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Humira, Cimzia, Enbrel and Remicade to Bear Stronger Infection Warnings

Sep 4, 2008 | Parker Waichman Alonso LLP

Federal regulators have ordered the makers of Humira, Cimzia, Enbrel, and Remicade to strengthen the existing warnings about opportunistic fungal infections linked to the drugs.  At least 45 people are known to have died from such infections.  The Food & Drug Administration (FDA) ordered the new labeling under authority it was granted with the passage of the Food and Drug Administration Amendments Act of 2007.

Humira, Cimzia, Enbrel and Remicade are known as tumor necrosis factor (TNF) blockers.  They are used to treat rheumatoid arthritis, Crohn's disease and other conditions.  The drugs work by suppressing the immune system. It has long been known that people taking TNF blockers run a risk of developing opportunistic infections, and the prescribing information for the drugs has included this information.  But now the FDA says that current warnings are inadequate.

The FDA's order came after the agency reviewed 240 reports of histoplasmosis, an infection caused by the fungusHistoplasma capsulatum, in patients being treated with Enbrel, Humira, or Remicade. The majority of the reports involved people in the Ohio River and Mississippi River valleys (the fungus is commonly found in those areas). In at least 21 of the reports, histoplasmosis was initially not recognized by health care professionals, and antifungal treatment was delayed. Twelve of those patients died.

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

The agency has given the makers of Humira, Cimzia, Enbrel and Remicade 30 days to submit the required safety labeling changes, including strengthened warnings and revisions to the Medication Guides, or to provide a reason why they do not believe labeling changes are necessary. If they do not submit new language, or if the FDA disagrees with the new language the company proposes, the Food and Drug Administration Amendments Act of 2007 provides strict timelines for resolving the labeling changes and allows the agency to issue an order directing the labeling change as deemed appropriate to address the new safety information.

The FDA is also reviewing TNF blockers over a possible link to cancer.  In June, the agency said it was investigating about 30 reports of leukemia, lymphoma and other cancers in children and young adults submitted between 1998, after the approval of the first TNF blocker, through April of this year. Approximately half of the reports were lymphomas, cancer of the immune system cells, that were both Hodgkin’s and non-Hodgkin’s based.

In April, the FDA had Amgen and Wyeth include a new black box warning on the Enbrel label stating that the drug has been associated with serious infections, including tuberculosis in some patients. The  Enbrel black box warning was prompted by global studies of over 20,000 patients taking Enbrel, where tuberculosis was observed in about 200 people.