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Cutivate Lotion

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Cutivate Lotion




CLINICAL PHARMACOLOGY

Mechanism Of Action

Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precise mechanism of action of CUTIVATE® Lotion in atopic dermatitis is unknown.

Pharmacodynamics

Vasoconstrictor Assay

Trials performed with CUTIVATE® Lotion indicate that it is in the medium range of potency as demonstrated in vasoconstrictor trials 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 an open label HPA axis suppression trial (Trial A), 42 pediatric subjects (ages 4 months to < 6 years) with moderate to severe atopic dermatitis covering ≥ 35% Body Surface Area (BSA) who were treated with an exaggerated dosing regimen of CUTIVATE® Lotion twice daily (rather than the indicated dosing regimen of once daily) for at least 3 to 4 weeks were assessed for HPA axis suppression. The mean BSA treated was 65%. None of the 40 evaluable subjects were suppressed. The criterion for HPA axis suppression was a serum cortisol level of less than or equal to 18 micrograms per deciliter at 30-minutes after cosyntropin stimulation.

Another open label HPA axis suppression trial (Trial B) enrolled 56 pediatric subjects (ages 3 months to 11 months) with moderate to severe atopic dermatitis covering ≥ 35% BSA. Subjects were treated with an exaggerated dosing regimen for of CUTIVATE® Lotion twice daily over a period of 3 or 4 weeks. The mean BSA treated was 54%. Out of 56 subjects, 49 were considered evaluable with respect to their adrenal axis function post-treatment. One of 49 subjects showed laboratory evidence of suppression immediately post treatment. The criterion for HPA axis suppression was a serum cortisol level of less than or equal to 18 micrograms per deciliter at 30-minutes after cosyntropin stimulation. Repeated test one week later showed the post cosyntropin stimulation testing serum cortisol returned to normal level (22.1 μg/dL). This 4-month old subject had a baseline treatment BSA of 94% and was reported to have received 100% of the twice-daily applications of CUTIVATE Lotion over the 27 day treatment period.

Pharmacokinetics

Absorption

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

Plasma fluticasone levels were measured in a subset of subjects 2 to 5 years and 11 months of age in HPA axis suppression trial (Trial A) described above. A total of 13 (62%) of 21 subjects tested had measurable fluticasone at the end of 3 to 4 weeks of treatment. The mean ± SD fluticasone plasma concentration was 0.16 ± 0.23 ng/mL. Three subjects aged 3, 4, and 4 years had fluticasone concentrations over 0.30 ng/mL, with one of them having a concentration of 0.82 ng/mL. No data were obtained for subjects < 2 years of age.

Distribution

The percentage of fluticasone propionate bound to human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone propionate is not significantly bound to human transcortin.

Metabolism

No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in a human skin homogenate.

Fluticasone propionate is metabolized in the liver by cytochrome P450 3A4-mediated hydrolysis of the 5fluoromethyl carbothiolate grouping. This transformation occurs in 1 metabolic step to produce the inactive 17β-carboxylic acid metabolite, the only known metabolite detected in man. This metabolite has approximately 2000 times less affinity than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

Clinical Studies

CUTIVATE® Lotion applied once daily was superior to vehicle in the treatment of atopic dermatitis in two clinical trials. The two trials enrolled 438 subjects with atopic dermatitis aged 3 months and older, of which 169 subjects were selected as having clinically significant signs of erythema, infiltration/papulation, and erosion/oozing/crusting at baseline. Clinically significant was defined as having moderate or severe involvement for at least two of the three signs (erythema, infiltrations/papulation, or erosion/oozing/crusting), in at least 2 body regions. Subjects who had moderate to severe disease in a single body region were excluded from the analysis.

Table 3 presents the percentage of subjects who completely cleared of erythema, infiltration/papulation and erosion/oozing/crusting at Week 4 out of those subjects with clinically significant baseline signs.

Table 3: Complete Clearance Rate For Patients with Clinically Significant Signs at Baseline

  CUTIVATE® Lotion Vehicle
Study 1 9/45 (20%) 0/37 (0%)
Study 2 7/44 (16%) 1/43 (2%)

Last reviewed on RxList: 1/28/2015
This monograph has been modified to include the generic and brand name in many instances.

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