Source: FDA, National Drug Code (US) Revision Year: 2021
Enstilar Foam combines the pharmacological effects of calcipotriene hydrate as a synthetic vitamin D3 analog and betamethasone dipropionate as a synthetic corticosteroid. However, while their pharmacologic and clinical effects are known, the exact mechanisms of their actions in the treatment of plaque psoriasis are unknown.
HPA axis suppression as indicated by a 30-minute post-stimulation cortisol level of ≤18 mcg/dL was evaluated in the following trials [see Warnings and Precautions (5.3)]:
Enstilar Foam is in the mid to potent range corticosteroid as demonstrated by studies in healthy subjects when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.
The PK of Enstilar Foam was investigated in both adults (N=35) and a subset of pediatric subjects with plaque psoriasis age 12 to 17 years (N=33) following once daily application of Enstilar Foam on the body and scalp for 4 weeks.
Enstilar Foam was applied to adult subjects with moderate to severe plaque psoriasis affecting a mean body surface area of 18% and mean scalp area of 50%. Following application of a mean ± SD weekly dose of 62 ± 28 grams of Enstilar Foam, calcipotriene was quantifiable in 1 of 35 (3%) subjects and its main metabolite, MC1080, in 3 of 35 (9%) subjects. For subjects with measurable concentrations, the maximal plasma concentrations (Cmax) and area under the concentration curve until the last measured time point (AUClast) for calcipotriene were 55.9 pg/mL and 82.5 pg*h/mL, respectively; and the mean ± SD Cmax and AUClast for MC1080 was 24.4 ± 1.9 pg/mL and 59.3 ± 5.4 pg*h/mL, respectively. Betamethasone dipropionate was quantifiable in 5 of 35 (14%) subjects and its main metabolite, betamethasone 17-propionate (B17P), was quantifiable in 27 of 35 (77%) subjects. The mean ± SD Cmax and AUClast for betamethasone dipropionate were 52.2 ± 19.7 pg/mL and 36.5 ± 27.4 pg*h/mL, respectively and for B17P were 147.9 ± 224.0 pg/mL and 683.6 ± 910.6 pg*h/mL, respectively.
Enstilar Foam was applied to pediatric subjects age 12 to 17 years with moderate plaque psoriasis affecting a mean body surface area of 16% and mean scalp area of 56%. Following application of a mean ± SD weekly dose of 47 ± 22 grams of Enstilar Foam, calcipotriene and its metabolite MC1080 were below the lower limit of quantification in all plasma samples. Betamethasone dipropionate was quantifiable in 12 of 33 (36%) subjects with the Cmax ranging from 31.1-480 pg/mL. The metabolite of betamethasone 17-propionate (B17P) was quantifiable in 6 of 33 (18%) subjects with the Cmax ranging from 30.8–91.7 pg/mL.
Calcipotriene: Calcipotriene metabolism following systemic uptake is rapid and occurs in the liver. The primary metabolites of calcipotriene are less potent than the parent compound.
Calcipotriene is metabolized to MC1046 (the α,β-unsaturated ketone analog of calcipotriene), which is metabolized further to MC1080 (a saturated ketone analog). MC1080 is the major metabolite in plasma. MC1080 is slowly metabolized to calcitroic acid.
Betamethasone dipropionate: Betamethasone dipropionate is metabolized to betamethasone 17-propionate (B17P) and betamethasone, including the 6β-hydroxy derivatives of those compounds by hydrolysis. Betamethasone 17-propionate (B17P) is the primary metabolite.
When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10, and 30 mcg/kg/day (9, 30, and 90 mcg/m²/day, respectively), no significant changes in tumor incidence were observed when compared to control.
A 104-week oral carcinogenicity study was conducted with calcipotriene in male and female rats at doses of 1, 5, and 15 mcg/kg/day (6, 30, and 90 mcg/m²/day, respectively). Beginning week 71, the dosage for high-dose animals of both genders was reduced to 10 mcg/kg/day (60 mcg/m²/day). A treatment-related increase in benign C-cell adenomas was observed in the thyroid of females that received 15 mcg/kg/day. A treatment-related increase in benign pheochromocytomas was observed in the adrenal glands of males that received 15 mcg/kg/day. No other statistically significant differences in tumor incidence were observed when compared to control. The relevance of these findings to patients is unknown.
When betamethasone dipropionate was applied topically to CD-1 mice for up to 24 months at dosages approximating 1.3, 4.2, and 8.5 mcg/kg/day in females, and 1.3, 4.2, and 12.9 mcg/kg/day in males (up to 26 mcg/m²/day and 39 mcg/m²/day, in females and males, respectively), no significant changes in tumor incidence were observed when compared to control.
When betamethasone dipropionate was administered via oral gavage to male and female Sprague Dawley rats for up to 24 months at dosages of 20, 60, and 200 mcg/kg/day (120, 360, and 1200 mcg/m²/day, respectively), no significant changes in tumor incidence were observed when compared to control.
Calcipotriene did not elicit any genotoxic effects in the Ames mutagenicity assay, the mouse lymphoma TK locus assay, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Betamethasone dipropionate did not elicit any genotoxic effects in the Ames mutagenicity assay, the mouse lymphoma TK locus assay, or in the rat micronucleus test.
Studies in rats with oral doses of up to 54 mcg/kg/day (324 mcg/m²/day) of calcipotriene indicated no impairment of fertility or general reproductive performance. Studies in male rats at oral doses of up to 200 mcg/kg/day (1200 mcg/m²/day), and in female rats at oral doses of up to 1000 mcg/kg/day (6000 mcg/m²/day), of betamethasone dipropionate indicated no impairment of fertility.
Two multicenter, randomized, double-blind trials were conducted in adult subjects with plaque psoriasis.
Efficacy was assessed with treatment success defined as the proportion of subjects at Week 4 who were “Clear” or “Almost Clear” according to the IGA. Subjects with “Mild” disease at baseline were required to be “Clear” to be considered a treatment success. Table 1 presents the efficacy results for these trials.
Table 1. Percentage of Subjects Achieving Treatment Success According to the Investigator’s Global Assessment of Disease Severity*:
| Enstilar Foam | Betamethasone dipropionate in vehicle | Calcipotriene in vehicle | Vehicle | |
|---|---|---|---|---|
| Trial One Week 4 | (N=100) 45.0% | (N=101) 30.7% | (N=101) 14.9% | |
| Trial Two Week 4 | (N=323) 53.3% | (N=103) 4.8% |
A randomized, double-blind, vehicle-controlled trial (NCT02899962) evaluated the long-term use of Enstilar Foam in subjects who achieved treatment success (defined as IGA score of “Clear” or “Almost Clear” with at least a 2 grade improvement from baseline) after an initial 4-week treatment with once daily Enstilar Foam. These subjects (N=521) were randomized to receive Enstilar Foam or vehicle foam twice weekly on 2 non-consecutive days for up to 52 additional weeks. Subjects experiencing loss of response (defined as an IGA score of at least “Mild”) were treated once daily with Enstilar Foam for 4 weeks, and those who regained an IGA score of “Clear” or “Almost Clear” after 4 weeks then continued randomized treatment. Disease severity was graded using a 5-point IGA. The majority of subjects in this trial (82%) had disease of “Moderate” severity at baseline, 11% of subjects had disease of “Mild” severity at baseline, and 7% of subjects had “Severe” disease at baseline. The extent of disease involvement assessed by mean body surface area was 8.3% (range 1 to 38%) at baseline.
The median time to loss of response was 56 days for subjects treated with Enstilar Foam twice weekly compared to 30 days for subjects treated with vehicle foam twice weekly. Over the 52-week assessment period, subjects in the Enstilar Foam twice weekly group experienced loss of response a median of 2.0 times compared to 3.0 times for subjects in the vehicle foam twice weekly group. Figure 1 presents the percentage of subjects maintaining an IGA score of “Clear” or “Almost Clear” through Week 52 after randomization.
Figure 1. Percentage of Subjects Maintaining an IGA Score of “Clear” or “Almost Clear” Through Week 52 After Randomization:
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