Clobex (Clobetasol Propionate Topical) - Description and Clinical Pharmacology

DESCRIPTION

CLOBEX (clobetasol propionate) Shampoo, 0.05%, contains clobetasol propionate, a synthetic fluorinated corticosteroid, for topical use. The corticosteroids constitute a class of primarily synthetic steroids used topically as anti-inflammatory and antipruritic agents.
The chemical name of clobetasol propionate is 21-chloro-9-fluoro-11β, 17-dihydroxy-16β-methylpregna-1, 4-diene-3, 20-dione 17-propionate.

It has the following structural formula:

Clobetasol propionate has a molecular weight of 466.97 (CAS Registry Number 25122-46-7). The molecular formula is C₂₅H₃₂CIFO₅. Clobetasol propionate is a white to practically white crystalline, odorless powder insoluble in water.

Each gram of CLOBEX (clobetasol propionate) Shampoo, 0.05%, contains 0.5 mg of clobetasol propionate in a translucent, colorless to pale yellow viscous liquid shampoo base consisting of alcohol, citric acid, coco-betaine, polyquaternium-10, purified water, sodium citrate, and sodium laureth sulfate.

CLINICAL PHARMACOLOGY

Mechanism of Action

Like other topical corticosteroids, CLOBEX (clobetasol propionate) Shampoo, 0.05%, has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A₂ inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A₂.

Pharmacodynamics

Vasoconstrictor Assay
CLOBEX Shampoo, 0.05%, is in the super-high range of potency as demonstrated in vasoconstrictor studies in healthy subjects when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression
In studies evaluating the potential for hypothalamic-pituitary-adrenal (HPA) axis suppression, use of CLOBEX (clobetasol propionate) Shampoo, 0.05%, resulted in demonstrable HPA axis suppression in 5 out of 12 (42%) adolescent subjects [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)].

Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle, the integrity of the epidermal barrier and occlusion.

Topical corticosteroids can be absorbed from normal intact skin. Inflammation and other disease processes in the skin may increase percutaneous absorption.

There are no human data regarding the distribution of corticosteroids to body organs following topical application. Nevertheless, once absorbed through the skin, topical corticosteroids are handled through metabolic pathways similar to systemically administered corticosteroids. They are metabolized, primarily in the liver, and are then excreted by the kidneys. In addition, some corticosteroids and their metabolites are also excreted in the bile.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Clobetasol propionate was not carcinogenic to rats when topically applied for 2 years at concentrations up to 0.005% which corresponded to doses up to 11 µg/kg/day (ratio of animal dose to proposed human dose of 0.03 on a mg/m²/day basis).

Clobetasol propionate at concentrations up to 0.001% did not increase the rate of formation of ultra violet light-induced skin tumors when topically applied to hairless mice 5 days per week for a period of 40 weeks.

Clobetasol propionate was negative in the in vitro mammalian chromosomal aberration test and in the in vivo mammalian erythrocyte micronucleus test.

The effect of subcutaneously administered clobetasol propionate on fertility and general reproductive toxicity was studied in rats at doses of 0, 12.5, 25, and 50 µg/kg/day. Males were treated beginning 70 days before mating and females beginning 15 days before mating through day 7 of gestation. A dosage level of less than 12.5 µg/kg/day clobetasol propionate was considered to be the no-observed-effect-level (NOEL) for paternal and maternal general toxicity based on decreased weight gain and for male reproductive toxicity based on increased weights of the seminal vesicles. The female reproductive NOEL was 12.5 µg/kg/day (ratio of animal dose to proposed human dose of 0.03 on a mg/m²/day basis) based on reduction in the numbers of estrous cycles during the pre-cohabitation period and an increase in the number of nonviable embryos at higher doses.

CLINICAL STUDIES

The safety and efficacy of CLOBEX Shampoo, 0.05%, have been evaluated in two clinical trials involving 290 subjects with moderate to severe scalp psoriasis. In both trials, subjects were treated with either CLOBEX Shampoo or the corresponding vehicle applied once daily for 15 minutes before lathering and rinsing for a period of 4 weeks. Efficacy results are presented in Table 2 below.

Table 2: Efficacy Results

	CLOBEX Shampoo, 0.05% N (%)		Shampoo Vehicle n (%)
	Study A	Study B	Study A	Study B
Total Number of Subjects	95	99	47	49
Success Rate1 at Endpoint2	40 (42.1%)	28 (28.3%)	1 (2.1%)	5 (10.2%)
Subjects with Scalp Psoriasis Parameter Clear (None) at Endpoint
Erythema3	17 (17.9%)	12 (12.1%)	3 (6.4%)	1 (2.0%)
Scaling3	21 (22.1%)	15 (15.2%)	0 (0%)	2 (4.1%)
Plaque Thickening3	35 (36.8%)	34 (34.3%)	5(10.6%)	5 (10.2%)

¹Success rate defined as the proportion of subjects with a-0 (clear) or 1 (minimal) on a 0 to 5 point physician's Global Severity Scale for scalp psoriasis.
²At four (4) weeks or last observation recorded for a subject during the treatment period (baseline if no post-baseline data were available).
³Subjects with 0 (clear) on a 0 to 3 point scalp psoriasis parameter scale.

Clinical studies of CLOBEX Shampoo, 0.05%, did not include sufficient numbers of non-Caucasian subjects to determine whether they respond differently than Caucasian subjects with regards to efficacy and safety.