ACZONE (Page 3 of 4)
ACZONE Gel, 5%, contains dapsone, a sulfone, in an aqueous gel base for topical dermatologic use. ACZONE Gel, 5% is a gritty translucent material with visible drug substance particles. Chemically, dapsone has an empirical formula of C12 H12 N2 O2 S. It is a white, odorless crystalline powder that has a molecular weight of 248. Dapsone’s chemical name is 4,4’-diaminodiphenylsulfone and its structural formula is:
Each gram of ACZONE Gel, 5%, contains 50 mg of dapsone, USP, in a gel of carbomer homopolymer type C; diethylene glycol monoethyl ether, NF; methylparaben, NF; sodium hydroxide, NF; and purified water, USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of dapsone gel in treating acne vulgaris is not known.
An open-label study compared the pharmacokinetics of dapsone after ACZONE Gel, 5%, (110 ± 60 mg/day) was applied twice daily (~BSA 22.5%) for 14 days (n=18) with a single 100 mg dose of oral dapsone administered to a subgroup of patients (n=10) in a crossover design. On Day 14 the mean dapsone AUC0-24h was 415 ± 224 ng•h/mL for ACZONE Gel, 5%, whereas following a single 100 mg dose of oral dapsone the AUC0-infinity was 52,641 ± 36,223 ng•h/mL. Exposure after the oral dose of 100 mg dapsone was approximately 100 times greater than after the topical ACZONE Gel, 5% dose, twice a day.
In a long-term safety study of ACZONE Gel, 5% treatment, periodic blood samples were collected up to 12 months to determine systemic exposure of dapsone and its metabolites in approximately 500 patients. Based on the measurable dapsone concentrations from 408 patients (M=192, F=216), obtained at month 3, neither gender, nor race appeared to affect the pharmacokinetics of dapsone. Similarly, dapsone exposures were approximately the same between the age groups of 12-15 years (N=155) and those greater than or equal to 16 years (N=253). There was no evidence of increasing systemic exposure to dapsone over the study year in these patients.
In VivoActivity: No microbiology or immunology studies were conducted during dapsone gel clinical trials.
Drug Resistance: No dapsone resistance studies were conducted during dapsone gel clinical trials. Because no microbiology studies were done, there are no data available as to whether dapsone treatment may have resulted in decreased susceptibility of Propionibacterium acnes , an organism associated with acne, to other antimicrobials that may be used to treat acne. Therapeutic resistance to dapsone has been reported for Mycobacterium leprae , when patients have been treated with oral dapsone.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Dapsone was not carcinogenic to rats when orally administered to females for 92 weeks or males for 100 weeks at dose levels up to 15 mg/kg/day (approximately 231 times the systemic exposure observed in humans as a result of use of the MRHD of ACZONE Gel, 5%, based on AUC comparisons).
No evidence of potential to induce carcinogenesis was observed in a dermal study in which dapsone gel was topically applied to Tg.AC transgenic mice for approximately 26 weeks. Dapsone concentrations of 3%, 5%, and 10% were evaluated; 3% material was judged to be the maximum tolerated dosage.
Dapsone was negative in a bacterial reverse mutation assay (Ames test), and was negative in a micronucleus assay conducted in mice. Dapsone was positive (clastogenic) in a chromosome aberration assay conducted with Chinese hamster ovary (CHO) cells.
The effects of dapsone on fertility and general reproductive performance were assessed in male and female rats following oral dosing. Dapsone reduced sperm motility at dosages of 3 mg/kg/day or greater (approximately 15 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 5%, based on AUC comparisons) when administered daily beginning 63 days prior to mating and continuing through the mating period. The mean numbers of embryo implantations and viable embryos were significantly reduced in untreated females mated with males that had been dosed at 12 mg/kg/day or greater (approximately 127 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 5%, based on AUC comparisons), presumably due to reduced numbers or effectiveness of sperm, indicating impairment of fertility. When administered to female rats at a dosage of 75 mg/kg/day (approximately 956 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 5%, based on AUC comparisons) for 15 days prior to mating and for 17 days thereafter, dapsone reduced the mean number of implantations, increased the mean early resorption rate, and reduced the mean litter size. These effects probably were secondary to maternal toxicity.
14 CLINICAL STUDIES
Two randomized, double-blind, vehicle-controlled, clinical trials were conducted to evaluate ACZONE Gel, 5%, for the treatment of subjects with acne vulgaris (N=1475 and 1525). The trials were designed to enroll subjects 12 years of age and older with 20 to 50 inflammatory and 20 to 100 non-inflammatory lesions at baseline. In these trials, subjects applied either ACZONE Gel, 5%, or vehicle control twice daily for up to 12 weeks. Efficacy was evaluated in terms of success on the Global Acne Assessment Score (no or minimal acne) and in the percent reduction in inflammatory, non-inflammatory, and total lesions.
The Global Acne Assessment Score was a 5-point scale as follows:
0 None: no evidence of facial acne vulgaris
1 Minimal: few non-inflammatory lesions (comedones) are present; a few inflammatory lesions
(papules/pustules) may be present
2 Mild: several to many non-inflammatory lesions (comedones) are present; a few inflammatory lesions
(papules/pustules) are present
3 Moderate: many non-inflammatory (comedones) and inflammatory lesions (papules/pustules) are present; no
nodulo-cystic lesions are allowed
4 Severe: significant degree of inflammatory disease; papules/pustules are a predominant feature; a few
nodulo-cystic lesions may be present; comedones may be present.
The success rates on the Global Acne Assessment Score (no or minimal acne) at Week 12 are presented in Table 4.
|Study 1*||Study 2*|
|ACZONE N=699||VehicleN=687||ACZONE N=729||VehicleN=738|
|Subjects with No or Minimal Acne||291 (42%)||223 (32%)||253 (35%)||206 (28%)|
*Analysis excludes subjects classified with minimal acne at baseline
Table 5 presents the mean percent reduction in inflammatory, non-inflammatory, and total lesions from baseline to Week 12.
|Study 1||Study 2|
|ACZONE N=745||VehicleN=740||ACZONE N=761||VehicleN=764|
The clinical trials enrolled about equal proportions of male and female subjects. Female subjects tended to have greater percent reductions in lesions and greater success on the Global Acne Assessment Score than males. The breakdown by race in the clinical trials was about 73% Caucasian, 14% Black, 9% Hispanic, and 2% Asian. Efficacy results were similar across the racial subgroups.
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