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DESCRIPTION
ZIANA (clindamycin phosphate 1.2% and tretinoin 0.025%) Gel, is an antibiotic and retinoid combination gel product with two active ingredients. Clindamycin phosphate is a water-soluble ester of the semi-synthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent antibiotic lincomycin.
The chemical name for clindamycin phosphate is Methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-α-D-galacto-octopyranoside 2-(dihydrogen phosphate). The structural formula for clindamycin phosphate is represented below:
Clindamycin phosphate:
Molecular Formula: C18H34ClN2O8PS Molecular Weight: 504.97
Molecular Formula: C18H34ClN2O8PS Molecular Weight: 504.97
The chemical name for tretinoin is 3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid (all-trans form). The structural formula for tretinoin is represented below:
Tretinoin:
Molecular Formula: C20H28O2 Molecular Weight: 300.44
Molecular Formula: C20H28O2 Molecular Weight: 300.44
ZIANA Gel contains the following inactive ingredients: purified water USP, glycerin USP, carbomer 981 NF, methylparaben NF, polysorbate 80 NF, edetate disodium USP, citric acid USP, propylparaben NF, butylated hydroxytoluene NF, and tromethamine USP.
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CLINICAL PHARMACOLOGY
Mechanisms of Action
Clindamycin
[see Microbiology].
Tretinoin
Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation.
Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.
Pharmacokinetics
In an open-label, multiple-dose study treating 12 subjects with moderate to severe acne, the percutaneous absorption of tretinoin following 14 consecutive daily applications of approximately 4 g of ZIANA Gel was minimal. Quantifiable tretinoin plasma concentrations ranged from 1.0 to 1.6 ng/mL, with unquantifiable plasma concentrations in 50% to 92% of subjects at any given timepoint following administration. The plasma concentrations of the key tretinoin metabolites, 13- cis -retinoic acid and 4-oxo-13-cis-retinoic acid, ranged from 1.0 to 1.4 ng/mL and from 1.6 to 6.5 ng/mL, respectively. Plasma concentrations for clindamycin generally did not exceed 3.5 ng/mL, with the exception of one subject whose plasma concentration reached 13.1 ng/mL.
Microbiology
Clindamycin binds to the 50S ribosomal subunits of susceptible bacteria and prevents elongation of peptide chains by interfering with peptidyl transfer, thereby suppressing bacterial protein synthesis. Clindamycin has been shown to have in vitro activity against Propionibacterium acnes, an organism which has been associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical trials with ZIANA Gel. P acnes resistance to clindamycin has been documented. Resistance to clindamycin is often associated with resistance to erythromycin.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, mutagenicity and impairment of fertility testing of ZIANA Gel have not been performed in any species.
Clindamycin
The carcinogenicity of a 1% clindamycin phosphate gel similar to ZIANA Gel was evaluated by daily application to mice for two years. The daily doses used in this study were approximately 13 and 72 times higher than the human dose of clindamycin phosphate from ZIANA Gel, assuming complete absorption and based on a body surface area comparison. No significant increase in tumors was noted in the treated animals. For purposes of comparisons of the animal exposure to human exposure, the recommended human topical clinical dose is defined as 1 g of ZIANA Gel applied daily to a 60 kg person.
Fertility (Segment 1) studies in rats treated orally with up to 300 mg/kg/day of clindamycin (approximately 290 times the amount of clindamycin delivered from the recommended clinical dose for ZIANA Gel, based on a body surface area comparison) revealed no effects on fertility or mating ability.
Tretinoin
In two independent studies with long-term topical application of tretinoin in mice, carcinogenicity was not observed. In both studies, tretinoin was administered topically (0.025% or 0.1%) three times per week for up to two years. No carcinogenicity was observed with maximum effects of dermal amyloidosis in the basal layer of the skin.
Tretinoin has been shown to enhance photoco-carcinogenicity in properly performed specific studies, employing concurrent or intercurrent exposure to the drug and UV radiation. The contribution of clindamycin to that effect is unknown. Although the significance of these studies to humans is not clear, patients should minimize exposure to sun.
The genotoxic potential of tretinoin was evaluated in an in vitro Ames Salmonella reversion test and an in vitro chromosomal aberration assay in Chinese hamster ovary cells. Both tests were negative.
In oral Segment 1 studies in rats treated with tretinoin, the no-observed-effect-level was 2 mg/kg/day (~78 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison).
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CLINICAL STUDIES
The safety and efficacy of once daily use of ZIANA Gel for treatment of acne vulgaris were assessed in three 12-week prospective, multi-center, randomized, blinded studies in patients 12 years and older. Studies 1 and 2 were of identical design, and compared ZIANA Gel to clindamycin in the vehicle gel, tretinoin in the vehicle gel, and the vehicle gel alone. Patients with mild, moderate, or severe acne were enrolled in the studies. The co-primary efficacy variables were:
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•Mean percent change from baseline at Week 12 in
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•inflammatory lesion counts,
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•non-inflammatory lesion counts, and
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•total lesion counts
•Percent of subjects who cleared or almost cleared at Week 12 as judged by an Evaluator's Global Severity (EGS) score.
The EGS scoring scale used in all of the clinical trials for ZIANA Gel is as follows:
Grade
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Description
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Clear
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Normal, clear skin with no evidence of acne vulgaris
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Almost Clear
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Rare non-inflammatory lesions present, with rare non-inflamed papules (papules must be resolving and may be hyperpigmented, though not pink-red)
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Mild
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Some non-inflammatory lesions are present, with few inflammatory lesions (papules/pustules only; no nodulocystic lesions)
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Moderate
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Non-inflammatory lesions predominate, with multiple inflammatory lesions evident: several to many comedones and papules/pustules, and there may or may not be one small nodulo-cystic lesion
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Severe
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Inflammatory lesions are more apparent many comedones and papules/pustules, there may or may not be a few nodulocystic lesions
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Very Severe
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Highly inflammatory lesions predominate, variable number of comedones, many papules/pustules and many nodulocystic lesions
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In Study 1, a total of 1,252 patients were enrolled, and in Study 2, a total of 1,288 patients were enrolled. The combined results are presented in Table 3.
Table 3: Efficacy Results at Week 12 in Studies 1 and 2.
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ZIANA Gel
N=845
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Clindamycin
N=426
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Tretinoin
N=846
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Vehicle
N=423
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Evaluator's Global Severity: N (%)
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Patients achieving success
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180 (21%)
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70 (16%)
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122 (14%)
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34 (8%)
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Inflammatory Lesion Count (% reduction from baseline)
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Mean
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48%
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42%
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39%
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26%
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Non-inflammatory Lesion Count (% reduction from baseline)
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Mean
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36%
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27%
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31%
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16%
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Total Lesion Count (% reduction from baseline)
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Mean
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41%
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34%
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34%
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20%
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In Study 3, ZIANA Gel was compared to clindamycin gel in a total of 2,010 patients with moderate or severe acne vulgaris (see Table 3). As with Studies 1 and 2, the co-primary endpoints were mean percent reduction in lesion counts (inflammatory, non-inflammatory and total) and the Evaluator's Global Severity score. In Study 3, success on the EGS score was assessed by the percentage of subjects who had at least 2 grades of improvement from Baseline to Week 12.
Table 4: Efficacy Results at Week 12 in Study 3
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ZIANA Gel
N = 1008
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Clindamycin
N = 1002
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Evaluator's Global Severity: N (%)
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Patients achieving success
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415 (41%)
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345 (34%)
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Inflammatory Lesion Count (% reduction from baseline)
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Mean
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61%
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55%
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Non-inflammatory Lesion Count (% reduction from baseline)
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Mean
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50%
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41%
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Total Lesion Count (% reduction from baseline)
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Mean
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54%
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47%
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