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Black box warning for topical calcineurin inhibitors and the death of common sense

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Black box warning for topical calcineurin inhibitors and the death of common sense
Alan B Fleischer Jr MD
Dermatology Online Journal 12 (6): 2

Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC.


Objective: This commentary is designed to provide a clinical viewpoint regarding the Food and Drug Administration (FDA) and its recent decision to imposed a "black box warning" on the topical calcineurin inhibitors, pimecrolimus and tacrolimus.
Design: Select references were used to review the relevant data
Results: Although there is a theoretic risk of oncogenesis because of the trivial systemic absorption of these agents and there exist anecdotes of cancer occurring amongst the millions of people who have used these agents, human data from randomized controlled trials suggest a protective effect from cancer. Although results from randomized controlled trials provide the highest level of evidence, the FDA chose to warn the public on the basis of weak and likely faulty data. Subsequent to the FDA actions, utilization of the best-studied class of agents for atopic dermatitis has fallen significantly.
Conclusions: These actions represent a "death of common sense" and have profound impact both on our ability to safely and effectively care for patients and our medicolegal risk.

Philip Howard, in his treatise, Death Of Common Sense: How Law Is Suffocating America [1], provides a series of outrageous anecdotes which clearly reveal that our body politic does not always make sound decisions based upon rational principles. Although this book is over a decade old, the lessons ring true today. The motivation behind political organizations may be self-serving principles and the acts of these organizations may work to the detriment of the public. When autonomous governmental agencies approach the world irrationally, fiction and conjecture become fact.

We entrust food and drug safety to our governmental regulatory agency, the Food and Drug Administration (FDA). Among other tasks, such as appeasing Congress and the public, this body of dedicated scientists is expected to weigh the benefits and risks of our therapeutic agents and thereby help the public and medical profession to make rational choices. In the recent past the FDA has elected to modify the labeling of the two topical calcineurin inhibitors, tacrolimus and pimecrolimus, to include a "black box warning" [2]. A black box warning is the highest level of five possible warning categories found in the package insert [3]. This warning, with associated medication guide, implies that these therapeutic agents pose a significant risk to our patients over the long term, and tacitly imply that other therapeutic options that do not bear such warnings may be less risky choices for our patients. Indeed, largely as a result of the discussion at hand, sales of these two agents have plummeted in the US since the public health advisory in March 2005.

From a scientific standpoint, oncogenic drugs do deserve the special attention of physicians to carefully weigh the risk-benefit relationship. Whereas the data are robust suggesting that high, sustained, systemic daily doses of these agents may pose cancer risks for both humans and animals, there is no demonstrated effect for either topical calcineurin inhibitor in terms of ability to respond to immunizations, infections, or any sign of immunosuppression [4]. Over 7-million patients worldwide have been treated with these agents [4], among the best studied topical agents in history, and no increased risk of cancer is demonstrated compared with baseline rates in the population. When 7-million people apply or ingest any drug or product, cancers are bound to occur. The question is, do they occur more frequently than expected?

Indeed, the data from randomized controlled trials suggest that these agents have a smaller cancer risk that their vehicles or topical corticosteroids (Table I). In the case of topical pimecrolimus, during randomized controlled trials, of 19,000 study subjects treated, two cancers occurred [5]. By contrast, in the comparator vehicle and corticosteroid treated subjects, of approximately 4,000 subjects, there were five cancers observed. In the case of topical tacrolimus, of approximately 4,000 subjects, no cancers occurred. In the vehicle and corticosteroid comparator arms, 2,300 subjects developed 3 cancers. Thus, the risk of cancer is strikingly less in the calcineurin treated subjects compared with those in the vehicle or corticosteroid arms. The likelihood of cancer occurring is decreased by 11.9 times compared with other treatment. For tacrolimus in randomized controlled trials, with no observed cancers, the risk of cancer in the vehicle or corticosteroid groups are infinitely higher than in the tacrolimus arm [6]. Note that all of the hematological malignancies and lymphomas occurred in the vehicle and corticosteroid-treated patients, with zero occurrences in the calcineurin subjects. Recall that randomized controlled trials provides the highest level of evidence, and these trials suggest either no effect or a cancer-protective effect.

The black box warnings state that "although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma), have been reported in patients treated with topical calcineurin inhibitors." As a clinician who sees many patients with cutaneous lymphomas, the majority have been misdiagnosed with eczematous conditions for years before an insightful clinician performs a diagnostic biopsy. Does this mean that the corticosteroids they used, moisturizers, or calcineurin inhibitors contributed to their disease? A similar statement may easily be stated about broccoli, that, "although a causal relationship has not been reported, patients who ingest broccoli have been noted to experience lung, breast and colon cancer." One could add "hemorrhoids, heartburn, and halitosis" and be equally correct. Of course, there is reasonable evidence suggesting that consumption of cruciferous vegetable including broccoli may decrease cancer risk [7, 8], but an FDA baseless pronouncement would be effective in reducing broccoli consumption.

One cannot exclude the possibility that events may occur over the long term that cannot be observed over the short-term. Longer term studies have been conducted with both tacrolimus and pimecrolimus that have never been conducted with topical corticosteroids, or any other topical medication class. Long-term safety studies are essential to help the public understand the real risks associated with exposures to agents and should continue.

The misinterpretation of these data by government bodies with their own political and nonscientific agendas is worrisome for those of us who need to treat patients. Do we choose to have a discussion with our patients about the theoretic risk of cancer in using this class of medications, or do we prescribe the more oncogenic agents (i.e., corticosteroids) that have no such warning? The reader should note that cancers have been associated with systemic corticosteroid use [9, 10], but as is the case with topical calcineurin agents there is no known causal association. Patients and physicians assume that data were carefully reviewed, and actions resulted from logic. Were logic important, then over-the-counter approval of the "morning after pill" would have occurred long ago [11]. But, regulatory agencies do not have to only address p values and adverse event reports, they must respond to political forces far larger than conceivable.

I for one am saddened that the public has been betrayed by the complete death of common sense. When a therapeutic agent has no demonstrated increased risk of causing a problem, but theoretic concerns are enough to produce warnings, we lapse into irrationality.

The case of calcineurin inhibitors is not unique in the US. In the case of systemic isotretinoin, which does not increase the risk of depression or suicide over baseline community levels [12], physicians and patients believe that these two are associated. This isotretinoin-depression belief system is entrenched, accepted and thereby results in adverse event reports. Now, the public believes there is an association between oncogenesis and these calcineurin agents. As the adage goes "if something is believed to be real, it is real in its consequences." Legal implications are a given, since the legal system has never concerned itself with truth or justice. We can all learn from this experience, and we may consider rereading Philip Howard's book.


1. Philip K Howard: Death of common sense: how law is suffocating America. Warner Books, 1994, New York.

2. Anonymous: New warnings for two eczema drugs. Available at: Accessed April 2, 2006.

3. Aaronson DW: The "black box" warning and allergy drugs. J Allergy Clin Immunol 2006;117:40-4.

4. Fonacier L, Spergel J, Charlesworth EN, Weldon,D, Beltrani V, Bernhisel-Broadbent J et al. Report of the topical calcineurin inhibitor task force of the American college of allergy, asthma and immunology and the American academy of allergy, asthma and immunology. J Allergy Clin Immunol 2005;115:1249-1253.

5. Hultsch T, Kapp A, Spergel J: Immunomodulation and safety of topical calcineurin inhibitors for the treatment of atopic dermatitis. Dermatology 2005;211:174-187.

6. Jaracz E, Maher R, Simon D, Kristy R, Park SL, Rico J. Safety profile of tacrolimus ointment: data from five years of post-marketing experience. Proceedings of 64th Annual Meeting of the American Academyof Dermatology; March 3-7, 2006; San Francisco, CA.

7. Brennan P, Hsu CC, Moullan N, Szeszenia-Dabrowska N, Lissowska K, Zaridze D. Effect of cruciferous vegetables on lung cancer in patients stratified by genetic status: a mendelian randomisation approach. Lancet 2005;366:1558-1560.

8. Osborne MP. Chemoprevention of breast cancer. Surg Clin North Am 1999;79:1207-1221.

9. Sorensen HT, Mellemkjaer L, Nielsen GL, Baron JA, Olsen JH, Karagas MR. Skin cancers and non-Hodgkin lymphoma among users of systemic corticosteroids: a population-based study. J Natl Cancer Inst 2004;96:709-711.

10. Karagas MR, Cushing Jr GL, Greenberg ER, Mott LA, Spencer SK, Nierenberg DW. Non-melanoma skin cancers and glucocorticoid therapy. Br J Cancer 2001;85:683-686

11. Zwillich T. Bush nominee faces threats. CBS News. Available at: health/webmd/main1412072.shtml. Accessed April 3, 2006.

12. Jick SS, Kremers HM, Vasiakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol 2000;136:1231-1236.

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