The agency say the manufacturers of Humira, Cimzia, Enbrel, and Remicade must strengthen existing warnings in the prescribing info and medication guides due to risks of developing histoplasmosis, an opportunistic fungal infection. Most of the cases in the Ohio River and Mississippi River valleys and in at least 21 of those, the infection wasn’t initially recognized. Twelve patients died.

The four drugs, known as tumor necrosis factor alpha blockers, or TNF-inhibitors, which suppress the immune system, are approved to treat such conditions as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, and Crohn’s disease. Humira is made by Abbott; Cimzia is made by UCB; Enbrel is sold by Amgen and Remicade is sold by Johnson & Johnson.

“Under the FDA’s new authorities, we can require safety label changes and a risk evaluation and mitigation strategy, known as REMS, when the agency becomes aware of new safety information,” Bob Rappaport, director of the FDA’s division of anesthesia, analgesia and rheumatology products in the Center for Drug Evaluation and Research, says in a statement.

Since the initial approval of the four TNF blockers, the FDA notes the prescribing info has included info about the risk of serious infections, including fungal infections. However, based on reports reviewed by FDA, the agency says health care professionals are not consistently recognizing cases of histoplasmosis and other invasive fungal infections, leading to delays in treatment.

The FDA says patients taking TNF blockers should be aware they are more susceptible to serious fungal infections. The agency reviewed one reported case of histoplasmosis in a patient taking Cimzia. The FDA, by the way, also received reports of cases of coccidioidomycosis and blastomycosis, including deaths, in patients treated with TNF blockers.

Meanwhile, the FDA notes that the manufacturers are required to submit safety labeling changes, including strengthened warnings and revisions to the Medication Guides to the FDA within 30 days 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.

Medication Guides will become part of a REMS for Humira and Remicade and are already part of a REMS for Enbrel and Cimzia. The manufacturers for all four of these drugs will also be required to educate prescribers about the risks.

UPDATE: Amgen sends us this statement.