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The TCIs offer the first new prescription non-steroidal medication alternative in our armamentarium for treating AD in adults and children in a generation. There are well-designed and executed evidence-based studies which demonstrate the efficacy of this class of drugs dating back to the mid-1990’s in Europe and the United States, and convincing safety data is discussed in several of the studies (Margolis, Arellano, Qureshi, and Orlow) reviewed herein.
The 2004 FDA-issued Public Health Advisory to health care providers regarding the safety of TCIs stated, in part, that the “long-term safety of topical calcineurin inhibitors has not been established. Although a causal relationship has not been established, rare cases of malignancy (eg. skin and lymphoma) have been reported in patients treated with TCIs ... Therefore continuous long-term use of TCIs ... in any age group should be avoided, and application limited to areas of involvement with AD ... (Neither agent) is indicated for use in children less than 2 years of age.” The advisory went on to recommend the use of TCIs only as “second line therapy for short-term and non-continuous chronic treatment ... in non-immunocompromised adults and children 2 years of age and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable.”
This move by the Pediatric Advisory Board and the FDA was likely prompted by a dramatic increase in off-label use of TCIs, which may have been precipitated by aggressive marketing to both primary care providers and consumers. The risk of cancer was based on the known immunomodulatory effects of the systemic calcineurin inhibitors and the concern of systemic absorption, particularly in children under 2 years old. Anxiety was further increased by selected animal data and case reports of malignancy in TCI clinical and post marketing studies.
When the mandatory black box warning on the packaging of both agents was instituted in January 2006, a number of national and international medical societies engaged in public discussion of the safety and efficacy of the TCIs. The American Academy of Dermatology, the Canadian Dermatology Association, and the American Academy of Allergy, Asthma, and Immunology advocated for reconsideration of the black box warning. In spite of lobbying by pediatric dermatologists in the American Academy of Pediatrics, the AAP failed to take a position on the TCIs.
The advocacy groups argued that the TCIs were approved by the FDA after consideration of safety and efficacy studies in 38,000 patients, including 14,000 children less than 17 years of age. They emphasized that there was no evidence of an increased rate of lymphoma when compared to data from the general population in the Surveillance Epidemiology and End Result Database. Moreover, the clinical and histologic patterns in the cases of lymphoma reported in patients treated with TCIs were not consistent with typical immunosuppression-related lymphomas. Multiple studies 1-7 showed no evidence of significant absorption of TCIs in short-term continuous or long-term intermittent treatment of AD in adults and children, and there was no evidence of interference with the effectiveness of immunization and delayed hypersensitivity skin responses or increased rate of systemic infections.
The FDA, National Eczema Association, and the preceding advocates of the TCIs acknowledge that this novel class of medications requires continued study, and that patients need close long-term monitoring. The TCI manufacturers, with the encouragement of the FDA, are supporting 10 year safety studies to generate additional safety data, which should be available by 2016.
At the present time, TCIs should be used in the context of a complete treatment regimen. The potential risks and benefits should be discussed carefully with parents and patients, and when the decision is made to prescribe a TCI, a discussion of the black box warning should be undertaken. Off-label use of the TCIs, particularly in children less than 2 years old, should be done judiciously. Controlled studies of the use of TCIs and topical steroids, as well as other agents, should be sponsored in adults and children with AD, particularly those less than 2 years of age.
References
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Breuer K, Werfel T, Kapp A. Safety and efficacy of topical calcineurin inhibitors in the treatment of childhood atopic dermatitis. Am J Clin Dermatol. 2005;6:65-77.
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Boguniewicz M. Fiedler VC, Raimer S, et al. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. J Allergy Clin Immunol. 1998;102:637-44. |
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Patel RR, Vander Straten MR, Korman NJ. The safety and efficacy of tacrolimus therapy in patients younger than 2 years with atopic dermatitis. Arch Dermatol. 2003;139(9):1184-1186 |
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Staab D, Kaufmann R, Bräutigam M, Wahn U. Treatment of infants with atopic eczema with pimecrolimus cream 1% improves parents' quality of life: a multicenter, randomized trial. Pediatr Allergy Immunol. 2005;16(6):527-533. |
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Ho VC, Gupta A, Kaufmann R, et al. Safety and efficacy of nonsteroid pimecrolimus cream 1% in the treatment of atopic dermatitis in infants. J Pediatr. 2003;142:155-162. |
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Kang S, Lucky AW, Pariser D, et al. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol. 2001;44:S58-64. |
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Papp KA, Werfel T, Fölster-Holst R, et al. Long-term control of atopic dermatitis with pimecrolimus cream 1% in infants and young children: a two-year study. J Am Acad Dermatol. 2005;52:240-246. |
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