To assess off-label use of the topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, in children during periods before and after regulatory action by the US Food and Drug Administration (FDA) in 2005.
We identified new pediatric (age <20 years) users of topical tacrolimus or pimecrolimus in US Medicaid from 2001 to 2009, and examined the annual rate of drug use (pre- and postregulatory action) by age. We assessed medical claims for diagnoses consistent with an indication for a TCI, and assessed prescriptions for evidence of first-line atopic dermatitis therapy use before TCI initiation.
There were 57 664 eligible pediatric tacrolimus users and 425 242 eligible pediatric pimecrolimus users at baseline. The rate of TCI use decreased substantially after FDA regulatory action. The proportion of new users younger than 2 years of age significantly decreased for both tacrolimus (36.7% to 22.5%, P < .001) and pimecrolimus (47.0% to 33.7%, P < .001) after regulatory actions. Previous use of topical corticosteroids increased by ∼7% for both TCIs from the pre- to postregulatory period. However, after regulatory actions, there was only a small increase in the proportion of tacrolimus or pimecrolimus users with an atopic dermatitis or eczema diagnosis before drug initiation, and high strength use of tacrolimus was unchanged.
The rate of TCI use in children younger than 2 years of age fell substantially after FDA regulatory action in 2005. Off-label use of TCI as first-line therapy changed little.
Dear Editor:
Like Manthripragada et al,1 we also documented a decrease in topical calcineurin inhibitor (TCI) use after the FDA's 2005-2006 actions.2 Unlike them however, we attribute this to suboptimal atopic dermatitis (AD) management rather than a decline in inappropriate TCI use. As non-clinicians, Manthripragada et al failed to recognize the challenges of managing pediatric AD in the context of the TCI Boxed Warning and limited evidence supporting the use of other treatments. Topical corticosteroids (TCS) are considered first-line treatment for most children with AD (including infants) despite a lack of safety and efficacy data beyond 2-4 weeks and few being labeled for use in patients <2 years of age.3 Conversely, TCIs have been well studied for long-term (>1 year) use in patients of all ages.2
We appreciate and share the FDA's concerns about potential risks associated with medications used to treat skin disease in infants and children. In this case, however, we feel that the FDA has disproportionately weighed a theoretical risk of malignancy (not substantiated by clinical evidence) against the impact of poorly-controlled AD and the risks associated with TCS and other treatments. Indeed, this is the only time in history that the FDA has issued a Boxed Warning based on theoretical risk. The carcinogenic signals observed in mice and monkeys after exposure to TCIs cited by the FDA and Manthripragada et al were only observed when animals demonstrated systemic immune suppression; this has not been observed with topical use in humans of any age (most likely due to low percutaneous absorption). On the other hand, long-term TCS use is known to cause skin thinning, which may enhance percutaneous absorption and lead to possible systemic immune suppression.
Many third-party payers use the Boxed Warning as support for pre-authorization requirements and medication denials (especially Medicaid, which insures ~50% of US children). Similar standards are not applied to TCS products with similarly restrictive labeling. Oftentimes, the same pharmacist/insurer who declines to fill/cover a TCI prescription due to age-related labeling will fill one for a TCS that has not even been studied in that age group. Because so few medications are FDA approved to treat skin diseases in infants and children, off-label use is often the only option for these patients. In addition, the FDA-approved indication for TCIs as second-line treatment ignores the need for first-line non-TCS treatment for AD affecting the face, periorbital area, or skin folds and for patients who have skin infections, need daily treatment, or are TCS intolerant.2
The changing patterns of TCI initiation observed by Manthripragada et al demonstrate the significant impact FDA actions can have on patient access to medications. The FDA's approval and review processes assure continued availability of safe and effective treatments. In this case, however, the FDA's decision to issue a Boxed Warning based on a theoretical risk is unprecedented and has served to erode patient-physician trust, restrict patient access to TCIs, increase use of unproven alternatives, provide fodder for frivolous lawsuits, discourage treatment innovation, and, ultimately, jeopardize patient care.
References
Conflict of Interest:
None of the authors have received financial compensation in relation to this letter.
Elaine C. Siegfried, MD is a full-time employee of Saint Louis University. She has participated in contract research with Astellas Pharma US (prior to 2001) and Novartis Pharmaceuticals Corporation (prior to 2004); financial compensation for this work was paid directly to her employer. She received travel expenses related to presentation of some of this contract research from Valeant Pharmaceuticals North America LLC (in 2012). She has received consulting fees from Novartis (prior to 2006).
Jennifer C. Jaworski, MS is a full-time employee of Prescott Medical Communications Group. She has provided medical writing and editorial support for other publications with financial support from Valeant.
Adelaide A. Hebert, MD is a full-time employee of the University of Texas Medical School at Houston. She has received consulting fees, been a member of speakers' bureaus, and/or served on advisory boards for Astellas, Novartis (prior to 2008), and Valeant. In addition, she has participated in contract research with Astellas and Novartis; financial compensation for this work was paid directly to her employer. She has also served as a member of data safety monitoring boards for Valeant and Novartis.