Betamethasone Dipropionate

6 ADVERSE REACTIONS Most common adverse reactions (<1%) are: erythema, folliculitis, pruritus, and vesiculation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 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, adverse reactions associated with the use of Augmented Betamethasone Dipropionate Ointment reported at a frequency of less than 1% included erythema, folliculitis, pruritus, and vesiculation. 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: skin atrophy, telangiectasias, burning, irritation, dryness, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, hypertrichosis, 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 Augmented Betamethasone Dipropionate Ointment 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 Augmented Betamethasone Dipropionate Ointment, 0.05% contains betamethasone dipropionate USP, a synthetic adrenocorticosteroid, for topical use. 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-16β -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: It is a white to creamy-white, odorless powder insoluble in water; freely soluble in acetone and in chloroform; sparingly soluble in alcohol. Each gram of Augmented Betamethasone Dipropionate Ointment, 0.05% contains 0.643 mg betamethasone dipropionate USP (equivalent to 0.5 mg betamethasone), in a white ointment base of propylene glycol; propylene glycol stearate; white petrolatum; and white wax. Chemical Structure

2 DOSAGE AND ADMINISTRATION Apply a thin film of Augmented Betamethasone Dipropionate Ointment to the affected skin areas once or twice daily. Therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary. Augmented Betamethasone Dipropionate Ointment is a super-high-potency topical corticosteroid. Treatment with Augmented Betamethasone Dipropionate Ointment 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) ] . Augmented Betamethasone Dipropionate Ointment should not be used with occlusive dressings unless directed by a physician. Avoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site. Avoid contact with eyes. Wash hands after each application. Augmented Betamethasone Dipropionate Ointment 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 ) Limit therapy to no more than 2 consecutive weeks. ( 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 Augmented Betamethasone Dipropionate Ointment 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. Augmented Betamethasone Dipropionate Ointment 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. ( 1 )

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 Augmented Betamethasone Dipropionate Ointment in corticosteroid responsive dermatoses is unknown. 12.2 Pharmacodynamics Vasoconstrictor Assay Trials performed with Augmented Betamethasone Dipropionate Ointment, 0.05% indicate that it is in the super-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 Augmented Betamethasone Dipropionate Ointment. 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. 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 Augmented Betamethasone Dipropionate Ointment in corticosteroid responsive dermatoses is unknown.

12.2 Pharmacodynamics Vasoconstrictor Assay Trials performed with Augmented Betamethasone Dipropionate Ointment, 0.05% indicate that it is in the super-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 Augmented Betamethasone Dipropionate Ointment. 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. 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.

20231110

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3 DOSAGE FORMS AND STRENGTHS Ointment, 0.05%. Each gram of Augmented Betamethasone Dipropionate Ointment, 0.05% contains 0.643 mg betamethasone dipropionate (equivalent to 0.5 mg betamethasone) in a white to off-white ointment base. Ointment, 0.05% ( 3 )

Betamethasone Dipropionate betamethasone dipropionate betamethasone dipropionate betamethasone propylene glycol propylene glycol monopalmitostearate white wax petrolatum

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.

NDA018741

Betamethasone Dipropionate

betamethasone dipropionate

66993-897

HUMAN PRESCRIPTION DRUG

TOPICAL

PRINCIPAL DISPLAY PANEL - 15 g Tube Box NDC 66993-897-15 PRASCO Augmented Betamethasone Dipropionate Ointment, 0.05%* *Strength expressed as betamethasone For topical use only. Not for oral, ophthalmic, or intravaginal use. Rx only 15 g PRINCIPAL DISPLAY PANEL - 15 g Tube Box

Manufactured for: Prasco Laboratories Mason, OH 45040, USA Manufactured by: Delpharm Montréal Inc. Pointe-Claire, QC H9R 1B4, Canada The trademarks depicted herein are owned by their respective companies. uspi-gog1460-ot-2106r000

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient 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 of Augmented Betamethasone Dipropionate Ointment and no longer than 2 consecutive weeks. Avoid contact with the eyes. Advise patients to report any visual symptoms to their healthcare providers. Avoid use of Augmented Betamethasone Dipropionate Ointment 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. Advise a woman to use Augmented Betamethasone Dipropionate Ointment on the smallest area of skin and for the shortest duration possible while pregnant or breastfeeding. Advise breastfeeding women not to apply Augmented Betamethasone Dipropionate Ointment directly to the nipple and areola to avoid direct infant exposure.

14 CLINICAL STUDIES The safety and efficacy of Augmented Betamethasone Dipropionate Ointment for the treatment of corticosteroid-responsive dermatoses, psoriasis and atopic dermatitis, have been evaluated in three randomized active-controlled trials, two in psoriasis and one in atopic dermatitis. A total of 378 subjects, of whom 152 received Augmented Betamethasone Dipropionate Ointment, were included in these trials. These trials evaluated Augmented Betamethasone Dipropionate Ointment applied twice daily, for 14 days. Augmented Betamethasone Dipropionate Ointment was shown to be effective in relieving signs and symptoms of psoriasis and atopic dermatitis.

8.5 Geriatric Use Clinical trials of Augmented Betamethasone Dipropionate Ointment included 225 subjects who were 65 years of age and over and 46 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 Augmented Betamethasone Dipropionate Ointment 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, DIPROLENE ® AF Cream 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 DIPROLENE AF Cream, 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. 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 Augmented Betamethasone Dipropionate Ointment in the treatment of diaper dermatitis.

8.1 Pregnancy Risk Summary There are no available data on Augmented Betamethasone Dipropionate Ointment use in pregnant women to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Observational studies suggest an increased risk of low birthweight infants with the use of greater than 300 grams of potent or very potent topical corticosteroid during a pregnancy. Advise pregnant women that Augmented Betamethasone Dipropionate Ointment may increase the risk of having a low birthweight infant and to use Augmented Betamethasone Dipropionate Ointment on the smallest area of skin and for the shortest duration possible. In animal reproduction studies, increased malformations, including umbilical hernias, cephalocele, and cleft palate, were observed after intramuscular administration of betamethasone dipropionate to pregnant rabbits. The available data do not allow the calculation of relevant comparisons between the systemic exposure of betamethasone dipropionate in animal studies to the systemic exposure that would be expected in humans after topical use of Augmented Betamethasone Dipropionate Ointment (see Data ) . The background risk of major birth defects and miscarriage for 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 risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Betamethasone dipropionate has been shown to cause malformations 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 Risk Summary There are no available data on Augmented Betamethasone Dipropionate Ointment use in pregnant women to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Observational studies suggest an increased risk of low birthweight infants with the use of greater than 300 grams of potent or very potent topical corticosteroid during a pregnancy. Advise pregnant women that Augmented Betamethasone Dipropionate Ointment may increase the risk of having a low birthweight infant and to use Augmented Betamethasone Dipropionate Ointment on the smallest area of skin and for the shortest duration possible. In animal reproduction studies, increased malformations, including umbilical hernias, cephalocele, and cleft palate, were observed after intramuscular administration of betamethasone dipropionate to pregnant rabbits. The available data do not allow the calculation of relevant comparisons between the systemic exposure of betamethasone dipropionate in animal studies to the systemic exposure that would be expected in humans after topical use of Augmented Betamethasone Dipropionate Ointment (see Data ) . The background risk of major birth defects and miscarriage for 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 risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Betamethasone dipropionate has been shown to cause malformations 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. 8.2 Lactation Risk Summary There are no data regarding the presence of betamethasone dipropionate in human milk, the effects on the breastfed infant, or the effects on milk production after topical application of Augmented Betamethasone Dipropionate Ointment to women who are breastfeeding. It is possible that topical administration 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 Augmented Betamethasone Dipropionate Ointment and any potential adverse effects on the breastfed infant from Augmented Betamethasone Dipropionate Ointment or from the underlying maternal condition. Clinical Considerations To minimize potential exposure to the breastfed infant via breast milk, use Augmented Betamethasone Dipropionate Ointment on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply Augmented Betamethasone Dipropionate Ointment directly to the nipple and areola to avoid direct infant exposure [see Use in Specific Populations (8.4) ] . 8.4 Pediatric Use Use of Augmented Betamethasone Dipropionate Ointment 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, DIPROLENE ® AF Cream 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 DIPROLENE AF Cream, 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. 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 Augmented Betamethasone Dipropionate Ointment in the treatment of diaper dermatitis. 8.5 Geriatric Use Clinical trials of Augmented Betamethasone Dipropionate Ointment included 225 subjects who were 65 years of age and over and 46 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 Augmented Betamethasone Dipropionate Ointment 0.05% is a white ointment supplied in 15-g (NDC 66993-897-15) and 50-g (NDC 66993-897-49) tubes. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].