Source: FDA, National Drug Code (US) Revision Year: 2021
None.
The propellants in Enstilar Foam are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application.
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)].
Systemic absorption of topical corticosteroids can cause reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of treatment. Factors that predispose a patient to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure, and young age.
Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test. If HPA axis suppression is documented, gradually withdraw Enstilar Foam, reduce the frequency of application, or substitute with a less potent corticosteroid.
The following trials evaluated the effects of Enstilar Foam on HPA axis suppression [see Clinical Pharmacology (12.2)]:
Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria.
Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios [see Use in Specific Populations (8.4)].
Use of more than one corticosteroid-containing product at the same time may increase the total systemic corticosteroid exposure.
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.
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.
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.
The rates of adverse reactions described below were from three randomized, multicenter, vehicle and/or active-controlled clinical trials in adult subjects with plaque psoriasis [see Clinical Studies (14)]. Subjects applied study product once daily for 4 weeks, and the median weekly dose of Enstilar Foam was 25 grams. Adverse reactions reported in <1% of adult subjects treated with Enstilar Foam included: application site irritation, application site pruritus, folliculitis, skin hypopigmentation, hypercalcemia, urticaria, and exacerbation of psoriasis.
In one uncontrolled clinical trial, 106 subjects aged 12 to 17 years with plaque psoriasis of the scalp and body applied Enstilar Foam once daily for up to 4 weeks. The median weekly dose was 40 grams. Adverse reactions reported in <1% of adolescent subjects treated were acne, erythema, application site pain, and skin reactions [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.2)].
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.
Available data with Enstilar Foam are not sufficient to evaluate a drug-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. Although there are no available data on use of the calcipotriene component in pregnant women, systemic exposure to calcipotriene after topical administration of Enstilar Foam is likely to be low [see Clinical Pharmacology (12.3)].
Observational studies suggest an increased risk of having low birth weight infants with the maternal use of potent or super potent topical corticosteroids (see Data). 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.
In animal reproduction studies, oral administration of calcipotriene to pregnant rats during the period of organogenesis resulted in an increased incidence of minor skeletal abnormalities, including enlarged fontanelles and extra ribs (see Data). Oral administration of calcipotriene to pregnant rabbits during the period of organogenesis had no apparent effects on embryo-fetal development. Subcutaneous administration of betamethasone dipropionate to pregnant rats and rabbits during the period of organogenesis resulted in fetal toxicity, including fetal deaths, reduced fetal weight, and fetal malformations (cleft palate and crooked or short tail) (see Data). The available data do not allow the calculation of relevant comparisons between the systemic exposures of calcipotriene and betamethasone dipropionate observed in animal studies to the systemic exposures that would be expected in humans after topical use of Enstilar Foam.
The background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Available observational studies in pregnant women did not identify a drug-associated risk of major birth defects, preterm delivery, or fetal mortality with the use of topical corticosteroids of any potency. However, when the dispensed amount of potent or super potent topical corticosteroids exceeded 300 grams during the entire pregnancy, maternal use was associated with an increased risk of low birth weight in infants.
Embryo-fetal development studies with calcipotriene were performed by the oral route in rats and rabbits. Pregnant rats received dosages of 0, 6, 18, or 54 mcg/kg/day (0, 36, 108, and 324 mcg/m²/day, respectively) on days 6-15 of gestation (the period of organogenesis). There were no apparent effects on maternal survival, behavior, or body weight gain, no effects on litter parameters, and no effects on the incidence of major malformations in fetuses. Fetuses from dams dosed at 54 mcg/kg/day exhibited a significantly increased incidence of minor skeletal abnormalities, including enlarged fontanelles and extra ribs.
Pregnant rabbits were dosed daily with calcipotriene at exposures of 0, 4, 12, or 36 mcg/kg/day (0, 48, 144, and 432 mcg/m²/day, respectively) on days 6-18 of gestation (the period of organogenesis). Mean maternal body weight gain was reduced in animals dosed at 12 or 36 mcg/kg/day. The incidence of fetal deaths was increased in the group dosed at 36 mcg/kg/day; reduced fetal weight was also observed in this group. The incidence of major malformations among fetuses was not affected. An increase in the incidence of minor skeletal abnormalities, including incomplete ossification of sternebrae, pubic bones, and forelimb phalanges, was observed in the group dosed at 36 mcg/kg/day.
Embryo-fetal development studies with betamethasone dipropionate were performed via subcutaneous injection in mice and rabbits. Pregnant mice were administered doses of 0, 156, 625, or 2500 mcg/kg/day (0, 468, 1875, and 7500 mcg/m²/day, respectively) on days 7 through 13 of gestation (the period of organogenesis). Betamethasone dipropionate induced fetal toxicity, including fetal deaths, reduced fetal weight, malformations (increased incidence of the cleft palate and crooked or short tail), and minor skeletal abnormalities (delayed ossification of vertebra and sternebrae). Fetal toxicity was observed at the lowest exposure that was evaluated (156 mcg/kg/day).
Pregnant rabbits were injected subcutaneously at dosages of 0, 0.625, 2.5, and 10 mcg/kg/day (0, 7.5, 30, and 120 mcg/m²/day, respectively) on days 6 through 18 of gestation (the period of organogenesis). Betamethasone dipropionate induced fetal toxicity, including fetal deaths, reduced fetal weight, external malformations (including malformed ears, cleft palate, umbilical hernia, kinked tail, club foot, and club hand), and skeletal malformations (including absence of phalanges of the first digit and cranial dysplasia) at dosages of 2.5 mcg/kg/day and above.
Calcipotriene was evaluated for effects on peri- and post-natal development when orally administered to pregnant rats at dosages of 0, 6, 18 or 54 mcg/kg/day (0, 36, 108, and 324 mcg/m²/day, respectively) from gestation day 15 through day 20 postpartum. No remarkable effects were observed on any parameter, including survival, behavior, body weight, litter parameters, or the ability to nurse or rear pups.
Betamethasone dipropionate was evaluated for effects on peri- and post-natal development when orally administered to pregnant rats at dosages of 0, 100, 300, and 1000 mcg/kg/day (0, 600, 1800, and 6000 mcg/m²/day, respectively) from gestation day 6 through day 20 postpartum. Mean maternal body weight was significantly reduced on gestation day 20 in animals dosed at 300 and 1000 mcg/kg/day. The mean duration of gestation was slightly, but statistically significantly, increased at 100, 300, and 1000 mcg/kg/day. The mean percentage of pups that survived to day 4 was reduced in relation to dosage. On lactation day 5, the percentage of pups with a reflex to right themselves when placed on their back was significantly reduced at 1000 mcg/kg/day. No effects on the ability of pups to learn were observed, and the ability of the offspring of treated rats to reproduce was not affected.
There is no information regarding the presence of topically administered calcipotriene and betamethasone dipropionate in human milk, the effects on the breastfed infant, or the effects on milk production. Concentrations of calcipotriene in plasma are low after topical administration, and therefore, concentrations in human milk are likely to be low [see Clinical Pharmacology (12.3)]. It is not known whether topical administration of large amounts of betamethasone dipropionate could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Enstilar Foam and any potential adverse effects on the breastfed child from Enstilar Foam or from the underlying maternal condition.
To minimize potential exposure to the breastfed infant via breast milk, use Enstilar Foam on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply Enstilar Foam directly to the nipple and areola to avoid direct infant exposure [see Use in Specific Populations (8.4)].
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.
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.
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