Safety of Topical Calcineurin Inhibitors for the Treatment of Atopic Dermatitis

Abstract

Atopic dermatitis is a chronic, highly pruritic, and frequently recurring inflammatory skin disease that can be burdensome to affected individuals as well as to their family members, the health care system, and society as a whole. Immunomodulatory agents, such as topical corticosteroids and topical calcineurin inhibitors (TCIs), target the underlying immunopathology of atopic dermatitis and are the foundation of pharmacologic treatment for disease exacerbations. Recent recommendations from the United States Food and Drug Administration prompted the addition of a black-box warning and medication guide for tacrolimus ointment and pimecrolimus cream (both TCIs). The recommendations were based on a theoretical risk of malignancy derived from safety profiles, animal data, and reported cases of malignancy from clinical trials and postmarketing safety surveillance of oral calcineurin inhibitors. We know of no data that suggest that TCI use increases the risk of malignancy. Several dermatologic associations have issued statements supporting the safety of TCIs, and independent oncology experts have concluded that reported lymphomas were not related to TCI use. The black-box warning added to the TCI prescribing information also states that no causal link has been established. Effective treatment of atopic dermatitis can help alleviate the burden this disease imposes, and TCIs remain important treatment options.

Off-label prescribing for allergic diseases in pre-school children

“…Nonetheless, since its introduction on the market in 2001, no definite causal relationship between the use of IT and malignancy has been established. 26 In this study, we confirmed that the off-label use of antiallergic drugs in pre-school-aged children for the treatment of moderate to severe allergic diseases is high. With few studies of long-term safety, the implications inherent in this type of use become evident.…”

“…The concerns of the regulatory authorities are based on the theoretical risk of systemic immunosuppression derived from the use of oral calcineurin inhibitors such as pimecrolimus or tacrolimus in transplant recipients, and the existence of rare instances of malignancy associated with their use. 26 However, pharmacokinetic data obtained from clinical trials in children aged <2 years did not suggest concentrations high enough to cause systemic immunosuppression, unlike oral administration, or demonstrate a correlation between systemic concentrations and percentage body surface area treated or the duration of treatment. 27 Likewise, there was no interference with the development of normal immune responses to vaccinations.…”

New and emerging trends in the treatment of atopic dermatitis

“…Pimecrolimus 1% cream is FDA-approved for the treatment of mild to moderate atopic dermatitis in patients 2 years of age or older. Tacrolimus 0.1% ointment is approved for the treatment of moderate to severe atopic dermatitis in patients 16 years of age or older, and tacrolimus 0.03% ointment is approved for use in patients 2 years of age or older (Paller et al 2005; Munzenberger and Montejo 2007; Wolverton 2007). …”

“…Symptoms include erythema, scaling and pruritus in affected areas, and often result in sleeplessness, psychological stress, poor self-esteem, anxiety, and poor school or work preformance. The cost of atopic dermatitis is estimated to be US$0.9 to 3.8 billion every year, with direct medical costs and out-of-pocket expenses averaging US$609/patient/year (Munzenberger and Montejo 2007). Topical steroids have been the mainstay of treatment for atopic dermatitis in both children and adults for over 50 years.…”

Daily Topical Tacrolimus Therapy Prevents Skin Rejection in a Rodent Hind Limb Allograft Model

“…2 Topical tacrolimus therapy has shown remarkable efficacy in the dermatology literature and has stimulated research in its mechanism of action in the skin. It has been found to have minimal systemic toxicity 3 and avoids the local side effects of topical steroids such as skin atrophy, telangiectasia, striae, and acne that limit its prolonged use. This favorable side-effect profile makes topical tacrolimus an attractive choice for prophylactic therapy and for treating acute rejection in composite tissue allografts.…”