Black box warning for atopic dermatitis agents may chill prescribing

In a trend that pediatricians should note carefully in their management of children with atopic dermatitis (eczema), dermatologists likely will exercise more caution in prescribing the topical calcineurin inhibitors (TCIs) Elidel cream (pimecrolimus, Novartis) and Protopic ointment (tacrolimus, Astellas Pharma) in response to the Food and Drug Administration's decision to add "black box" warnings to these drugs' labels, an expert pediatric dermatologist told the publication Dermatology Times recently.

As a result of the FDA's final decision, announced this past Jan. 19, "Without question, physicians will be more careful about prescribing these medications, particularly off-label for indications beyond atopic dermatitis," says Amy S. Paller, M.D., Walter J. Hamlin professor and chair of dermatology and professor of pediatrics at Northwestern University's Feinberg School of Medicine.

She also predicts that dermatologists will show more caution in prescribing the 0.1 percent strength for children, and will avoid prescribing tacrolimus and pimecrolimus at all for children under 2 years of age, per the FDA's recommendation.

"The concern that is being highlighted is that the long-term safety of these products has not been established. In particular, we are informing physicians and patients that we have received rare reports of cancer (skin and lymphoma) in patients who have used these products," an FDA spokesperson told Dermatology Times.

In particular, the FDA says it had received voluntary reports of about 78 cases (combined) in users of pimecrolimus and tacrolimus as of October 2005.

"We really wanted to be sure that we understood what the data were telling us and were able to communicate it in an accurate way," said Julie G. Beitz, M.D., an acting director of one of the FDA's drug evaluation offices, explaining why it took one year from the date of the agency's original advisory to settle the matter.

The statement on the black box that investigators found no causal link between the drugs and cancer can be interpreted as either disquieting or reassuring, sources say.

Dr. Paller says the warning is "inappropriate. Black boxes are not based on theoretically possible consequences."

Unintended consequences of the FDA's decision likely will include "greater use of steroids and alternative therapies for which we have no good testing data and often little experience," she adds, noting that some formularies already have dropped the medications.

"Another consequence is that black boxes may be slapped onto many other valuable products that we need to practice dermatology," while the effort required to get Elidel and Protopic may discourage some doctors and patients from trying altogether, Dr. Paller says.

"The American Academy of Dermatology (AAD) disagrees with this action taken by the FDA. The data does not prove that the proper topical use of pimecrolimus and tacrolimus is dangerous," Clay J. Cockerell, M.D., outgoing AAD president, says in a prepared statement.

As of mid-January, Novartis Pharmaceutical Corp. (NPC) knew of 28 healthcare provider-verified malignancies in more than 6 million patients treated with Elidel worldwide, according to Thomas Hultsch, M.D., senior medical director for dermatology at Novartis.

"It is important to note that none of the lymphoma malignancies reported here are the kind that one would expect in immune-suppressed patients," such as Epstein-Barr virus-positive B-cell lymphomas, Dr. Hultsch adds. According to an NPC statement, the malignancy rate in Elidel-treated patients is no higher than that of the general population.

Similarly, animal testing that Astellas submitted to the FDA during Protopic's application process used doses more than 40 times higher than the recommended human dose, says M. Joyce Rico, M.D., vice president of research and development, medical sciences, for Astellas U.S.
"One of the studies showed that if one exposed mice to concentrations of Elidel 27 times the highest concentration ever seen in a child, for two years, there was no evidence of any lymphoma," adds Jeffrey M. Weinberg, M.D., assistant clinical professor of dermatology, Columbia University.

Accordingly, he says the Elidel labeling change "was not spurred by any new side effects that were observed. All it reflects is a more conservative approach by the FDA after the Vioxx (rofecoxib, Merck & Co.) incident."

Over time, he says, "Six million people are going to develop many different illnesses. The question is, are (these malignancies) caused by the medication? The answer is, a causal relationship has not been established."