Included as part of the PRECAUTIONS section.
The propellants in Enstilar Foam are flammable. Instruct
the patient to avoid fire, flame, and smoking during and immediately following
Hypercalcemia And Hypercalciuria
hypercalciuria have been observed with use of Enstilar Foam. If hypercalcaemia
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 4 weeks has not been evaluated [see
Effects On Endocrine System
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
The following trials evaluated
the effects of Enstilar Foam on HPA axis suppression:
- In a trial evaluating the
effects of Enstilar Foam on the HPA axis, 35 adult subjects applied Enstilar
Foam on the body and scalp. Adrenal
suppression was not observed in any subjects after 4 weeks of treatment. In
another trial, 33 pediatric subjects age 12 to 17 years applied Enstilar Foam
on the body and scalp. Adrenal suppression occurred in 3 (9%) of the subjects.
CushingÃ¢â¬™s Syndrome And Hyperglycemia
Systemic effects of topical
corticosteroids may also include Cushing's syndrome, hyperglycemia, and
Additional Considerations For Endocrine
Pediatric patients may be more
susceptible to systemic toxicity due to their larger skin surface to body mass
ratios [see Use In Specific Populations].
Use of more than one
corticosteroid-containing product at the same time may increase the total systemic
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.
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 [see ADVERSE
Patient Counseling Information
See FDA-approved patient
labeling (PATIENT INFORMATION and Instructions for Use).
Instruct patients that Enstilar
Foam is flammable; avoid heat, flame, or smoking when applying this medication.
- Shake before use and spray the
foam by holding the can in any orientation except horizontally.
- Do not to use more than 60
grams every 4 days.
- Discontinue therapy when control is achieved unless directed otherwise by the
- 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
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].
HPA Axis Suppression, CushingÃ¢â¬™s
Syndrome, And Hyperglycemia
Advise patients that Enstilar
Foam can cause HPA access suppression, CushingÃ¢â¬™s syndrome, and/or hyperglycemia
[see WARNINGS AND PRECAUTIONS].
Ophthalmic Adverse Reactions
Advise patients to avoid
contact of Enstilar Foam with eyes and to report any visual symptoms [see WARNINGS
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].
- Advise breastfeeding women not
to apply Enstilar Foam directly to the nipple and areola to avoid direct infant
exposure [see Use In Specific Populations].
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.
Use In Specific Populations
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].
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 estimated background risk
of major birth defects and miscarriage of 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
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
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]. 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 (see Clinical
Considerations). The developmental and health benefits of breastfeeding
should be considered along with the motherÃ¢â¬™s clinical need for Enstilar® Foam
and any potential adverse effects on the breastfed child from Enstilar Foam or
from the underlying maternal condition.
Clinical Considerations 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].
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, ADVERSE
REACTIONS and CLINICAL PHARMACOLOGY].
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
and CLINICAL PHARMACOLOGY].
CushingÃ¢â¬™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
The safety and effectiveness of
Enstilar Foam in pediatric patients less than 12 years of age have not been
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.