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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
ENSTILAR (NDA-207589)
(BETAMETHASONE DIPROPIONATE; CALCIPOTRIENE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/16/2020 (SUPPL-10)
5 Warnings and Precautions
5.3 Effects on Endocrine SystemHypothalamic-Pituitary-Adrenal Axis Suppression
Additions and/or revisions underlined:
… The following trials evaluated the effects of
Enstilar Foam on HPA axis suppression [see
Clinical Pharmacology (12.2)]:
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 adolescent subjects age 12 to 17 years applied Enstilar Foam on the body and scalp. Adrenal suppression occurred in 3 (9%) of the subjects.
In a trial, 21 subjects aged 18 years and older with plaque psoriasis applied Enstilar Foam once daily for 4 weeks and then twice weekly on 2 non-consecutive days for 52 weeks, including once daily for 4 weeks if loss of response occurred. Adrenal suppression was observed in 2 (10%) of the subjects.
6 Adverse Reactions
6.1 Clinical Trials Experience
Clinical Trials Conducted in Subjects 12 to 17 years with Psoriasis
Additions and/or revisions underlined:
… 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)].
6.2 Postmarketing Experience
Additions and/or revisions underlined:
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 pain/burning.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or revisions underlined:
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 to use more than 60 grams every 4 days.
…
Before you use Enstilar Foam, tell your healthcare provider about all of your medical conditions, including if you:
Newly added information:
Have thinning skin (atrophy) at the treatment site
Before you use Enstilar Foam, tell your healthcare provider about all of your medical conditions, including if you:
Newly added information:
Gently rub in Enstilar Foam to your affected areas.
Additions and/or revisions underlined:
What are the possible side effects of Enstilar Foam?
Enstilar Foam may cause serious side effects, including:
Enstilar® Foam can pass through your skin. Too much Enstilar Foam passing through your skin can cause your adrenal glands to stop working properly. Your healthcare provider may do blood tests to check for adrenal gland problems. Your healthcare provider may tell you to stop or temporarily stop treatment with Enstilar Foam.
Skin problems, including reactions where Enstilar Foam is applied, and allergic reactions (allergic contact dermatitis). Tell your healthcare provider if you have any skin problems, including:
thinning of your skin
dryness
burning
changes in skin color
inflammation
redness
itching
infection
irritation
raised bumps on your skin
07/30/2019 (SUPPL-5)
5 Warnings and Precautions
5.3 Effects on Endocrine System(additions underlined)
Hypothalamic-Pituitary-Adrenal Axis Suppression
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:
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.
Cushing’s Syndrome and Hyperglycemia
Systemic effects of topical corticosteroids may also include Cushing's syndrome, hyperglycemia, and glucosuria.
Additional Considerations for Endocrine Adverse Reactions
Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios .
Use of more than one corticosteroid-containing product at the same time may increase the total systemic corticosteroid exposure.
(new subsection added)
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 Adverse Reactions
6.1 Clinical Trials Experience(additions underlined)
…
Clinical Trials Conducted in Subjects 18 years and older with Psoriasis
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. 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.
Clinical Trials Conducted in Subjects 12 to 17 years with 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 pediatric subjects treated were acne, erythema, application site pain, and skin reactions.
(additions underlined)
…
Ophthalmic adverse reactions of cataracts, glaucoma, increased intraocular pressure, and central serous chorioretinopathy have been reported with the use of topical corticosteroids, including topical betamethasone products.
8 Use in Specific Populations
8.1 Pregnancy(PLLR conversion, please refer to label for complete information)
(PLLR conversion)
Risk Summary
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. 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 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.
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.
(additions underlined)
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%).
…
The safety and effectiveness of Enstilar Foam in pediatric patients less than 12 years of age have not been established.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(additions underlined)
…
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.
HPA Axis Suppression, Cushing’s Syndrome, and Hyperglycemia
Advise patients that Enstilar Foam can cause HPA access suppression, Cushing’s syndrome, and/or hyperglycemia.
Ophthalmic Adverse Reactions
Advise patients to avoid contact of Enstilar Foam with eyes and to report any visual symptoms.
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 .
Advise breastfeeding women not to apply Enstilar Foam directly to the nipple and areola to avoid direct infant exposure.
…
07/30/2019 (SUPPL-6)
5 Warnings and Precautions
5.3 Effects on Endocrine System(additions underlined)
Hypothalamic-Pituitary-Adrenal Axis Suppression
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:
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.
Cushing’s Syndrome and Hyperglycemia
Systemic effects of topical corticosteroids may also include Cushing's syndrome, hyperglycemia, and glucosuria.
Additional Considerations for Endocrine Adverse Reactions
Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios .
Use of more than one corticosteroid-containing product at the same time may increase the total systemic corticosteroid exposure.
(new subsection added)
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 Adverse Reactions
6.1 Clinical Trials Experience
(additions underlined)
…
Clinical Trials Conducted in Subjects 18 years and older with Psoriasis
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. 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.
Clinical Trials Conducted in Subjects 12 to 17 years with 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 pediatric subjects treated were acne, erythema, application site pain, and skin reactions.
6.2 Postmarketing Experience
(additions underlined)
…
Ophthalmic adverse reactions of cataracts, glaucoma, increased intraocular pressure, and central serous chorioretinopathy have been reported with the use of topical corticosteroids, including topical betamethasone products.
8 Use in Specific Populations
8.1 Pregnancy
(PLLR conversion, please refer to label for complete information)
8.2 Lactation
(PLLR conversion)
Risk Summary
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. 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 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.
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.
8.4 Pediatric Use
(additions underlined)
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%).
…
The safety and effectiveness of Enstilar Foam in pediatric patients less than 12 years of age have not been established.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(additions underlined)
…
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.
HPA Axis Suppression, Cushing’s Syndrome, and Hyperglycemia
Advise patients that Enstilar Foam can cause HPA access suppression, Cushing’s syndrome, and/or hyperglycemia.
Ophthalmic Adverse Reactions
Advise patients to avoid contact of Enstilar Foam with eyes and to report any visual symptoms.
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 .
Advise breastfeeding women not to apply Enstilar Foam directly to the nipple and areola to avoid direct infant exposure.
…
07/30/2019 (SUPPL-7)
8 Use in Specific Populations
8.1 Pregnancy
(PLLR conversion, please refer to label for complete information)
8.2 Lactation
(PLLR conversion)
Risk Summary
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. 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 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.
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.