Tazorac

CLINICAL PHARMACOLOGY

Tazarotene is a retinoid prodrug which is converted to its active form, the cognate carboxylic acid of tazarotene (AGN 190299), by rapid deesterification in animals and man. AGN 190299 (“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.

Psoriasis

The mechanism of tazarotene action in psoriasis is not defined. Topical tazarotene blocks induction of mouse epidermal ornithine decarboxylase (ODC) activity, which is associated with cell proliferation and hyperplasia. In cell culture and in vitro models of skin, tazarotene suppresses expression of MRP8, a marker of inflammation present in the epidermis of psoriasis patients at high levels. In human keratinocyte cultures, it inhibits cornified envelope formation, whose build-up is an element of the psoriatic scale. Tazarotene also induces the expression of a gene which may be a growth suppressor in human keratinocytes and which may inhibit epidermal hyperproliferation in treated plaques. However, the clinical significance of these findings is unknown.

Acne

The mechanism of tazarotene action in acne vulgaris is not defined. However, the basis of tazarotene's therapeutic effect in acne may be due to its anti-hyperproliferative, normalizing-of-differentiation and antiinflammatory effects. Tazarotene inhibited corneocyte accumulation in rhino mouse skin and cross-linked envelope formation in cultured human keratinocytes. The clinical significance of these findings is 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.

The human in vivo studies described below were conducted with tazarotene gel applied topically at approximately 2 mg/cm² and left on the skin for 10 to 12 hours. Both the peak plasma concentration (Cmax) and area under the plasma concentration time curve (AUC) refer to the active metabolite only.

Two single, topical dose studies were conducted using 14C-tazarotene gel. Systemic absorption, as determined from radioactivity in the excreta, was less than 1% of the applied dose (without occlusion) in six psoriatic patients and approximately 5% of the applied dose (under occlusion) in six healthy subjects. One non-radiolabeled single-dose study comparing the 0.05% gel to the 0.1% gel in healthy subjects indicated that the Cmax and AUC were 40% higher for the 0.1% gel.

After 7 days of topical dosing with measured doses of tazarotene 0.1% gel on 20% of the total body surface without occlusion in 24 healthy subjects, the Cmax for tazarotenic acid was 0.72 RMG 0.58 ng/mL (mean RMG SD) occurring 9 hours after the last dose, and the AUC0-24hr for tazarotenic acid was 10.1 RMG 7.2 ng·hr/mL. Systemic absorption was 0.91 RMG 0.67% of the applied dose.

In a 14-day study in five psoriatic patients, measured doses of tazarotene 0.1% gel were applied daily by nursing staff to involved skin without occlusion (8 to 18% of total body surface area; mean RMG SD: 13 RMG 5%). The Cmax for tazarotenic acid was 12.0 RMG 7.6 ng/mL occurring 6 hours after the final dose, and the AUC0-24hr for tazarotenic acid was 105 RMG 55 ng·hr/mL. Systemic absorption was 14.8 RMG 7.6% of the applied dose. Extrapolation of these results to represent dosing on 20% of total body surface yielded estimates for tazarotenic acid with Cmax of 18.9 RMG 10.6 ng/mL and AUC0-24hr of 172 RMG 88 ng·hr/mL.

An in vitro percutaneous absorption study, using radiolabeled drug and freshly excised human skin or human cadaver skin, indicated that approximately 4 to 5% of the applied dose was in the stratum corneum (tazarotene: tazarotenic acid = 5:1) and 2 to 4% was in the viable epidermis-dermis layer (tazarotene:tazarotenic acid = 2:1) 24 hours after topical application of the gel.

Clinical Studies

Psoriasis

In two large vehicle-controlled clinical studies, tazarotene 0.05% and 0.1% gels applied once daily for 12 weeks were significantly more effective than vehicle in reducing the severity of the clinical signs of stable plaque psoriasis covering up to 20% of body surface area. In one of the studies, patients were followed up for an additional 12 weeks following cessation of therapy with TAZORAC® (tazarotene gel) Gel. Mean baseline scores and changes from baseline (reductions) after treatment in these two studies are shown in the following table:

Plaque Elevation, Scaling and Erythema in Two Controlled Clinical Trials for Psoriasis

    TAZORAC® 0.05% Gel TAZORAC® 0.1% Gel Vehicle Gel
Trunk/Arm/Leg Lesions Knee/Elbow Lesions Trunk/Arm/Leg Lesions Knee/Elbow Lesions Trunk/Arm/Leg Lesions Knee/Elbow Lesions
N=108 N=111 N=108 N=111 N=108 N=112 N=108 N=112 N=108 N=113 N=108 N=113
Plaque B* 2.5 2.6 2.6 2.6 2.5 2.6 2.6 2.6 2.4 2.6 2.6 2.6
Elevation C-12* -1.4 -1.3 -1.3 -1.1 -1.4 -1.4 -1.5 -1.3 -0.8 -0.7 -0.7 -0.6
C-24* -1.2   -1.1   -1.1   -1.0   -0.9   -0.7  
Scaling B* 2.4 2.5 2.5 2.6 2.4 2.6 2.5 2.7 2.4 2.6 2.5 2.7
C-12* -1.1 -1.1 -1.1 -0.9 -1.3 -1.3 -1.2 -1.2 -0.7 -0.7 -0.6 -0.6
C-24* -0.9   -0.8   -1.0   -0.8   -0.8   -0.7  
Erythema B* 2.4 2.7 2.2 2.5 2.4 2.8 2.3 2.5 2.3 2.7 2.2 2.5
C-12* -1.0 -0.8 -0.9 -0.8 -1.0 -1.1 -1.0 -0.8 -0.6 -0.5 -0.5 -0.5
C-24* -1.1   -0.7   -0.9   -0.8   -0.7   -0.6  
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).

Global improvement over baseline at the end of 12 weeks of treatment in these two studies is shown in the following table:

  TAZORAC® 0.05% Gel TAZORAC® 0.1% Gel Vehicle Gel
N=81 N-93 N=79 N=69 N=84 N=91
100% improvement 2 (2%) 1 (1%) 0 0 1 (1%) 0
≥ 75% improvement 23 (28%) 17 (18%) 30 (38%) 17 (25%) 10 (12%) 9 (10%)
≥ 50% improvement 42 (52%) 39 (42%) 51 (65%) 36 (52%) 28 (33%) 21 (23%)
1-49% improvement 21 (26%) 32 (34%) 18 (23%) 23 (33%) 27 (32%) 32 (35%)
No change or worse 18 (22%) 22 (24%) 10 (13%) 10 (14%) 29 (35%) 38 (42%)

The 0.1% gel was more effective than the 0.05% gel, but the 0.05% gel was associated with less local irritation than the 0.1% gel (see ADVERSE REACTIONS section).

Acne

In two large vehicle-controlled studies, tazarotene 0.1% gel applied once daily was significantly more effective than vehicle in the treatment of facial acne vulgaris of mild to moderate severity. Percent reductions in lesion counts after treatment for 12 weeks in these two studies are shown in the following table:

Reduction in Lesion Counts after Twelve Weeks of Treatment in Two Controlled Clinical Trials for Acne

  TAZORAC® 0.1% Gel Vehicle Gel
N=150 N=149 N=148 N=149
Noninflammatory lesions 55% 43% 35% 27%
Inflammatory lesions 42% 47% 30% 28%
Total lesions 52% 45% 33% 27%

Global improvement over baseline at the end of 12 weeks of treatment in these two studies is shown in the following table:

  TAZORAC® 0.1% Gel Vehicle Gel
N=105 N=117 N=117 N=110
100% improvement 1 (1%) 0 0 0
≥ 75% improvement 40(38%) 21(18%) 23(20%) 11(10%)
≥ 50% improvement 71(68%) 56(48%) 47(40%) 32(29%)
1-49% improvement 23(22%) 49(42%) 48(41%) 46(42%)
No change or worse 11(10%) 12(10%) 22(19%) 32(29%)

Last reviewed on RxList: 4/19/2011
This monograph has been modified to include the generic and brand name in many instances.

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