Avage

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 RARγand may modify gene expression. The clinical significance of these findings is unknown.

The mechanism of tazarotene action in the amelioration of fine wrinkling, facial mottled hypo- and hyperpigmentation, and benign facial lentigines is unknown. A histological study of tazarotene cream 0.1% applied in subjects with fine wrinkling and mottled hyperpigmentation but otherwise normal skin for 24 weeks showed that tazarotene cream was associated with significantly greater proportions of patients who had an increase from baseline in the number of granular cell layers and in epidermal edema. The clinical significance of these changes 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 (>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.

Tazarotene cream 0.1% was topically applied once daily to either the face (6 females and 2 males) or to 15% of body surface area (8 females and 8 males) over four weeks in patients with fine wrinkling and mottled hyperpigmentation. In the “face-only” dosing group, the maximum average Cmax and AUC0-24 hr values of tazarotenic acid occurred on Day 15 with mean ± SD values of Cmax and AUC0-24 hr of tazarotenic acid being 0.236 ± 0.255 ng/mL (N = 8) and 2.44 ± 1.38 ng·hr/mL (N = 8), respectively. The mean Cmax and AUC0-24 hr values of tazarotenic acid from patients in the 15% body surface area dosing group were approximately 10 times higher than those from patients in the face-only dosing group. The single highest Cmax throughout the study period was 3.43 ng/mL on day 29 from patients in the 15% body surface area dosing group. Gender had no influence on the systemic bioavailability of tazarotenic acid.

Blood samples were collected from one of the two phase 3 studies to evaluate the systemic exposure following application of tazarotene cream 0.1% once daily for 24 weeks (double-blind period) followed by 28 weeks (open-label) under clinical conditions. The mean plasma tazarotenic acid concentrations following topical treatment with tazarotene cream 0.1% over 52 weeks ranged between 0.092 ± 0.073 ng/mL and 0.127 ± 0.142 ng/mL. The single highest observed tazarotenic acid concentration throughout the 52-week study was 0.705 ng/mL (observed at week 36). Systemic availability of tazarotenic acid was minimal and remained steady following once daily application of tazarotene cream 0.1% to the faces of patients in the study for up to 52 weeks.

Clinical Studies

In two double-blind controlled studies in which tazarotene cream 0.1% was compared with its vehicle, applications were made once daily for 24 weeks to the facial skin of subjects with mild to severe fine wrinkling, facial mottled hypo- and hyperpigmentation, and benign facial lentigines due to overexposure to the sun. Treatment was as an adjunct to a comprehensive skin care and sun avoidance program which included use of sunscreens, protective clothing, and non-prescription emollient cream. At two to four week intervals the severity of fine wrinkling, mottled hypo- and hyperpigmentation, and benign facial lentigines were graded on a scale of 0=none, 1=minimal, 2=mild, 3=moderate, and 4=severe. The results of both studies demonstrate that tazarotene cream 0.1% was significantly superior to its vehicle for fine wrinkling, mottled hypo- and hyperpigmentation, and benign facial lentigines expressed as the proportion of subjects with an improvement of at least one grade from baseline.

Approximately 97% of subjects in clinical trials were white (Caucasian) with 80% of subjects in the clinical studies having Fitzpatrick skin type classifications I-III. The distribution of subject skin types were: Type I –12%; Type II – 26%; Type III – 40%; and Type IV 22%. Patients with skin types V and VI were not studied. Insufficient non-white patients (Asian, Hispanic, or other) were studied to make an adequate determination of efficacy of AVAGE® (tazarotene) Cream in such patients.

Percentage of Patients with Improvement in Fine Wrinkling after 24 Weeks of Treatment

  StudyA StudyB
Taz. 0.1%
N=283
Vehicle
N=280
Taz.
N=284
0.1%
N=284
2 or more Grades Improvement 5% 1% 13% 5%
1 Grade Improvement 35% 15% 45% 18%
No Change 59% 83% 42% 76%
Worsened 1% 1% 0% 1%

Fine Wrinkling was graded on a 5-point scale (0=none, 1=minimal, 2=mild, 3=moderate, 4=severe) using a photonumeric guideline for investigators.

Percentage of Patients with Improvement in Mottled Hyperpigmentation after 24 Weeks of Treatment

  StudyA StudyB
Taz. 0.1%
N=283
Vehicle
N=280
Taz.
N=284
0.1%
N=284
2 or more Grades Improvement 17% 1% 28% 10%
1 Grade Improvement 42% 17% 54% 30%
No Change 41% 80% 18% 59%
Worsened <1% 3% <1% 1%

Mottled Hyperpigmentation was graded on a 5-point scale (0=none, 1=minimal, 2=mild, 3=moderate, 4=severe) using a photonumeric guideline for investigators.

In the 24 week studies, efficacy was also demonstrated in mottled hypopigmentation and benign facial lentigines, which were secondary endpoints in those studies.

The duration of the mitigating effects on facial fine wrinkling, mottled hyper- and hypopigmentation, and benign facial lentigines following discontinuation of AVAGE® (TAZAROTENE) Cream 0.1% has not been studied.

Last reviewed on RxList: 10/8/2008
This monograph has been modified to include the generic and brand name in many instances.

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