Tazorac Cream

Tazorac Cream

CLINICAL PHARMACOLOGY

Mechanism 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.

Pharmacodynamics

The pharmacodynamics of TAZORAC® Cream are unknown.

Pharmacokinetics

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, acne 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 TAZORAC® 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 Cmax of tazarotenic acid was 2.31 ± 2.78 ng/mL occurring 8 hours after the final dose, and the AUC0-24h was 31.2 ± 35.2 ng•hr/mL on day 15 in the five subjects who were administered clinical doses of 2 mg cream/cm² .

During clinical trials with TAZORAC® 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.

TAZORAC® Cream 0.1% was applied once daily to either the face (N=8) or to 15% of body surface area (N=10) of female subjects with moderate to severe acne vulgaris. The mean Cmax and AUC values of tazarotenic acid peaked at day 15 for both dosing groups during a 29 day treatment period. Mean Cmax and AUC0-24h values of tazarotenic acid from subjects in the 15% body surface area dosing group were more than 10 times higher than those from subjects in the face-only dosing group. The single highest Cmax throughout the trial period was 1.91 ng/mL on day 15 in the exaggerated dosing group. In the face-only group, the mean ± SD values of Cmax and AUC0-24h of tazarotenic acid on day 15 were 0.10 ± 0.06 ng/mL and 1.54 ± 1.01 ng·hr/mL, respectively, whereas in the 15% body surface area dosing group, the mean ± SD values of Cmax and AUC0-24h of tazarotenic acid on day 15 were 1.20 ± 0.41 ng/mL and 17.01 ± 6.15 ng·hr/mL, respectively. The steady state pharmacokinetics of tazarotenic acid had been reached by day 8 in the face-only and by day 15 in the 15% body surface area dosing groups.

In a Phase 3 clinical trial, TAZORAC® Cream, 0.1% was applied once daily for 12 weeks to each of 48 subjects (22 females and 26 males) with facial acne vulgaris. The mean ± SD values of plasma tazarotenic acid at weeks 4 and 8 were 0.078 ± 0.073 ng/mL (N=47) and 0.052 ± 0.037 ng/mL (N=42), respectively. The highest observed individual plasma tazarotenic acid concentration was 0.41 ng/mL at week 4 from a female subject. The magnitude of plasma tazarotenic acid concentrations appears to be independent of gender, age, and body weight.

Clinical Studies

In two 12-week vehicle-controlled clinical trials, TAZORAC® Cream, 0.05% and 0.1% was significantly more effective than vehicle in reducing the severity of stable plaque psoriasis. TAZORAC® 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 TAZORAC® 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

Score TAZORAC® Cream, 0.05% TAZORAC® 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
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, TAZORAC® 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 TAZORAC® Cream, 0.05% and 0.1% than with vehicle. TAZORAC® Cream, 0.1% was also generally more effective than TAZORAC® Cream, 0.05% in reducing the severity of the individual signs of disease. However, TAZORAC® Cream, 0.1% was associated with a greater degree of local irritation than TAZORAC® Cream, 0.05%.

Table 2: Mean Decreases in Plaque Elevation, Scaling and Erythema in Two Controlled Clinical Trials for Psoriasis

Lesion   TAZORAC® Cream, 0.05% TAZORAC® Cream, 0.1% Vehicle Cream
Trunk/Arm/ Leg lesions Knee/Elbow lesions All Treated Trunk/Arm/ Leg lesions Knee/Elbow lesions All Treated Trunk/Arm/ Leg lesions Knee/Elbow lesions All Treated
Trial 1
N=218
Trail 2
N=210
Trail 1
N=218
Trail 2
N=210
Trail 1
N=218
Trail 2
N=210
Trail 1
N=221
Trail 2
N=211
Trail 1
N=221
Trail 2
N=211
Trail 1
N=221
Trail 2
N=211
Trail 1
N=229
Trail 2
N=214
Trail 1
N=229
Trail 2
N=214
Trail 1
N=229
Trail 2
N=214
Plaque elevation B#
C12
C24
2.29
-0.83*
-0.75*
2.50
-0.98*
2.40
-0.91*
-0.73*
2.52
-1.04*
2.28
-0.75*
-0.60*
2.51
-0.90*
2.34
-1.08*
-0.87*
2.52
-1.25*
2.35
-0.96*
-0.73*
2.49
-1.21*
-0.63*
2.32
-0.83*
2.51
-1.08*
-0.57
2.28
-0.59
2.51
-0.69
2.35
-0.57
-0.49
2.51
-0.68
2.29
-0.48
-0.42
2.51
-0.61
Scaling B#
C12
C24
2.26
-0.75
-0.68
2.45
-0.90
2.47
-0.78*
-0.62*
2.60
-0.98*
2.32
-0.67*
-0.51*
2.47
-0.80
2.37
-0.84*
-0.79*
2.45
-1.06*
2.40
-0.76*
-0.61*
2.57
-1.13*
2.36
-0.73*
-0.59*
2.53
-1.03*
2.34
-0.66
-0.56
2.46
-0.79
2.45
-0.62
-0.45
2.61
-0.76
2.31
-0.46
-0.34
2.53
-0.70
Erythema B#
C12
C24
2.26
-0.49
-0.52
2.51
-0.65*
2.17
-0.44
-0.44
2.40
-0.66*
2.23
-0.40
-0.41
2.48
-0.62
2.25
-0.49
-0.55
2.53
-0.82*
2.17
-0.57*
-0.52*
2.42
-0.82*
2.21
-0.42*
-0.39*
2.51
-0.78*
2.24
-0.42
-0.43
2.47
-0.46
2.17
-0.38
-0.34
2.34
-0.44
2.24
-0.37
-0.33
2.47
-0.47
Plaque elevation, scaling and erythema scored on a 0-4 scale with 0=none, 1=mild, 2=moderate, 3=severe and 4=very severe.
B#=Mean Baseline Severity;
C-12=Mean Change from Baseline at end of 12 weeks of therapy;
C-24=Mean Change from Baseline at week 24 (12 weeks after the end of therapy).
*Denotes statistically significant difference compared with vehicle.

Acne

In two large vehicle-controlled trials, subjects age 12 years and over with facial acne vulgaris of a severity suitable for monotherapy with a topical agent were enrolled. After face cleansing in the evening, TAZORAC® Cream, 0.1% was applied once daily to the entire face as a thin layer. TAZORAC® Cream, 0.1% was significantly more effective than vehicle in the treatment of facial acne vulgaris. Efficacy results after 12 weeks of treatment are shown in Table 3:

Table 3: Efficacy Results after Twelve Weeks of Treatment in Two Controlled Clinical Trials for Acne

  TAZORAC® Cream, 0.1% Vehicle Cream
Trial 1
N=218
Trial 2
N=206
Trial 1
N=218
Trial 2
N=205
Median Percent Reduction in        
  Noninflammatory lesions 46%* 41%* 27% 21%
  Inflammatory lesions 41%* 44%* 27% 25%
   Total lesions 44%* 42%* 24% 21%
Percent of Subjects with No Acne or Minimal Acne 18%* 20%* 11% 6%
Percent of Subjects with No Acne, Minimal Acne, or Mild Acne 55%* 53%* 36% 36%
*Denotes statistically significant difference compared with vehicle.

Last reviewed on RxList: 1/22/2014
This monograph has been modified to include the generic and brand name in many instances.

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