A topical corticosteroid boxed warning on the risk of hypothalamic pituitary adrenal axis suppression in pediatric patients may be an appropriate risk management tactic, an FDA advisory committee said.

A boxed warning for pediatric patients being treated with topical steroids for atopic dermatitis was one of several risk management programs suggested by FDA's Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee during a meeting Oct. 29.

"This justifies a box warning on HPA axis suppression because anything less than a box warning, you won't really get physician attention," voting consultant Robert Fink, MD, Children's National Medical Center, said. Topical corticosteroid labeling already includes precautions about HPA axis suppression.

Other recommendations by the advisory committee included additional studies to determine risk, patient package inserts, "Dear Health Care Provider" letters and provider educational programs.

While members noted the importance of informing parents and physicians about the risk of HPA axis suppression from topical steroid use, they said the statement should not be interpreted as a recommendation to use the products (see ¹ Also see "Protopic, Elidel Safety Labeling May Be Reviewed, FDA Tells Pediatric Cmte." - Pink Sheet, 10 November, 2003. ).

Under current practice, immunosuppression studies for topical corticosteroids are first conducted in older pediatric patients and, absent any evidence of suppression, then carried out in younger children. FDA asked whether "sequential testing" should continue.

"We have had some objections to doing it the way we have been doing it," FDA Office of Counter-terrorism & Pediatric Drug Development Director Dianne Murphy, MD, noted. "It has had some consequences for product development."

FDA Division of Dermatologic & Dental Drug Products Director Jonathan Wilkin, MD, added that "it's not a way to minimize burden for industry per se, it's really trying to find a data set that is necessary and sufficient."

Wilkin explained that the application of "regulatory elegance" could reduce the number of steps needed to obtain data from topical steroid suppression studies.

"Organic chemists talk about an 'elegant organic synthesis' as one where you have the fewest number of steps and you get the highest yield. Mathematicians talk about an 'elegant proof,' which is the fewest logical steps which really make the case," he said.

"There are limited resources, and it does ultimately affect the price of drugs," Wilkin acknowledged.

Committee members generally believed that sequential testing could continue, but stressed that the products need to be tested in younger children.

"Most of us would say sequential is okay, but at some point we want to make sure it is looked at in [younger] children so that some statement about whether it is contraindicated or not could be made," Subcommittee Chair Joan Chesney, MD, University of Tennessee, said.

Dermatologic & Ophthalmic Drugs Advisory Committee member Roselyn Epps, MD, Children's National Medical Center, agreed: "It will be a little more burdensome to industry," but "you would pick up certain problems that would certainly be amplified in younger age groups."

A search by FDA of the Adverse Event Reporting System on Sept. 11, 2003 found 22 cases of immunosuppression among patients ages six weeks to 15 years taking topical corticosteroids.

The reports included seven cases of adrenal suppression, 13 reports of Cushing's syndrome and 10 cases of growth retardation. The small number of cases is due to underreporting and "lack of clinical suspicion," FDA said.

The agency is developing criteria to evaluate HPA axis suppression using an adrenal stimulation test. Currently, patients with an ACTH stimulation cortisol level of 18 mcg/dL or below who experience a significant physiologic stress should be treated with stress doses of glucocorticoids.

"We are going to get specific discussion from experts on exactly what criteria to use on the cosyntropin testing," Wilkin said. "We didn't see that as a specific question that we would discuss today. There are other experts, including some that are here today, that will help us on this."

Topical Corticosteroid Boxed Warning On Immunosuppression Urged By Cmte.

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