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The FDA ( Food and Drug Administration ) has informed healthcare professionals that the Boxed Warning for the entire class of Tumor Necrosis Factor-alpha ( TNF-alpha ) blockers has been updated to include the risk of infection from two bacterial pathogens, Legionella and Listeria. In addition, the Boxed Warning and Warnings and Precautions sections of the labels for all of the TNF-alpha blockers have been revised so that they contain consistent information about the risk for serious infections and the associated disease-causing pathogens.

The class of TNF-alpha blockers are biologic products that include Remicade ( Infliximab ), Enbrel ( Etanercept ), Humira ( Adalimumab ), Cimzia ( Certolizumab pegol ), and Simponi ( Golimumab ).
TNF-alpha blockers are used to treat Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and/or juvenile idiopathic arthritis.
Since TNF-alpha blockers are immunosuppressants, patients who take these biologic products are at increased risk of serious infections.

Serious, including fatal, infections are a known risk of TNF-alpha blockers. These infections can involve various organ systems and sites due to bacterial, mycobacterial ( e.g., tuberculosis ), fungal ( e.g., histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, blastomycosis, pneumocystosis ), viral ( e.g., hepatitis B ), and other opportunistic pathogens.

Recently, FDA reviewed cases of infection in patients treated with TNF-apha blockers. The addition of Legionella and Listeria to the drug labels of the TNF-alpha blockers will provide healthcare professionals with more information about opportunistic pathogens that can cause serious infections in patients treated with TNF-alpha blockers.

Data summary

There are currently five TNF-alpha blockers available in the United States. Remicade ( Infliximab ) was FDA-approved in August 1998, Enbrel ( Etanercept ) in November 1998, Humira ( Adalimumab ) in December 2002, Cimzia ( Certolizumab pegol ) in April 2008, and Simponi ( Golimumab ) in April 2009.

FDA has identified cases of Legionella pneumonia in patients treated with TNF-alpha blockers. A search of the FDA's Adverse Event Reporting System ( AERS ) database between years 1999 and 2010 identified reports of 80 patients who developed Legionella pneumonia after having received Infliximab, Adalimumab, Etanercept, and Golimumab. The median age of the patients was 56 years ( range 25 to 85 years ). The most frequent indication for TNF-alpha blocker administration in the case series was rheumatoid arthritis ( 65% ). The median duration of TNF-alpha blocker administration prior to onset of Legionella pneumonia was 10.4 months ( range less than 1 to 73 months ). Of the 80 cases, reports for 30 patients provided information regarding laboratory confirmation of Legionella infection. Many of the patients received Methotrexate, corticosteroids, or both drugs, concomitantly. There were 14 deaths in the case series.

A search of the English-language medical literature identified published case reports of 23 patients who developed Legionella pneumonia after being treated with TNF-alpha blockers for rheumatologic disorders, inflammatory bowel disease, and psoriasis. The 23 patients were aged between 26 to 71 years. The administered TNF-alpha blockers included Infliximab, Adalimumab, and Etanercept. Twenty-two of the patients received concomitant immunosuppressive drugs ( Methotrexate and/or corticosteroids most commonly ). Four patients experienced severe pneumonia requiring mechanical ventilation, and five patients received treatment in a hospital intensive care unit. Three of the 23 patients died. One patient developed a second episode of Legionella pneumonia following re-initiation of a TNF-alpha blocker.

FDA has received adverse event reports of serious infections due to Listeria monocytogenes in patients treated with TNF-alpha blockers. A search of the English-language medical literature identified 26 published cases of Listeria infection in TNF-alpha blocker-treated patients, including meningitis, bacteremia, endophthalmitis, and sepsis. Seven fatalities were reported. Many of the reports noted that the patients had also received concomitant immunosuppressive drugs. In addition, FDA identified fatal Listeria infections in a review of data regarding laboratory-confirmed infections that occurred in pre-marketing phase 2 and phase 3 clinical trials and from post-marketing surveillance.

The pathogens Legionella and Listeria have been added to the Boxed Warning for the entire class of TNF-alpha blockers, so that healthcare professionals are aware that these pathogens can cause serious and potentially fatal outcomes in patients treated with TNF-alpha blockers.

Source: FDA, 2011

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