PracticalDermatology

In March 2020, The CARES Act was passed to continue to aid response efforts and ease the economic impact of COVID-19. But in addition to COVID-19 relief, the bill included the OTC Drug Monogragh Reform Act, which made significant changes to the way certain over-the-counter (OTC) drugs, including OTC hydroquinone, are regulated in the US.

In 1972, the FDA established an over-the-counter drug review process. The OTC Drug Review established conditions under which OTC drugs were generally recognized as safe and effective (GRASE) and not misbranded. These GRASE conditions were described in OTC drug monographs for each OTC therapeutic drug class. Drugs on the market were classified into one of three categories: Category I: generally recognized as safe and effective (GRASE) and not misbranded; Category II: not GRASE; Category III: lacking sufficient data on safety and efficacy to permit classification.

Some categories of OTC drugs, including hydroquinone and sunscreens, were marketed for years without a final monograph. In 2006, the FDA issued a notice of proposed rulemaking that would establish that OTC skin bleaching drug products as not generally recognized as safe and effective (GRASE) and misbranded. The notice included reports of new data that indicated “some evidence” of carcinogenicity in male and female rats and in female mice and indicated that more studies were needed to rule out risk of topical hydroquinone to humans. The FDA also reported that hydroquinone has been shown to cause disfiguring effects (ochronosis) after unmonitored, long-term use of concentrations as low as 1 to 2%.

Although hydroquinone-containing product classification remained in limbo and products continued to be marketed for years under the non-final OTC monograph proceedings for OTC skin bleaching drug products, as part of the CARES Act, a final monograph determination was made based on the 2006 proposal that hydroquinone products be classified as Category II. Therefore, all OTC hydroquinone products had to be removed from the market on September 23, 2020.

Many physicians and manufacturers were initially caught off guard by the legislation that was buried in the CARES Act. Now that OTC hydroquinone products have been unavailable for a little more than a year, Practical Dermatology® magazine talked to Seemal R. Desai, MD, FAAD, clinical assistant professor of dermatology at the University of Texas Southwestern Medical Center and the Founder of Innovative Dermatology in Dallas, TX, about the effects on consumers, patients, and dermatologists, and concerns about access to care.

How has the removal of OTC hydroquinone affected patient access to hydroquinone?

Dr. Desai: The good news is that patients still have access to seeing a board-certified dermatologist and getting hydroquinone as a prescription option, and that has not changed. (TriLuma [fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%, Galderma]—the only prescription hydroquinone-containing formulation to have come to market under an NDA—remains available on the market.) But I do think that the limitation of OTC hydroquinone has been detrimental to our patients.

The regulation of hydroquinone in 2020 due to the CARES Act really affected the access to OTC hydroquinone. To me, that’s an access issue, because we know that there are so many patients who don’t come to see a dermatologist, but who suffer from hyperpigmentation. And there were formulations of low-potency hydroquinone available over-the-counter that can help these patients do really well.

Many patients, especially patients with skin of color and underrepresented minority patients, do have access to care issues. And when you’re dealing with access to care issues, we must be aware that these nuances are real. We have to make sure that the right treatments are available for the right indication. In my opinion, there were over-the-counter formulations that did benefit our patients. For example, a patient who didn’t have insurance, didn’t have access to a dermatologist, didn’t want to wait six months for an appointment, and didn’t have the ability to pay a co-pay or buy an expensive prescription, but whose pigmentary disease issue or brown spots were not super severe—an over-the-counter option could have benefited that patient.

Some may argue, “Oh, it’s good, because it puts the prescription in our hands as the dermatologists. Patients must come see us. And then you don’t have safety issues.” Keep in mind that over-the-counter hydroquinone concentrations were usually 1% to 2% in these lightening creams, so they were very low concentrations. And in general, those very low concentrations were well-tolerated. Yes, there can be adverse events with hydroquinone, the most concerning of which is the development of ochronosis, which is a paradoxical side effect of hydroquinone. And yes, that theoretically could be seen at any concentration of hydroquinone. It’s usually seen at the higher concentrations and with prolonged use of those higher concentrations. The OTC formulations really were exceedingly well tolerated and usually did not cause adverse events.

I especially think that during the COVID pandemic, this was a really bad thing, because people couldn’t come see us. People couldn’t get appointments, let alone even get prescriptions. And we’ve also seen some shortages at the compounding pharmacy level, with certain topical prescription lightening ingredients. Again, when it comes to an access issue, just having one source where you can get hydroquinone in general, which is at the pharmacy level, led to some challenges.

Are there safety concerns or worries that patients will try to find hydroquinone overseas or through other means?

Dr. Desai: Absolutely. The other problem with over-the-counter hydroquinone getting pulled from the US market is that patients now have access to buying bleaching creams from overseas, which can contain very high levels of hydroquinone—8%, 10%. And some of these over-the-counter creams that aren’t regulated in some countries also contain mercury and arsenic-like extracts. I think the lack of access to OTC here can be a potential driver for patients buying products that are even more unsafe than these low concentrations that we have in the US.

Skin bleaching has become a major issue.¹ In many countries around the world, skin lightening and skin bleaching is multi-billion dollar industry that contains the high concentrations of hydroquinone, and even topical steroids, mercury, and arsenic extract containing products for skin fairness and lightening, which can be very, very toxic. Skin lightening agents can be used to effectively treat hyperpigmentation disorders, but excessive skin bleaching practices are harmful to our patients and to the society. We need to change the messaging that that propagates the idea that lighter skin is more beautiful skin.

It’s really on us as the dermatologist, as the doctor, to educate our patients about the dangers of purchasing these skin lightening and bleaching products overseas.

What is the next step? Are there advocacy efforts underway to bring OTC hydroquinone back to the market?

Dr. Desai: Yes, there is advocacy happening to the FDA. The problem is this is an OTC-based issue. It’s not a prescription-based issue. We really need the OTC companies that manufacture these products to help lead the charge with industry advocacy with physician experts involved. Physician advocacy alone is not going to be enough on this.

Has this changed the way you talk to patients about hydroquinone treatment? Has this caused an increase in concern about the safety of hydroquinone?

Dr. Desai: When my patients come to me, I talk to them about prescription therapy. We don’t typically have a discussion about over-the-counter except to say I definitely don’t want them buying lightening and bleaching creams online, especially if they have ingredients that I’m not aware of. So anytime a patient asks me if they can buy this item online because they’ve seen it there, I explain that the first thing is we need to examine the ingredients and the ingredient profile. I do a lot of education around ingredient safety and ingredient awareness. I typically put my patients on my prescription regimen. It definitely requires a lot of counseling and a lot of education for patients who are suffering from hyperpigmentation, because many of these patients are desperate.

1. Desai SR, Khanna R. The skin bleaching epidemic: Reply to “Regulation of skin lightening agents in the United States and implications for public health”. J Am Acad Dermatol. 2021 Aug 23:S0190-9622(21)02363-X.