A Safety Assessment of Topical Calcineurin Inhibitors in the Treatment of Atopic Dermatitis

Mark Lebwohl, MD; Tara Gower, PhD

October 10, 2006

Abstract

Atopic dermatitis (AD) is a common childhood disease that can disrupt the lives of patients and their families and, in turn, affect their quality of life. The goal of treatment is the long-term control of AD by minimizing the frequency and severity of flares. Topical corticosteroids of various potencies have been the mainstay of pharmacologic treatment of AD flares. In the past few years, the introduction of topical calcineurin inhibitors (TCIs) has provided physicians with an effective, well-tolerated alternative to topical corticosteroids. In January 2006, a boxed warning and a patient medication guide were added to TCI product labels in the United States after the US Food and Drug Administration raised concerns about their safety. These concerns were based on rare cases of skin malignancy and lymphoma, and a theoretical risk stemming from the systemic use of calcineurin inhibitors in animal studies and transplant patients. However, the boxed warning states that no causal link has been established between TCI use and malignancy. Pharmacokinetic studies have also shown that treatment with TCIs leads to only minimal systemic absorption. In addition, controlled, blinded studies have found no evidence of systemic immunosuppression and no causal relationship between the use of TCIs and the occurrence of lymphoma or other malignancies. Overall, TCIs have been shown to be an effective and valuable treatment option for AD.

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Table 1. Incidence of Application-Site Burning in Pimecrolimus and Tacrolimus Clinical Trials ^[20,27,32]
	Tacrolimus Ointment
	Tacrolimus Ointment		Vehicle
Application-Site Burning (%)	0.03%	0.1%
12-week pediatric trial (N = 351)	42.7	33.4	29.0
12-week adult trial (N = 631)	45.6	57.7	25.8
	Pimecrolimus Cream 1%
	Pimecrolimus		Vehicle
6-week pediatric trial (N = 403)	10.4		12.5
6-month adult trial (N = 192)	10.4		3.1

Table 2. No Effect of Pimecrolimus Treatment on Delayed-Type Hypersensitivity. In a 1 Year Study, Response to Recall Antigens Was Not Significantly Different Between Control and Pimecrolimus-Treated Patients*
Skin Antigen	Pimecrolimus n = 82 (%)	Control n = 30 (%)	P Value
Tetanus	63.4	60.0	.826
Diphtheria	42.7	23.3	.079
Streptococcus	7.3	0.0	.190
Tuberculin	17.1	13.3	.776
Candida	13.4	3.3	.176
Trichophyton	8.5	10.0	.726
Proteus	18.3	6.7	.151
Negative control	3.7	0.0	.563
1 positive antigen	73.0	67.0	.820

*Reprinted with permission from Pediatrics.^[27] Copyright 2002, American Academy of Pediatrics
P value from time to first occurrence analysis (log-rank test)

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