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Acanya (Benzoyl Peroxide / Clindamycin Phosphate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ACANYA (clindamycin phosphate and benzoyl peroxide) Gel, 1.2%/2.5% is a combination product with two active ingredients in an aqueous gel formulation intended for topical use. 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

Benzoyl peroxide is an antibacterial and keratolytic agent. The structural formula for benzoyl peroxide is represented below:

Benzoyl peroxide:

Molecular Formula: C14H10O4          Molecular Weight: 242.23

ACANYA Gel contains the following inactive ingredients: purified water, carbomer 980, propylene glycol, and potassium hydroxide. Each gram of ACANYA Gel contains 1.2% of clindamycin phosphate which is equivalent to 1% clindamycin.

CLINICAL PHARMACOLOGY

Mechanisms of Action

Clindamycin: Clindamycin is a lincosamide antibacterial [see Microbiology ].

Benzoyl Peroxide: Benzoyl peroxide is an oxidizing agent with bacteriocidal and keratolytic effects but the precise mechanism of action is unknown.

Pharmacokinetics

The systemic absorption of clindamycin was investigated in an open-label, multiple-dose trial in 16 adult subjects with moderate to severe acne vulgaris treated with 1 gram of ACANYA Gel applied to the face once daily for 30 days. Twelve subjects (75%) had at least one quantifiable clindamycin plasma concentration above the lower limit of quantification (LOQ = 0.5 ng/mL) on Day 1 or Day 30. On Day 1, the mean (± standard deviation) peak plasma concentrations (Cmax) was 0.78 ± 0.22 ng/mL (n=9 with measurable concentrations), and the mean AUC0-t was 5.29 ± 0.81 h.ng/mL (n=4). On Day 30, the mean Cmax was 1.22 ± 0.88 ng/mL (n=10), and the mean AUC0-t was 8.42 ± 6.01 h.ng/mL (n=6). Clindamycin plasma concentrations were below LOQ in all subjects at 24 hours post-dose on the three tested days (Day 1, 15, and 30).

Benzoyl peroxide has been shown to be absorbed by the skin where it is converted to benzoic acid.

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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity and impairment of fertility testing of ACANYA Gel 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 amount of clindamycin and 3.6, 10.8, and 60 times amount of benzoyl peroxide in the highest recommended adult human dose of 2.5 g ACANYA Gel based on mg/m2, respectively) 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 amount of clindamycin and 2.4, 7.2, and 24 times amount of benzoyl peroxide in the highest recommended adult human dose of 2.5 g ACANYA Gel based on mg/m2, respectively) for up to 97 weeks did not cause any increase in tumors. In a 52-week dermal photocarcinogenicity study in hairless mice, (40 weeks of treatment followed by 12 weeks of observation), the median time to onset of skin tumor formation decreased and the number of tumors per mouse increased relative to controls following chronic concurrent topical administration of the higher concentration benzoyl peroxide formulation (5000 and 10000 mg/kg/day, 5 days/week) and exposure to ultraviolet radiation.

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 ACANYA Gel 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 amount of clindamycin in the highest recommended adult human dose of 2.5 g ACANYA Gel, based on mg/m2) revealed no effects on fertility or mating ability.

CLINICAL STUDIES

The safety and efficacy of once daily use of ACANYA Gel 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 ACANYA Gel 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 two grade improvement from baseline on an Evaluator's Global Severity (EGS) score.

The EGS scoring scale used in all of the clinical trials for ACANYA Gel 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

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

Table 2: Trial 1 Results
Trial 1 ACANYA
Gel
Clindamycin
Gel
Benzoyl
Peroxide
Gel
Vehicle
Gel
N = 399 N = 408 N = 406 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 ACANYA
Gel
Clindamycin Gel Benzoyl
Peroxide
Gel
Vehicle Gel
N = 398 N = 404 N = 403 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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