Clindamycin Phosphate and Benzoyl Peroxide (Page 3 of 5)

12.4 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 and benzoyl peroxide individually have 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 is not known.

P. acnes resistance to clindamycin has been documented. Resistance to clindamycin is often associated with resistance to erythromycin.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and impairment of fertility testing of Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/2.5% have not been performed.

Benzoyl peroxide has been shown to be a tumor promoter and progression agent in a number of animal studies. Benzoyl peroxide in acetone at doses of 5 and 10 mg administered topically twice per week for 20 weeks induced skin tumors in transgenic Tg.AC mice. The clinical significance of this is unknown.

Carcinogenicity studies have been conducted with a gel formulation containing 1% clindamycin and 5% benzoyl peroxide. In a 2-year dermal carcinogenicity study in mice, treatment with the gel formulation at doses of 900, 2700, and 15000 mg/kg/day (1.8, 5.4, and 30 times the MRHD for clindamycin and 3.6, 10.8, and 60 times the MRHD for benzoyl peroxide, respectively, based on BSA comparisons) did not cause any increase in tumors. However, topical treatment with a different gel formulation containing 1% clindamycin and 5% benzoyl peroxide at doses of 100, 500, and 2000 mg/kg/day caused a dose-dependent increase in the incidence of keratoacanthoma at the treated skin site of male rats in a 2-year dermal carcinogenicity study in rats. In an oral (gavage) carcinogenicity study in rats, treatment with the gel formulation at doses of 300, 900, and 3000 mg/kg/day (1.2, 3.6, and 12 times the MRHD for clindamycin and 2.4, 7.2, and 24 times the MRHD for benzoyl peroxide, respectively, based on BSA comparisons) for up to 97 weeks did not cause any increase in tumors.

Clindamycin phosphate was not genotoxic in the human lymphocyte chromosome aberration assay. Benzoyl peroxide has been found to cause DNA strand breaks in a variety of mammalian cell types, to be mutagenic in S. typhimurium tests by some but not all investigators, and to cause sister chromatid exchanges in Chinese hamster ovary cells.

Fertility studies have not been performed with Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/2.5% or benzoyl peroxide, but fertility and mating ability have been studied with clindamycin. Fertility studies in rats treated orally with up to 300 mg/kg/day of clindamycin (approximately 120 times the MRHD for clindamycin, based on BSA comparisons) revealed no effects on fertility or mating ability.

14 CLINICAL STUDIES

The safety and efficacy of once daily use of clindamycin phosphate and benzoyl peroxide gel, 1.2%/2.5% were assessed in two 12-week multi-center, randomized, blinded trials in subjects 12 years and older with moderate to severe acne vulgaris. The two trials were identical in design and compared clindamycin phosphate and benzoyl peroxide gel, 1.2%/2.5% to clindamycin in the vehicle gel, benzoyl peroxide in the vehicle gel, and the vehicle gel alone.

The co-primary efficacy variables were:

(1) Mean absolute change from baseline at Week 12 in:

Inflammatory lesion counts
Non-inflammatory lesion counts

(2) Percent of subjects who had a 2-grade improvement from baseline on an Evaluator’s Global Severity (EGS) score.

The EGS scoring scale used in all of the clinical trials for clindamycin phosphate and benzoyl peroxide gel, 1.2%/2.5% 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 nodulocystic 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

The results of Trial 1 at Week 12 are presented in Table 2:

Table 2: Trial 1 Results

Trial 1

Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/2.5%

N=399

Clindamycin Gel

N=408

Benzoyl Peroxide Gel

N=408

Vehicle Gel

N=201

EGSS Clear or Almost Clear

115 (29%)

84 (21%)

76 (19%)

29 (14%)

2-grade reduction from baseline

131 (33%)

100 (25%)

96 (24%)

38 (19%)

Inflammatory

Lesions:

Mean

absolute change

14.8

12.2

13.0

9.0

Mean

percent (%)

reduction

55.0%

47.1%

49.3%

34.5%

Non-Inflammatory Lesions:

Mean

absolute

change

22.1

17.9

20.6

13.2

Mean

percent (%)

reduction

45.3%

38.0%

40.2%

28.6%

The results of Trial 2 at Week 12 are presented in Table 3:

Table 3: Trial 2 Results

Trial 2

Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/2.5%

N=398

Clindamycin Gel

N=404

Benzoyl Peroxide Gel

N=403

Vehicle Gel

N=194

EGSS Clear or Almost Clear

113 (28%)

94 (23%)

94 (23%)

21 (11%)

2-grade reduction from baseline

147 (37%)

114 (28%)

114 (28%)

27 (14%)

Inflammatory

Lesions:

Mean

absolute change

13.7

11.3

11.2

5.7

Mean

percent (%)

reduction

54.2%

45.3%

45.7%

23.3%

Non-Inflammatory Lesions:

Mean

absolute

change

19.0

14.9

15.2

8.3

Mean

percent (%)

reduction

41.2%

34.3%

34.5%

19.2%

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