5.1 Effects on Endocrine System

Betamethasone Dipropionate Cream USP (Augmented), 0.05% can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or after withdrawal of treatment.

Factors that predispose 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.

Betamethasone dipropionate cream (augmented), 0.05% was applied once daily at 7 grams per day for 1 week to diseased skin, in adult subjects with psoriasis or atopic dermatitis, to study its effects on the HPA axis. The results suggested that the drug lowered adrenal corticosteroid secretion, although plasma cortisol levels did not go below the lower limit of the normal range.

In an open-label pediatric trial of 60 evaluable subjects (3 months to 12 years of age), 19 subjects showed evidence of HPA axis suppression. Four (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.

If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids.

Cushing’s syndrome and hyperglycemia may also occur with topical corticosteroids. These events are rare and generally occur after prolonged exposure to excessively large doses, especially of high-potency topical corticosteroids.

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)].

5.2 Ophthalmic Adverse Reactions

Use of topical corticosteroids, including Betamethasone Dipropionate Cream USP (Augmented), 0.05%, may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported postmarketing with the use of topical corticosteroid products, including Betamethasone Dipropionate Cream USP (Augmented), 0.05% [see Adverse Reactions (6.2)].

Avoid contact of Betamethasone Dipropionate Cream USP (Augmented), 0.05% with eyes. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

5.3 Allergic Contact Dermatitis

Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation. Such an observation should be corroborated with appropriate diagnostic patch testing. If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted.

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.

8.1 Pregnancy

Risk Summary

There are no available data on Betamethasone Dipropionate Cream USP (Augmented), 0.05% 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 Betamethasone Dipropionate Cream USP (Augmented), 0.05% may increase the risk of having a low birthweight infant and to use Betamethasone Dipropionate Cream USP (Augmented), 0.05% 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 Betamethasone Dipropionate Cream USP (Augmented), 0.05% (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 excretion of betamethasone dipropionate in breast milk, the effects on the breastfed infant, or the effects on milk production after topical application of Betamethasone Dipropionate Cream USP (Augmented), 0.05% to women who are breastfeeding.

It is possible that 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 Betamethasone Dipropionate Cream USP (Augmented), 0.05% and any potential adverse effects on the breastfed infant from Betamethasone Dipropionate Cream USP (Augmented), 0.05% or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breast milk, use Betamethasone Dipropionate Cream USP (Augmented), 0.05% on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply Betamethasone Dipropionate Cream USP (Augmented), 0.05% directly to the nipple and areola to avoid direct infant exposure [see Use in Specific Populations (8.4)].

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.

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.

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.

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.

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.