Tovet (emollient Formulation) (Page 2 of 4)

8.2 Lactation

Risk Summary

There is no information regarding the presence of clobetasol propionate in breast milk or its effects on the breastfed infant or on milk production. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of clobetasol propionate 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 Tovet Foam and any potential adverse effects on the breastfed infant from Tovet Foam or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breast milk, use Tovet Foam on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply Tovet Foam directly to the nipple and areola to avoid direct infant exposure.

8.4 Pediatric Use

Use in pediatric patients younger than 12 years is not recommended because of the risk of HPA axis suppression.

After two weeks of twice-daily treatment with clobetasol propionate foam, 0.05% (emulsion), 7 of 15 subjects (47%) aged 6 to 11 years demonstrated HPA axis suppression. The laboratory suppression was transient; in all subjects serum cortisol levels returned to normal when tested 4 weeks post-treatment.

In 92 subjects aged 12 to 17 years, safety was similar to that observed in the adult population. Based on these data, no adjustment of dosage of Tovet Foam in adolescent patients aged 12 to 17 years is warranted [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 HPA axis suppression and Cushing’s syndrome when they are treated with topical corticosteroids. They are therefore also at greater risk of adrenal insufficiency during and/or after withdrawal of treatment.

HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles (in infants), headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children.

Adverse effects, including striae, have been reported with inappropriate use of topical corticosteroids in infants and children.

8.5 Geriatric Use

A limited number of subjects aged 65 years or older have been treated with clobetasol propionate foam, 0.05% (emulsion) (n = 58) in US clinical trials. While the number of subjects is too small to permit separate analysis of efficacy and safety, the adverse reactions reported in this population were similar to those reported by younger subjects. Based on available data, no adjustment of dosage of Tovet Foam in geriatric patients is warranted.

10 OVERDOSAGE

Topically applied Tovet Foam can be absorbed in sufficient amounts to produce systemic effects.

11 DESCRIPTION

Tovet (clobetasol propionate) Foam, 0.05% (Emulsion) is a white to off-white petrolatum-based emulsion aerosol foam containing the active ingredient clobetasol propionate, USP, a synthetic corticosteroid for topical dermatologic use. Clobetasol, an analog of prednisolone, has a high degree of glucocorticoid activity and a slight degree of mineralocorticoid activity.

Clobetasol propionate is 21-chloro-9-fluoro-11ß,17-dihydroxy-16ß-methylpregna-1,4-diene-3,20-dione 17-propionate, with the empirical formula C₂₅ H₃₂ ClFO₅ , and a molecular weight of 466.97.

The following is the chemical structure:

Clobetasol Propionate, USP

Clobetasol propionate is a white to almost white crystalline powder, practically insoluble in water.

Each gram of Tovet Foam contains 0.5 mg clobetasol propionate, USP. The foam also contains anhydrous citric acid, cetyl alcohol, cyclomethicone, glycerin, isopropyl myristate, polyoxyl 20 cetostearyl ether, potassium citrate monohydrate, propylene glycol, purified water, sorbitan monolaurate, and phenoxyethanol as a preservative.

Tovet Foam is dispensed from an aluminum can pressurized with a hydrocarbon (propane/butane) propellant.

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 in corticosteroid-responsive dermatoses is unknown.

12.2 Pharmacodynamics

In a trial evaluating the potential for HPA axis suppression using the cosyntropin stimulation test, clobetasol propionate foam, 0.05% (emulsion) demonstrated reversible adrenal suppression after two weeks of twice-daily use in subjects with atopic dermatitis of at least 30% body surface area (BSA). The proportion of subjects aged 12 years and older demonstrating HPA axis suppression was 16.2% (6 out of 37). In this trial HPA axis suppression was defined as serum cortisol level ≤18 mcg/dL 30 minutes post cosyntropin stimulation. The laboratory suppression was transient; in all subjects serum cortisol levels returned to normal when tested 4 weeks post treatment. [see Warnings and Precautions (5.1), Use In Specific Populations (8.4)].

12.3 Pharmacokinetics

Topical corticosteroids can be absorbed from intact healthy skin. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the product formulation and the integrity of the epidermal barrier. Occlusion, inflammation, and/or other disease processes in the skin may increase percutaneous absorption. The use of pharmacodynamic endpoints for assessing the systemic exposure of topical corticosteroids may be necessary due to the fact that circulating levels are often below the level of detection. Once absorbed through the skin, topical corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some corticosteroids and their metabolites are also excreted in the bile.

Following twice-daily application of clobetasol propionate foam, 0.05% (emulsion) for one week to 32 adult subjects with mild to moderate plaque-type psoriasis, mean peak plasma concentrations (±SD) of 59 ± 36 pg/mL of clobetasol were observed at around 5 hours post dose on Day 8.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of clobetasol propionate foam, 0.05% (emulsion) or clobetasol propionate.

In a 90-day repeat-dose toxicity study in rats, topical administration of clobetasol propionate foam, 0.05% (emulsion) at dose concentrations from 0.001% to 0.1% or from 0.03 to 0.3 mg/kg/day of clobetasol propionate resulted in a toxicity profile consistent with long-term exposure to corticosteroids including adrenal atrophy, histopathological changes in several organ systems indicative of severe immune suppression and opportunistic fungal and bacterial infections. A no observable adverse effect level could not be determined in this study. Although the clinical relevance of the findings in animals to humans is not clear, sustained glucocorticoid-related immune suppression may increase the risk of infection and possibly the risk for carcinogenesis.

Clobetasol propionate was non-mutagenic in the Ames test, the mouse lymphoma test, the Saccharomyces cerevisiae gene conversion assay, and the E. coli B WP2 fluctuation test. In the in vivo mouse micronucleus test, a positive finding was observed at 24 hours, but not at 48 hours, following oral administration at a dose of 2,000 mg/kg.

Studies in the rat following subcutaneous administration of clobetasol propionate at dosage levels up to 0.05 mg/kg per day revealed that the females exhibited an increase in the number of resorbed embryos and a decrease in the number of living fetuses at the highest dose.

14 CLINICAL STUDIES

In a randomized trial of subjects 12 years and older with moderate to severe atopic dermatitis, 251 subjects were treated with clobetasol propionate foam, 0.05% (emulsion) and 126 subjects were treated with vehicle foam. Subjects were treated twice daily for 2 weeks. At the end of treatment, 131 of 251 subjects (52%) treated with clobetasol propionate foam, 0.05% (emulsion) compared with 18 of 126 subjects (14%) treated with vehicle foam achieved treatment success. Treatment success was defined by an Investigator’s Static Global Assessment (ISGA) score of clear (0) or almost clear (1) with at least 2 grades improvement from baseline, and scores of absent or minimal (0 or 1) for erythema and induration/papulation.

In an additional randomized trial of subjects 12 years and older with mild to moderate plaque-type psoriasis, 253 subjects were treated with clobetasol propionate foam, 0.05% (emulsion) and 123 subjects were treated with vehicle foam. Subjects were treated twice daily for 2 weeks. At the end of treatment, 41 of 253 subjects (16%) treated with clobetasol propionate foam, 0.05% (emulsion) compared with 5 of 123 subjects (4%) treated with vehicle foam achieved treatment success. Treatment success was defined by an ISGA score of clear (0) or almost clear (1) with at least 2 grades improvement from baseline, scores of none or faint/minimal (0 or 1) for erythema and scaling, and a score of none (0) for plaque thickness.