Fabior (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis:

A long-term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to rats showed no indications of increased carcinogenic risk. Based on pharmacokinetic data from a shorter-term study in rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic exposure in rats approximately 2 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

A long-term topical application study of up to 0.1% tazarotene in a gel formulation in mice terminated at 88 weeks showed that dose levels of 0.05, 0.125, 0.25, and 1 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41 weeks due to severe dermal irritation) revealed no apparent carcinogenic effects when compared with vehicle control animals. AUC at the highest dose in mice was 49 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

In evaluation of photocarcinogenicity, median time to onset of tumors was decreased and the number of tumors increased in hairless mice following chronic topical dosing with exposure to ultraviolet radiation at tazarotene concentrations of 0.001%, 0.005%, and 0.01% in a gel formulation for up to 40 weeks.

Mutagenesis:

Tazarotene was non-mutagenic in the Ames assay and did not produce structural chromosomal aberrations in a human lymphocyte assay. Tazarotene was non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and was non-clastogenic in the in vivo mouse micronucleus test.

Impairment of Fertility:

No impairment of fertility was observed in rats when male animals were treated for 70 days prior to mating and female animals were treated for 14 days prior to mating and continuing through gestation and lactation with topical doses of tazarotene gel up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure at the 0.125 mg/kg/day dose in rats would be equivalent to 7.6 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of up to 1 mg/kg/day tazarotene. AUC at the highest dose in rats was 23 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

No effect on parameters of mating performance or fertility was observed in female rats treated for 15 days prior to mating and continuing through gestation day 7 with oral doses of tazarotene up to 2 mg/kg/day. However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at that dose [see Pregnancy (8.1)]. AUC at the highest dose in rats was 42 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

Reproductive capabilities of F1 animals, including F2 survival and development, were not affected by topical administration of tazarotene gel to female F0 parental rats from gestation day 16 through lactation day 20 at the maximum tolerated dose of 0.125 mg/kg/day. Based on data from another study, the AUC in rats would be equivalent to 7.6 times the AUC in acne patients treated with 2 mg/cm2 of FABIOR Foam 0.1% over a 15% body surface area.

14 CLINICAL STUDIES

In 2 multi-center, randomized, double-blind, vehicle-controlled trials, a total of 1,485 subjects with moderate-to-severe acne vulgaris were randomized 1:1 to FABIOR Foam or vehicle applied once daily for 12 weeks. Acne severity was evaluated using lesion counts and the 6-point Investigator’s Global Assessment (IGA) scale (see Table 2). At baseline, 80% of subjects were graded as “moderate” or Grade 3 and 20% were graded as “severe” or Grade 4 on the IGA scale. At baseline, subjects had an average of 79.8 total lesions of which the mean number of inflammatory lesions was 31.9 and the mean number of non-inflammatory lesions was 47.8. Subjects ranged in age from 12 to 45 years, with 860 (58%) subjects aged 12 to 17 years; 428 (29%) subjects aged 18 to 25 years; 143 (10%) subjects aged 26 to 35 years and 54 (4%) subjects aged 36 to 45 years. Subjects enrolled in the trials by race were white (77%), black (15%), Asian (4%), and other (4%). Hispanics comprised 18% of the population. An equal number of males (49%) and females (51%) were enrolled. Treatment success was defined as a score of “clear” (Grade 0) or “almost clear” (Grade 1) and at least 2‑grade improvement from the baseline score to Week 12.

Table 2. Investigator’s Global Assessment Scale

Grade

Description

0

Clear

Clear skin with no inflammatory or non-inflammatory lesions.

1

Almost clear

Rare non-inflammatory lesions with no more than rare papules.

2

Mild

Greater than Grade 1, some non-inflammatory lesions with no more than a few inflammatory lesions (papules/pustules only, no nodular lesions).

3

Moderate

Greater than Grade 2, up to many non-inflammatory lesions and may have some inflammatory lesions, but no more than one small nodular lesion.

4

Severe

Greater than Grade 3, up to many non-inflammatory and inflammatory lesions, but no more than a few nodular lesions.

5

Very severe

Many non-inflammatory and inflammatory lesions and more than a few nodular lesions. May have cystic lesions.

Absolute and percent reductions in lesion counts and the IGA scale after 12 weeks of treatment in these 2 trials are shown in Table 3. Each trial needed to have a statistically significant reduction in 2 out of 3 lesion counts at Week 12.

Table 3. Reductions in Lesion Counts and Improvements in Investigator’s Global Assessment at Week 12
Trial 1 Trial 2
FABIOR
Foam
N = 371
Vehicle
Foam
N = 372
FABIOR
Foam
N = 373
Vehicle
Foam
N = 369

Inflammatory Lesions

Mean absolute reduction from Baseline

18.0

14.0

18.0

15.0

Mean percent reduction from Baseline

58%

45%

55%

45%

Non-inflammatory Lesions

Mean absolute reduction from Baseline

28.0

17.0

26.0

18.0

Mean percent reduction from Baseline

55%

33%

57%

41%

Total Lesions

Mean absolute reduction from Baseline

46.0

31.0

43.0

33.0

Mean percent reduction from Baseline

56%

39%

56%

43%

Investigator’s Global Assessment (IGA), n (%)

Minimum 2‑grade improvement and IGA of 0 or 1

107 (29%)

60 (16%)

103 (28%)

49 (13%)

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