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Clinical Studies: Two adequate and well-controlled efficacy and safety studies were conducted in 641 patients between the ages of 21 to 75 years, having skin phototypes I-IV and moderate to severe melasma of the face. TRI-LUMA Cream was compared with the 3 possible combinations of 2 of the 3 active ingredients [(1) hydroquinone 4% (HQ) + tretinoin 0.05% (RA); (2) fluocinolone acetonide 0.01% (FA) + tretinoin 0.05% (RA); (3) fluocinolone acetonide 0.01% (FA) + hydroquinone 4% (HQ)], contained in the same vehicle as TRI-LUMA Cream. Patients were instructed to apply their study medication each night, after washing their face with a mild soapless cleanser, for 8 weeks. Instructions were given to apply a thin layer
of study medication to the hyperpigmented lesion, making sure to cover the entire lesion including the outside borders extending to the normal pigmented skin. Patients were provided a mild moisturizer for use as needed. A sunscreen with SPF 30 was also provided with instructions for daily use. Protective clothing and avoidance of sunlight exposure to the face was recommended. Patients were evaluated for melasma severity at Baseline and at Weeks 1 ,2, 4, and 8 of treatment. Primary efficacy was based on the proportion of patients who had an investigators' assessment of treatment success, defined as the clearing of melasma at the end of the eight-week treatment period. The majority of patients enrolled in the two studies were white (approximately 66%) and female (approximately 98%). TRILUMA Cream was demonstrated to be significantly more effective than any of the other combinations of the active ingredients. (See Table 1.)
Click on icon to see table/diagram/imagep-value is from Cochran-Mantel-Haenszel chi-square statistics controlling for pooled investigator and comparing TRI-LUMA Cream to the other treatment groups. In the Investigators' assessment of melasma severity at Day 56 of treatment, the following table shows the clinical improvement profile for all patients treated with TRI-LUMA Cream based on severity of their melasma at the start of treatment. (See Table 2.)
Click on icon to see table/diagram/imageAssessment Scale: Cleared (melasma lesions approximately equivalent to surrounding normal skin or with minimal residual hyper-pigmentation); Mild (slightly darker than the surrounding normal skin); Moderate (moderately darker than the surrounding normal skin); Severe (markedly darker than the surrounding normal skin). Patients experienced improvement of their melasma with the use of TRI-LUMA Cream as early as 4 weeks. However, among 7 patients who had clearing at the end of 4 weeks of treatment with TRI-LUMA Cream, 4 of them did not maintain the remission after an additional 4 weeks of treatment.
After 8 weeks of treatment with the study drug, patients entered into an open-label extension period in which TRI-LUMA Cream was given on an as-needed basis for the treatment of melasma. The remission periods appeared to shorten between progressive courses of treatment. Additionally, few patients maintained complete clearing of melasma (approximately 1 to 2%).
Pharmacokinetics: Percutaneous absorption of unchanged tretinoin, hydroquinone and fluocinolone acetonide into the systemic circulation of two groups of healthy volunteers (Total n = 59) was found to be minimal following 8 weeks of daily application of 1g (Group I, n = 45) or 6g (Group II, n = 14) of TRI-LUMA Cream.
For tretinoin, quantifiable plasma concentrations were obtained in 57.78% (26 out of 45) of Group I and 57.14% (8 out of 14) of Group II subjects. The exposure to tretinoin as reflected by the Cmax values ranged from 2.01 to 5.34 ng/mL (Group I) and 2.0 to 4.99 ng/mL (Group II). Thus, daily application of TRI-LUMA Cream resulted in a minimal increase of normal endogenous levels of tretinoin. The circulating tretinoin levels represent only a portion of total tretinoin-associated retinoids, which would include metabolites of tretinoin and that sequestered into peripheral tissues.
For hydroquinone, quantifiable plasma concentrations were obtained in 18% (8 out of 44) Group I subjects. The exposure to hydroquinone as reflected by the Cmax values ranged from 25.55 to 86.52 ng/mL. All Group II subjects (6g dose) had post-dose plasma hydroquinone concentrations below the quantitation limit. For Fluocinolone acetonide, Groups I and II subjects had all post-dose plasma concentrations below quantitation limit.
