TCIs' 'black box' signals caution

March 1, 2006

National report -- 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 tells Dermatology Times.

As a result of the FDA's final decision, announced 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 tells Dermatology Times.

"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.

No causal links

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.

"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.