5.1 Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression and Other Adverse Endocrine Effects

LEXETTE is a topical corticosteroid that has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis.

Systemic effects of topical corticosteroids may include reversible HPA axis suppression, with the potential for glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of treatment of the topical corticosteroid. The potential for hypothalamic-pituitary adrenal (HPA) suppression with LEXETTE was evaluated in the following studies:

• In a study of 25 adult subjects with moderate to severe plaque psoriasis involving ≥15% of their body surface area. LEXETTE produced laboratory evidence of HPA axis suppression when used twice daily for two weeks in 6 out of 25 (24%) adult subjects with plaque psoriasis. All subjects returned to normal HPA axis function at follow-up at least 4 weeks after stopping the treatment [see Clinical Pharmacology (12.2)].
• In another clinical study, 24 subjects 12 to less than 18 years old with stable plaque psoriasis involving 10% or more of their body surface area applied LEXETTE to affected areas twice daily for two weeks. Of the 23 subjects evaluated for HPA axis suppression, laboratory evidence of adrenal suppression occurred in 6 subjects (26.1%), whom recovered upon retesting after at least 4 weeks of stopping the treatment [see Clinical Pharmacology (12.2)].

Because of the potential for systemic absorption, use of topical corticosteroids, including LEXETTE, may require that patients be evaluated periodically for evidence of HPA axis suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of more potent corticosteroids, use over large surface areas, prolonged use, occlusive use, use on an altered skin barrier, concomitant use of multiple corticosteroid-containing products, liver failure, and young age. An ACTH stimulation test may be helpful in evaluating patients for HPA axis suppression.

If HPA axis suppression is documented, attempt to gradually withdraw the drug, reduce the frequency of application, or substitute a less potent steroid. Manifestations of adrenal insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids.

Systemic effects of topical corticosteroids may also include Cushing's syndrome, hyperglycemia, and glucosuria. Use of more than one corticosteroid-containing product at the same time may increase the total systemic exposure to topical corticosteroids.

Pediatric patients may be more susceptible than adults to systemic toxicity from the use of topical corticosteroids due to their larger surface-to-body mass ratios [see Use in Specific Populations (8.4)].

5.2 Local Adverse Reactions

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

5.3 Ophthalmic Adverse Reactions

Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported in postmarketing experience with the use of topical corticosteroid products.

Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

5.4 Concomitant Skin Infections

Use an appropriate antimicrobial agent if a skin infection is present or develops. If a favorable response does not occur promptly, discontinue use of LEXETTE until the infection has been adequately treated.

5.5 Allergic Contact Dermatitis

Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation. Consider confirmation of a clinical diagnosis of allergic contact dermatitis by appropriate patch testing. Discontinue LEXETTE if allergic contact dermatitis is established.

5.6 Flammability

LEXETTE is flammable. Avoid fire, flame, or smoking during and immediately following application.

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 practice.

In randomized, multicenter, vehicle-controlled clinical trials, 351 adults with plaque psoriasis were treated with LEXETTE twice daily for up to two weeks (up to approximately 50 grams per week). Table 1 presents selected adverse reactions that occurred in at least 1% of subjects.

Skin atrophy (n=1) and telangiectasia (n=2) were reported with LEXETTE, but not with vehicle foam.

6.2 Postmarketing Experience

Because the 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 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 halobetasol propionate.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of LEXETTE in patients younger than 12 years of age have not been established; therefore, use in children younger than 12 years is not recommended.

The safety and effectiveness of LEXETTE for the treatment of stable plaque psoriasis in subjects 12 to less than 18 years of age is supported by evidence from adequate and well-controlled studies in adults and from one open-label safety study in 24 subjects aged 12 to less than 18 years. Subjects 12 to less than 18 years with stable plaque psoriasis covering a minimum of 10% of the total body surface area at baseline were treated twice daily for 2 weeks with LEXETTE. Hypothalamic-pituitary adrenal (HPA) axis function (ACTH stimulation test) was evaluated in a subset of 23 subjects. After 2 weeks of treatment, 6 of 23 subjects (26.1%) experienced laboratory evidence of adrenal suppression (i.e., cortisol serum level of ≤18 µg/dL) that recovered upon retesting after at least 4 weeks of stopping the treatment [see Clinical Pharmacology (12.2)].

Because of higher skin surface area to body mass ratios, 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 or after withdrawal of treatment. Adverse reactions including striae have been reported with use of topical corticosteroids in infants and children [see Warnings and Precautions (5.1)].

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, headaches, and bilateral papilledema [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

Clinical studies with LEXETTE included 131 subjects aged 65 years and over. No overall differences in safety or effectiveness were observed between these subjects and those younger than 65 years.

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 plaque psoriasis is unknown.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

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 from normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption.

In the HPA-axis and pharmacokinetic study, as described above in Clinical Pharmacology (12.2), pharmacokinetics was evaluated in a subgroup of 23 adult subjects with moderate to severe plaque psoriasis following twice daily treatment for 14 days. Plasma concentration of halobetasol propionate (HBP) was measurable in all subjects and steady state was achieved by Day 14. The mean (± standard deviation) Cmax concentration for HBP on Day 14 was 199.7 ± 217.3 pg/mL, with the corresponding median Tmax value of 1 hour (range 0 – 12 hours); mean area under the halobetasol propionate concentration versus time curve over the dosing interval (AUCt) was 1434.9 ± 1310.6 pg∙h/mL.

In the HPA axis study in subjects 12 to less than 18 years [see Clinical Pharmacology (12.2)], trough plasma concentrations of HBP were measured on Day 8 and Day 15 in 23 subjects following twice daily treatment for 14 days. On Day 8, nine (9) of the 23 evaluable subjects had morning trough concentrations of halobetasol propionate in plasma that were above the quantifiable limit (≥20.0 pg/mL); mean halobetasol concentration was 154.6 ± 308.67 pg/mL. Similarly, on Day 15, nine (9) of the 23 evaluable subjects had morning trough concentrations of halobetasol propionate above the quantifiable limit; mean halobetasol concentration was 59.9 ± 90.15 pg/mL. Of the 9 subjects with quantifiable plasma concentrations at Day 15, seven (7) also had quantifiable plasma concentrations at Day 8.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of halobetasol propionate.

In a 90-day repeat-dose toxicity study in rats, topical administration of LEXETTE at dose concentrations from 0.005% to 0.05% or from 0.011 to 0.11 mg/kg/day of halobetasol 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 of carcinogenesis.

Halobetasol propionate was not found to be genotoxic in the Ames/Salmonella assay, in the Chinese hamster CHO/HGPRT assay, in the mouse micronucleus test, in the sister chromatid exchange test in somatic cells of the Chinese hamster, or in the chromosome aberration test in somatic cells of Chinese hamsters. Positive mutagenicity effects were observed in two genotoxicity assays: Chinese hamster nuclear anomaly test and mouse lymphoma gene mutation assay in vitro.

Studies in the rat following oral administration at dose levels up to 0.05 mg/kg/day indicated no impairment of fertility or general reproductive performance.

16.1 How Supplied

LEXETTE, 0.05% is a white to off-white foam. It is supplied in aluminum cans of:

50 grams (NDC 51862-604-50)

100 grams (2 cans of 50 grams) (NDC 51862-604-02)

16.2 Storage

Store at 20°-25°C (68°-77°F); excursions permitted to 15ºC and 30ºC (59ºF to 86ºF). Contents under pressure. Do not puncture or incinerate. Do not expose to heat or store at temperatures above 120°F (49°C). Do not freeze.

16.3 Handling

LEXETTE is flammable; avoid heat, flame, or smoking when using this product.