5.1 Effects on Endocrine System

Clobetasol propionate foam, 0.05% (emulsion) has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis.

Systemic absorption of clobetasol propionate foam, 0.05% (emulsion) has caused reversible HPA axis suppression with the potential for clinical glucocorticoid insufficiency. This may occur during treatment or upon withdrawal of the topical corticosteroid. Use of clobetasol propionate foam, 0.05% (emulsion) for longer than 2 weeks may suppress the immune system [see Nonclinical Toxicology (13.1)].

In a trial including 37 subjects 12 years and older with atopic dermatitis of at least 30% body surface area (BSA), adrenal suppression was identified in 6 out of 37 subjects (16.2%) after 2 weeks of treatment with clobetasol propionate foam, 0.05% (emulsion) [see Clinical Pharmacology (12.2)].

Because of the potential for systemic absorption, use of clobetasol propionate foam, 0.05% (emulsion) may require that patients be periodically evaluated for HPA axis suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of more potent steroids, use over large surface areas, use over prolonged periods, use under occlusion, use on an altered skin barrier, and use in patients with liver failure.

An adrenocorticotrophic hormone (ACTH) stimulation test may be helpful in evaluating patients for HPA axis suppression. If HPA axis suppression is documented, an attempt should be made to gradually withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Manifestations of adrenal insufficiency may require systemic corticosteroids. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids.

Cushing's syndrome, hyperglycemia, and unmasking of latent diabetes mellitus can also result from systemic absorption of topical corticosteroids.

Use of more than 1 corticosteroid-containing product at the same time may increase the total systemic corticosteroid exposure.

Pediatric patients may be more susceptible to systemic toxicity from equivalent doses because of their larger skin surface-to-body mass ratios [see Use in Specific Populations (8.4)].

5.2 Local Adverse Reactions with Topical Corticosteroids

Local adverse reactions may be more likely to occur with occlusive use, prolonged use, or use of higher potency corticosteroids. Reactions may include atrophy, striae, telangiectasias, burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, and miliaria. Some local adverse reactions may be irreversible.

Allergic contact dermatitis to any component of topical corticosteroids is usually diagnosed by a failure to heal rather than a clinical exacerbation. Clinical diagnosis of allergic contact dermatitis can be confirmed by patch testing.

If irritation develops, treatment with Tovet Foam should be discontinued and appropriate therapy instituted.

5.3 Ophthalmic Adverse Reactions

Use of topical corticosteroids, including Tovet Foam, may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported postmarketing with the use of topical corticosteroids, including topical clobetasol products [see Adverse Reactions (6.2)].

Avoid contact of Tovet Foam with eyes. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

5.4 Concomitant Skin Infections

Concomitant skin infections should be treated with an appropriate antimicrobial agent. If the infection persists, Tovet Foam should be discontinued until the infection has been adequately treated.

5.5 Flammable Contents

The propellant in Tovet Foam is flammable. Avoid fire, flame, or smoking during and immediately following application. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120°F (49°C).

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 821 subjects exposed to clobetasol propionate foam, 0.05% (emulsion) and vehicle foam, the pooled incidence of local adverse reactions in trials for atopic dermatitis and psoriasis with clobetasol propionate foam, 0.05% (emulsion) was 1.9% for application site atrophy and 1.6% for application site reaction. Most local adverse events were rated as mild to moderate and they were not affected by age, race, or gender.

6.2 Postmarketing Experience

Because these 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.

The following adverse reactions have been identified during post-approval use of clobetasol formulations: erythema, pruritus, burning, alopecia, and dryness.

The following additional local adverse reactions have been reported with topical corticosteroids: folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, irritation, striae, and miliaria. They may occur more frequently with the use of occlusive dressings and higher potency corticosteroids, such as clobetasol propionate.

Cushing's syndrome has been reported in infants and adults as a result of prolonged use of topical clobetasol propionate formulations.

Ophthalmic adverse reactions may include cataracts, glaucoma, increased intraocular pressure, and central serous chorioretinopathy.

8.1 Pregnancy

8.2 Lactation

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.

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.

13.1 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.

16.1 How Supplied

Tovet® (clobetasol propionate) Foam, 0.05% (Emulsion) contains 0.5 mg of clobetasol propionate, USP per gram. The white emulsion aerosol foam is available as follows:

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

FLAMMABLE. AVOID FIRE, FLAME, OR SMOKING DURING AND IMMEDIATELY FOLLOWING APPLICATION. Contents under pressure. Do not puncture or incinerate. Do not expose to heat or store at temperatures above 120°F (49°C).

Keep out of reach of children.

Effects on Endocrine System

Tovet Foam may cause HPA axis suppression. Advise patients that use of topical corticosteroids, including Tovet Foam, may require periodic evaluation for HPA axis suppression. Topical corticosteroids may have other endocrine effects. Concomitant use of multiple corticosteroid-containing products may increase the total systemic exposure to topical corticosteroids. Patients should inform their physician(s) that they are using Tovet Foam if surgery is contemplated [see Warnings and Precautions (5.1)].

Ophthalmic Adverse Reactions

Advise patients to report any visual symptoms to their healthcare providers [see Warnings and Precautions (5.3)].

Local Adverse Reactions

Report any signs of local adverse reactions to the physician. Advise patients that local reactions and skin atrophy are more likely to occur with occlusive use or prolonged use [see Warnings and Precautions (5.2)].

Pregnancy

Advise a pregnant woman that use of Tovet Foam may cause fetal harm and to use Tovet Foam on the smallest area of skin and for the shortest duration possible [see Use in Specific Populations (8.1)].

Lactation

Advise a woman to 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 [see Use in Specific Populations (8.2)].

Important Administration Instructions

Patients using topical corticosteroids should receive the following information and instructions:

• This medication is to be used as directed by the physician. It is for external use only. Unless directed by the prescriber, it should not be used on the face, or in skin-fold areas, such as the underarms or groin. Avoid contact with the eyes or other mucous membranes. Wash hands after use.
• As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, contact the physician.
• Do not use for more than 50 grams per week of Tovet Foam, or an amount greater than 21 capfuls per week [see Dosage and Administration (2)].
• This medication is flammable; avoid heat, flame, or smoking when applying this product.