TAZORAC(tazarotene) gel 0.05% - America[美国药品]

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TAZORAC(tazarotene) gel 0.05%

2015-09-06 08:55:08 来源: 作者: 【大中小】浏览:328次评论:0条

SPL UNCLASSIFIED SECTION

DESCRIPTION

TAZORAC® Gel is a translucent, aqueous gel and contains the compound tazarotene, a member of the acetylenic class of retinoids. It is for topical dermatologic use only. The active ingredient is represented by the following structural formula:

Formula: C21H21NO2S

Molecular Weight: 351.46

Chemical Name: Ethyl 6-[(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate

Contains:

Active: Tazarotene 0.05% or 0.1% (w/w)

Preservative: Benzyl alcohol 1% (w/w)

Inactives: Ascorbic acid; butylated hydroxyanisole; butylated hydroxytoluene; carbomer homopolymer type B; edetate disodium; hexylene glycol; poloxamer 407; polyethylene glycol 400; polysorbate 40; purified water; and tromethamine.

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 anti-inflammatory 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 ± 0.58 ng/mL (mean ± SD) occurring 9 hours after the last dose, and the AUC0-24hr 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 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 ± SD: 13 ± 5%). The Cmax for tazarotenic acid was 12.0 ± 7.6 ng/mL occurring 6 hours after the final dose, and the AUC0-24hr 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 Cmax of 18.9 ± 10.6 ng/mL and AUC0-24hr 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.

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® 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
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).
		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 Elevation	B* C-12* C-24*	2.5 -1.4 -1.2	2.6 -1.3	2.6 -1.3 -1.1	2.6 -1.1	2.5 -1.4 -1.1	2.6 -1.4	2.6 -1.5 -1.0	2.6 -1.3	2.4 -0.8 -0.9	2.6 -0.7	2.6 -0.7 -0.7	2.6 -0.6
Scaling	B* C-12* C-24*	2.4 -1.1 -0.9	2.5 -1.1	2.5 -1.1 -0.8	2.6 -0.9	2.4 -1.3 -1.0	2.6 -1.3	2.5 -1.2 -0.8	2.7 -1.2	2.4 -0.7 -0.8	2.6 -0.7	2.5 -0.6 -0.7	2.7 -0.6
Erythema	B* C-12* C-24*	2.4 -1.0 -1.1	2.7 -0.8	2.2 -0.9 -0.7	2.5 -0.8	2.4 -1.0 -0.9	2.8 -1.1	2.3 -1.0 -0.8	2.5 -0.8	2.3 -0.6 -0.7	2.7 -0.5	2.2 -0.5 -0.6	2.5 -0.5

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%)

INDICATIONS AND USAGE

TAZORAC® (tazarotene) Gel 0.05% and 0.1% are indicated for the topical treatment of patients with stable plaque psoriasis of up to 20% body surface area involvement.

TAZORAC® (tazarotene) Gel 0.1% is also indicated for the topical treatment of patients with facial acne vulgaris of mild to moderate severity.

The efficacy of TAZORAC® Gel in the treatment of acne previously treated with other retinoids or resistant to oral antibiotics has not been established.

CONTRAINDICATIONS

Retinoids may cause fetal harm when administered to a pregnant woman.

In rats, tazarotene 0.05% gel, administered topically during gestation days 6 through 17 at 0.25 mg/kg/day (1.5 mg/m2/day) resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits dosed topically with 0.25 mg/kg/day (2.75 mg/m2 total body surface area/day) tazarotene gel during gestation days 6 through 18 were noted with single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies. Systemic daily-exposure (AUCde) to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits represented 0.62 and 6.7 times, respectively, the AUC0-24h observed in psoriatic patients treated with 2 mg/cm2 of tazarotene gel 0.1% (extrapolated for topical application over a 20% body surface area), and 0.78 and 8.4 times, respectively, the maximum AUC0-24h in acne patients treated with 2 mg/cm2 of tazarotene gel 0.1% over a 15% (targeted) body surface area.

As with other retinoids, when tazarotene was given orally to experimental animals, developmental delays were seen in rats, and teratogenic effects and post-implantation loss were observed in rats and rabbits at AUCde values that were 0.55 and 13.2 times, respectively, the AUC0-24h observed in psoriatic patients treated with 2 mg/cm2 of tazarotene gel 0.1% (extrapolated for topical application over a 20% body surface area), and 0.68 and 16.4 times, respectively, the maximum AUC0-24h in acne patients treated with 2 mg/cm2 of tazarotene gel 0.1% over a 15% (targeted) body surface area.

In a study of the effect of oral tazarotene on fertility and early embryonic development in rats, decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights, all classic developmental effects of retinoids, were observed when female rats were administered 2 mg/kg/day from 15 days before mating through gestation day 7. A low incidence of retinoid-related malformations at that dose was reported to be related to treatment. This dose produced an AUCde that was 1.7 times the AUC0-24h observed in psoriatic patients treated with 2 mg/cm2 tazarotene gel 0.1% (extrapolated for topical application over a 20% body surface area) and 2.1 times the maximum AUC0-24h in acne patients treated with 2 mg/cm2 of tazarotene gel 0.1% over a 15% (targeted) body surface area.

SYSTEMIC EXPOSURE TO TAZAROTENIC ACID IS DEPENDENT UPON THE EXTENT OF THE BODY SURFACE AREA TREATED. IN PATIENTS TREATED TOPICALLY OVER SUFFICIENT BODY SURFACE AREA, EXPOSURE COULD BE IN THE SAME ORDER OF MAGNITUDE AS IN THESE ORALLY TREATED ANIMALS. ALTHOUGH THERE MAY BE LESS SYSTEMIC EXPOSURE IN THE TREATMENT OF ACNE OF THE FACE ALONE DUE TO LESS SURFACE AREA FOR APPLICATION, TAZAROTENE IS A TERATOGENIC SUBSTANCE, AND IT IS NOT KNOWN WHAT LEVEL OF EXPOSURE IS REQUIRED FOR TERATOGENICITY IN HUMANS (SEE CLINICAL PHARMACOLOGY: PHARMACOKINETICS).