FDA Drug Safety Communication: Drug labels for the Tumor Necrosis Factor-alpha (TNFα) blockers now include warnings about infection with Legionella and Listeria bacteria
Additional Information for Patients
Additional Information for Healthcare Professionals
[9-07-2011] The U.S. Food and Drug Administration (FDA) is informing healthcare professionals that the Boxed Warning for the entire class of Tumor Necrosis Factor-alpha (TNFα) 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 TNFα blockers have been revised so that they contain consistent information about the risk for serious infections and the associated disease-causing pathogens.
Facts about TNFα blockers
- The class of TNFα blockers are biologic products that include Remicade (infliximab), Enbrel (etanercept), Humira (adalimumab), Cimzia (certolizumab pegol), and Simponi (golimumab).
- TNFα blockers are used to treat Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and/or juvenile idiopathic arthritis.
- Since TNFα 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 TNFα 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 (organisms that usually do not cause disease in healthy people, but can cause serious illness when a person's immune system (resistance) has weakened).
Recently, FDA reviewed cases of infection in patients treated with TNFα blockers (see Data Summary below). The addition of Legionella and Listeria to the drug labels of the TNFα blockers will provide healthcare professionals with more information about opportunistic pathogens that can cause serious infections in patients treated with TNFα blockers.
It is important for healthcare professionals to be aware of the new labeling changes.
Additional Information for Patients
- TNFα blockers can lower the ability of the immune system to fight infections.
- Patients should inform their healthcare professional if they are being treated for an infection or have infections that keep coming back.
- Patients should read the Medication Guide that accompanies their prescription for a TNFα blocker.
- Patients should contact their healthcare professional if they have any questions or concerns about TNFα blockers.
- Patients should report serious side effects from the use of TNFα blockers to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of this page.
Additional Information for Healthcare Professionals
- Patients treated with TNFα blockers are at increased risk for developing serious infections involving multiple organ systems and sites that may lead to hospitalization or death due to bacterial, mycobacterial, fungal, viral, parasitic, and other opportunistic pathogens.
- The bacterial pathogens Legionella and Listeria have been added to the Boxed Warning for the entire class of TNFα blockers.
- The risks and the benefits of TNFα blockers should be considered prior to initiating therapy in patients with chronic or recurrent infection and patients with underlying conditions that may predispose them to infection.
- Patients greater than 65 years old and patients taking concomitant immunosuppressants may be at greater risk of infection.
- Prior to initiating TNFα blockers and periodically during treatment, patients should be evaluated for active tuberculosis and tested for latent infection.
- Patients should be monitored for signs and symptoms of serious infections while taking TNFα blockers.
- Empiric antifungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
- Healthcare professionals should encourage patients to read the Medication Guide that accompanies their prescription for a TNFα blocker.
- Healthcare professionals should report adverse events involving TNFα blockers to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of this page.
There are currently five TNFα 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 TNFα 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 TNFα blocker administration in the case series was rheumatoid arthritis (65%). The median duration of TNFα blocker administration prior to onset of Legionella pneumonia was 10.4 months (range <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 TNFα blockers for rheumatologic disorders, inflammatory bowel disease, and psoriasis.1-11 The 23 patients were aged between 26 to 71 years. The administered TNFα 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 TNFα blocker.3
FDA has received adverse event reports of serious infections due to Listeria monocytogenes in patients treated with TNFα blockers. A search of the English-language medical literature identified 26 published cases of Listeria infection in TNFα blocker-treated patients, including meningitis, bacteremia, endophthalmitis, and sepsis.12-17 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 TNFα blockers, so that healthcare professionals are aware that these pathogens can cause serious and potentially fatal outcomes in patients treated with TNFα blockers.
- Hofmann A, Beaulieu Y, Bernard F, Rico P. Fulminant legionellosis in two patients treated with infliximab for Crohn's disease: case series and literature review. Can J Gastroenterol. 2009; 23:829-33.
- Kroesen S, Widmer AF, Tyndall A, Hasler P. Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. Rheumatology. 2003;42:617-21.
- Tubach F, Ravaud P, Salmon-Céron D, Petitpain N, Brocq O, Grados F, et al. Emergence of Legionella pneumophila pneumonia in patients receiving tumor necrosis factor-alpha antagonists. Clin Infect Dis. 2006;43:e95-100.
- Dixon WG, Watson K, Lunt M, Hyrich KL, Silman AJ, Symmons DP; British Society for Rheumatology Biologics Register. Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 2006;54:2368-76.
- Beigel F, Jürgens M, Filik L, Bader L, Lück C, Göke B, et al. Severe Legionella pneumophila pneumonia following infliximab therapy in a patient with Crohn's disease. Inflamm Bowel Dis. 2009;15:1240-4.
- Wondergem MJ, Voskuyl AE, van Agtmael MA. A case of legionellosis during treatment with a TNFalpha antagonist. Scand J Infect Dis. 2004;36:310-1.
- Jinno S, Pulido S, Pien BC. First reported United States case of Legionella pneumophila serogroup 1 pneumonia in a patient receiving anti-tumor necrosis factor-alpha therapy. Hawaii Med J. 2009;68:109-12.
- Kohn A, Daperno M, Armuzzi A, Cappello M, Biancone L, Orlando A, et al. Infliximab in severe ulcerative colitis: short-term results of different infusion regimens and long-term follow-up. Aliment Pharmacol Ther. 2007;26:747-56.
- Li Gobbi F, Benucci M, Del Rosso A. Pneumonitis caused by Legionella pneumoniae in a patient with rheumatoid arthritis treated with anti-TNF-alpha therapy (infliximab). J Clin Rheumatol. 2005;11:119-20.
- Mancini G, Erario L, Gianfreda R, Oliva A, Massetti AP, Mastroianni CM, et al. Tuberculosis and Legionella pneumophila pneumonia in a patient receiving anti-tumour necrosis factor-alpha (anti-TNF-alpha) treatment. Clin Microbiol Infect. 2007;13:1036-7.
- Eisendle K, Fritsch P. Fatal fulminant legionnaires' disease in a patient with severe erythodermic psoriasis treated with infliximab after long-term steroid therapy. Br J Dermatol. 2005;152:585-6.
- Kesteman T, Yombi JC, Gigi J, Durez P. Listeria infections associated with infliximab: case reports. Clin Rheumatol. 2007;26:2173-5.
- Slifman NR, Gershon SK, Lee JH, Edwards ET, Braun MM. Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents. Arthritis Rheum. 2003;48:319-24.
- Jessel P, Safdar N, McCune WJ, Saint S, Kaul DR. Clinical problem-solving. Thinking inside the box. N Engl J Med. 2010;363:574-9.
- Peña-Sagredo JL, Hernández MV, Fernandez-Llanio N, Giménez-Ubeda E, Muñoz-Fernandez S, Ortiz A, et al. Listeria monocytogenes infection in patients with rheumatic diseases on TNF-alpha antagonist therapy: the Spanish Study Group experience. Clin Exp Rheumatol. 2008;26:854-9.
- Murphy G, Schmidt-Martin D, Hynes BG, Harney S. Systemic listeriosis with adalimumab therapy. J Clin Rheumatol. 2009;15:369-70.
- Ramos JM, García-Sepulcre MF, Masiá M, Brotons A, Grau MC, Gutiérrez F. Listeria monocytogenes infection in patients with inflammatory bowel diseases receiving anti-tumor necrosis factor therapy. Rev Esp Enferm Dig. 2010;102:614-6.
- Information on Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi)
- FDA Drug Safety Podcast for Healthcare Professionals: Drug labels for the Tumor Necrosis Factor-alpha (TNFÎ±) blockers now include warnings about infection with Legionella and Listeria bacteria
- Comunicado de Seguridad de Medicamentos de la FDA: Las etiquetas de los medicamentos antagonistas del factor de necrosis tumoral alfa (TNFα) incluyen ahora advertencias sobre infección con las bacterias Legionella y Listeria