The FDA recently issued a public health advisory informing healthcare providers and patients about a potential cancer risk associated with the use of Elidel® (pimecrolimus) Cream and Protopic® (tacrolimus) Ointment. Elidel cream and Protopic ointment are topical immunosuppressant calcineurin inhibitors that are applied to the skin for treatment of atopic dermatitis, or eczema. They are the only approved drugs in this class.
Concern about the use of these products was based on information from animal studies, case reports in a small number of patients, and information on how these drugs work. Animal studies showed that three different species of animal developed cancer following exposure to these drugs. These studies were conducted at doses much higher than generally used by patients and the risk of cancer increased with increasing drug dose and duration. These products work by suppressing the body's immune system. A form of tacrolimus known as Prograf® is used in pill form or by injection to prevent organ rejection in patients with liver and kidney transplants. Prograf is known to cause both skin cancer and lymphomas in humans by suppressing the body's normal defenses against cancer. The cancer risk increases with higher doses and longer treatment courses. Since the approval of Elidel and Protopic, FDA received reports of lymphoma and skin cancer in children and adults treated with these drugs, but whether the reported cancers are associated with these products has not been clearly established. Both Elidel and Protopic are sometimes absorbed through the skin, although usually in very low amounts. Occasionally, children who have been treated with Elidel or Protopic have shown blood levels of these drugs.
Based on these concerns, the FDA is recommending: using minimum amounts of Elidel and Protopic for short periods of time; using these products as second-line agents, not first choice treatments; and avoiding use in children younger than age 2. FDA also plans to add a black box warning to the health professional label on these products and issue a medication guide for patients outlining these restrictions on their use.
The American Academy of Dermatology responded to this action by the FDA in a statement issued on March 10, 2005. "The American Academy of Dermatology is disappointed that the FDA has taken this action, despite the fact that there is no data that proves proper use of pimecrolimus and tacrolimus is dangerous in people," said dermatologist Clay J. Cockerell, MD, president of the American Academy of Dermatology. "Because these medications are applied to the skin, virtually none of it gets inside the body. It's not the same as taking a pill. These are valuable medications, and if used properly, they significantly reduce the debilitating impact of eczema and allow millions of our patients to live normal lives."
On February 15, 2005, dermatologist Robert A. Silverman, MD, of Fairfax, VA, spoke on behalf of the Academy at an FDA pediatric advisory committee hearing, urging the FDA not to impose a black box warning or other labeling restrictions because such steps could limit access to these medications, or limit treatment options if qualified patients decide not to use these medications based on fear of cancer risk.
Advocates representing eczema patients also spoke out against more restrictive labeling. "These medications have been the only treatments that have given my children anything resembling a normal quality of life," said LaDonna Williams, executive director, Inflammatory Skin Disease Institute (ISDI) and mother of two children with severe atopic dermatitis. "Every day we see first hand how these medications improve the lives of patients and their families." said Ruthann Newton, support group coordinator for the ISDI.
"The health, safety, and welfare of our patients being treated with these topical medications is of paramount importance to dermatologists," said Dr. Cockerell. "We are concerned that these warnings will confuse and unnecessarily worry our patients. We urge patients to get the facts on how to appropriately manage their eczema from their dermatologist."
What does all this mean to individuals with ichthyosis? Dr Amy Paller comments: "In summary, there is no human evidence that these topical medications cause any serious health risk in humans. The lymphoma type of cancer that is caused by high doses of these medications, when taken internally, is a specific type that has not been described in patients using the topical form, despite a few reports among the large patient population applying topical medications of other forms of lymphoma. The animal studies with very high dosages and systemic levels of medication are the basis for concern. These studies have not been performed with the alternative agents, topical steroids, but topical steroids have been available for several decades. Although the long-term experience in humans may well be quite different than in animals, it is important to monitor individuals using these topical medications and to use good sun protection, at least for the next few decades until we can be sure that there are no important side effects. Of note, individuals with ichthyosis (and especially Netherton syndrome) may have greater absorption through their skin than persons with normal skin or even atopic dermatitis. Many individuals with ichthyosis are itchy and use Elidel or Protopic to control the itching and/or eczema that can accompany ichthyosis. Given the possibility that more Elidel or Protopic is absorbed through the skin in persons with ichthyosis, these agents should be used only selectively for ichthyosis and with regular monitoring by a knowledgeable physician. Assessment of blood levels can be performed as a part of the monitoring process."
Sources:
U.S. Food and Drug Administration Website, Center for Drug Evaluation and Research www.fda.gov/cder/drug/advisory/elidel_protopic.htm
American Academy of Dermatology Website www.aad.org/public/News/NewsReleases/fda_decision.htm.
Dr. Amy Paller is Professor and Chair, Dermatology, and Professor, Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL. Dr. Paller is a member of the Medical and Scientific Advisory Board and the Board of Directors of F.I.R.S.T., and the Medical Editor of the Focus.
