Comparison of a Skin-Lightening Cream Targeting Melanogenesis on Multiple Levels to Triple Combination Cream for Melasma

March 2013 | Volume 12 | Issue 3 | Original Article | 270 | Copyright © March 2013

Gary D. Monheit MDa and Frank Dreher PhDb

aTotal Skin & Beauty Dermatology Center, Birmingham, AL bNeocutis Inc, San Francisco, CA

The safety and efficacy of a novel skin-lightening cream (SLC) with 4% hydroquinone (HQ), which additionally contains 4 skin-brightening actives, was compared with a triple combination cream (TCC) with 4% HQ, 0.05% tretinoin, and 0.01% fluocinolone acetonide for the treatment of melasma under measures of sun protection. The study was a randomized, investigator-blinded, split-face study including 20 Caucasian females with at least mild epidermal or mixed melasma. Evaluations were made before treatment, after 4 and 8 weeks, and after 12 weeks at the end of the once-daily treatment period with the creams. The evaluations included the investigator's tolerability assessments, the Investigator's Global Assessment, the Melasma Area and Severity Index (MASI), and a participant questionnaire. Under the conditions of the present study, the SLC was comparable in both efficacy and tolerability with the well-established TCC treatment for facial melasma. The MASI reduction became significant for both creams after 4 weeks and reached -77% for SLC and -79% for TCC cream after 12 weeks of once-daily use under measures of sun protection. None of the subjects discontinued treatment because of an intolerability or adverse event. About one-third of the subjects experienced at least one local intolerability (eg, erythema, dryness, or peeling) with both creams over the entire study period, while the remaining subjects did not experience any intolerabilities.

J Drugs Dermatol. 2013;12(3):270-274.


Melasma is one of the most common disorders of skin hyperpigmentation.1 It presents as irregular brown, tan, or gray macules on sun-exposed skin. It appears most frequently in women, although approximately 10% of cases occur in men; and while it occurs in all skin types, it is most common in darker skin types. Although the pathogenesis of melasma is not fully understood, both sun exposure and female hormones— either endogenous in the setting of pregnancy or exogenous in the form of oral contraceptives or hormone replacement therapy—are important contributors.
In addition to limiting sun exposure through sun avoidance and sunscreen use, commonly available topical melasma treatments include hydroquinone (HQ) alone or in combination with retinoids and corticosteroids, as well as kojic acid, arbutin, azelaic acid, and other agents.2-4 Another method of lightening hyperpigmentation is with exfoliating agents such as α-hydroxy acids (AHAs) or other peeling agents, including trichloroacetic acid (TCA), but clinical response may be unsatisfactory, and some of these methods may be significantly irritating.4
In 1975, Kligman and Willis proposed a triple combination formulation containing 5% HQ, 0.1% tretinoin, and 0.1% dexamethasone for treating melasma, which was shown to be effective in treating epidermal melasma after 5 to 7 weeks of daily use.5 The authors noted that this combination appeared additive, since efficacy decreased with the omission of any of the 3 components. In 2003, a triple combination cream (TCC) based on the Kligman-Willis formulation was approved in the United States for melasma. It contained 4% HQ, 0.05% tretinoin, and 0.01% fluocinolone acetonide, a moderate-potency steroid. In 2 randomized, multicenter, investigator-blinded studies with a population of 641 patients with moderate to severe melasma, TCC produced a complete clearing of melasma in 26.1% of patients by week 8.6 As with the Kligman-Willis formulation, it was shown that combinations of 2 of its components were less effective than TCC in achieving clearing. In addition to its high efficacy, TCC was shown to be safe and well tolerated.
More recently, a split-face, investigator-blinded, 12-week study by Grimes compared the efficacy and tolerability of 3 commercially available creams containing 4% HQ in the treatment of melasma.7 The test creams included TCC; a cream containing microencapsulated HQ, 0.15% retinol, and antioxidants; and a cream containing HQ with 0.3% retinol and antioxidants. In one treatment arm, twice-daily microencapsulated HQ/0.15% retinol was compared with twice-daily HQ/0.3% retinol. In the other treatment arm, once-daily TCC was compared with twice-daily microencapsulated HQ/0.15% retinol. The authors concluded that once-daily TCC produced equal or superior efficacy to the other 4% HQ creams that were used twice daily.
HQ as monotherapy or in combination has been considered the gold standard for the treatment of hyperpigmentation.8 However, in 2006, the US Food and Drug Administration (FDA) proposed that all HQ skin-lightening products, whether pre-