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TNF blockers to carry stronger infection warning.

The Food and Drug Administration has announced that it will require warnings about fungal infections in the labels of tumor necrosis factor-[alpha] blockers be strengthened to reflect reports of histoplasmosis and other opportunistic fungal infections, some of which have been fatal.

The FDA will require that the upgraded warnings include advice to health care providers to consider histoplasmosis in patients on one of these agents "who develop serious illnesses that prove difficult to diagnose or who develop serious infections that are not responding" to treatment, so that appropriate treatment is not delayed, Dr. Jeffrey Siegel said at an FDA press briefing. The FDA also is advising that health care providers work with infectious disease specialists to diagnose and treat patients with histoplasmosis and to consider empiric antifungal therapy based on the likelihood of histoplasmosis, even before test results provide definitive proof, particularly in those patients who live in or have traveled to endemic areas.

"We are asking health care providers to be more vigilant in looking out for possible signs and symptoms of histoplasmosis and other fungal infections" and to educate their patients to recognize these signs and symptoms, added Dr. Siegel, clinical team leader of the division of anesthesia, analgesia, and theumatology products in the FDA's Center for Drug Evaluation and Research.

The FDA learned of a woman taking a TNF blocker who died of a histoplasmosis infection after having been ill for a long period of time without having been diagnosed. The FDA then identified 240 reports of histoplas patients treated with etanercept adalimumab, or infliximab. In 21 of the cases, histoplasmosis was not initially diagnosed, which led to a prolonged hospitalization and death in 12 cases. Overall, among the 240 cases, there were 45 deaths.

Most of the patients were living in the Ohio River Valley and the Mississippi River Valley, where Histoplasma capsulatum is endemic. About 52% of the cases were in patients with rheumatoid arthritis, and affected patients have ranged in age from 8 to 86 years (mean age 47 years). The FDA is not aware of any pediatric deaths, Dr. Siegel said.

Four TNF-[alpha] blockers are approved in the United States--adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), and infliximab (Remicade)--for indications that include rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, and Crohn's disease.

The product labels have always included warnings about the risks of infections, including fungal infections associated with treatment.

There was an additional report of histoplasmosis in a patient treated with certolizumab pegol, which has not been on the market for as long as the other three. There have also been cases of coccidioidomycosis and blastomycosis, some of which were fatal, reported in patients treated with TNF blockers, but the number of cases has been "considerably smaller" than the number of histoplasmosis cases, Dr. Siegel said.

The manufacturers will be required to strengthen the wording in the warnings and precautions sections of each drug's labels, which includes the boxed warning, as well as in the medication guides, which are distributed to patients with each prescription.

Dr. Siegel noted that the patients who were not correctly diagnosed were not necessarily neglected and that a histoplasmosis infection can be extremely difficult to diagnose; even the appropriate tests can produce false-negative results. Symptoms of histoplasmosis include fever, cough, shortness of breath and fatigue, and unexplained weight loss.

The FDA can now require companies to make safety-related changes under the FDA Amendments Act of 2007; the companies must submit the labeling changes within 30 days or must provide a reason they do not believe they are necessary. Previously, the agency would initiate a discussion about labeling changes with the company, and the changes would be made in agreement between the agency and company.

So far, the manufacturers of the TNF blockers have been cooperating, Dr. Siegel said.

For more information, go to'safety/2008/safety08.htm #TNF2.


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Title Annotation:News; tumor necrosis factor
Author:Mechcatie, Elizabeth
Publication:Internal Medicine News
Geographic Code:1USA
Date:Nov 1, 2008
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