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Expert Interview
Topical Pimecrolimus, Tacrolimus, and the Risk for Cancer: An Expert Interview With Lawrence Eichenfield, MD

Editor's Note:
On March 10, 2005, the US Food and Drug Administration (FDA) issued a Public Health Advisory about the potential cancer risk associated with topical pimecrolimus (Elidel) and tacrolimus (Protopic) .[1,2] The FDA also announced that it will be adding a "black-box" warning to the labeling for the 2 drugs. This action was based on a February 15, 2005, recommendation from the FDA Pediatric Advisory Committee.

These drugs, which are referred to as topical immunomodulators or topical calcineurin inhibitors, inhibit inflammatory cytokine transcription in activated T cells and other inflammatory cells through calcineurin inhibition. Tacrolimus, which was approved in 2000, and pimecrolimus, which was approved in 2001, are indicated for the treatment of atopic dermatitis, or eczema.

Kristin Richardson, Program Director of Medscape Dermatology, interviewed Lawrence Eichenfield, MD, to discuss the implications of the FDA's actions.

Medscape: What was your reaction to the FDA's recommendation for a black-box warning for pimecrolimus and tacrolimus?

Dr. Eichenfield: Let's establish where we are: We know that the Pediatric Advisory Committee has recommended a black-box warning for topical tacrolimus and pimecrolimus, but this warning has not been effected, and the exact language of the warning is not yet clear.

I, like many dermatologists who have looked at the cumulative evidence, understand the intent of the FDA and the need to educate patients, but I am concerned that a black-box warning is disproportionate given the weight of the evidence we have. The black-box warning has historically been reserved for alarming, serious, life-threatening situations.

I do understand the desire of the FDA to educate the populace about potential carcinogenesis, and, of course, these drugs -- like any drugs -- have risks as well as benefits. There was wide, rapid adoption of topical calcineurin inhibitors by primary care providers and pediatricians, and heavy direct-to-consumer advertising; nearly 2 million prescriptions were written for children between June 2003 and May 2004. But I am concerned that there is a disconnect between the level of risk based on the data and the language that is being used to address this risk. I am also concerned about the potential medical-legal implications for physicians.

Medscape: Could you describe the context in which the FDA took this action?

Dr. Eichenfield: There were several issues. It is known that systemic forms of these drugs, or drugs like them, can be associated with systemic cancers, especially lymphoma. (Tacrolimus is available as a systemic drug indicated for the prevention of rejection following solid organ transplantation; pimecrolimus is not available as a systemic drug.) There were particular concerns about pediatric patients because of children's higher ratio of body surface area to body weight. There were also postmarketing reports of malignancies in children and adults as well as a postmarketing nonhuman primate study with an oral formulation of pimecrolimus that demonstrated the occurrence of lymphoma.

Medscape: Could you give a brief overview of the data?

Dr. Eichenfield: First, it should be noted that much of the data were available at the time the drugs were approved. The new data are the postmarketing reports of malignancies and the nonhuman primate study with oral pimecrolimus.

It should also be emphasized that these are topical drugs, and there is minimal systemic absorption with topical tacrolimus and pimecrolimus. If you look at the data, it doesn't appear that the frequency and type of lymphomas reported are what you would expect to see if they could be attributed to the long-term use of these drugs. Lymphomas that occur in the context of immunomodulatory or immunosuppressive therapy have characteristic features. The histology and clinical presentation of the cases of lymphoma reported do not match up with the characteristics usually associated with posttransplant lymphoproliferative disorder or lymphoma occurring in the immunocompromised setting. A panel of 5 independent oncologists found no definitive link between pimecrolimus and tacrolimus and increased risk of lymphoma.[3] There really isn't strong evidence of attributable cancer to date associated with topically applied tacrolimus or pimecrolimus.

If you look at the number of reported cases of lymphoma, it is actually lower than would be expected in the background population. The epidemiologic problem, of course, is that not every case gets reported. But there is excellent information capture during clinical trials, and the cumulative clinical trial data for pimecrolimus were analyzed by the pharmaceutical company for the number of malignancies during clinical trials. The number of malignancies was lower in the pimecrolimus-treated patients than in control patients, who were randomized to receive either a topical corticosteroid or vehicle. In the 19,000 pimecrolimus-treated patients there were 2 cancers, and 1 was a squamous cell carcinoma. In the 4000 patients treated with either topical corticosteroid or vehicle, there were 5 cancers -- 4 in corticosteroid-treated patients and 1 in a vehicle-treated patient.

There is another question worth asking when considering a potential association between topical immunomodulatory agents used to treat atopic dermatitis and the development of malignancies: "Is the incidence of malignancy higher in patients with atopic dermatitis?" Also, most patients with atopic dermatitis who have been treated with either pimecrolimus or tacrolimus also have a history of topical corticosteroid use, and it is not known whether and how topical corticosteroids may affect carcinogenesis.

In terms of the postmarketing nonhuman primate study that showed lymphoma development in monkeys, that study used an oral formulation of pimecrolimus that was 30 times the highest dose ever recorded in a human with topical use.

Another issue that the pediatric dermatology community has looked at is the effect on the immune system. In large practices, we have not seen systemic immunosuppression or infections in patients using these drugs, with the exception of eczema herpeticum. And this experience is supported by clinical trials. A study just published in the Journal of the American Academy of Dermatology showed that pimecrolimus cream 1% used for 2 years improved atopic dermatitis in infants and did not interfere with the development of antibodies after vaccination.[4] There is no evidence of systemic immunosuppression in atopic dermatitis patients as a result of topical application of pimecrolimus or tacrolimus.

Medscape: How have physician and patient organizations responded to the FDA's recommendations?

Dr. Eichenfield: The American Academy of Dermatology has issued a statement that it is disappointed by the FDA action, and the president of the Academy, Clay Cockerell, MD, pointed out in the statement that he is concerned that the action will result in the undertreatment of eczema patients. The National Eczema Association has pointed out that the drugs have improved the quality of life of millions of eczema patients and their families, and their Scientific Advisory Committee plans to conduct an independent study on the risk and benefits of these drugs and to support long-term studies. The American College of Allergy, Asthma, and Immunology and the American Academy of Allergy, Asthma, and Immunology formed a joint task force that concluded, in a thorough and thoughtful report, that "based on current data, the risk-benefit ratio of topical pimecrolimus and tacrolimus is equivalent or superior to most conventional therapies for the treatment of chronic relapsing eczema."[3]

Medscape: What advice would you give now to physicians, patients, and caregivers about the use of these drugs?

Dr. Eichenfield: Physicians who have been prescribing these topicals needn't worry that they have been giving a cancer-causing agent to their patients; there really is no evidence of any attributable cancers to date after the topical administration of pimecrolimus or tacrolimus. With patients who are already using these drugs, I would recommend that physicians be reassuring and emphasize that the risk is a potential risk at this point. These drugs aren't carcinogens -- they don't cause mutations -- the concern is based on a theoretic potential to impair local immunosurveillance.

For new prescriptions, I would recommend that physicians educate patients and families about the concerns that have emerged, especially long-term use in young children less than 2 years of age. The physician should work with the family to educate them about the risks and benefits of treatment, and should of course encourage open communication about the approach to treatment while not allowing the disease to get out of control. It must be emphasized that atopic dermatitis is a condition with documented, extreme, life-altering effects on quality of life. And of course patients and parents should be advised to be careful about sun protection and to avoid tanning parlors.

Current FDA guidelines recommend that these drugs are indicated for the short-term or intermittent long-term treatment of moderate-to-severe atopic dermatitis in patients 2 years or older who are unresponsive or intolerant of alternative, conventional therapies or in whom these therapies are inadvisable due to potential risks. They are recommended as second-line treatments. However, when disease severity is considered, first-line treatment is not outside the wording of the indications. For example, I would have no concern at all using these agents as first-line treatment in a child with a history of persistent or frequently recurrent facial dermatitis, where protracted use of corticosteroids would be inadvisable. I think the topical calcineurin inhibitors remain crucial in the long-term intermittent treatment of eczema. I have published algorithms on the use of topical calcineurin inhibitors that incorporate disease severity in a step-wise approach, and I think these algorithms are as reasonable today as they were when they were published.[5]