With more than 3000 cutaneous diseases that may be treated by dermatologists, there is a wide gap between the number of possible presenting symptoms and the number of effective therapies approved by the US Food and Drug Administration (FDA) specifically for these disorders. As such, the use of medications on an off-label basis ꟷ defined as the “prescription of medications for unapproved indications or in unapproved dosage, dosage form, or route of administration” ꟷ is especially common in dermatology practice.1

An earlier study found that off-label prescribing for dermatologic diseases ranged from 17% to 73% in a representative sample of physicians in the United States. Such prescriptions were most common for acne rosacea (73%) and actinic keratosis (52%) and were least common for atopic dermatitis (17%) and psoriasis (16%).2

The “multitudes of diagnosis, the need for therapeutic options, and the long time required by the regulatory agencies to approve new medications make off-label prescriptions for dermatologic diseases so common,” wrote Katlein França, MD, PhD, and Sergio Litewka, MD, MPH, of the University of Miami Miller School of Medicine, Florida in a review published in the International Journal of Dermatology.1

They discussed treatments that are frequently used in this context, :


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Botulinum toxin. In addition to its FDA-approved indications for facial esthetic purposes and treatment of primary axillary hyperhidrosis, botulinum toxin is commonly used off-label by dermatologists. Emerging evidence suggests that the drug may be effective in treating a wide range of conditions including pruritic dermatitis, inflammatory dermatitis, fissures and ulcerations, scarring, vulvodynia, and more. 

Biologic drugs. Although multiple biologics are FDA-approved for the treatment of psoriasis and psoriatic arthritis, various off-label uses in dermatology have been reported, such as eczema, hidradenitis suppurativa, lichen planus, topical epidermal necrolysis, acne vulgaris, alopecia areata, aphthous stomatitis, pruritus, keloid, and wound healing, in addition to numerous other conditions.

Spironolactone. This potassium-sparing diuretic has long been used in the treatment of hyperaldosteronism, heart failure, cirrhosis of the liver accompanied by edema and ascites, and nephrotic syndrome. Because of its anti-androgenic activity, spironolactone is now used in the off-label treatment of androgen-dependent dermatologic disorders including adult female acne, hirsutism, hidradenitis suppurativa, and female pattern hair loss.

Topical calcineurin inhibitors. These agents have been approved by the FDA for the treatment of atopic dermatitis in patients 2 years or older. Promising results have also been observed for several off-label uses such as allergic contact dermatitis, seborrheic dermatitis, psoriasis, rosacea, lichen planus, and vitiligo.

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Topical vitamin D analogues. Although the FDA has approved their use for psoriasis treatment, these medications are also prescribed off-label for a range of cutaneous disorders. For example, a systematic review of 165 articles rendered a moderate to strong recommendation for the “use of topical vitamin D in combination with corticosteroids and phototherapy in vitiligo and as monotherapy for various ichthyoses, morphea, pityriasis alba, prurigo nodularis, and polymorphous light eruption.”3

França and Litewka noted that further research is needed to investigate the safety and efficacy of these various novel indications and to standardize dose protocols pertaining to their use.

 “Off-label prescriptions are considered legal, and physicians have the freedom to prescribe any approved drug for any other indication, regardless of the fact that the indication is not approved by regulatory agencies,” they concluded. “While there is no consensus on this subject, physicians are advised to prescribe medications that have a well-accepted therapeutic value in the medical community and only for indications that they believe are in the best interest of the patient.”

To learn more about off-label prescribing in dermatology practice, Dermatology Advisor interviewed Shawn Kwatra, MD, assistant professor of dermatology at Johns Hopkins University School of Medicine, Baltimore, Maryland and Raja Sivamani, MD, MS, AP, adjunct associate professor of clinical dermatology and director of clinical research at the University of California, Davis, and medical editor of LearnSkin.com.

Dermatology Advisor: What are some commonly used off-label treatments in dermatology? 

Shawn Kwatra, MD: Many dermatologic diseases do not have formal indications, so there is a lot of off-label prescribing in our field. In addition, given the ability to compound topical medicines, dermatology has many conditions treated with off-label formulations. One example is melasma, a condition with hyperpigmented patches, most commonly on the faces of women. Many treatments combine different formulations of hydroquinone with other compounds.

The treatment of chronic itch also uses a variety of off-label treatments. Patients may need to be managed with compounded creams, antidepressants, and the gabapentinoid class of medications. 

Raja Sivamani, MD: Off-label treatments are common in medicine, especially in dermatology. The reason is that not every disease has an FDA-approved treatment, especially if it is rare. In other cases, there are medications that have not been studied for FDA approval but are in common use for a condition through collective experience.

One example is the use of spironolactone for the treatment of acne. Spironolactone has a few supporting studies and is commonly used in the treatment of adult female acne, but it is not an FDA-approved treatment for this purpose.4 However, we have a good understanding of how to use it safely and effectively in the treatment of acne.

On the other hand, there are rare diseases that may not have any FDA-approved treatments, and off-label prescribing is necessary for treatment. Some examples include diseases like necrobiosis lipoidica diabeticorum, cutaneous sarcoidosis, and erythema multiforme major ꟷ diseases rare enough that running large phase 3 studies may not be feasible, and off-label use of medications is necessary for treatment.  

Dermatology Advisor: The review by França and Litewka mentions the ethical implications of this practice, including considerations pertaining to informed consent from patients. What are the relevant issues here for clinicians? For example, how should they address informed consent in off-label prescribing? 

Dr Kwatra: If there haven’t been properly conducted randomized controlled trials for a particular indication, we know less about the adverse event profile of the medication. It’s important for patients to know this and to be aware of the risk for adverse reactions. 

Dr Sivamani: It’s almost unethical to withhold potential treatment options by simply relying on FDA-approved treatment, because many uncommon dermatologic diseases do not have many FDA-approved treatment options and we still need to figure out a reasonable solution for our patients. That said, it’s important to have an open conversation [with patients] about medications that are used off-label and explain that you are [prescribing] a medication that is not FDA-approved for their condition but that you are [prescribing] it for a rational reason.

Many patients and the general public erroneously believe that off-label use of a medication is illegal, and this is an opportunity to educate them that it is not only legal but may make the difference in finding a therapy that could be useful. Also, it’s important to discuss off-label prescribing with the patient so that they are not confused if the pharmacist mentions to them that the prescribed medication is off-label. 

Dermatology Advisor: What are additional recommendations for clinicians regarding this topic?

Dr Kwatra: There is always a balance between treatment with approved therapies vs doing all you can to help your patient when there aren’t approved therapies. For dermatology, most conditions have only a few approved therapies. I think doing your best to make your patient aware of the risks, benefits, and potential adverse events is a must. 

Dr Sivamani: It’s important to let the patient know that even when used off-label the medication has still been reviewed by the FDA at some point, so it is still regulated. Also, it is important to discuss the dose so that the patient is informed of the typical dosing used in the FDA-approved indication and how and why you may be modifying that for off-label use to treat the patient’s condition. 

Dermatology Advisor: What are remaining needs in this area in terms of research and education?

Dr Kwatra: There is a huge lack in dermatology for clinical research studies of common conditions. There are many drugs used off-label but a paucity of properly controlled studies. In addition, more education needs to be provided on available therapies, the relative strength of evidence, and more rigorous information on monitoring and adverse event profiles so that clinicians and patients can be more educated when deciding whether or not to use off-label therapies. 

Dr Sivamani: We are able to use medications off-label as it allows us to expand our toolkit for helping our patients. There is a need for more education around the fact that off-label use of FDA-approved medications is different from the use of non-approved medications, in which the treatment may not be as standardized as an FDA-approved medication. Another important point is that the general public needs to be better educated on what it means to use a medication off-label and why physicians may use off-label medications. 

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References

  1. França K, Litewka S. Controversies in off-label prescriptions in dermatology: the perspective of the patient, the physician, and the pharmaceutical companies. Int J Dermatol. 2019;58(7):788-794. doi:10.1111/ijd.14222
  2. Sugarman JH, Fleischer AB Jr, Feldman SR. Off-label prescribing in the treatment of dermatologic disease. J Am Acad Dermatol. 2002;47(2):217-223 doi:org/10.1067/mjd.2002.120469
  3. Wat H, Dytoc M. Off-label uses of topical vitamin D in dermatology: a systematic review. J Cutan Med Surg. 2014;18(2):91-108. doi:.org/10.2310/7750.2013.13109
  4. Charny JW, Choi JK, James WD. Spironolactone for the treatment of acne in women, a retrospective study of 110 patients. Int J Womens Dermatol. 2017;3(2):111–115. doi:10.1016/j.ijwd.2016.12.002