of the drug Mylotarg (gemtuzumab ozogamicin) for patients with acute myeloid leukemia (AML), a bone marrow cancer. The company took the action at the request of the U.S. Food and Drug Administration after results from a recent clinical trial raised new concerns about the product’s safety and the drug failed to demonstrate clinical benefit to patients enrolled in trials.

Mylotarg was approved in May 2000 under the FDA’s accelerated approval program. This program allows the agency to approve a drug to treat serious diseases with an unmet medical need based on a surrogate endpoint – a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that directly measures how a patient feels, functions, or survives.

Under accelerated approval, the company is required to conduct additional clinical trials after approval to confirm the drug’s benefit. If those trials fail to confirm clinical benefit to patients, or if the company does not pursue the required confirmatory trials with due diligence, the FDA can withdraw the drug from the market using expedited procedures.

Mylotarg was approved to treat patients ages 60 years and older with recurrent AML who were not considered candidates for other chemotherapy. The initial approval was based on the surrogate endpoint of response rate (i.e., the percentage of patients whose leukemia decreased or disappeared in laboratory tests), observed in 142 patients with AML across three clinical trials.

A confirmatory, post approval clinical trial was begun by Wyeth (now Pfizer) in 2004. The trial was designed to determine whether adding Mylotarg to standard chemotherapy demonstrated an improvement in clinical benefit (survival time) to AML patients. The trial was stopped early when no improvement in clinical benefit was observed, and after a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone.

At initial approval, Mylotarg was associated with a serious liver condition called veno-occlusive disease, which can be fatal. This rate has increased in the postmarket setting.

“Mylotarg was granted an accelerated approval to allow patient access to what was believed to be a promising new treatment for a devastating form of cancer,” said Richard Pazdur, M.D., director, Office of Oncology Drug Products, part of FDA’s Center for Drug Evaluation and Research. “However, a confirmatory clinical trial and years of postmarketing experience with the product have not shown evidence of clinical benefit in patients with AML.”

As a result of the withdrawal, Mylotarg will not be commercially available to new patients. Patients who are currently receiving the drug may complete their therapy following consultation with their health care professional. Health care professionals should inform all patients receiving Mylotarg of the product’s potential safety risks.

Following the withdrawal, any future use of Mylotarg in the United States will require submission of an investigational new drug application to FDA.

Mylotarg is manufactured by New York City-based Pfizer.

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FDA Takes Actions on Darvon, Other Pain Medications Containing Propoxyphene

The U.S. Food and Drug Administration is taking several actions to reduce the risk of overdose in patients using pain medications such as Darvon and Darvocet that contain propoxyphene. The actions were taken because of data linking propoxyphene and fatal overdoses.

The agency is requiring manufacturers of propoxyphene-containing products to strengthen the label, including the boxed warning, emphasizing the potential for overdose when using these products. These manufacturers will also be required to provide a medication guide to patients stressing the importance of using the drugs as directed.

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.

“Physicians need to be aware of the risk of overdose when prescribing these drugs. They should carefully review patient histories and make appropriate treatment decisions based on the warnings and directions stated within the drug’s label,” said Janet Woodcock, M.D, director of the FDA’s Center for Drug Evaluation and Research. “Prescribers and patients should be aware of propoxyphene’s potential risks when used at doses higher than those recommended. Therefore, the FDA is requiring manufacturers to provide more information to help physicians and patients decide whether propoxyphene is the appropriate pain therapy.”

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.

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.

Also today, the FDA denied a citizen petition from the public interest group Public Citizen requesting a phased withdrawal of propoxyphene. The agency said in its response that despite the FDA’s serious concerns about propoxyphene, the benefits of using the medication for pain relief at recommended doses outweighs the safety risks at this time. The FDA also noted that it plans to further evaluate the safety of propoxyphene and will take additional regulatory action if necessary. Details of this decision can be found at:
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm170268.htm.

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.

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Mayo Clinic Study Finds Increased Risk of Pneumococcal Disease in Asthma Patients

/PRNewswire-USNewswire/ -- Mayo Clinic research shows adults with asthma are at increased risk of serious pneumococcal disease caused by Streptococcus pneumoniae, the most common bacteria causing middle ear infections and community acquired pneumonia. It also causes blood stream infections and brain infections. According to the Centers for Disease Control, pneumococcal infection is one of the leading causes of death from a vaccine-preventable disease. The researchers recommend including asthma as an indication for pneumococcal vaccination in adults. The results of the study were recently published in the October edition of the Journal of Allergy and Clinical Immunology.

"We found that adults with invasive pneumococcal disease, a serious, potentially fatal disease, are seven times more likely to be asthmatics. Our study also showed that 17 percent of the burden of invasive pneumococcal disease can be attributable to asthma at a population level. This is quite a significant impact on the burden of invasive pneumococcal disease," says Young Juhn, M.D., a pediatric and adolescent medicine physician-scientist at Mayo Clinic and lead author of the study. "Invasive pneumococcal disease is a vaccine-preventable disease. The implication is that we have the ability to significantly reduce instances of this potentially fatal disease by expanding the indication for the pneumococcal vaccine to include adults with asthma."

Researchers used a population-based, retrospective case-control study of 3,941 records from the Rochester, Minn. population to see if there was a higher incidence of pneumococcal disease among people with asthma. Adults diagnosed with asthma were almost seven times more likely to develop invasive pneumococcal diseases than adults who were not diagnosed with asthma. In children the sample size for was not large enough to draw a definitive conclusion.

"The Advisory Committee on Immunization Practices (ACIP), which is the governing body for immunization practices in the United States, voted unanimously to include asthma as a pneumococcal vaccine condition at the recent ACIP meeting in October, 2008. Adults with asthma should receive the pneumococcal vaccine," says Dr. Juhn.

Further research implications include finding out why a connection exists between instances of pneumococcal disease and asthma, determining whether the connection between asthma and this particular bacterial infection also exists with other bacterial infections, such as pertussis (whooping cough), and the connection between asthma and other non-infectious diseases, such as inflammatory bowel disease, juvenile diabetes, and rheumatoid arthritis. Dr. Juhn does not believe all asthmatic patients react the same way. He is looking for a subset of asthmatic patients who have an increased susceptibility to microbial infection.

Study authors, in addition to Dr. Juhn, include Hirohito Kita, M.D., Department of Allergic Diseases Research, Mayo Clinic; Barbara Yawn, M.D., Department of Epidemiology, Mayo Clinic; Thomas Boyce, M.D., Department of Pediatric Infectious Diseases, Mayo Clinic; Kwang Yoo, M.D., Ph.D., Department of Internal Medicine, Kunkook University, Republic of Korea; Michaela McGree, Department of Biostatistics, Mayo Clinic; Amy Weaver, Department of Biostatistics, Mayo Clinic; Peter Wollan, Ph.D., Department of Epidemiology, Mayo Clinic; and Robert Jacobson, M.D., Department of Pediatric and Adolescent Medicine, Mayo Clinic.

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