Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice

Elaine C Siegfried, Jennifer C Jaworski, Adelaide A Hebert, Elaine C Siegfried, Jennifer C Jaworski, Adelaide A Hebert

Abstract

Topical calcineurin inhibitors (TCIs), commercially available since 2000-2001, are the first and only topical medications approved for chronic treatment of atopic dermatitis (AD) in pediatric patients and remain a welcomed alternative to topical corticosteroids. In January 2006, the US Food and Drug Administration (FDA) issued a boxed warning requirement based on a theoretical risk of malignancy (including lymphoma) with TCI use. However, in the years since, analyses of epidemiologic and clinical data have failed to demonstrate a causal relationship between TCI use and malignancy or lymphoma risk, especially for pimecrolimus cream. In fact, the observed number of malignancies and lymphomas observed both in post-marketing surveillance and reported to the FDA using its adverse events reporting system is much lower among TCI-exposed patients than the expected number for the general population. Furthermore, among children enrolled in post-marketing pediatric registry studies for both tacrolimus and pimecrolimus followed for up to 5.5 years [10,724 patient-years (PY)] or 6.5 years (16,219 PY), respectively, the observed number of malignancies and lymphomas is very low and similar to the number expected for a sample of similar size in the general population. In addition to reporting these comparative malignancy and lymphoma data, this article provides a historical overview of the boxed warning requirement and critically evaluates the preclinical, clinical, and epidemiological evidence that has thus far failed to substantiate a relationship between TCI use and malignancy. The authors also provide practical clinical advice for optimizing AD management and patient care in the context of the boxed warning.

Figures

Fig. 1
Fig. 1
US pimecrolimus cream and tacrolimus ointment prescriptions (2002–2008). Interval for each year is January 1–December 31 except where noted. Values are percent of prescriptions dispensed for infants (® National in briefing document from Patty Greene, Drug Use Data Analyst, Division of Epidemiology, Office of Surveillance and Epidemiology, FDA Center for Drug Evaluation and Research. BPCA drug use review: Comparison of Elidel® cream and Protopic® ointment utilization trends following 2006 labeling changes, 17 July 2009. Available from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM204723.pdf. Accessed 2 April 2012. Data source (2002–2003): IMS Health National Prescription Audit Plus™ in briefing document from David Moeny, Pharmacist/Drug Use Specialist, Division of Surveillance, Research and Communication Support, FDA Center for Drug Evaluation and Research. Pediatric drug use analysis for topical calcineurin inhibitors, 16 July 2004. Available from http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2_01_05_Cleared%20version%20Elidel-Protopic%20Drug%20Use%20Review%20D040389%207-2004.pdf. Accessed 23 May 2012. aInterval is June 1–May 31
Fig. 2
Fig. 2
Worldwide pimecrolimus cream and tacrolimus ointment sales (2000–2011). Data source for pimecrolimus cream: Novartis 2002–2003 corporate annual reports. Available from http://www.unglobalcompact.org/participant/7016-Novartis-International-AG. Accessed 2 April 2012; Novartis 2004–2008 corporate annual reports. Available from http://www.novartis.com/newsroom/corporate-publications/archive.shtml. Accessed 2 April 2012. Elidel worldwide sales 2009–2011. Available from http://www.evaluatepharma.com/Universal/View.aspx?type=Search&query=elidel. Accessed 29 March 2012. Data source for tacrolimus ointment: Astellas and Fujisawa 2001–2011 corporate annual reports. Available from http://www.astellas.com/en/ir/library/annual_report.html. Accessed 2 April 2012. (Using yearly conversion rates available from http://www.mac.doc.gov/japan-korea/statistics/exchange.htm. Accessed 29 March 2012.) aFujisawa merged with Yamanouchi to become Astellas in 2004. bNovartis promotion scaled back Q1 2007, ceased Q3 2007. cMeda acquired global rights to pimecrolimus cream Q2 2011 and immediately licensed North American rights to Valeant

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