Calcipotriene and Betamethasone Dipropionate Foam, 0.005%/0.064%

Enstilar® Foam contains calcipotriene hydrate and betamethasone dipropionate. It is intended for topical use only.

Calcipotriene hydrate is a synthetic vitamin D3 analog.

Chemically, calcipotriene hydrate is 9,10-secochola-5,7,10(19),22-tetraene-1,3,24-triol,24-cyclo-propyl-,monohydrate, (1α,3ß,5Z,7E,22E,24S) with the empirical formula C27H40O3,H20, a molecular weight of 430.6, and the following structural formula:

Calcipotriene hydrate is a white to almost white, crystalline compound.

Betamethasone dipropionate is a synthetic corticosteroid.

Betamethasone dipropionate has the chemical name pregna-1,4-diene-3,20-dione-9-fluoro-11-hydroxy-16-methyl-17,21-bis(1 oxypropoxy)-(11β,16β), with the empirical formula C28H37FO7, a molecular weight of 504.6, and the following structural formula:

Betamethasone dipropionate is a white to almost white crystalline powder.

Enstilar® Foam is a white to off-white opalescent liquid in a pressurized aluminum spray can with a continuous valve and actuator. The propellants used in Enstilar® Foam are dimethyl ether and butane. At administration the product is a white to off-white foam after evaporation of the propellants. Each gram of Enstilar® Foam contains 52.2 mcg calcipotriene hydrate (equivalent to 50 mcg of calcipotriene) and 0.643 mg of betamethasone dipropionate (equivalent to 0.5 mg of betamethasone) in a base of white petrolatum, PPG-11 stearyl ether, mineral oil, all-rac-alpha-tocopherol, and butylhydroxytoluene.

Dosage Forms And Strengths

Enstilar® Foam is a white to off-white opalescent liquid in a pressurized aluminum spray can with a continuous valve and actuator. At administration the product is a white to off-white foam after evaporation of the propellants. Each gram of Enstilar® Foam contains 52.2 mcg calcipotriene hydrate (equivalent to 50 mcg of calcipotriene) and 0.643 mg of betamethasone dipropionate (equivalent to 0.5 mg of betamethasone).

Storage And Handling

Enstilar® Foam is a white to off-white opalescent liquid in a pressurized aluminum spray can with a continuous valve and actuator. At administration the product is a white to off-white foam after evaporation of the propellants.

Enstilar® Foam is available in aluminum cans of:

1 x 60 g (NDC 50222-302-60)
2 x 60 g (NDC 50222-302-66)

• Store Enstilar® Foam at 20 °- 25°C (68° -77°F); excursions pe rmitted between 15 °-30°C (59°-86°F) [See USP Controlled Room Temperature].
• Contents under pressure. Do not puncture or incinerate. Do not expose to heat or store at temperatures above 120°F (49°C). Do not freeze.
• The product should be used within six m onths after it has been opened.

• Enstilar® Foam is flammable; avoid heat, flame or smoking when using this product.

Manufactured by: Colep Laupheim GmbH & Co. KG Fockestraße 12 88471 Laupheim Germany (DE). Distributed by: LEO Pharma Inc. 1 Sylvan Way, Parsippany, NJ 07054. Revised: Mar 2016

No information provided.

Mechanism Of Action

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 plaque psoriasis are unknown.

Pharmacodynamics

Effects of once daily application of Enstilar® Foam for 4 weeks on calcium metabolism in adult subjects (N=564) with plaque psoriasis were examined in three randomized, multicenter, prospective vehicle- and/or active-controlled clinical trials. Following once daily application of Enstilar® Foam, elevated serum calcium levels outside the normal range were observed in 3 subjects. Elevated urinary calcium levels outside the normal range were observed in 17 subjects.

Pharmacokinetics

The pharmacokinetics (PK) of Enstilar® Foam was investigated in adult subjects (N = 35) with moderate to severe plaque psoriasis with a mean body surface area involvement of 17.5% and mean scalp involvement of 50.2%. Plasma concentrations of calcipotriene and betamethasone dipropionate and their main metabolites were measured after 4 weeks of once daily application of Enstilar® Foam. Following application of a mean ± SD total weekly dose of 61.8 ± 27.7 grams of Enstilar® Foam, calcipotriene was quantifiable in 1 of 35 (2.9%) subjects and its main metabolite, MC1080, in 3 of 35 (8.6%) 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 (14.3%) subjects and its main metabolite, betamethasone 17-propionate (B17P), was quantifiable in 27 of 35 (77.1%) 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. The clinical significance of these findings is unknown.

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,ß-unsaturated ketone analog of calcipotriene),which is metabolized further to MC1080 (a saturated ketone analog). MC1080 is the main 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 6ß-hydroxy derivatives of those compounds by hydrolysis. B17P is the primary metabolite.

Clinical Studies

Two multicenter, randomized, double-blind trials were conducted in subjects with plaque psoriasis. In Trial One, 302 subjects were randomized to 1 of 3 treatment groups: Enstilar® Foam, betamethasone dipropionate in the same vehicle, or calcipotriene hydrate in the same vehicle. In Trial Two, 426 subjects were randomized to 1 of 2 treatment groups: Enstilar® Foam or the vehicle alone. Baseline disease severity was graded using a 5-point Investigator's Global Assessment (IGA). At baseline subjects scored “Mild”, “Moderate”, or “Severe”. The majority of subjects in both trials (76% and 75%) had disease of “Moderate” severity at baseline, 14% and 15% of subjects had disease of “Mild” severity at baseline and 10% of subjects had “Severe” disease at baseline in both trials. The extent of disease involvement assessed by mean body surface area was 7.1% (range 2 to 28%) and 7.5% (range 2 to 30%). In both trials, subjects were treated once daily for up to 4 weeks.

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*

No information provided. Please refer to the WARNINGS AND PRECAUTIONS sections.