National report — The Food and Drug Administration (FDA) has given notice that it is proposing to ban hydroquinone-containing products by year end.
In the Federal Register, the FDA proposed rule that would establish that over-the-counter (OTC) "skin bleaching drug products" are not generally recognized as safe and effective (GRASE) and are misbranded. If finalized, the rule would lead to a ban of all hydroquinone-containing products — both OTC and prescription — with the exception of TriLuma Cream (fluocinolone acetonide 0.01 percent, hydroquinone 4 percent, tretinoin 0.05 percent, Galderma Laboratories).
The banned products would be considered new drugs requiring an approved new drug application (NDA) for continued marketing. TriLuma Cream would be exempt because it is the only commercially available hydroquinone-containing product with an approved NDA.In issuing the proposed rule, the FDA cited new data and information on the safety of hydroquinone. Specifically, risks of ochronosis with even low concentrations (1 percent to 2 percent) and carcinogenicity in preclinical models are mentioned.
The FDA is accepting comments on the proposed rule through December 27, 2006. Thereafter, the agency is expected to deliberate over a period of 120 days before making a final ruling. If the verbiage in the proposal is unchanged, the result would be prohibition of the distribution of all outlined products within 30 days after Federal Register publication of the final rule — or as early as April, 2007.
Physicians who are informed about the safety of hydroquinone and recognize its clinical importance as the gold standard for the management of hyperpigmentation are concerned about the impact of the proposed rule and are urging their colleagues to take action.
Pearl Grimes, M.D., director, Vitiligo and Pigmentation Institute of Southern California, Los Angeles, has undertaken a comprehensive review of the safety of hydroquinone and recently coauthored a paper on that topic with James Nordlund, M.D., and Jean-Paul Ortonne, M.D. [J Eur Acad Dermatol Venereol 2006;20:781-787]. Dr. Grimes believes the current database, encompassing 56 years of clinical experience and including data from a host of clinical studies, suggests the benefits of hydroquinone outweigh its risks.
"If these polices are implemented, access to hydroquinone will be greatly reduced, and we can expect that the time and cost involved in preparing an NDA will prohibit many manufacturers from seeking FDA approval for this older, non-patented medication. As a result, patients will suffer," says Dr. Grimes, who is also clinical professor of dermatology, David Geffen School of Medicine, University of California, Los Angeles.
Amit G. Pandya, M.D., professor of dermatology, University of Texas Southwestern Medical Center, Dallas, agrees that finalization of the proposed rule will be to the detriment of patients.
"Fortunately, we will still have TriLuma Cream available. However, many patients with mild hyperpigmentation respond well to an OTC product containing a lower concentration. It will be a loss if they do not have access to the non-prescription or other prescription hydroquinone alternatives — especially considering that alternatives used in OTC products for skin lightening, including kojic acid and glycolic acid — are not as effective as hydroquinone," he says.
History of safety concerns
The proposed rule from the FDA was the result of its ongoing review of OTC drug products.
In 1978, the FDA published a notice of proposed rulemaking to establish a monograph for OTC skin bleaching drug products, and on Sept. 3, 1982, a tentative final monograph was published (47 FR 39108).
In that early document, the FDA proposed that hydroquinone at concentrations of 1.5 percent to 2 percent be categorized as GRASE as an active ingredient in OTC skin bleaching drug products. (Manufacturers of hydroquinone products in strengths above 2 percent began marketing their products as prescription drugs to comply with the tentative final monograph.)
Meanwhile, studies of the safety of hydroquinone have been underway at the Environmental Protection Agency since 1979, and concerns about carcinogenicity were raised by National Toxicology Program studies reported in 1989 and 1992.