Protopic, Elidel Safety Labeling May Be Reviewed, FDA Tells Pediatric Cmte.

FDA plans to discuss the pediatric safety profile of topical immunosuppressants with Novartis and Fujisawa after an advisory committee recommended stronger warnings about the potential carcinogenicity of Elidel and Protopic .

"We are going to take all the information that we have heard and discuss it with the two [companies] that are currently involved," Dermatologic & Dental Drug Products Division Director Jonathan Wilkin, MD, said at the conclusion of a meeting of the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee Oct. 30.

FDA may follow up with the committee, Wilkin said. "We are going to work hard internally and may come back and find out from your group if we got it right."

Wilkin noted that neither sponsor had the opportunity to present during the Oct. 30 meeting. "I think we might have heard a somewhat different portrayal of the actual risk if industry had had an opportunity to go over the data," he said.

The meeting was held to discuss methods to track any potential cancer risk from use of topical calcineurin inhibitors (including Elidel and Protopic) in children. Calcineurin inhibitors have shown carcinogenic signals in nonclinical studies.

[Editor's Note: To view a ¹ webcast of this meeting, visit FDAAdvisoryCommittee.com.]

Novartis' Elidel (pimecrolimus) and Fujisawa's Protopic (tacrolimus) are approved for second-line treatment of atopic dermatitis in patients two years of age and older when these patients fail to respond to or do not tolerate, other approved therapies.

Although both Elidel and Protopic are topical formulations, both result in "modest" systemic exposure to the active ingredient, FDA noted.

Since Elidel was approved at the end of 2001, 3.2 mil. prescriptions have been written, FDA said. Of the total, 17% were for children two years of age and younger, and 36% were for those between three and 16. Pediatric adverse event reports for Elidel are primarily for skin reactions, but include infections and non-malignant tumor growth.

Since Protopic's approval at the end of 2000, about 2 mil. scripts have been written; 8% for children up to two years and 29% for children between three and 16. Pediatric AE reports were predominately skin and application site reactions, and also include infections. Malignancies were reported in adults.

The committee recommended educational programs for physicians and a boxed warning in labeling to reinforce that the products are not approved for use in children less than two years of age.

Subcommittee Chair Joan Chesney, MD, University of Tennessee College of Medicine, maintained that "the vast majority of physicians who are prescribing these don't even think about or know about a potential cancer risk."

"I am particularly concerned about the widespread use of this drug under age two," voting consultant Robert Fink, MD, Children's National Medical Center, added. "I almost favor a registration of providers, but if that is felt to be too restrictive, I think a box warning about non-approval and contraindication...under age two is really important," he said.

Committee members also recommended revising the patient package insert to inform the patient or parent of the potential risk, issuing a "Dear Health Care Provider" letter, providing education programs for physicians, and conducting additional studies.

"It seems to me unavoidable that the patient information sheet and the information that goes to doctors, not just for package inserts but educational programs and so on, need to explain why this is a second-line drug and that there is this great concern about lethal toxicity," voting consultant Norman Fost, MD, University of Wisconsin Hospital, said.

"There is no evidence of it in humans yet, or at least not enough to say anything concrete, but based on the animal data there is serious concern," he said.

Although the committee recommended specific risk management steps, FDA's Wilkin suggested that the agency is not yet ready to consider formal actions.

"We had planned this session of the advisory committee to talk about uncertainty and how to study for it," Wilkin said. "I don't know that the FDA group really came with the preparation to talk about risk management per se."

However, the discussion of the safety profile for topical immunosuppressants came on the heels of the committee's Oct. 29 recommendation that labeling for topical corticosteroids carry stronger warnings about the risk of hypothalmic pituitary adrenal axis suppression in pediatric patients (see ² (Also see "Topical Corticosteroid Boxed Warning On Immunosuppression Urged By Cmte." - Pink Sheet, 10 Nov, 2003.) ).

Wilkin noted that Protopic and Elidel are labeled as second-line to topical corticosteroids, based on the carcinogenicity risk identified in animal studies.

However, he suggested that the second-line message may not be reaching prescribers. "I'm not implying that the manufacturers are presenting the data that way, but I saw a headline in one of the throwaway journals 'Move Over Steroids,'" Wilkin said.

"There is a great deal of enthusiasm for things that are new...whether it is a new drug product or anything else, there is a lot of hope that goes into it."

"Our concern with the topical calcineurin inhibitors is from the systemic exposures that it seems to be a cumulative dose that has something to do with the eventual development," he said. "I think it's labeled so that physicians can make good choices. Not every patient can take topical corticosteroids."

Wilkin stressed that FDA will strive for a "measured communication response."

"We need to make an important distinction when we are working in risk management to carefully define the line between pharmaco-fear-mongering or scaring and conveying uncertainty," he said.

"We want to be very careful, but we don't want to be overly careful," Wilkin said. "We want balance."

Dermatologic & Ophthalmic Drugs Advisory Committee member Robert Stern, MD, Beth Israel Deaconess Medical Center, suggested that the communication burden should be on the manufacturers.

"I think it is a matter of promotion, both to consumers and to physicians," Stern declared. "I wonder whether the two sponsors might come forward and say we are going to make an effort to make sure that people understand the labeled indications."

"I would second that," Fost added. "I would bet that the miracle of CME is at the root of this also....Drugs that are approved for narrow indications get used expansively through the miracle of pharmaceutical-sponsored CME."

Stern urged the sponsors to abandon direct-to-consumer marketing of the drugs. Novartis has supported Elidel with an extensive DTC campaign, including TV commercials (³ (Also see "Novartis Sales Growth Strategy Is DTC Ads, “Cleverly Crafted” Phase IVs" - Pink Sheet, 27 Oct, 2003.), p. 33). Fujisawa, which has a co-promotion agreement with GlaxoSmithKline for Protopic, has used a more limited DTC campaign.

To measure the clinical risk of malignancy of topical immunosuppressants, the committee suggested using existing cancer registry databases.

"If there is to be a study looking at exposures and lymphomas, then the state registries could play a key role," voting consultant and RTI Health Solutions VP Elizabeth Andrews, MD, said.

"One could identify the patients and exposures through some mechanism, whether through an automated database or through patient recruitment, and link that information with cancer registries for ascertainment of lymphoma," she said.

The postmarketing commitments for the topical immunosuppressants include registry studies to assess the risk of developing cutaneous or systemic malignancies in pediatric patients who undergo long-term intermittent treatment with the drugs.

However, the estimated 10-year latency period between exposure to the drugs and development of tumors, coupled with a rare incidence in children, makes it difficult to conduct postmarketing studies.

Committee members also asked about the cost to conduct pediatric trials. The range "given to us in writing" is $500,000 for a small pharmacokinetic study to $30 mil. for randomized clinical trials, Office of Counter-terrorism & Pediatric Drug Development Director Dianne Murphy, MD, said.

Voting consultant David Danford, MD, University of Nebraska Medical Center, asked whether there are any promising products in the pipeline for atopic dermatitis. "At the beginning, before we have very much information, they all look wonderful," Wilkin responded.