ULTRAVATE Lotion Ref.[11105] Active ingredients: Ulobetasol

Vasoconstriction

A vasoconstrictor assay in healthy subjects with ULTRAVATE lotion 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 the following two studies. In both studies, 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, ACTH). In the first study, ULTRAVATE lotion was applied to 20 adult subjects with moderate to severe plaque psoriasis. A mean dose of 3.5 grams ULTRAVATE lotion was applied twice daily for two weeks and produced HPA axis suppression in 5 of 20 (25%) subjects. The effects of HPA axis suppression were reversible on retesting at least four weeks after discontinuation of the treatment. In the second study, ULTRAVATE lotion was applied to 16 adolescent subjects 12 years to less than 17 years of age with moderate to severe plaque psoriasis affecting a mean body surface area of 11.5% (range from 10% to 14%). The mean dose was 3.6 grams applied twice daily for two weeks. A subset of 14 of the 16 completed subjects had evaluable ACTH stimulation tests, and HPA axis suppression was observed in 1 of these 14 subjects (7%). In the second study also, the effects of HPA axis suppression were reversible on retesting at least four weeks after discontinuation of the treatment.

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 clinical study [see Clinical Pharmacology (12.2)], pharmacokinetics was evaluated in a subgroup of 12 adult subjects. On Day 8, blood was taken just prior to and at 1, 2, 4, 6, 8, and 12 hours following the last application. Plasma concentration of halobetasol propionate (HBP) was measurable in all subjects. Based on the geometric mean plasma concentrations at 12 hours post-application across time, steady-state was achieved by Day 8. The mean (±standard deviation) C_max concentrations for ULTRAVATE lotion on Day 8 was 201.1 ± 157.5 pg/mL, with the corresponding median Tmax value of 3 hours (range 0–6 hours); mean area under the halobetasol propionate concentration versus time curve over the dosing interval (AUC_τ) was 1632 ± 1147 pg•h/mL.

Specific Populations

Pediatric Patients

In the pediatric HPA study [see Clinical Pharmacology (12.2)], trough plasma concentrations of HBP were measured on Day 8 and Day 15 in a subset of 14 subjects. The HBP levels in the plasma were below the quantification limit (20 pg/mL) for all subjects at all time points with the exception of one subject at Day 15 (trough concentration of HBP of 28.2 pg/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 halobetasol propionate lotion at dose concentrations from 0.05% to 0.1% or from 0.25 to 0.5 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 (NOAEL) 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 50 µg/kg/day indicated no impairment of fertility or general reproductive performance.

ULTRAVATE lotion was evaluated for the treatment of moderate to severe plaque psoriasis in two multicenter, randomized, double-blind, vehicle-controlled trials.

These trials were conducted in 443 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 global evaluation scale, on which a subject scored either moderate or severe. Overall, 57% of subjects were male and 86% were Caucasian.

Subjects applied ULTRAVATE lotion 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). Table 2 presents these results.

Table 2. Overall Treatment Success in Subjects with Plaque Psoriasis at Week 2:

^* Subjects whose condition was cleared or almost cleared of all signs of psoriasis and with at least a two grade improvement from baseline.

The secondary measures of efficacy were Treatment Success for individual signs of psoriasis (scaling, erythema, and plaque elevation) at the end of treatment (see Table 3).

Table 3. Individual Signs Treatment Success in Subjects with Plaque Psoriasis at Week 2:

^* Subjects who were cleared or almost cleared of the designated clinical sign with at least a two grade improvement from baseline.