Boxed Warnings: What Should Dermatology Clinicians Know?

In the 2024 Fall Clinical Dermatology Conference for PAs and NPs session "When (Boxed) Warnings Are Not Relevant: Examples in Dermatology," Jason Hawkes, MD, MS,medical dermatologist based in Sacramento, California, critically evaluated the relevance and impact of boxed warnings in dermatologic medications. Hawkes discussed how certain boxed warnings—mandated by regulatory agencies like the FDA—can, as he explained during the session, “sometimes be misleading or counterproductive, emphasizing the need for a nuanced understanding of these warnings within clinical practice.”¹

Understanding Boxed Warnings

Boxed warnings, often referred to as "black box warnings," are the most stringent warnings issued by the FDA. These warnings highlight serious or life-threatening risks associated with a drug. Hawkes traced the origin of these warnings to the 1966 Fair Packaging and Labeling Act, with significant updates made in 2006 under the Code of Federal Regulations (CFR) 201.57(e). The main purpose of these warnings is to inform healthcare professionals about severe adverse reactions and potential safety hazards of medications, aiming to ensure patient safety.

Pros and Cons of Boxed Warnings

Hawkes outlined several pros and cons of boxed warnings. In an interview with Dermatology Times, he said, “The box warnings have a double-edged sword. We see that there are pros to the box warnings, and even just the full prescribing label in general, which is a great reference for clinicians. The downside—these are not evidence-based documents.”

Boxed warning pros include the useful reference and guide for clinicians, efficacy and risks are outlined, transparency is promoted, and in some states like Florida and Illinois, they establish a standard of care. Cons include data being based on limited population samples rather than real-world clinical settings, the scientific rigor needed to establish causation is not always reflected, patients and practitioners can experience misinterpretation and unnecessary alarm, and warnings are rarely reversed or updated to reflect new scientific evidence.

Examples in Dermatology

Hawkes provided specific examples from dermatology where boxed warnings may not be entirely relevant or could potentially cause more harm than good.

He said, “One of the important topics that I hit in this lecture was this concern that dupilumab (Dupixent) was causing cutaneous T-cell lymphoma. This is an important topic because this is an excellent therapy for patients living with atopic dermatitis (AD).But what we learn about when we look at AD is that there's a few things that are important for clinicians to consider one, just having AD increases your risk of lymphoma. And two, we have this sort of spectrum of disease. We think that AD might actually be on the spectrum with cutaneous T-cell lymphoma.”

• Calcineurin inhibitors for AD: Topical calcineurin inhibitors like pimecrolimus (Elidel) are associated with rare cases of malignancy. However, long-term studies, including a 10-year study involving 8000 patients, showed no increased cancer risk. Despite these findings, the boxed warning has led to significant patient concern.²
• IL-17 Inhibitors and inflammatory bowel disease (IBD): Drugs likesecukinumab (Cosentyx) carry warnings about the potential exacerbation of IBD. However, a review of 38 randomized controlled trials involving IL-17 treatment for psoriasis found only 12 new IBD cases among 16,690 participants. This suggests the baseline risk of IBD remains low, and the warning may cause unnecessary hesitation in prescribing effective treatments.³
• Psoriasis and suicidality: Warnings about IL-17 inhibitors potentially causing suicidality stem from limited and conflicting data. For instance, long-term studies on drugs like brodalumab (Siliq) and bimekizumab (Bimzelx) indicate that their risk of inducing suicidality is comparable to that of the general psoriasis population and does not justify the heightened concern.⁴

Hawkes emphasized the importance of evaluating boxed warnings and turning to science. He said, “We need to balance boxed warnings with the science because we don't want to eliminatea very good therapy, which has happened in the past, or people have moved away from a medication simply because of black box warning. And yet that was one of the most highly effective medications we have for particular diseases.”

References

1. Hawkes J. When (boxed) warnings are not relevant: examples in dermatology. Presented at: 2024 Fall Clinical Dermatology Conference for PAs and NPs; May 31-June 2, 2024; Scottsdale, AZ.
2. Siegfried EC, Jaworski JC, Hebert AA. Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice. Am J Clin Dermatol. 2013;14(3):163-178. doi:10.1007/s40257-013-0020-1
3. Onac IA, Clarke BD, Tacu C, et al. Secukinumab as a potential trigger of inflammatory bowel disease in ankylosing spondylitis or psoriatic arthritis patients. Rheumatology (Oxford). 2021;60(11):5233-5238. doi:10.1093/rheumatology/keab193
4. Koo J, Marangell LB, Nakamura M, et al. Depression and suicidality in psoriasis: review of the literature including the cytokine theory of depression. J EurAcad Dermatol Venereol. 2017;31(12):1999-2009. doi:10.1111/jdv.14460