What are the warnings?

The U.S. Food and Drug Administration just announced that the manufacturers of Humira, Cimzia, Enbrel, and Remicade must strengthen the existing “Black Box” warnings because of the risk of developing opportunistic fungal infections. These warnings are located in the Warnings and Precaution sections of the drugs' prescribing information and Medication Guides. The FDA hopes that this new requirement will help health care professionals be more vigilant in watching for these adverse events. The agency also believes the warnings are necessary to ensure that the benefits of these drugs outweigh their risks.

Since the time the FDA first approved each of these medications, the prescribing information for these drugs has included information about the risk of serious infections, including fungal infections. However, over the past several years, there have been several hundred reports of serious fungal infections that were not initially diagnosed, causing delays in treatment. The FDA is concerned that health care professionals are not consistently recognizing cases of histoplasmosis and other invasive fungal infections in a timely manner.

The FDA is requiring the drug manufacturers to submit the safety labeling changes to the FDA within 30 days or to provide a reason why they do not believe labeling changes are necessary. If they do not comply, or if the FDA disagrees with the new language the company proposes, the agency may issue an order directing the labeling change as deemed appropriate to address the new safety information. Medication Guides will become part of a mitigation strategy (called 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.

How many people have been affected?

FDA has reviewed 240 reports of histoplasmosis 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. While it is a relatively small number in comparison to the tens of thousands of people who take TNF inhibitors, it is of great concern to the agency because these serious infections and deaths can be prevented.

The FDA has also reviewed one reported case of histoplasmosis in a patient taking Cimzia and has received reports of cases of coccidioidomycosis and blastomycosis both resulting in several deaths.

What should patients know?

The FDA highlighted some information it believes is important for people on TNF therapy to know. The bullet points are quoted below.

• Patients treated with TNF blockers have an increased risk for infections. Some patients have had serious infections while receiving TNF blockers. In some cases, patients needed to be hospitalized for treatment. These serious infections include infections caused by viruses, fungi, or bacteria including tuberculosis (TB), including infections that have spread throughout the body. Some patients have died from these infections.
• If you have weight loss, persistent fever, sweating, cough, shortness of breath, or fatigue, promptly seek medical attention.
• Tell your doctor where you live and about recent travel in and outside the USA. The risk of some infections is greater in regions where different microorganisms (bacteria, fungi, viruses, parasites) are more common.
• Tell your doctors that you are taking a TNF blocker. A doctor may make different decisions about your medical treatment if he or she knows that you are taking a TNF blocker. o Tell your doctor about all of your medical conditions, including if you have an infection that won't go away or a history of an infection that keeps coming back.

For more information from the FDA see: http://www.fda.gov/cder/drug/InfoSheets/HCP/TNF_blockersHCP.htm