TRI-Luma (Fluocinolone / Hydroquinone / Tretinoin) - Description and Clinical Pharmacology

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DESCRIPTION

TRI-LUMA® Cream (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) contains fluocinolone acetonide, USP, hydroquinone, USP, and tretinoin, USP, in a hydrophilic cream base for topical application.

Fluocinolone acetonide is a synthetic fluorinated corticosteroid for topical dermatological use and is classified therapeutically as an anti-inflammatory. It is a white crystalline powder that is odorless and stable in light.

The chemical name for fluocinolone acetonide is: (6α,11β,16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-pregna-1,-4-diene-3,20-dione.

The molecular formula is C₂₄H₃₀F₂O₆ and molecular weight is 452.50. Fluocinolone acetonide has the following structural formula:

Hydroquinone is classified therapeutically as a depigmenting agent. It is prepared from the reduction of p -benzoquinone with sodium bisulfite. It occurs as fine white needles that darken on exposure to air.

The chemical name for hydroquinone is: 1,4-benzenediol.

The molecular formula is C₆H₆O₂ and molecular weight is 110.11.

Hydroquinone has the following structural formula:

Tretinoin is all- trans -retinoic acid formed from the oxidation of the aldehyde group of retinene to a carboxyl group. It occurs as yellow to light-orange crystals or crystalline powder with a characteristic odor of ensilage. It is highly reactive to light and moisture. Tretinoin is classified therapeutically as a keratolytic.

The chemical name for tretinoin is: (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid.

The molecular formula is C₂₀H₂₈O₂ and molecular weight is 300.44.

Tretinoin has the following structural formula:

Each gram of TRI-LUMA® Cream contains Active: fluocinolone acetonide 0.01% (0.1 mg), hydroquinone 4% (40 mg), and tretinoin 0.05% (0.5 mg). Inactive: butylated hydroxytoluene, cetyl alcohol, citric acid, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid, and stearyl alcohol.

CLINICAL PHARMACOLOGY

One of the components in TRI-LUMA® Cream, hydroquinone, is a depigmenting agent, and may interrupt one or more steps in the tyrosine-tyrosinase pathway of melanin synthesis. However, the mechanism of action of the active ingredients in TRI-LUMA® Cream in the treatment of melasma is unknown.

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.

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 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%). TRI-LUMA® Cream was demonstrated to be significantly more effective than any of the other combinations of the active ingredients.

PRIMARY EFFICACY ANALYSIS:

Investigators’ Assessment of Treatment Success* At the End of 8 Weeks of Treatment

TRI-LIMA ® HQ+RA FA+RA FA+HQ

*Treatment success was defined as melasma severity score of zero (melasma lesions cleared of hyperpigmentation).

p-value is from Cochran-Mantel-Haenszel chi-square statistics controlling for pooled investigator and comparing TRI-LUMA®

Cream to the other treatment groups.

Study No. 1 Number of Patients 85 83 85 85

No. of Successes 32 12 0 3

Proportion of Successes 38% 15% 0 4%

p-value <0.001 <0.001 <0.001

Study No. 2 Number of Patients 76 75 76 76

No. of Successes 10 3 3 1

Proportion of Successes 13% 4% 4% 1%

p-value 0.045 0.042 0.005

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.

Investigators’ Assessment of Change iin Melasma Severity from Baseline to Day 56 of Treatment (combined results from studies 1 and 2)

Number (%) of Patients at Day 56 ^a

Baseline Cleared ^b Mild ^b Moderate ^b Severe ^b Missing ^b

Severity Rating N N (%) N (%) N (%) N (%) N (%)

^a Assessment based on patients with severity scores at Day 56. Percentages are based on the total number in the treatment group population.

^b Does not include patients who cleared before Day 56 or were missing from the Day 56 assessment.

TRI-LUMA® Moderate 124 36 (29) 63 (51) 18 (15) 0 (0) 7 (6%)

Cream N=161 Severe 37 6 (16) 19 (51) 9 (24) 2 (5) 1 (3%)

Assessment Scale: Cleared (melasma lesions approximately equivalent to surrounding normal skin or with minimal residual hyperpigmentation); 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. Among the 7 patients that cleared at the end of 4 weeks of treatment with TRI-LUMA® Cream at which time treatment was stopped, 3 patients maintained remission while 4 patients had relapse at the final 8th week evaluation point.

After 8 weeks of treatment with the study drug, patients entered into an open-label long-term safety study in which TRI-LUMA® CREAM was given on an as-needed basis for the treatment of melasma. The objective was to provide evidence of local and systemic safety with cumulative use of TRI-LUMA® Cream for longer than 6 months, up to one year. Patients were instructed to apply TRI-LUMA® Cream once daily at nighttime after washing their face with a mild soapless cleanser, also provided a mild moisturizer for use as needed and a sunscreen with SPF 30 for daily use, in combination with the use of protective clothing and avoidance of sunlight exposure to the face. Patients were treated daily until melasma is resolved, and then retreated when melasma recurred. The majority of patients used TRI-LUMA® for no more than two courses of treatment and these patients experienced longer remissions. Both the duration of treatment and interval of time between treatment courses decreased with increasing number of treatment courses. Additionally, 24 patients (approximately 8%) cleared of melasma without re-occurrence, for a period of one year.

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TRI-Luma (Fluocinolone Acetonide / Hydroquinone / Tretinoin) - Description and Clinical Pharmacology

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