5.1 Flammability

The propellants in Enstilar Foam are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application.

5.2 Hypercalcemia and Hypercalciuria

Hypercalcemia and hypercalciuria have been observed with use of Enstilar Foam. If hypercalcemia or hypercalciuria develop, discontinue treatment until parameters of calcium metabolism have normalized. The incidence of hypercalcemia and hypercalciuria following Enstilar Foam treatment of more than 56 weeks has not been evaluated [see Clinical Pharmacology (12.2)].

5.3 Effects on Endocrine System

5.4 Allergic Contact Dermatitis

Allergic contact dermatitis has been observed with topical calcipotriene and topical corticosteroids. Allergic contact dermatitis to a topical corticosteroid is usually diagnosed by observing a failure to heal rather than a clinical exacerbation. Corroborate such an observation with appropriate diagnostic patch testing.

5.5 Ophthalmic Adverse Reactions

Use of topical corticosteroids, including Enstilar® Foam, may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported with the postmarketing use of topical corticosteroid products. Avoid contact with Enstilar Foam with eyes. Enstilar Foam may cause eye irritation. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Postmarketing reports for local adverse reactions to Enstilar Foam included application site burning.

Postmarketing reports for local adverse reactions to topical corticosteroids included atrophy, striae, telangiectasia, dryness, perioral dermatitis, secondary infection, and miliaria.

Ophthalmic adverse reactions of cataracts, glaucoma, and increased intraocular pressure have been reported with the use of topical corticosteroids, including topical betamethasone products.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of Enstilar Foam for the treatment of mild to severe plaque psoriasis have been established in pediatric patients age 12 to 17 years. The use of Enstilar Foam for this indication is supported by evidence from adequate and well-controlled trials in adults and from one uncontrolled trial in 106 adolescents age 12 to 17 years with psoriasis of the body and scalp. Calcium metabolism was evaluated in all pediatric subjects and no cases of hypercalcemia or clinically relevant changes in urinary calcium were reported. Hypothalamic pituitary adrenal (HPA) axis suppression was evaluated in a subset of 33 pediatric subjects with moderate plaque psoriasis of the body and scalp (mean body surface area involvement of 16% and mean scalp area involvement of 56%). After 4 weeks of once daily treatment with a mean weekly dose of 47 grams, HPA axis suppression was observed in 3 of 33 subjects (9%) [see Warnings and Precautions (5.2), Adverse Reactions (6.1) and Clinical Pharmacology (12.2)].

Because of a higher ratio of skin surface area to body mass, children under the age of 12 years are at particular risk of systemic adverse effects when they are treated with topical corticosteroids. Pediatric patients are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency with the use of topical corticosteroids including Enstilar Foam [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2)].

Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients treated with topical corticosteroids.

Local adverse reactions including striae have been reported with use of topical corticosteroids in pediatric patients.

The safety and effectiveness of Enstilar Foam in pediatric patients less than 12 years of age have not been established.

8.5 Geriatric Use

Of the total number of subjects in the controlled clinical studies of Enstilar Foam, 97 subjects were 65 years and over, and 21 were 75 and over.

No overall differences in safety or effectiveness of Enstilar Foam were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Calcipotriene Hydrate

Calcipotriene hydrate is a synthetic vitamin D analog and has the chemical name 9,10-secochola-5,7,10(19),22-tetraene-1,3,24-triol,24-cyclo-propyl-,monohydrate, (1α,3β,5Z,7E,22E,24S) with the empirical formula C27H40O3∙H2O), a molecular weight of 430.6, and the following structural formula (calcipotriene hydrate is a white to almost white, crystalline compound):

Betamethasone Dipropionate

Betamethasone dipropionate is a synthetic corticosteroid and 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

Each gram of Enstilar Foam contains 50 mcg of calcipotriene (equivalent to 52.2 mcg of calcipotriene hydrate) and 0.643 mg of betamethasone dipropionate (equivalent to 0.5 mg of betamethasone) in a base of white petrolatum, polyoxypropylene stearyl ether, mineral oil, all-rac-alpha-tocopherol, and butylhydroxytoluene. 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. Enstilar Foam has the appearance of a non-expanding foam that gradually collapses after spraying.

12.1 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 the treatment of plaque psoriasis are unknown.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Long-term Use

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

16.1 How Supplied

Enstilar (calcipotriene and betamethasone dipropionate) Foam, 0.005%/0.064% 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. It is available as:

• 60 gram can (NDC 50222-302-60)
• 120 gram (2 cans of 60 gram) (NDC 50222-302-66)

16.2 Storage

• Store Enstilar Foam at 20°C - 25°C (68°F - 77°F); excursions permitted between 15°C - 30°C (59°F - 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.
• Unused product should be discarded six months after the can has been opened.
• Keep out of the reach of children.

16.3 Handling

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

Flammability

Instruct patients that Enstilar Foam is flammable; avoid heat, flame, or smoking when applying this medication.

Administration Instructions

• Shake before use and spray the foam by holding the can in any orientation except horizontally.
• Gently rub in Enstilar Foam to your affected areas.
• Do not use more than 60 grams every 4 days.
• Discontinue therapy when control is achieved unless directed otherwise by the healthcare provider.
• Avoid use of Enstilar Foam on the face, underarms, groin or eyes. If this medicine gets on face or in mouth or eyes, wash area right away.
• Do not occlude the treatment area with a bandage or other covering unless directed by the healthcare provider. Instruct the patients not to use other products containing calcipotriene or a corticosteroid with Enstilar Foam without first talking to the healthcare provider.
• Wash hands after application.

Local Reactions and Skin Atrophy

Advise patients that local reactions and skin atrophy are more likely to occur with occlusive use, prolonged use or use of higher potency corticosteroids.

Hypercalcemia and Hypercalciuria

Advise patients that hypercalcemia and hypercalciuria have been observed with the use of Enstilar Foam [see Warnings and Precautions (5.2)].

HPA Axis Suppression, Cushing's Syndrome, and Hyperglycemia

Advise patients that Enstilar Foam can cause HPA axis suppression, Cushing's syndrome, and/or hyperglycemia [see Warnings and Precautions (5.3)].

Ophthalmic Adverse Reactions

Advise patients to avoid contact of Enstilar Foam with eyes and to report any visual symptoms [see Warnings and Precautions (5.5)].

Pregnancy and Lactation

• Advise pregnant women that Enstilar Foam may increase the potential risk of having a low birth weight infant and to use Enstilar Foam on the smallest area of skin and for the shortest duration possible [see Use in Specific Populations (8.1)].
• Advise breastfeeding women not to apply Enstilar Foam directly to the nipple and areola to avoid direct infant exposure [see Use in Specific Populations (8.2)].