Tazarotene .5 mg/g Cream — NDC 72162-2420-6 (Billing 72162-2420-06)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Tazarotene is a retinoid prodrug which is converted to its active form, the carboxylic acid of tazarotene, by deesterification. Tazarotenic acid binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγ, but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings is unknown.

12.3Pharmacokinetics Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Little parent compound could be detected in the plasma. Tazarotenic acid was highly bound to plasma proteins (greater than 99%).

Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones and other polar metabolites which were eliminated through urinary and fecal pathways. The half-life of tazarotenic acid was approximately 18 hours, following topical application of tazarotene to normal or psoriatic skin. In a multiple dose trial with a once daily dose for 14 consecutive days in 9 psoriatic subjects (male=5; female=4), measured doses of tazarotene cream, 0.1% were applied by medical staff to involved skin without occlusion (5 to 35% of total body surface area: mean ± SD: 14 ± 11%).

The C max of tazarotenic acid was 2.31 ± 2.78 ng/mL occurring 8 hours after the final dose, and the AUC 0-24h was 31.2 ± 35.2 ng•hr/mL on day 15 in the five subjects who were administered clinical doses of 2 mg cream/cm 2 . During clinical trials with tazarotene cream, 0.05% or 0.1% treatment for plaque psoriasis, three out of 139 subjects with their systemic exposure monitored had detectable plasma tazarotene concentrations, with the highest value at 0.09 ng/mL. Tazarotenic acid was detected in 78 out of 139 subjects (LLOQ = 0.05 ng/mL).

Three subjects using tazarotene cream 0.1% had plasma tazarotenic acid concentrations greater than 1 ng/mL. The highest value was 2.4 ng/mL. However, because of the variations in the time of blood sampling, the area of psoriasis involvement, and the dose of tazarotene applied, actual maximal plasma levels are unknown.

12.1Mechanism of Action Tazarotene is a retinoid prodrug which is converted to its active form, the carboxylic acid of tazarotene, by deesterification. Tazarotenic acid binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγ, but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings is unknown.

12.3Pharmacokinetics Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Little parent compound could be detected in the plasma. Tazarotenic acid was highly bound to plasma proteins (greater than 99%).

Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones and other polar metabolites which were eliminated through urinary and fecal pathways. The half-life of tazarotenic acid was approximately 18 hours, following topical application of tazarotene to normal or psoriatic skin. In a multiple dose trial with a once daily dose for 14 consecutive days in 9 psoriatic subjects (male=5; female=4), measured doses of tazarotene cream, 0.1% were applied by medical staff to involved skin without occlusion (5 to 35% of total body surface area: mean ± SD: 14 ± 11%).

The C max of tazarotenic acid was 2.31 ± 2.78 ng/mL occurring 8 hours after the final dose, and the AUC 0-24h was 31.2 ± 35.2 ng•hr/mL on day 15 in the five subjects who were administered clinical doses of 2 mg cream/cm 2 . During clinical trials with tazarotene cream, 0.05% or 0.1% treatment for plaque psoriasis, three out of 139 subjects with their systemic exposure monitored had detectable plasma tazarotene concentrations, with the highest value at 0.09 ng/mL. Tazarotenic acid was detected in 78 out of 139 subjects (LLOQ = 0.05 ng/mL).

Three subjects using tazarotene cream 0.1% had plasma tazarotenic acid concentrations greater than 1 ng/mL. The highest value was 2.4 ng/mL. However, because of the variations in the time of blood sampling, the area of psoriasis involvement, and the dose of tazarotene applied, actual maximal plasma levels are unknown.

14 CLINICAL STUDIES In two 12-week vehicle-controlled clinical trials, tazarotene cream, 0.05% and 0.1% was significantly more effective than vehicle in reducing the severity of stable plaque psoriasis. Tazarotene cream, 0.1% and 0.05% demonstrated superiority over vehicle cream as early as 1 week and 2 weeks, respectively, after starting treatment. In these trials, the primary efficacy endpoint was “clinical success,” defined as the proportion of subjects with none, minimal, or mild overall lesional assessment at Week 12, and shown in Table 1. “Clinical success” was also significantly greater with tazarotene cream, 0.05% and 0.1% versus vehicle at most follow-up visits.

Table 1. Subject Numbers and Percentages for Overall Lesional Assessment Scores and “Clinical Success” at Baseline (BL), End of Treatment (Week 12) and 12 Weeks After Stopping Therapy (Week 24) # in Two Controlled Clinical Trials for Psoriasis Tazarotene Cream, 0.05% Tazarotene Cream, 0.1% Vehicle Cream Trial 1 N=218 Trial 2 N=210 Trial 1 N=221 Trial 2 N=211 Trial 1 N=229 Trial 2 N=214 Score BL Wk 12 Wk 24 BL Wk 12 BL Wk 12 Wk 24 BL Wk 12 BL Wk 12 Wk 24 BL Wk 12 None (0) 0 1 (0.5%) 1 (0.5%) 0 2 (1%) 0 0 0 0 6 (3%) 0 0 1 (0.4%) 0 1 (0.5%) Minimal (1) 0 11 (5%) 12 (6%) 0 7 (3%) 0 12 (5%) 14 (6%) 0 11 (5%) 0 7 (3%) 6 (3%) 0 1 (0.5%) Mild (2) 0 79 (36%) 60 (28%) 0 76 (36%) 0 75 (34%) 53 (24%) 0 90 (43%) 0 49 (21%) 43 (19%) 0 54 (25%) Moderate (3) 141 (65%) 86 (39%) 90 (41%) 100 (48%) 74 (35%) 122 (55%) 97 (44%) 107 (48%) 96 (45%) 62 (29%) 139 (61%) 119 (52%) 114 (50%) 97 (45%) 99 (46%) Severe (4) 69 (32%) 39 (18%) 51 (23%) 80 (38%) 36 (17%) 91 (41%) 36 (16%) 46 (21%) 86 (41%) 29 (14%) 81 (35%) 51 (22%) 61 (27%) 93 (44%) 47 (22%) Very Severe (5) 8 (4%) 2 (0.9%) 4 (2%) 30 (14%) 15 (7%) 8 (4%) 1 (0.5%) 1 (0.5%) 29 (14%) 13 (6%) 9 (4%) 3 (1%) 4 (2%) 24 (11%) 12 (6%) “Clinical Success” 0 91 (42%*) 73 (33%*) 0 85 (40%*) 0 87 (39%*) 67 (30%*) 0 107 (51%*) 0 56 (24%) 50 (22%) 0 56 (26%) 0 no plaque elevation above normal skin level; may have residual non-erythematous discoloration; no psoriatic scale 1 essentially flat with possible trace elevation; may have up to moderate erythema (red coloration); no psoriatic scale 2 slight but definite elevation of plaque above normal skin level; may have up to moderate erythema (red coloration); fine scales with some lesions partially covered 3 moderate elevation with rounded or sloped edges to plaque; moderate erythema (red coloration); somewhat coarser scales with most lesions partially covered 4 marked elevation with hard, sharp edges to plaque; severe erythema (very red coloration); thick scales with virtually all lesions covered and a rough surface 5 very marked elevation with very hard, sharp edges to plaque; very severe erythema (extreme red coloration); very coarse, thick scales with all lesions covered and a very rough surface Clinical Success defined as an overall lesional assessment score of none, minimal, or mild. # Trial 1 had post-treatment period observations for 12 weeks after stopping therapy, which were not part of Trial 2. * Denotes statistically significant difference for “Clinical Success” compared with vehicle.

At the end of 12 weeks of treatment, tazarotene cream, 0.05% and 0.1% was consistently superior to vehicle in reducing the plaque thickness of psoriasis. Improvements in erythema and scaling were generally significantly greater with tazarotene cream, 0.05% and 0.1% than with vehicle. Tazarotene cream, 0.1% was also generally more effective than tazarotene cream, 0.05% in reducing the severity of the individual signs of disease.

However, tazarotene cream, 0.1% was associated with a greater degree of local irritation than tazarotene cream, 0.05%. Table 2. Mean Decreases in Plaque Elevation, Scaling and Erythema in Two Controlled Clinical Trials for Psoriasis Tazarotene Cream, 0.05% Tazarotene Cream, 0.1% Vehicle Cream Lesion Trunk/Arm/ Leg lesions Knee/Elbow lesions All Treated Trunk/Arm/ Leg lesions Knee/E… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 risks. 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 the rat equivalent to 0.6 times that seen in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/kg/cm 2 over a 35% body surface area in a controlled pharmacokinetic study.

A long-term topical application study of up to 0.1% of 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 to vehicle control animals. Systemic exposures at the highest dose was 3.9 times that seen in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm 2 over a 35% body surface area in a controlled pharmacokinetic study.

In evaluation of photo co-carcinogenicity, median time to onset of tumors was decreased, and the number of tumors increased in hairless mice following chronic topical dosing with intercurrent 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 found to be 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 occurred 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 in the rat would be equivalent to 0.6 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm 2 over a 35% body surface area in a controlled pharmacokinetic study.

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. That dose produced a systemic exposure that was 1.9 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm 2 over a 35% body surface area. No impairment 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 up to 2 mg/kg/day of tazarotene.

However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at that dose [see Use in Specific Populations ( 8.1 )] . That dose produced a systemic exposure that was 3.4 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm 2 over a 35% 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 systemic drug exposure in the rat would be equivalent to 0.6 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm 2 over a 35% body surface area.