Ziana Gel

Ziana Gel

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 (clindamycin phosphate, tretinoin) 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 (clindamycin phosphate, tretinoin) . 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 (clindamycin phosphate, tretinoin) have not been performed in any species.

Clindamycin

The carcinogenicity of a 1% clindamycin phosphate gel similar to ZIANA Gel (clindamycin phosphate, tretinoin) 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 (clindamycin phosphate, tretinoin) , 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 (clindamycin phosphate, tretinoin) 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 (clindamycin phosphate, tretinoin) , 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).

CLINICAL STUDIES

The safety and efficacy of once daily use of ZIANA Gel (clindamycin phosphate, tretinoin) 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 (clindamycin phosphate, tretinoin) 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:

(1) Mean percent change from baseline at Week 12 in

  • inflammatory lesion counts,
  • non-inflammatory lesion counts, and
  • total lesion counts

(2) 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 (clindamycin phosphate, tretinoin) is as follows:


Grade Description
Clear Normal, clear skin with no evidence of acne vulgaris
Almost Clear Rare non-inflammatory lesions present, with rare non-inflamed papules (papules must be resolving and may be hyperpigmented, though not pink-red)
Mild Some non-inflammatory lesions are present, with few inflammatory lesions (papules/pustules only; no nodulocystic lesions)
Moderate 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
Severe Inflammatory lesions are more apparent many comedones and papules/pustules, there may or may not be a few nodulocystic lesions
Very Severe Highly inflammatory lesions predominate, variable number of comedones, many papules/pustules and many nodulocystic lesions

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.

  ZIANA
Gel
N=845
Clindamycin
N=426
Tretinoin
N=846
Vehicle
N=423
Evaluator's Global Severity: N (%)
Patients 180 70 122 34
achieving success* (21%) (16%) (14%) (8%)
Inflammatory Lesion Count (% reduction from baseline)
Mean 48% 42% 39% 26%
Non-inflammatory Lesion Count (%reduction from baseline)
Mean 36% 27% 31% 16%
Total Lesion Count (% reduction from baseline)
Mean 41% 34% 34% 20%

* Success was defined as cleared or almost cleared at Week 12

In Study 3, ZIANA Gel (clindamycin phosphate, tretinoin) 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

  ZIANA Gel
N = 1008
Clindamycin
N = 1002
Evaluator's Global Severity: N (%)
Patients achieving success* 415 (41%) 345 (34%)
Inflammatory Lesion Count (% reduction from baseline)
Mean 61% 55%
Non-inflammatory Lesion Count (% reduction from baseline)
Mean 50% 41%
Total Lesion Count (% reduction from baseline)
Mean 54% 47%

* Success was defined as at least a 2-grade improvement at Week 12 from baseline.

Last reviewed on RxList: 3/22/2007
This monograph has been modified to include the generic and brand name in many instances.

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