VELTIN (Page 3 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of VELTIN Gel or the effect of VELTIN Gel on fertility. VELTIN Gel was negative for mutagenic potential when evaluated in an in vitroAmes Salmonella reversion assay. VELTIN Gel was equivocal for clastogenic potential in the absence of metabolic activation when tested in an in vitrochromosomal aberration assay.

Clindamycin: Once-daily dermal administration of 1% clindamycin as clindamycin phosphate in the gel vehicle (32 mg/kg/day, 13 times the recommended clinical dose based on body surface area comparison) to mice for up to 2 years did not produce evidence of tumorigenicity.

Fertility studies in rats treated orally with up to 300 mg/kg/day of clindamycin (240 times the recommended clinical dose based on body surface area comparison) revealed no effects on fertility or mating ability.

Tretinoin: In 2 independent mouse studies where tretinoin was administered topically (0.025% or 0.1%) 3 times per week for up to 2 years no carcinogenicity was observed, with maximum effects of dermal amyloidosis. However, in a dermal carcinogenicity study in mice, tretinoin applied at a dose of 5.1 mcg (1.4 times the recommended clinical dose based on body surface area comparison) 3 times per week for 20 weeks acted as a weak promoter of skin tumor formation following a single application of dimethylbenz[α]anthracene (DMBA).

In a study in female SENCAR mice, papillomas were induced by topical exposure to DMBA followed by promotion with 12-O-tetradecanoylphorbol-13-acetate or mezerein for up to 20 weeks. Topical application of tretinoin prior to each application of promoting agent resulted in a reduction in the number of papillomas per mouse. However, papillomas resistant to topical tretinoin suppression were at higher risk for pre-malignant progression.

Tretinoin has been shown to enhance photocarcinogenicity in properly performed specific studies, employing concurrent or intercurrent exposure to tretinoin and UV radiation. The photocarcinogenic potential of the clindamycin tretinoin combination is unknown. Although the significance of these studies to humans is not clear, patients should avoid exposure to sun.

The genotoxic potential of tretinoin was evaluated in an in vitroAmes Salmonella reversion test and an in vitrochromosomal aberration assay in Chinese hamster ovary cells. Both tests were negative.

In oral fertility studies in rats treated with tretinoin, the no-observed-effect-level was 2 mg/kg/day (64 times the recommended clinical dose based on body surface area comparison).

14 CLINICAL STUDIES

The safety and efficacy of VELTIN Gel, applied once daily for the treatment of acne vulgaris, was evaluated in 12-week multi-center, randomized, blinded trials in subjects 12 years and older.

Treatment response was defined as the percent of subjects who had a 2-grade improvement from baseline to Week 12 based on the Investigator’s Global Assessment (IGA) and a mean absolute change from baseline to Week 12 in 2 out of 3 (total, inflammatory and non-inflammatory) lesion counts. The IGA scoring scale used in all the clinical trials for VELTIN Gel is as follows:

0

Clear

Normal, clear skin with no evidence of acne vulgaris.

1

Almost Clear

Skin almost clear; rare non-inflammatory lesions present, with rare non-inflamed papules (papules must be resolving and may be hyperpigmented, though not pink-red) requiring no further treatment in the Investigator’s opinion.

2

Mild

Some non-inflammatory lesions are present, with few inflammatory lesions (papules/pustules only, no nodulo-cystic lesions).

3

Moderate

Non-inflammatory lesions predominate, with multiple inflammatory lesions evident; several-to-many comedones and papules/pustules, and there may or may not be 1 small nodulo-cystic lesion.

4

Severe

Inflammatory lesions are more apparent; many comedones and papules/pustules, there may or may not be a few nodulo-cystic lesions.

5

Very Severe

Highly inflammatory lesions predominate; variable numbers of comedones, many papules/pustules and nodulo-cystic lesions.

In Trial 1, 1,649 subjects were randomized to VELTIN Gel, clindamycin gel, tretinoin gel, and vehicle gel. The median age of subjects was 17 years and 58% were females. At baseline, subjects had an average of 71 total lesions of which the mean number of inflammatory lesions was 25.5 lesions and the mean number of non-inflammatory lesions was 45.1 lesions. The majority of subjects enrolled with a baseline IGA score of 3. The efficacy results at Week 12 are presented in Table 3.

Table 3. Efficacy Results at Week 12

Trial 1

VELTIN Gel N = 476

Clindamycin Gel N = 467

Tretinoin Gel N = 464

Vehicle Gel N = 242

Investigator’s Global Assessment

Percentage of subjects achieving 2-Grade Improvement

36.3%

26.6%

26.1%

20.2%

Percentage of subjects achieving an IGA of 0 or 1 with a 2-Grade Improvement

33.2%

24.0%

22.6%

17.8%

Inflammatory Lesions:

Mean absolute reduction

15.5

14.5

13.9

11.1

Mean percentage (%) reduction

60.4%

56.5%

54.5%

43.3%

Non-inflammatory Lesions:

Mean absolute reduction

23.2

19.5

22.1

17.0

Mean percentage (%) reduction

51.0%

42.9%

47.3%

36.0%

Total Lesions:

Mean absolute reduction

38.7

34.0

36.0

28.1

Mean percentage (%) reduction

55.0%

49.0%

50.5%

39.1%

The safety and efficacy of clindamycin-tretinoin gel was also evaluated in 2 additional 12-week, multi-centered, randomized, blinded trials in subjects 12 years and older. A total of 2,219 subjects with mild-to-moderate acne vulgaris were treated once daily for 12 weeks. Of the 2,219 subjects, 634 subjects were treated with clindamycin-tretinoin gel. These trials demonstrated consistent outcomes.

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