Off-Label Treatments: Thinking Out of the Box for Skin Diseases

 Off-label therapies for dermatologic diseases can be at least as effective, sometimes cheaper and, on occasion, safer than drugs with an FDA indication, a dermatologist emphasized when reviewing some of his favorite options. 

“The FDA does not dictate practice. Approval simply means that regulatory criteria were met, but many therapies have never been submitted for regulatory approval,” Ted Rosen, MD, professor of dermatology at Baylor College of Medicine in Houston, said at the Society of Dermatology Physician Associates (SDPA) Annual Summer Conference 2026. 

Verruca and condyloma acuminata, or genital warts, provide examples. For verucca vulgaris, imiquimod is an approved treatment even if several over-the-counter therapies, such as salicylic acid, are also effective for uncomplicated cases, according to Rosen. Moreover, he said there are multiple off-label therapies to consider for recalcitrant lesions.

In a presentation on off-label treatments for skin diseases at the meeting, Rosen singled out oral zinc sulfate, adapalene, bleomycin, and the human papillomavirus (HPV) vaccine.

Support Off-Label Choices With Citations

He provided multiple references for each of these options, including a 2009 randomized, placebo-controlled trial of oral zinc sulfate (ZnSO₄) published in the Journal of the American Academy of Dermatology, which evaluated a starting dose of 10 mg/kg per day in patients with recalcitrant viral warts. After a month, nearly 60% were cleared. After 2 months, the clearance rate climbed to nearly 80% without recurrences, Rosen noted.

The earliest reference for the topical retinoid adapalene is a small open-label 2011 study of 0.1% adapalene gel applied to plantar warts, published in the Indian Journal of Dermatology. Warts were pared and treatment was applied, generally followed by occlusion. In the study, which involved 10 patients with 118 warts, all warts were cleared in an average of 39 days with no sequalae, including irritation.

For warts, bleomycin and the HPV vaccine are both administered intralesionally. The more recent of the two bleomycin studies Rosen cited was published in 2021 of patients with resistant palmoplantar and periungual warts. In that retrospective review, a once-per-month 1 mg/mL injection into warts led to complete clearance in nearly 90% of patients over a mean of 2.5 years. Although nearly 16% recurred within 3 months of the last injection, there were no severe side effects. 

Of the references for the HPV vaccine as a treatment of recalcitrant warts, Rosen cited an article published in 2020 in the Journal of the American Academy of Dermatology. It compared intralesional to intramuscular injections of the HPV vaccine ranging from 0.1 to 0.3 mL administered every 2 weeks until patients cleared (with a maximum of 6 injections). In the study of 44 patients, the greater complete clearance with the intralesional injection (81.8% vs 63.3%) did not reach statistical significance, but Rosen said he considered the rates of efficacy high for a group that had failed multiple prior therapies.

Based on this and other studies of the HPV vaccine, Rosen recommended a once weekly intralesional dose of 0.1 mL HPV vaccine, predicting a clearance rate in recalcitrant warts of greater than 80% within 5 doses. 

For some dermatologic diseases there are no approved therapies, Rosen noted, but rather than reach for an off-label JAK inhibitor, he said there are often inexpensive alternatives.

Granuloma annulare (GA) is an example, he said. Options, in addition to JAK inhibitors, include such expensive therapies as monoclonal antibodies targeted at TNF-alpha or other inflammatory cytokines, or dupilumab, but Rosen suggested excimer laser or scarification as options that are not always considered.

A 2012 case report of a woman with generalized GA for more than 40 years who was successfully treated with an excimer laser has been followed by others. Rosen said that treatment with two passes per session, performed weekly, has been associated with complete resolution of refractory GA within 4-6 months without recurrence at 6 months. 

The evidence for successfully treating GA with scarification dates to a case report published in 1982. Scarification is not without risks, including scarring or the Koebner phenomenon, but Rosen said that a drug-free approach is appealing to many patients.

Heating Pads Are a Versatile Tool 

The simple heating pad is another drug-free therapy for warts, including genital warts, that Rosen puts to use for a number of dermatologic diseases, citing 2013 evidence for genital warts, and 2017 evidence for molluscum contagiosum. He also reports having empirical success with hyperthermia for clearing solar purpura. However, Rosen emphasized that the pad must be capable of reaching a temperature of 111 °F (43.9 °C).

For all of these skin disorders, complete resolution requires repeated applications of the heating pad over various periods ranging from weeks to months, but lesions resolve without pain or risk (unless there is an inappropriate length of exposure). However, only a few of the commercially available heating pads reach the target temperature, he said.

Rosen, whose list of clinical pearls using off-label or under-the-radar therapies was long, emphasized that many clinicians are uncomfortable with using treatments that are not supported by an FDA-approved indication. This can be a particular problem for physician associates (PAs), the audience Rosen was addressing. He suggested those early in their career might not be comfortable with using drugs for non-approved indications.

Rosen said that PAs or any other clinician with limited experience always have the option of presenting a treatment plan to a mentor, such as a collaborating physician, but he said references can also increase their comfort level. 

“Look it up,” he told Medscape Medical News, when asked what steps clinicians should take when considering off-label therapies. He also pointed out that almost all the therapies he suggested are supported by evidence, and most were low risk, meaning that even a case report might be sufficient in a situation where alternatives are limited and serious adverse events would not be expected.

“Clinicians should make sure they are comfortable with their therapeutic choices, but it can also help to put a supportive reference in the medical record,” Rosen said.

Participating in the same session on off-label treatments at the SDPA meeting, Matthew Zirwas, MD, of Bexley Dermatology outside Columbus, Ohio, agreed. 

He, too, had a long list of therapies he uses off-label, and many of his pearls were drugs supported by evidence with relatively low risks. He recommended oral roflumilast, a phosphodiesterase-4 (PDE4) inhibitor approved for treating COPD that is now available as a generic for inflammatory diseases, as an example. Risks are low and the once-daily pill is convenient, he noted.

Zirwas recommended half of a single 500 µg pill daily for the first month before switching to the full dose as a safety precaution. He listed oral roflumilast as a treatment or as an adjunctive therapy for such diseases as GA, hand eczema, lichen planus, atopic dermatitis, and pemphigus.

“Due to efficacy, cost, ease of use, this has become my first-line agent for most inflammatory [diseases] if I don’t have a highly effective, FDA-approved agent that I can easily get for the patient,” he said.

Rosen reported a financial relationship with Sanofi/Genzyme not relevant to the presentation. Zirwas reported financial relationships with AbbVie, Acrotech, Advanced Derm Solutions, Aldeyra, Henkel, Amgen, AnaptysBio, Apogee, Arcutis, Beiersdorf, Biocon, Boehringer Ingelheim, Bristol-Myers Squibb, Cara, Celldex, Evelo, Evommune, Galderma, Incyte, Janssen, L’Oreal, Leo, Lilly, Luum, Meta, Nimbus, Novartis, Pelthos, Pfizer, Q32 Bio, Regeneron, Sanofi, Sun, Supernus, Takeda, UCB, Verrica, and Zai Labs.

https://www.medscape.com/viewarticle/label-treatments-thinking-out-box-skin-diseases-2026a1000jxw