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Protopic and Elidel: Eczema Drugs Have a Cancer Risk

Posted by medconsumers on May 1, 2006

Early this year, the Food and Drug Administration issued a warning about two prescription topical creams for the common skin disease, eczema. Both Elidel and Protopic must now include written material for professionals and patients that warns of a cancer risk based on “information from animal studies, case reports in a small number of patients, and knowledge of how drugs in this class work.”

Though the warning says, “a small number” of people who have used the products “have had cancer (for example, skin or lymphoma),” evidence from the FDA’s own reporting system indicates that this may be an understatement. Pretty alarming for drugs that are applied to the skin, primarily for young children. Doubly so, considering the fact that less than 10% of all serious adverse drug reactions are reported to the FDA.

People with eczema, also known as atopic dermatitis, and parents of children with this chronic skin disorder are often desperate for a treatment that alleviates the severe itchiness and inflammation. Eczema primarily afflicts babies and children, but can continue into adulthood in about 50% or show up  (rarely) for the first time in adulthood. There is no cure. A drug might beat it back for a short time, but flare-ups are common.

Elidel (generic name: pimecrolimus) and Protopic (generic name: tacrolimus) control eczema by suppressing the immune system, and they can be extremely effective in producing improvements. Until they came along, corticosteroid cream was the standard treatment. Hopes for the newer drugs stem from fears about the side effects of corticosteroid cream like thinning of the skin and adrenal gland suppression. Novartis, the company that makes Elidel, and Astellas Pharma (formerly Fujisawa), maker of Protopic, fed these fears by promoting their products as “steroid-free.”

One example is Fujisawa’s fraudulent ad for Protopic that appeared six years ago in Prevention magazine stating, “Breakthrough research has finally uncovered a new kind of medicine for eczema. Made of a natural substance, this new treatment is steroid free.” The ad implies safety. But in reality both Elidel and Protopic are in the same drug class as Prograf, a powerful immunosuppressant drug that prevents liver or kidney transplant rejections. In fact, Protopic and Prograf (generic name: tacrolimus), which comes with a warning of “infection and development of lymphoma,” are the same drug!

FDA Explains Itself

Why hasn’t the FDA withdrawn the drugs, given their obvious dangers and the existence of a safer alternative? “FDA believes that the benefits of Elidel and Protopic outweigh the risks of these products,” responded Julie Beitz, MD, of the FDA’s Center for Drug Evaluation and Research, who would answer questions only by e-mail by way of a press officer. “The  new warnings in the professional labels and in the Medication Guides* for these products convey what our concerns are, however, a causal link has not been established between the reports of cancer and use of these products.”

The FDA warning states that it may “take human studies of ten years or longer to determine whether Elidel or Protopic is linked to cancer.” Despite the lack of long-term data and what is surely an undercount of cancers associated with use of these drugs, Dr. Beitz defends the FDA position, “While there is under-reporting of adverse events to the FDA, we also know that use of these products is great, so relative to all users, the number of reports we have received is small.”

To some dermatologists, the question of whether Elidel and Protopic pose more than a rare cancer risk seems to hinge on how much is absorbed into the skin. In a January 19, 2006 press release that disagrees with the  FDA’s decision to issue an warning, Clay J. Cockerell, MD, president of the American Academy of Dermatology, said, “Because these medications are applied to the skin, virtually none of it gets inside the body.”

That statement was quoted to Dr. Beitz, who commented, “We agree that very little of the drug is absorbed in general, however, we have data to show that some patients do absorb the drug to greater degrees. Additional factors to consider: 1) how long the patient is using the product; 2) how large an area of skin the product is being applied to; and 3) the fact that areas affected with atopic dermatitis are not normal and may allow for more absorption.” Babies under two should not be treated with either drug, according to the FDA warning.

“Infants have higher surface area to volume so they will have higher blood levels of the drug and their skin is more permeable,” said Peter M. Elias, MD, professor of dermatology, University of California, San Francisco, in a telephone interview. “The companies have over-marketed these drugs suggesting, for example that they are safe for infants by showing images of infants [in promotional materials].” The ads implying Elidel and Protopic are safer than corticosteroids are ridiculous, he continued, adding that neither drug has been shown to be safer or more effective than topical steroids in a head-to-head comparison as maintenance therapy for eczema. “Low- to mid-potency steroids are quite safe in eczema, although many clinicians prefer an even less potent agent, such as hydrocortisone, in infants,” said Dr. Elias.

When the FDA was deciding whether to approve these drugs in 2000, Dr. Elias wrote a letter to the agency expressing concerns, particularly about Protopic, which he described as “a powerful and potentially toxic immunosuppressive drug.” In the letter, which remains on the FDA Web site, Dr. Elias told the agency that he is “alarmed at what appears to be a potentially cavalier and uncritical attitude about the indications and long-term safety of topical tacrolimus [generic name for Protopic]. [This drug] is absorbed into the circulation through inflamed skin, and in low-body weight children it can produce transient therapeutic (transplant) drug levels.”

Dr. Elias sees a limited role for the drugs, “Protopic should be reserved for severe, recalcitrant flares of eczema in children and adults, and Elidel for similar bad flares in infants. Elidel might also be useful for periorbital dermatitis due to risk of glaucoma from steroids. But in all these examples, the use should be short term—days, weeks, but not months—and only in conjunction with sunscreens, which should always be used when these drugs are applied to sun-exposed skin. There is no rationale for long-term therapy with either drug.”

Pressure Not to Warn the Public

In the five to six years since the FDA approved each drug, Novartis and Astellas/Fujisawa mounted a massive, often misleading, advertising campaign aimed at doctors and the public. And in the last two years, both companies waged an aggressive campaign against the FDA’s planned warning. Under great pressure not to act, the FDA went ahead and called a meeting of its pediatric advisory committee in February 2005, which recommended a label change warning doctors and patients about the risk associated with both Elidel and Protopic.

The next month, a cancer warning appeared on the FDA Web site. (It is not known how many doctors or patients would think to look on the FDA’s Web site for new warnings.) As of January 2006, a Medication Guide for patients with the warning is supposed to be included with all prescriptions of Elidel and Protopic. The Guide does not spell out the safe duration (if there is one) of short-term use, though makes it clear that neither drug should be the first-choice treatment for eczema.

There are reasons to think that these efforts will go unheeded. Several studies show that only one in ten doctors read the drug label which is the most complete source of information about a drug’s use and harms. (Consumers are not much better.) A recent survey showed doctors are overwhelmed with drug warnings and have difficulty keeping them all straight. In the case of Protopic and Elidel, the dermatologists’ professional organizations were actively working against the FDA’s plan to issue a  warning. The Society for Pediatric Dermatology, in a letter dated November 30, 2005, advised its members to write the FDA to tell the agency that warnings are not warranted because “abrupt discontinuation of these medications out of fear [will result] in disease flares in many children.” Furthermore, the letter claimed that an analysis of the clinical data presented to the FDA have not supported a malignancy risk.

“The great resistance in the dermatologic community to the FDA warning is based in part on the fact that many of the opinion leaders are in conflict of interest situations that too often go undisclosed,” said Dr. Elias, referring to funding from Novartis and Astellas that pays for the speakers bureau, conferences, and continuing education. And he doesn’t think much of the evidence cited to support objections to the FDA warning about Elidel and Protopic. “There are 55 articles about the safety of both drugs that claim to be long term,” Dr. Elias explained. “However, they are not, in fact, long term; the longest study lasted only six months; many are repeats—the same study published in multiple journals—and others are written by the drug company journal editor.” [Note: There are longer studies indicating the drugs are safe and effective, but they are funded by either Astellas or Novartis.]

It is quite possible that one day lawsuits will generate  the publicity needed to adequately warn the public about inappropriate use of Elidel and Protopic. Several law firms now have Web sites specifically devoted to the drugs. One such firm headed by Larry M. Roth has a Web site ( that features his detailed article on the history of FDA approval of topical immunosuppressants and reports of serious reactions, complete with extensive footnotes. It describes cancers, deaths, and other severe  reactions reported to the FDA.

In a telephone interview, Laurilyn Cook-Arrington, a paralegal at Larry M. Roth, PA, said the law firm had retrieved this information from the FDA’s Adverse Events Reporting System with a Freedom of Information Act request. (Manufacturers are required “by regulation” to report serious drugs reactions to AERS.) Ms. Cook-Arrington said the firm has been gathering information on topical immunosuppressant drugs for three years. “Hundreds of potential claimants have contacted our firm in the last year. And many of these claims include deaths. Almost 50% of them are made on behalf of children. They involve skin cancers, as well as systemic malignancies like leukemia, Hodgkin’s disease, and multiple myeloma.”

What to do:

  • If you are using Elidel or Protopic, inform yourself about these medications. Start with the warnings at the FDA Web site ( Consumers and doctors can report serious adverse drug reactions to the FDA’s Medwatch Program 1(800) FDA-1088.
  • Ask your doctor about prescription emollients to reduce the amount of topical drugs needed to control eczema. According to Dr. Elias, “Topical prescription emollients alter biochemical abnormalities in the skin, lead to fewer flare ups, and fight off infection.” They can be used as the first treatment or as maintenance after short-term treatment with an immunomodulator, explained Dr. Elias, who is also chief science officer at Ceranix, makers of a yet-to-be-available emollient, EpiCeram.

Maryann Napoli, Center for Medical Consumers ©
May 2006

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