Outside the Box: TCIs for Pediatric Atopic Dermatitis

Janis C. Kelly

October 14, 2013

Attempts by the US Food and Drug Administration (FDA) to change how physicians prescribe the topical calcineurin inhibitors tacrolimus (Protopic, Astellas) and pimecrolimus (Elidel, Meda Pharma), the only topical agents approved for chronic treatment of atopic dermatitis (AD) in children, were only partly effective, according to a study published online October 14 in Pediatrics.

"[O]ff-label use of TCIs as a first-line therapy in pediatric patients did not decrease and continues to remain a concern," write Angelika D. Manthripragada, PhD, and colleagues. Dr. Manthripragada was formerly in the FDA's Office of Surveillance and Epidemiology and is now an employee of Amgen Inc.

Time to Open the Box?

However, many pediatric dermatologists argue the real concern should be how to get the "black box" warning removed or modified.

"An important message is that there are no alternatives for the TCIs. These are the only drugs well-studied and FDA-approved for long-term (>1 month) treatment of children with atopic dermatitis," Elaine C. Siegfried, MD, professor of pediatrics and dermatology at St. Louis University in Missouri, told Medscape Medical News.

Dr. Siegfried, who chairs the pediatric dermatology working group for the National Institute of Child Health and Human Development Best Pharmaceuticals for Children Act review committee, added, "The TCIs have been scrutinized more than any other skin care drug, including topical corticosteroids. The black box warning and publications that accentuate poorly substantiated concerns not only erode the physician–patient relationship and place physicians at risk for frivolous lawsuits, they also discourage industry from investing in new drug development for atopic dermatitis and drive patients to less well-studied (and possibly higher-risk) unregulated products. One of the most shocking examples I saw was an infant whose desperate parents used an entire large tube of cream purchased at a flea market, containing bovine orchic glandular extract (and a heavy dose of fragrance)."

FDA Began TCI Warnings in 2005

The TCIs were subjects of a March 2005 FDA public health advisory, had a boxed warning added to their labeling in January 2006, and had the warning sent to physicians as a "Dear Health Care Provider" letter in March 2006. According to the FDA advisory, TCIs should be used only as second-line agents, for short periods of time, and in children at least 2 years old.

The agency's concern was sparked by preclinical data showing an increase in "carcinogenicity signals" in mice and monkeys exposed to TCIs and by increased risk for lymphoproliferative disorders and cancer observed in transplant recipients who received systemic TCIs, according to Dr. Manthripragada and colleagues. Regulatory objectives were to decrease use of TCIs in children younger than 2 years and to decrease "off-label" use of TCIs as first-line therapy in patients with AD who did not have an atopic dermatitis or eczema diagnosis before the beginning of drug treatment.

In their current analysis of Medicaid claims data, Dr. Manthripragada and colleagues found a "substantial decrease" in rate of TCI use in children younger than 2 years after the 2005 FDA regulatory action, but little change in off-label use of TCIs as first-line therapy.

"The FDA's regulatory actions also did not lead to a marked reduction in off-label use of these products as first-line therapies," the authors write. "This is particularly concerning given that this type of off-label use could result in children not receiving the most effective and safest drug in an appropriate manner."

Government Shutdown Delays Answers

That contention is stoutly disputed by the Best Pharmaceuticals for Children Act dermatology subcommittee, which recommended in November 2012 that the FDA reconsider the "black box" warning.

According to the minutes from that conference, Lawrence Eichenfield, MD, chief of pediatric and adolescent dermatology, University of California, San Diego, said TCIs do not lead to cancer, are safe for children aged 3 months and older with severe AD, and may be well suited to long-term management. Dr. Eichenfield also testified on behalf of the American Academy of Dermatology Association and of the Society for Pediatric Dermatology in opposition to the "black box" warning at the FDA's May 2011 pediatric advisory committee meeting. At that meeting he said, "In the 5 years since labeling, there has been no compelling evidence of a causal link of TCI use with malignancy in children." At the Best Pharmaceuticals for Children Act meeting, Dr. Eichenfield said the FDA black box warning risks had not been proven, and that if the agency decides not to remove the warning box, the subcommittee wants FDA input and perhaps a change in labeling.

Dr. Siegfried told Medscape Medical News that after a 9-month delay, the subcommittee was expecting to receive a formal FDA response during a scheduled October conference call, but the call was abruptly cancelled when the partial government shutdown went into effect October 1.

Data Still Lacking on TCI/Lymphoma Risk

Dr. Manthripragada had presented a literature review on TCIs and pediatric malignancies at the May 2011 FDA pediatric advisory committee meeting. She said there was no evidence of an association between TCIs and B-cell lymphoma and that literature review suggested a possible association between topical tacrolimus use and increased T-cell lymphoma risk, but that the reported associations could be caused by protopathic bias (in which a drug is inadvertently prescribed for an early manifestation of a disease that has not yet been diagnosed), and that early lymphoma skin lesions "may be misdiagnosed as AD." She reported finding little evidence of an association between pimecrolimus and T-cell lymphoma.

In a more recent review, Dr. Siegfried reached similar conclusions regarding lymphoma risk with TCIs.

"In January 2006, the [FDA] issued a boxed warning requirement based on a theoretical risk of malignancy (including lymphoma) with TCI use. However, in the years since, analyses of epidemiologic and clinical data have failed to demonstrate a causal relationship between TCI use and malignancy or lymphoma risk, especially for pimecrolimus cream. In fact, the observed number of malignancies and lymphomas observed both in post-marketing surveillance and reported to the FDA using its adverse events reporting system is much lower among TCI-exposed patients than the expected number for the general population. Furthermore, among children enrolled in post-marketing pediatric registry studies for both tacrolimus and pimecrolimus followed for up to 5.5 years [10,724 patient-years (PY)] or 6.5 years (16,219 PY), respectively, the observed number of malignancies and lymphomas is very low and similar to the number expected for a sample of similar size in the general population," Dr. Siegfried wrote.

"The FDA is justifiably concerned about drug-associated risks, but the problem is their greater focus on the risks of the drug than the risks of the disease. Categorizing atopic dermatitis as a non-life-threatening skin disease trivializes the impact of this disease on healthcare costs and quality of life. In other words, eczema will not kill you, it can just ruin your life. This disease represents a significant unmet child health medical need," she told Medscape Medical News.

Moreover, according to Dr. Siegfried, third-party payers are using the FDA-approved indications to validate denied coverage of the TCIs.

"The same standards are never applied to generic corticosteroids, even the most potent ones not approved for use under age 18. Denied access to TCIs is especially unfair for the 50% of children in this country who are Medicaid-insured and have no other steroid-sparing alternatives. Children with moderate to severe eczema who cannot get Elidel or Protopic are at high risk for either poor disease control (and progression) or corticosteroid overuse (and skin atrophy, percutaneous absorption, and adrenal suppression)," Dr. Siegfried said.

Dr. Manthripragada is now an employee of Amgen Inc. The other authors have disclosed no relevant financial relationships. Dr. Siegfried has received research support, consulting fees, and/or travel expenses from Astellas Pharma US, Novartis Pharmaceuticals Corporation, and Valeant Pharmaceuticals.

Pediatrics. Published online October 14, 2013. Full text

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