TAZORAC Cream Ref.[27423] Active ingredients: Tazarotene

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 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/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 C_maxand AUC values of tazarotenic acid peaked at day 15 for both dosing groups during a 29 day treatment period. Mean C_max and AUC_0-24h 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 C_max 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 C_max and AUC_0-24h 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 C_max and AUC_0-24h 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.

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/cm² over a 35% body surface area in a controlled pharmacokinetic study. This estimated systemic exposure in rats was 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% cream at 2 mg/cm² over a 15% body surface area.

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/cm² over a 35% body surface area in a controlled pharmacokinetic study, and 13 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² over a 15% body surface area.

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/cm² over a 35% body surface area in a controlled pharmacokinetic study, and 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² 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. 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/cm² over a 35% body surface area, and 6.3 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² over a 15% 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/cm² over a 35% body surface area and 11 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² 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 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/cm² over a 35% body surface area, and 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm² over a 15% body surface area.

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:

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:

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:

^* Denotes statistically significant difference compared with vehicle.