ROCKVILLE, Maryland—The US Food and Drug Administration (FDA) on September 4 warned healthcare professionals to be on guard for histoplasmosis and other invasive fungal infections in patients taking tumor necrosis factorα inhibitors (TNF blockers).

According to the agency, “[P]ulmonary and disseminated histoplasmosis, coccidioidomycosis, blastomycosis and other opportunistic infections [have occurred in patients] 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.”¹

Translating FDA warning into practice

The MedWatch warning advises clinicians to watch for and warn patients to promptly report any signs and symptoms of possible systemic fungal infection. These include

• fever
• malaise
• weight loss
• sweats
• cough
• dypsnea
• and/or pulmonary infiltrates, or other serious systemic illness with or without concomitant shock

According to the directive, “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) is identified.”

“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.”

The FDA also recommends consultation with an infectious diseases specialist when feasible and advises clinicians to consider stopping the TNF blocker until the infection has been diagnosed and adequately treated. TNF blockers may be restarted after recovery from the infection, but the decision to restart them should include a reevaluation of their benefits and risks, especially in patients who live in regions of endemic mycoses.

Agency to require more warnings on label

The agency also will require makers of TNF blockers to add information about the risk of invasive fungal infections in the Boxed Warning and Warnings sections of the drugs’ prescribing information and the Medication Guide for patients, and to educate prescribers about this risk.

FDA reviewed 240 reports of histoplasmosis in patients receiving Remicade^® (infliximab) (207 cases), Enbrel^® (etanercept) (17 cases), or Humira^® (adalimumab) (16 cases). The majority of cases were from Histoplasma capsulatum-endemic areas in the Ohio and Mississippi River valleys. FDA has reviewed one reported case of histoplasmosis in a patient taking Cimzia^® (certolizumab pegol), which was approved in April 2008. In at least 21 of the reports, histoplasmosis was initially unrecognized and antifungal treatment was delayed. Twelve of these 21 patients died.

“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,” the agency commented.

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 online 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.

Reference

1. US Food and Drug Administration MedWatch alert. FDA Website. http://www.fda.gov/medwatch/safety/2008/safety08.htm#TNF2.