Betamethasone Dipropionate

6 ADVERSE REACTIONS • The most common adverse reaction reported in 0.4% of adult patients is stinging. (6.1) • The most common adverse reactions reported in 10% of pediatric patients are signs of skin atrophy, telangiectasia, bruising, shininess. (6.1, 8.4) To report SUSPECTED ADVERSE REACTIONS, contact Perrigo at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 clinical practice. In controlled clinical trials, involving 242 adult subjects, the adverse reaction associated with the use of betamethasone dipropionate cream (augmented), 0.05% reported at a frequency of 0.4% was stinging. It occurred in 1 subject. In a controlled clinical trial involving 67 pediatric subjects from 3 months to 12 years of age, the adverse reactions associated with the use of betamethasone dipropionate cream (augmented), 0.05% occurred in 7 of 67 (10%) subjects. Reported reactions included signs of skin atrophy (telangiectasia, bruising, shininess). 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 topical corticosteroids may also include: burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, hypertrichosis, skin atrophy, striae, and miliaria. Hypersensitivity reactions, consisting of predominantly skin signs and symptoms, e.g., contact dermatitis, pruritus, bullous dermatitis, and erythematous rash have been reported. 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.

4 CONTRAINDICATIONS Betamethasone Dipropionate Cream USP (Augmented), 0.05% is contraindicated in patients who are hypersensitive to betamethasone dipropionate, to other corticosteroids, or to any ingredient in this preparation. • Hypersensitivity to any component of this medicine. (4)

11 DESCRIPTION Betamethasone Dipropionate Cream USP (Augmented), 0.05% contains betamethasone dipropionate USP, a synthetic adrenocorticosteroid, for topical use in a cream base. Betamethasone, an analog of prednisolone, has a high degree of corticosteroid activity and a slight degree of mineralocorticoid activity. Betamethasone dipropionate is the 17,21-dipropionate ester of betamethasone. Chemically, betamethasone dipropionate is 9-fluoro-11β,17,21-trihydroxy-16 β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate, with the empirical formula C 28 H 37 FO 7 , a molecular weight of 504.6, and the following structural formula: Betamethasone dipropionate is a white to creamy white, odorless crystalline powder, insoluble in water. Each gram of Betamethasone Dipropionate Cream USP (Augmented), 0.05% contains: 0.643 mg betamethasone dipropionate USP (equivalent to 0.5 mg betamethasone) in a white cream base of carbomer homopolymer type C; ceteareth-30; chlorocresol; cyclomethicone; glyceryl oleate/propylene glycol; propylene glycol; purified water; sodium hydroxide; sorbitol solution; white petrolatum; and white wax. chemical-structure

2 DOSAGE AND ADMINISTRATION Apply a thin film of Betamethasone Dipropionate Cream USP (Augmented), 0.05% to the affected skin areas once or twice daily. Therapy should be discontinued when control is achieved. Betamethasone Dipropionate Cream USP (Augmented), 0.05% is a high-potency corticosteroid. Treatment with Betamethasone Dipropionate Cream USP (Augmented), 0.05% should not exceed 50 g per week because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis [ see Warnings and Precautions (5.1) ]. Betamethasone Dipropionate Cream USP (Augmented), 0.05% should not be used with occlusive dressings unless directed by a physician. Avoid contact with eyes. Wash hands after each application. Avoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site. Betamethasone Dipropionate Cream USP (Augmented), 0.05% is for topical use only. It is not for oral, ophthalmic, or intravaginal use. • Apply a thin film to the affected skin areas once or twice daily. (2) • Discontinue therapy when control is achieved. (2) • Use no more than 50 g per week. (2) • Do not use with occlusive dressings unless directed by a physician. (2) • Avoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site. (2) • Not for oral, ophthalmic, or intravaginal use. (2)

1 INDICATIONS AND USAGE Betamethasone Dipropionate Cream USP (Augmented), 0.05% is a corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 13 years of age or older. Betamethasone Dipropionate Cream USP (Augmented), 0.05% is a corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 13 years of age and older.0

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precise mechanism of action of Betamethasone Dipropionate Cream USP (Augmented), 0.05% in corticosteroid responsive dermatoses is unknown. 12.2 Pharmacodynamics Vasoconstrictor Assay Trials performed with betamethasone dipropionate cream (augmented), 0.05% indicate that it is in the high range of potency as demonstrated in vasoconstrictor trials in healthy subjects when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence. 12.3 Pharmacokinetics No pharmacokinetics trials have been conducted with Betamethasone Dipropionate Cream USP (Augmented), 0.05%. The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings [ see Dosage and Administration (2) ]. Topical corticosteroids can be absorbed through normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids [ see Dosage and Administration (2) ]. Once absorbed through the skin, topical corticosteroids enter pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees, are metabolized primarily in the liver, and excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.

12.1 Mechanism of Action Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precise mechanism of action of Betamethasone Dipropionate Cream USP (Augmented), 0.05% in corticosteroid responsive dermatoses is unknown.

12.2 Pharmacodynamics Vasoconstrictor Assay Trials performed with betamethasone dipropionate cream (augmented), 0.05% indicate that it is in the high range of potency as demonstrated in vasoconstrictor trials in healthy subjects when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.

12.3 Pharmacokinetics No pharmacokinetics trials have been conducted with Betamethasone Dipropionate Cream USP (Augmented), 0.05%. The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings [ see Dosage and Administration (2) ]. Topical corticosteroids can be absorbed through normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids [ see Dosage and Administration (2) ]. Once absorbed through the skin, topical corticosteroids enter pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees, are metabolized primarily in the liver, and excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.

20220401

4

3 DOSAGE FORMS AND STRENGTHS Cream, 0.05%. Each gram of Betamethasone Dipropionate Cream USP (Augmented), 0.05% contains 0.643 mg betamethasone dipropionate (equivalent to 0.5 mg betamethasone) in a white cream base. • Cream, 0.05% (3)

Betamethasone Dipropionate Betamethasone Dipropionate Betamethasone Dipropionate Betamethasone CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) CETEARETH-30 CHLOROCRESOL CYCLOMETHICONE GLYCERYL OLEATE PROPYLENE GLYCOL WATER SODIUM HYDROXIDE SORBITOL PETROLATUM WHITE WAX

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of betamethasone dipropionate. Betamethasone was negative in the bacterial mutagenicity assay ( Salmonella typhimurium and Escherichia coli ), and in the mammalian cell mutagenicity assay (CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus assay. Studies in rabbits, mice, and rats using intramuscular doses up to 1, 33, and 2 mg/kg, respectively, resulted in dose-related increases in fetal resorptions in rabbits and mice.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of betamethasone dipropionate. Betamethasone was negative in the bacterial mutagenicity assay ( Salmonella typhimurium and Escherichia coli ), and in the mammalian cell mutagenicity assay (CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus assay. Studies in rabbits, mice, and rats using intramuscular doses up to 1, 33, and 2 mg/kg, respectively, resulted in dose-related increases in fetal resorptions in rabbits and mice.

ANDA076592

Betamethasone Dipropionate

Betamethasone Dipropionate

71205-275

HUMAN PRESCRIPTION DRUG

TOPICAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Rx Only NDC 71205-275-15 Betamethasone Dipropionate Cream USP (Augmented*), 0.05% (Potency expressed as Betamethasone) *Vehicle Augments the Penetration of the Steroid. For Dermatologic Use Only. Not for Ophthalmic Use. NET WT 15 g 71205-275-15

Manufactured By Perrigo, Bronx, NY 10457 Distributed By Perrigo® Allegan, MI 49010 • www.perrigo.com Relabeled By Proficient Rx LP Thousand Oaks, CA 91320 Rev 08-18 0N200 RC JX2

17 PATIENT COUNSELING INFORMATION Inform patients of the following: • Discontinue therapy when control is achieved, unless directed otherwise by the physician. • Use no more than 50 grams per week. • Avoid contact with the eyes. • Advise patients to report any visual symptoms to their healthcare providers. • Avoid use of Betamethasone Dipropionate Cream USP (Augmented), 0.05% on the face, underarms, or groin areas unless directed by the physician. • Do not occlude the treatment area with bandage or other covering, unless directed by the physician. • Note that local reactions and skin atrophy are more likely to occur with occlusive use, prolonged use or use of higher potency corticosteroids.

14 CLINICAL STUDIES The safety and efficacy of betamethasone dipropionate cream (augmented), 0.05% for the treatment of corticosteroid-responsive dermatoses have been established in two randomized and active controlled trials in subjects with chronic plaque psoriasis. A total of 81 subjects who received betamethasone dipropionate cream (augmented), 0.05% were included in these trials. These trials evaluated betamethasone dipropionate cream (augmented), 0.05% applied once or twice daily for 14 and 21 days, respectively, on bilateral paired psoriatic lesions. Betamethasone dipropionate cream (augmented), 0.05% was shown to be effective in relieving the signs and symptoms of chronic plaque psoriasis.

8.5 Geriatric Use Clinical trials of betamethasone dipropionate cream (augmented), 0.05% included 104 subjects who were 65 years of age and over and 8 subjects who were 75 years of age and over. No overall differences in safety or effectiveness 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. However, greater sensitivity of some older individuals cannot be ruled out.

8.4 Pediatric Use Use of Betamethasone Dipropionate Cream USP (Augmented), 0.05% in pediatric patients younger than 13 years of age is not recommended due to the potential for HPA axis suppression [ see Warnings and Precautions (5.1) ]. In an open-label HPA axis safety trial in subjects 3 months to 12 years of age with atopic dermatitis, betamethasone dipropionate cream (augmented), 0.05% was applied twice daily for 2 to 3 weeks over a mean body surface area of 58% (range 35% to 95%). In 19 of 60 (32%) evaluable subjects, adrenal suppression was indicated by either a ≤5 mcg/dL pre-stimulation cortisol, or a cosyntropin post-stimulation cortisol ≤18 mcg/dL and/or an increase of <7 mcg/dL from the baseline cortisol. Out of the 19 subjects with HPA axis suppression, 4 subjects were tested 2 weeks after discontinuation of betamethasone dipropionate cream (augmented), 0.05%, and 3 of the 4 (75%) had complete recovery of HPA axis function. The proportion of subjects with adrenal suppression in this trial was progressively greater, the younger the age group [ see Warnings and Precautions (5.1) ]. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of systemic toxicity when treated with topical drugs. They are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency upon the use of topical corticosteroids. Rare systemic effects such as Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients, especially those with prolonged exposure to large doses of high potency topical corticosteroids. Local adverse reactions including skin atrophy have also been reported with use of topical corticosteroids in pediatric patients. Avoid use of Betamethasone Dipropionate Cream USP (Augmented), 0.05% in the treatment of diaper dermatitis.

8.1 Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Betamethasone Dipropionate Cream USP (Augmented), 0.05% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Betamethasone dipropionate has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0.05 mg/kg. The abnormalities observed included umbilical hernias, cephalocele, and cleft palate.

Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Betamethasone Dipropionate Cream USP (Augmented), 0.05% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Betamethasone dipropionate has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0.05 mg/kg. The abnormalities observed included umbilical hernias, cephalocele, and cleft palate.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Betamethasone Dipropionate Cream USP (Augmented), 0.05% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Betamethasone dipropionate has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0.05 mg/kg. The abnormalities observed included umbilical hernias, cephalocele, and cleft palate. 8.3 Nursing Mothers Systemically administered corticosteroids appear in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids can result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Betamethasone Dipropionate Cream USP (Augmented), 0.05% is administered to a nursing woman. 8.4 Pediatric Use Use of Betamethasone Dipropionate Cream USP (Augmented), 0.05% in pediatric patients younger than 13 years of age is not recommended due to the potential for HPA axis suppression [ see Warnings and Precautions (5.1) ]. In an open-label HPA axis safety trial in subjects 3 months to 12 years of age with atopic dermatitis, betamethasone dipropionate cream (augmented), 0.05% was applied twice daily for 2 to 3 weeks over a mean body surface area of 58% (range 35% to 95%). In 19 of 60 (32%) evaluable subjects, adrenal suppression was indicated by either a ≤5 mcg/dL pre-stimulation cortisol, or a cosyntropin post-stimulation cortisol ≤18 mcg/dL and/or an increase of <7 mcg/dL from the baseline cortisol. Out of the 19 subjects with HPA axis suppression, 4 subjects were tested 2 weeks after discontinuation of betamethasone dipropionate cream (augmented), 0.05%, and 3 of the 4 (75%) had complete recovery of HPA axis function. The proportion of subjects with adrenal suppression in this trial was progressively greater, the younger the age group [ see Warnings and Precautions (5.1) ]. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of systemic toxicity when treated with topical drugs. They are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency upon the use of topical corticosteroids. Rare systemic effects such as Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients, especially those with prolonged exposure to large doses of high potency topical corticosteroids. Local adverse reactions including skin atrophy have also been reported with use of topical corticosteroids in pediatric patients. Avoid use of Betamethasone Dipropionate Cream USP (Augmented), 0.05% in the treatment of diaper dermatitis. 8.5 Geriatric Use Clinical trials of betamethasone dipropionate cream (augmented), 0.05% included 104 subjects who were 65 years of age and over and 8 subjects who were 75 years of age and over. No overall differences in safety or effectiveness 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. However, greater sensitivity of some older individuals cannot be ruled out.

16 HOW SUPPLIED/STORAGE AND HANDLING Betamethasone Dipropionate Cream USP (Augmented), 0.05% is available as follows: 15 g tube (NDC 71205-275-15) Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature].