FDA is using its new drug safety authority to require label changes within 30 days for all four products in the tumor necrosis factor inhibitor class.

FDA announced Sept. 4 that it is requiring re-labeling for the class by applying one of the lowest level tiers of authority granted under the Risk Evaluation and Mitigation Strategies authorities: to require a MedGuide.

The action comes after an analysis revealed continuing problems with the incidence of serious infections with the drugs, specifically fungal infections.

The mandated label changes affect Amgen/Wyeth's Enbrel (etanercept), Johnson & Johnson's Remicade (infliximab), Abbott's Humira (adalimumab) and UCB's Cimzia (certolizumab pegol). By using the REMS authority, FDA is assuring a more rapid and coordinated label change by all companies.

The mandatory REMS will have two components: the first is updated MedGuides, which will be supported by a less defined educational component. The agency focused on the relabeling through much of its description of the action, mentioning an education effort at the end of its statement.

Cimzia and Enbrel already have REMS programs in place. Cimzia was approved with one in April. A REMS had been expected for Enbrel in conjunction with its review for pediatric psoriasis (¹ 'The Pink Sheet,' Aug. 4, 2008, In Brief). Amgen says that the Enbrel REMS program started with a MedGuide in June, and that "the pediatric psoriasis indication under discussion could contain additional elements to the Enbrel REMS."

UCB and Amgen will need to update their existing programs to incorporate the new information on the fungal infections, while Abbott and J&J will need to add REMS programs for Humira and Remicade, though the products already have MedGuides in place.

Education Programs Are The Wildcard

Revising the MedGuides and making the labeling changes will be straightforward, but the mention of additional education programs suggests that FDA may have more requirements in mind to make sure that the marketers are getting the information about how to detect the fungal infection out to the medical community.

The companies did not comment directly on the form that future education programs might take. FDA said that it considers the media attention that the agency generated around the relabeling as a first part of an overall alert and education effort.

"We anticipate that the public has and will learn of these warnings through the media outreach that was conducted this week," an FDA press official said.

Requiring a more formal education program, with systems for testing the effectiveness of the program, is the next level of risk management activity FDA can include in a REMS, beyond a MedGuide. Innovative programs proposed by FDA or industry to educate prescribers could signal a budding trend for prescription medications.

So far, the risk communication efforts for the concerns about fungal infections with the anti-TNF agents have entailed a media call about the announcement, a MedWatch alert from FDA, and an "Information for Healthcare Professionals" sheet (see chart: " ² Education Programs For TNF Blockers To Test FDA's Powers ").

When it comes to communicating the label changes and the MedGuide, the TNF sponsors (and prescribers) are used to "Dear Health Care Professional" letters, having sent several over the years.

The most recent one came in March, when labeling for Enbrel was expanded to add the boxed warning on risk of infection, focusing on tuberculosis, which was already on labeling for Remicade and Humira (³ Also see "Enbrel Label Gets “Black Box” On Tuberculosis Risk" - Pink Sheet, 17 March, 2008.).

In the past, there have been signs that the TNF manufacturers have conveyed some of their safety messages effectively to prescribers.

After J&J's Centocor subsidiary launched the initial risk management program on TB, in August 2001, J&J reported that efforts to increase TB screening prior to initiating treatment were working, citing anecdotal evidence of about 90 percent of patients being tested for latent TB infection (⁴ Also see "Remicade Relabeling Is Increasing Rate Of TB Screening, J&J Says" - Pink Sheet, 22 October, 2001., p. 29).

The extent of the eventual education programs will indicate how satisfied FDA is with the relabeling.

The new labeling changes are not substantially different from previous agency actions. They will be implemented more promptly because the agency has authority to require them. By mentioning that it is interested in education, the agency may be alerting the sponsors that it can ask for a more ambitious program if the relabeling does not work.

What FDA Is Trying To Fix

Further educational efforts may be necessary because the sponsors have had a hard time getting enough attention from the medical community to the infection risks and conveying how to diagnose the infections.

The risk of opportunistic infections is not uncommon among patients taking the immunosuppressants, and has long been in the TNF labeling. What is troubling FDA now is that fungal infections in particular have been undiagnosed and that late detection has led to reported fatalities.

A recent analysis by FDA found 240 infections in TNF-treated patients from histoplasma capsulatum; treatment was delayed for 21 because the infection was not initially recognized, and 12 of those patients died. Of the 240 cases, there were a total of 45 fatalities.

On a product-by-product breakdown, FDA identified 207 cases of histoplasmosis infection in patients using Remicade, 17 with Enbrel, 16 with Humira and one with Cimizia. "However, we cannot translate [those figures] into rates because of differing numbers of patients who have received the different products," the agency said, adding that external factors, such as exposure duration, must also be taken into account.

"We don't want to give the impression that these conditions were neglected," Jeffrey Siegel, clinical team leader of the Division of Anesthesia, Analgesia and Rheumatology Products, told an FDA call on the announcement.

"Even if physicians get the appropriate diagnostic tests, there are situations where those tests may be falsely negative, leading the physician off the path of making the definitive diagnosis."

Histoplasmosis - a respiratory infection with flu-like symptoms - mainly affects people living in the Ohio and Mississippi river valleys, where the fungus is commonly found.

Inside The Box

Manufacturers of the TNF blockers are required to submit safety labeling changes, including strengthened warnings and revisions to Medication Guides, or offer a reason against the change, to the agency within 30 days. FDA's announcement made clear that the agency has the ability to enforce the labeling it wants.

"If they do not submit new language, or if the FDA disagrees with the new language the company proposes, [FDAAA] 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 agency asserts.

The TNF manufacturers want to make the labeling efforts suffice. In comments issued after FDA's announcement, Abbott, Amgen and J&J expressed willingness to comply.

The new "black box" warning will highlight the risk of fungal infections, namely histoplasmosis.

The labeling update also will stress early detection and proper treatment, "bringing to the attention of health care providers the importance of determining the patients who are at risk for histoplasmosis," Siegal said, adding that language will also include information on the use of anti-fungal therapy in patients who have a condition that may represent histoplasmosis.

The TNF blockers already have language about the risk of infection in a boxed warning, with detailed information on tuberculosis. Fungal infections are including in the expanded warnings section, as part of a list of the various infections seen post-marketing.

Other safety-related label changes are also potentially on the way for the TNF class. FDA noted on the Sept. 4 call that a six-month evaluation of analyses to determine whether there is an increased risk of cancer among pediatrics using TNF blockers is progressing on track (⁵ Also see "TNF Blockers’ Link To Cancer In Children Is Under FDA Investigation" - Pink Sheet, 9 June, 2008. p. 13).

- Carlene Olsen (c.olsen@elsevier.com)

TNF Blocker Fungal Infection: FDA Uses REMS For Relabeling, Education

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