Sunday Sept. 7, 2008 (foodconsumer.org) -- The Food and Drug Administration on Sept. 4, 2008 announced its decision to request the drug makers of four TNF-blocker drugs named Humira, Cimzia, Enbrel, and Remicade to strengthen the existing warnings to alert physicians and patients to the increased risk of fugal infections.

TNF-alpha blockers known as tumor necrosis factor alpha blockers suppress the immune system and increase risk of opportunistic fungal infections which if treatment is not quickly given could lead to death.

The FDA decision authorized under the Food and Drug Administration Amendments Act of 2007 came after the agency has reviewed 240 reports of histoplasmosis, an infection caused by the fungus Histoplasma capsulatum, in patients being treated with Enbrel, Humira, or Remicade.

The agency said in its announcement that at least in 21 reports, histoplasmosis developed, but was not recognized by doctors and antifugal treatment was delayed, resulting in 12 deaths from the infections.

The majority of reports came from the Ohio River and Mississippi River valleys where the fungus is commonly found.

The FDA said it has also reviewed one case of histoplasmosis in a patient who took Cimzia and also received reports of cases of coccidioidomycosis and blastomycosis, including deaths, in patients treated with TNF blockers.

These TNF-blocker drugs are approved to treat an array of conditions including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, and Crohn's disease.

The drug makers have 30 days to respond. They may still reject the request if they can convince the FDA that adding warnings is not necessary.

The following is some information regarding the warnings intended for health care professionals cited in verbatim from the FDA.

FDA ALERT [9/4/2008]:  FDA is notifying healthcare professionals that histoplasmosis and other invasive fungal infections are not consistently recognized in patients taking tumor necrosis factor-α blockers (TNF blockers), Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab) .  This has resulted in delays in appropriate treatment, sometimes resulting in death.

FDA has received reports of patients developing pulmonary and disseminated histoplasmosis, coccidioidomycosis, blastomycosis and other opportunistic infections while taking TNF blockers. In some patients, the diagnosis of histoplasmosis was initially unrecognized and antifungal treatment was delayed.  Some of these patients died from histoplasmosis. There were also deaths in patients with coccidioidomycosis and blastomycosis.

For patients taking TNF blockers who present with signs and symptoms of possible systemic fungal infection, such as fever, malaise, weight loss, sweats, cough, dypsnea, and/or pulmonary infiltrates, or other serious systemic illness with or without concomitant shock, healthcare professionals should ascertain if patients live in or have traveled to areas of endemic mycoses.  For patients at risk of histoplasmosis and other invasive fungal infections, clinicians should consider empiric antifungal treatment until the pathogen(s) are identified.  Consultation with an infectious diseases specialist should be sought when feasible. As with any serious infection, consider stopping the TNF blocker until the infection has been diagnosed and adequately treated.

FDA will require the makers of the tumor necrosis factor-α blockers (TNF blockers) to further highlight the information about the risk of invasive fungal infections, such as histoplasmosis, in the Boxed Warning and Warnings sections of the drugs’ prescribing information and the Medication Guide for patients. FDA will also require that the makers of the TNF blockers educate prescribers about this risk.

This information reflects FDA's current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.

To report any unexpected adverse or serious events associated with the use of these drugs, please contact the FDA MedWatch program and complete a form on line at http://www.fda.gov/medwatch/report/hcp.htm or report by fax to 1-800-FDA-0178, by mail using the postage-paid address form provided on line, or by telephone to 1-800-FDA-1088.

Considerations for Healthcare Professionals

• TNF blockers are immunosuppressants.  Patients taking TNF blockers are at risk for developing invasive fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis, and other opportunistic infections. Healthcare practitioners should be alert to these risks of TNF blockers in patients who live in regions of endemic mycoses.

• Patients should be closely monitored during and after treatment with TNF blockers for the development of signs and symptoms of possible systemic fungal infection including fever, malaise, weight loss, sweats, cough, dypsnea, pulmonary infiltrates on X-ray, or serious systemic illness including shock.  Patients who develop an infection should have their TNF blocker discontinued and undergo a complete diagnostic workup, which may include fungal cultures, histopathological or cytological evaluations, antigen detection and serum antibody titers.

• For patients who reside or travel in regions where mycoses are endemic, invasive fungal infections should be suspected if they develop the signs and symptoms of possible systemic fungal infection .  The decision to administer empiric antifungal therapy in these patients should be made in consultation with an infectious diseases specialist with expertise in the diagnosis and treatment of invasive fungal infections when feasible.

• TNF blockers may be restarted after recovery from the infection.  The decision to restart the TNF blocker should include a reevaluation of the benefits and risks of TNF blockers, especially in patients who live in regions of endemic mycoses. Both the decision to restart TNF blocker therapy and the duration of antifungal therapy should be made in consultation with an infectious disease specialist, when feasible.

Information for the Patient

Prescribers should discuss the following information with patients and their caregivers:

• Patients treated with TNF blockers have an increased risk for infections. Some patients have had serious infections while receiving TNF blockers. In some cases, patients needed to be hospitalized for treatment. These serious infections include infections caused by viruses, fungi, or bacteria including tuberculosis (TB), including infections that have spread throughout the body. Some patients have died from these infections.

• If you have weight loss, persistent fever, sweating, cough, shortness of breath, or fatigue, promptly seek medical attention. 

• Tell your doctor where you live and about recent travel in and outside the USA.  The risk of some infections is greater in regions where different microorganisms (bacteria, fungi, viruses, parasites) are more common. 

• Tell your doctors that you are taking a TNF blocker.  A doctor may make different decisions about your medical treatment if he or she knows that you are taking a TNF blocker. 

• Tell your doctor about all of your medical conditions, including if you have an infection that won't go away or a history of an infection that keeps coming back.

Background Information and Data

TNF blockers suppress the immune system by blocking the activity of TNF, a substance in the body that can cause inflammation and lead to immune system-related diseases.  There are currently four TNF blockers available in the United States: Cimzia, Enbrel, Humira, and Remicade. The TNF blockers have demonstrated benefit and are each approved to treat one or more of a number of immune system diseases including juvenile idiopathic arthritis (JIA), rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, and ankylosing spondylitis.  Remicade is approved for use in children to treat Crohn’s disease. Enbrel and Humira are approved for use in children to treat JIA.

Since TNF blockers are immunosuppressants, patients that take these drugs are at increased risk of serious infections, including invasive fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis, cryptococcosis, as well as other opportunistic infections. Since the initial approval of the four TNF blockers, the prescribing information for these drugs has included information about the risk of serious infections, including fungal infections.  However, based on the reports reviewed by FDA, healthcare professionals are not consistently recognizing cases of histoplasmosis and other invasive fungal infections, leading to delays in treatment. Some patients with invasive fungal infections have died.

FDA reviewed 240 reports of histoplasmosis in patients receiving Remicade (207 cases), Enbrel (17 cases), or Humira (16 cases). The majority of cases were from Histoplasma capsulatum-endemic areas in the Ohio and Mississippi River valleys.  In at least 21 of the reports, histoplasmosis was initially unrecognized and antifungal treatment was delayed.  Twelve of these 21 patients died. FDA has reviewed 1 reported case of histoplasmosis in a patient taking Cimzia, which was approved in April 2008.  FDA has also received reports of cases, including deaths, of coccidioidomycosis and blastomycosis in patients receiving TNF blockers.