LEXETTE Topical foam Ref.[10381] Active ingredients: Ulobetasol

Vasoconstrictor Assay

A vasoconstrictor assay in healthy subjects with LEXETTE indicated that the formulation is in the super-high range of potency as compared to other topical corticosteroids; however, similar blanching scores do not necessarily imply therapeutic equivalence.

Hypothalamic-pituitary adrenal (HPA) axis suppression

The potential for hypothalamic-pituitary adrenal (HPA) suppression was evaluated in a study of 25 adult subjects with moderate to severe plaque psoriasis involving a mean body surface area of 18.4%. A mean dose of 3.7 g LEXETTE was applied twice daily for two weeks and produced laboratory evidence of HPA axis suppression in 6 of 25 (24%) subjects. In this study, the criteria for HPA-axis suppression was a serum cortisol level of less than or equal to 18 micrograms per deciliter 30 minutes after stimulation with cosyntropin (adrenocorticotropic hormone). These effects were reversible as recovery of HPA axis function was generally prompt with the discontinuation of treatment [see Warnings and Precautions (5.1)].

The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption.

In the HPA-axis and pharmacokinetic study, as described above in Clinical Pharmacology (12.2), pharmacokinetics was evaluated in a subgroup of 23 adult subjects with moderate to severe plaque psoriasis following twice daily treatment for 14 days with a mean daily dose of 7.4 g. Plasma concentration of halobetasol propionate was measureable in all subjects and steady state was achieved by Day 14. The mean (± standard deviation) C_max concentration for LEXETTE on Day 14 was 199.7 ± 217.3 pg/mL, with the corresponding median T_max value of 1 hour (range 0 – 12 hours); mean area under the halobetasol propionate concentration versus time curve over the dosing interval (AUC_t) was 1434.9 ± 1310.6 pg∙h/mL.

Long-term animal studies have not been performed to evaluate the carcinogenic potential of halobetasol propionate.

In a 90-day repeat-dose toxicity study in rats, topical administration of LEXETTE at dose concentrations from 0.005% to 0.05% or from 0.011 to 0.11 mg/kg/day of halobetasol propionate resulted in a toxicity profile consistent with long-term exposure to corticosteroids including adrenal atrophy, histopathological changes in several organ systems indicative of severe immune suppression, and opportunistic fungal and bacterial infections. A no observable adverse effect level could not be determined in this study. Although the clinical relevance of the findings in animals to humans is not clear, sustained glucocorticoid-related immune suppression may increase the risk of infection and possibly the risk of carcinogenesis.

Halobetasol propionate was not found to be genotoxic in the Ames/Salmonella assay, in the Chinese hamster CHO/HGPRT assay, in the mouse micronucleus test, in the sister chromatid exchange test in somatic cells of the Chinese hamster, or in the chromosome aberration test in somatic cells of Chinese hamsters. Positive mutagenicity effects were observed in two genotoxicity assays: Chinese hamster nuclear anomaly test and mouse lymphoma gene mutation assay in vitro.

Studies in the rat following oral administration at dose levels up to 0.05 mg/kg/day indicated no impairment of fertility or general reproductive performance.

LEXETTE was evaluated for the treatment of moderate to severe plaque psoriasis in two multicenter, randomized, double-blind, vehicle-controlled trials (Study 1 [NCT02368210] and Study 2 [NCT02742441]).

These trials were conducted in 560 subjects 18 years of age and older with plaque psoriasis involving between 2% and 12% body surface area. Baseline disease severity was determined using a static, five-level Investigator’s Global Assessment (IGA) scale, on which a subject scored either moderate or severe. Overall, approximately 60% of subjects were male and approximately 90% were Caucasian.

Subjects applied LEXETTE or vehicle to all affected areas twice daily for up to 14 consecutive days.

The primary measure of efficacy was Overall Treatment Success, defined as the proportion of subjects who were cleared or almost cleared with at least a two-grade improvement from baseline at Week 2 (end of treatment) based on the IGA. The trials also evaluated treatment success for the individual signs of psoriasis (plaque elevation, scaling, and erythema) at the end of treatment. Table 2 presents these results.

Table 2. Efficacy Results at Week 2 in Subjects with Plaque Psoriasis:

* Subjects whose condition was cleared or almost cleared of all signs of psoriasis and with at least a two-grade improvement from baseline based on the IGA.
^† Subjects who were cleared or almost cleared of the designated clinical sign with at least a two-grade improvement from baseline. Individual signs were rated by severity using a five-point scale ranging from 0 (clear) to 4 (severe). Subjects with baseline value of 0 or 1 were excluded.