1.1 Indication

IMPEKLO lotion is a super-high potent topical corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 18 years of age or older.

1.2 Limitations of Use

IMPEKLO lotion should not be used in the treatment of rosacea or perioral dermatitis.

Use in patients under 18 years of age is not recommended due to numerically high rates of HPA axis suppression [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)].

5.1 Effects on the Endocrine System

Clobetasol propionate is a highly potent topical corticosteroid that has been shown to suppress the HPA axis at the lowest doses tested.

Systemic absorption of topical corticosteroids has caused reversible adrenal suppression with the potential for clinical glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of the topical corticosteroid.

The effect of clobetasol propionate lotion, 0.05% on HPA axis function was assessed in adults in two trials, one for psoriasis and one for atopic dermatitis. In total, 8 of 10 evaluable subjects with moderate to severe plaque psoriasis experienced adrenal suppression following 4 weeks of clobetasol propionate lotion, 0.05% therapy. In follow-up testing, 1 of 2 subjects remained suppressed after 8 days.

Furthermore, 5 of 9 evaluable subjects with moderate to severe atopic dermatitis experienced adrenal suppression following 2 weeks of clobetasol propionate lotion, 0.05% therapy. Of the 3 subjects that had follow-up testing, one subjects failed to recover adrenal function 7 days post-treatment. The proportion of subjects suppressed may be underestimated because the adrenal glands were stimulated weekly with cosyntropin in these trials.

Because of the potential for systemic absorption, use of topical corticosteroids 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, young age, concomitant use of multiple corticosteroid-containing products and use in patients with liver failure.

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

An adrenocorticotropic 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 supplemental systemic corticosteroids. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids.

Pediatric patients may be more susceptible to systemic toxicity from use of topical corticosteroids. Use in patients under 18 years of age is not recommended due to numerically high rates of HPA axis suppression [see Use in Specific Populations (8.4)].

5.2 Ophthalmic Adverse Reactions

Use of topical corticosteroids, including IMPEKLO, may increase the risks of glaucoma and posterior subcapsular cataract. Glaucoma and cataracts have been reported in postmarketing experience with the use of topical corticosteroid products, including topical clobetasol products.

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

5.3 Local Adverse Reactions with Topical Corticosteroids

Local adverse reactions may occur more frequently with the use of occlusive dressings and higher potency corticosteroids, including clobetasol propionate. These reactions are listed in an approximate decreasing order of occurrence: folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, striae, miliaria, skin atrophy and telangiectasia. Some local adverse reactions may be irreversible. Clobetasol propionate is not recommended in patients with acne vulgaris, rosacea or perioral dermatitis.

5.4 Allergic Contact Dermatitis

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.

5.5 Concomitant Skin Infections

In the presence of dermatologic infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, use of IMPEKLO lotion should be discontinued until the infection has been adequately controlled.

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 with clobetasol propionate lotion, 0.05%, the following adverse reactions have been reported: burning/stinging, skin dryness, irritation, erythema, folliculitis, pruritus, skin atrophy, and telangiectasia. The pooled incidence of local adverse reactions in trials for psoriasis and atopic dermatitis with clobetasol propionate lotion, 0.05% at 1% or greater was:

Most local adverse events were rated as mild to moderate and they are not affected by age, race or gender.

Systemic absorption of topical corticosteroids has produced hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients.

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 propionate lotion, 0.05%.

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Endocrine Disorders: Cushing’s syndrome, adrenal suppression

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Eye Disorders: cataracts, glaucoma and increased intraocular pressure.

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Skin: rash, pain of skin, skin exfoliation, skin chapped, scaling, induration/papulation, lichenification.

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Other: psoriasis (aggravation), plaque elevation, excoriation.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Use of clobetasol propionate lotion, 0.05% in pediatric patients is not recommended due to the potential for HPA axis suppression [see Warnings and Precautions (5.1)].

The HPA axis suppression potential of clobetasol propionate lotion, 0.05% has been studied in adolescents (12 to 17 years of age) with moderate to severe atopic dermatitis covering a minimum of 20% of the total body surface area. Subjects were treated twice daily for 2 weeks with clobetasol propionate lotion, 0.05%. After 2 weeks of treatment, 9 out of 14 of the subjects experienced adrenal suppression. One out of 4 subjects who were retested remained suppressed two weeks post-treatment.

Because of 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 glucocorticosteroid insufficiency during and/or after withdrawal of treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children.

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 absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

8.5 Geriatric Use

Clinical studies of clobetasol propionate lotion, 0.05% did not include sufficient numbers of subjects aged 65 and over to adequately determine whether they respond differently than younger subjects. In general, dose selection for an elderly patient should be made with caution, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

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

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 occlusion.

Topical corticosteroids can be absorbed from normal intact skin. Inflammation and other disease processes in the skin may increase percutaneous absorption.

There are no human data regarding the distribution of corticosteroids to body organs following topical application. Nevertheless, once absorbed through the skin, topical corticosteroids are handled through metabolic pathways similar to systemically administered corticosteroids. They are metabolized, primarily in the liver, and are then excreted by the kidneys. In addition, some corticosteroids and their metabolites are also excreted in the bile.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study, clobetasol propionate was topically applied to rats at concentrations up to 0.005%. No drug-related increase in tumor incidence was observed.

Clobetasol propionate was negative in the in vitro mammalian chromosomal aberration test and in the in vivo mammalian erythrocyte micronucleus test.

In a fertility and reproductive toxicity study, clobetasol propionate was administered subcutaneously to rats at doses of 0, 12.5, 25, and 50 μg/kg/day. Males were treated beginning 70 days before mating and females beginning 15 days before mating through day 7 of gestation. A NOEL could not be determined for paternal and maternal toxicity or male reproductive toxicity because of decreased weight gain in both sexes and increased seminal vesicle weights in males. The female reproductive NOEL was 12.5 μg/kg/day because higher doses reduced the number of estrous cycles during the pre-cohabitation period and increased in the number of nonviable embryos.