The Value of the Black Box Warning in Dermatology

July 2015 | Volume 14 | Issue 7 | Editorials | 660 | Copyright © July 2015

Laura Winterfield MD MPH,a Ruth Ann Vleugels MD MPH,b and Kelly K. Park MD MSLa

aDivision of Dermatology, Loyola University Stritch School of Medicine, Maywood, IL
bDepartment of Dermatology, Brigham and Women's Hospital, Boston, MA

Boxed, or “black box” warnings are issued by the United States Food and Drug Administration (US FDA) as a means to label drugs associated with serious adverse events. However, there is no clear metric to determine how and when the boxed warning is applied. Inconsistencies in the review process, language, timing, and dissemination of these warnings impact dermatologists and their patients. Appropriate patient selection and monitoring can help minimize risk to patients when prescribing drugs with boxed warnings. Future changes in the manner in which the boxed warning is issued and in its subsequent clinical application may improve the utility of these warnings for dermatologists and ultimately, patient safety.

Clinical Case

A 63-year-old white male with diabetes mellitus type II returns to your clinic for follow-up of non-healing neuropathic diabetic foot ulcers. He has not responded to multiple wound care modalities and is interested in other therapeutic options. You consider adding becaplermin to your patient’s current regimen. Becaplermin (0.01% Regranex® gel), recombinant human platelet-derived growth factor-BB that has been topically formulated, is indicated for chronic lower extremity diabetic ulcers. Currently, it is the only approved growth factor for use in wound healing. Multicenter, randomized, double-blinded placebo-controlled studies have shown statistically significant efficacy of becaplermin in increasing complete ulcer healing and in decreasing time to healing when combined with appropriate wound care.1
The most common side effects of becaplermin listed in its package insert are erythematous cutaneous eruptions and burning sensation at the application site.2 In clinical trials, the most common adverse events observed were infection, cellulitis, skin ulceration, and osteomyelitis, none of which are included in the package insert.1 Serious adverse events were demonstrated in similar percentages of the becaplermin gel (24%), placebo gel (25%), and good wound care monotherapy (28%) groups, and the majority of these events were thought to be related to common sequelae of diabetes or nonhealing diabetic ulcers, rather than to the becaplermin gel itself.1
Becaplermin also comes with a boxed warning which states, “Warning: Increased Rate of Mortality Secondary to Malignancy.” The warning continues to note that “An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of Regranex® Gel in a postmarketing postmarketing retrospective cohort study. Regranex® Gel should only be used when the benefits can be expected to outweigh the risks. Regranex® Gel should be used with caution in patients with known malignancy.”2
This boxed warning was applied in 2008, when a long-term study of a medical claims database compared patients who had received becaplermin to matched comparators. In patients who were observed for a median of approximately 20 months in order to identify malignancies, patients using becaplermin had a relative risk (RR) of 2.7 for developing cancer compared to those receiving vehicle/standard of care (3% versus 1%, respectively). 2 The incidence of mortality from all cancers in patients using 3 or more tubes of becaplermin was 3.9 per 1,000 person years, whereas this incidence was 0.9 per 1,000 person years in the comparators (adjusted rate ratio of 5.2).2 The FDA reviewed this data and “concluded that the increase in the risk of death from cancer in patients who used three or more tubes of Regranex was five times higher than in those patients who did not use Regranex®. However, the risk of getting new cancers among Regranex® users was not increased compared to non-users. The duration of follow-up of patients in this study was not long enough to detect new cancers. In response, the manufacturer of Regranex® has added this information and a Boxed Warning to the labeling for the product.”3
Recently, long-term follow-up from the same database has been published and shows no overall elevated cancer mortality risk with becaplermin (RR 1.0). The study goes on to suggest that despite the original boxed warning, there is no statistically significant increase in mortality from all cancers in patients using more than 3 tubes of becaplermin (RR 2.4).4 The study authors “found no convincing evidence that cancer incidence RRs are increased among becaplermin initiators relative to comparators who are similar but who did not receive becaplermin.”4
As a dermatologist, reading the most recent medical literature reveals a better safety profile than anticipated from the becaplermin black box warning and package insert. Furthermore, in selected populations being treated for diabetic foot ulcers, the combination of becaplermin and good wound care may be cost effective.5 Given that nonhealing neuropathic diabetic foot ulcers are often recalcitrant to treatment and have a limited set of treatment options as well as your patient’s lack of improvement with other wound care approaches, you discuss the risks and benefits of becaplermin with him. He elects to proceed with this therapy. The typical treatment regimen is recommended, which involves applying becaplermin once daily until complete healing has occurred. This treatment may be modified if complete healing does not occur after 20 weeks or if the ulcer does not reduce in size by 30% after 10 weeks of therapy.2


The US Food and Drug Administration (FDA) is charged with bringing drugs to market in a safe and efficient manner. The