Black box recommended for atopic dermatitis creams

March 2005

Two nonsteroidal topical immunosuppressants used to treat atopic dermatitis should carry a black box warning because they carry a possible risk of malignancy and other adverse events, according to the FDA’s Pediatric Advisory Committee.

The committee made the recommendations last month, after reviewing various safety and efficacy reports of possible adverse events associated with the two topical ointments, tacrolimus (Protopic, Fujisawa) and pimecrolimus (Elidel, Novartis).

Both drugs are approved for use as a second-line treatment of atopic dermatitis in patients 2 years of age and older when other approved therapies fail. Pimecrolimus is used to treat mild-to-moderate atopic dermatitis and tacrolimus is indicated for moderate-to-severe cases.

Committee members discussed the data and potential recommendations after hearing evidence of severe adverse events in several primate studies.

Director of the Division of Dermatologic and Dental Drug Products, FDA, Jonathan Wilkin, MD, summarized the findings regarding the consequences of long-term, continuous use of calcineurin inhibitors with one word — “uncertainty.”

“The goal of labeling is to give information and its level of uncertainty to the physician and patients,” he said. “We take the view that the public should be told about uncertainty when data … are inconclusive.”

The panel decided, based on the available scientific findings, that there is reason enough to communicate this information to physicians and patients through a black box warning label.

Recommendations made

The FDA investigated reports of lymphoma and skin cancer in children and adults treated with tacrolimus and pimecrolimus.

The committee concluded that although there was a lack of sufficient human data to date indicating adverse events, animal data warranted a need to relay a message to physicians, patients and consumers.

Barbara Hill, PhD, also of the FDA’s Division of Dermatologic and Dental Drug Products, reviewed the pharmacology and animal toxicology data available for the topical immunosuppressants and said that the formation of lymphoma was found to be dose and time dependent.

Therefore, the committee suggested communicating a potential “increased risk of cancer, with respect to dose duration and latency.”

The committee also thought it important to remind physicians that tacrolimus and pimecrolimus are only indicated as a last-line therapy for children younger than age 2.

After much discussion, the committee suggested relaying this information via black box labeling, with most of the committee members voting for such action. “Dear Health Care Provider” letters, medication guides and patient package inserts were among the other ways suggested to most effectively disseminate the information.

The committee unanimously agreed that there is a strong need for ongoing surveillance and future studies to establish the likelihood of such adverse events in children and adults.

Atopic dermatitis

Source: Teresita Laude, MD

Cause for concern

According to the FDA’s Adverse Event Reporting Symptom (AERS) database, there were 54 adverse events reported in children younger than age 2 and eight malignancies in all age groups, from the approval of pimecrolimus on Dec. 13, 2001, through Sept. 22, 2004.

Most of the adverse events were skin related, and 15 children were hospitalized, FDA officials reported. Of the eight malignancies, four were in children, although none younger than the age 2.

According to an FDA review of recent drug use data collected from June 2003 to May 2004 by Caremark’s Dimension Rx system, children ages 1 and 2 accounted for 12.7% of total prescriptions for pimecrolimus and 8% of tacrolimus prescriptions.

Between June 2003 and May 2004, physicians administered almost 2 million prescriptions for these drugs for children. And although not approved for infants, the creams were prescribed for about 500,000 children younger than 2 years of age.

According to drug use data in the AERS report, since pimecrolimus’s approval in December 2001 through November 2004, over 8.7 million prescriptions have been dispensed, and of those, 14% were administered to children younger than age 2. An estimated 44% of those prescriptions were administered to patients between 2 and 16 years of age.

As for tacrolimus, since approval in December 2000 through November 2004, an estimated 3.5 million prescriptions have been filled, with 7% of those administered for children younger than 2. Children 2 to 16 years of age accounted for 34% of those prescriptions.

Mathias Hukkelhoven, PhD, senior vice president and global head of Drug Regulatory Affairs at Novartis, presented data indicating that in clinical studies, 5 million patients have been treated since December 2001. Among those, there have been six reports of possible severe adverse events, mainly lymphoma and skin tumors.

“Clinical data do not show increased risk of malignancies,” he said. “Systemic immunosuppression is clinically implausible based on the pharmacokinetics.”

M. Joyce Rico, MD, with the consulting staff and department of dermatology, Fujisawa Healthcare, said extensive clinical trials of more than 19,000 patients and 7,600 pediatric patients treated with tacrolimus found no signal of increased risk of systemic infections in transplant recipients or increased risk of herpes, malignancy or impairment of systemic immune response.

“There is no evidence of systemic accumulation; if detected, they are transient,” she said. “Because there is minimal systemic absorption, the likelihood of malignancies is remote.”

Amy Paller, MD, Fujisawa Healthcare consultant and professor of dermatology and pediatrics at Northwestern University Medical School, said atopic dermatitis affects up to 20% of children, primarily in the first five years of life.

For more information:

• Visit www.fda.gov/oc/advisory/default.htm.