TAZORAC Gel Ref.[27424] Active ingredients: Tazarotene

The pharmacodynamics of TAZORAC Gel in the treatment of plaque psoriasis and facial acne vulgaris are unknown.

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 (C_max) 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 subjects with psoriasis 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 C_max 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 C_max for tazarotenic acid was 0.72 ± 0.58 ng/mL (mean ± SD) occurring 9 hours after the last dose, and the AUC_0-24hr for tazarotenic acid was 10.1 ± 7.2 ng·hr/mL. Systemic absorption was 0.91 ± 0.67% of the applied dose.

In a 14-day study in five subjects with psoriasis, 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 ± SD: 13 ± 5%). The C_max for tazarotenic acid was 12.0 ± 7.6 ng/mL occurring 6 hours after the final dose, and the AUC_0-24hr for tazarotenic acid was 105 ± 55 ng·hr/mL. Systemic absorption was 14.8 ± 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 C_max of 18.9 ± 10.6 ng/mL and AUC_0-24hr of 172 ± 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.

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 0.3 times that seen in subjects treated with the MRHD of tazarotene gel, 0.1%.

A long-term study with topical administration 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 to vehicle control animals. Systemic exposure at the highest dose was 2 times that seen in subjects treated with the MRHD of tazarotene gel, 0.1%.

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.

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 at the highest dose was 0.3 times that observed in subjects treated with the MRHD of tazarotene gel, 0.1%.

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, which produced systemic exposure that was approximately equivalent to that observed in subjects treated with the MRHD of tazarotene gel, 0.1%.

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 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, which produced systemic exposure 2 times that observed in subjects treated with the MRHD of tazarotene gel, 0.1% [see Use in Specific Populations (8.1)].

Psoriasis

In two large vehicle-controlled clinical trials, TAZORAC Gel, 0.05% and 0.1% applied once daily for 12 weeks was significantly more effective than vehicle in reducing the severity of the clinical signs of plaque psoriasis covering up to 20% of body surface area. In one of the studies, subjects were followed up for an additional 12 weeks following cessation of therapy with TAZORAC Gel. Mean baseline scores and changes from baseline (reductions) after treatment in these two trials are shown in Table 1.

Table 1. Plaque Elevation, Scaling, and Erythema in Two Controlled Clinical Trials for Psoriasis:

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 trials is shown in Table 2.

Table 2. Global Improvement over Baseline after Twelve Weeks of Treatment in Two Controlled Clinical Trials for Psoriasis:

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 (6.1)].

Acne

In two large vehicle-controlled trials, TAZORAC Gel, 0.1% 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 trials are shown in Table 3.

Table 3. Reduction in Lesion Counts after Twelve Weeks of Treatment in Two Controlled Clinical Trials for Acne:

Global improvement over baseline at the end of 12 weeks of treatment in these two trials is shown in Table 4.

Table 4. Global Improvement over Baseline after Twelve Weeks of Treatment in Two Controlled Clinical Trials for Acne: