5.1 Effects on the Endocrine System

Clobetasol Propionate Cream can cause reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or after withdrawal of treatment. Because of the potential for systemic absorption, use of topical corticosteroids, including Clobetasol Propionate Cream, may require that patients be evaluated periodically for evidence of HPA axis suppression.
Factors that predispose a patient 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. In a trial evaluating the effects of Clobetasol Propionate Cream on the HPA axis, subjects with plaque psoriasis applied Clobetasol Propionate Cream twice daily to at least 20% of involved Body Surface Area (BSA) for 15 days. Abnormal ACTH stimulation tests suggestive of HPA axis suppression were seen in 3
of 24 (12.5%) subjects on Clobetasol Propionate Cream [see Clinical Pharmacology (12.2)]. In another trial to evaluate the effects of Clobetasol Propionate Cream on the HPA axis, subjects with moderate to severe plaque psoriasis applied Clobetasol Propionate Cream twice daily to at least 25% of involved BSA for 28 consecutive days. Abnormal ACTH stimulation test suggestive of HPA axis suppression was seen in 8 of 26 (30.8%) of
subjects on Clobetasol Propionate Cream.

If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. If signs and symptoms of steroid withdrawal occur, supplemental systemic corticosteroids may be required. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids.

Systemic effects of topical corticosteroids may also manifest as Cushing’s syndrome, hyperglycemia, and glucosuria. These complications are rare and generally occur after prolonged exposure to larger than recommended doses, particularly with high-potency topical corticosteroids.
Use of more than one corticosteroid-containing product at the same time may increase the total systemic exposure to topical corticosteroids.
Minimize the unwanted risks from endocrine effects by mitigating risk factors favoring increased systemic bioavailability and by using the product as recommended [see Dosage and Administration (2)].

Pediatric patients may be more susceptible to systemic toxicity 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 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 Clobetasol Propionate Cream. Some local
adverse reactions may be irreversible.

5.3 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 Clobetasol Propionate Cream until the infection has been adequately treated.

5.4 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, discontinue the topical corticosteroid and institute appropriate therapy.

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.

Clobetasol Propionate Cream was evaluated in two randomized, multicenter, prospective, vehicle-controlled clinical trials in subjects with moderate to severe plaque psoriasis. Subjects applied Clobetasol Propionate Cream or vehicle cream twice daily for 14 days. A total of 354 subjects applied Clobetasol Propionate Cream and 178 subjects applied vehicle.

The adverse reaction that occurred in at least 1% of subjects treated with Clobetasol Propionate Cream and at a higher incidence than in subjects treated with vehicle cream was application site discoloration (2% versus 1%).

Less common local adverse events occurring in < 1% of subjects treated with Clobetasol Propionate Cream were application site atrophy, telangiectasia and rash.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of clobetasol propionate: striae, irritation, dryness, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, hypertrichosis and miliaria. 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.

8.1 Pregnancy

Risk Summary

There are no available data on Clobetasol Propionate Cream in pregnant women to inform a drug-associated risk for adverse development outcomes. Published data report a significantly increased risk of low birthweight with the use of greater than 300 grams of potent or very potent topical corticosteroids during a pregnancy. Advise pregnant women of the potential risk to a fetus and to use Clobetasol Propionate Cream on the smallest area of skin and for the shortest duration possible (see Data). In animal reproduction studies, increased malformations, such as cleft palate and skeletal abnormalities, were observed after subcutaneous administration of clobetasol propionate to pregnant mice and rabbits. No comparisons of animal exposure with human exposure are provided due to minimal systemic exposure noted after topical administration of Clobetasol Propionate Cream [see Clinical Pharmacology (12.3)].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk or birth defect loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Multiple observational studies found no significant associations between maternal use of topical corticosteroids of any potency and congenital malformations, preterm delivery, or fetal mortality. However, when the dispensed amount of potent or very potent topical corticosteroid exceeded 300 g during the entire pregnancy, use was associated with an increase in low birth weight infants [adjusted RR, 7.74 (95% CI, 1.49-40.11)]. In addition, a small cohort study, in which 28 sub-Saharan women using potent topical corticosteroids (27/28 used clobetasol propionate 0.05%) for skin lightening during pregnancy, noted a higher incidence of low birth weight infants in the exposed group. The majority of exposed subjects treated large areas of the body [a mean quantity of 60 g/month (range, 12-170g)] over long periods of time.

Animal Data

In an embryofetal development study in mice, subcutaneous administration of clobetasol propionate resulted in fetotoxicity at the highest dose tested ( 1mg/kg) and malformations at the lowest dose tested (0.03 mg/kg). Malformations seen included cleft palate and skeletal abnormalities. In an embryofetal development study in rabbits, subcutaneous administration of clobetasol propionate resulted in malformations at doses of 0.003 and 0.01 mg/kg. Malformations seen included cleft palate, cranioschisis, and other skeletal abnormalities.

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 other’s clinical need for Clobetasol Propionate Cream and any potential adverse effects on the breastfed infant from Clobetasol Propionate Cream or from the underlying maternal condition.

Clinical Considerations

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

8.4 Pediatric Use

The safety and effectiveness of Clobetasol Propionate Cream in patients younger than 18 years of age have not been established; therefore, use in children younger than 18 years is not recommended. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of systemic toxicity, including HPA axis suppression when treated with topical drugs [see Warnings and Precautions (5.1)].

Rare systemic toxicities 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 striae and skin atrophy have also been reported with use of topical corticosteroids in pediatric patients.

Avoid use of Clobetasol Propionate Cream in the treatment of diaper dermatitis.

8.5 Geriatric Use

Clinical studies of Clobetasol Propionate Cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience with topical corticosteroids has not identified differences in responses between the elderly and younger patients.

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. The contribution to efficacy by individual components of the vehicle has not been established.

12.2 Pharmacodynamics

Vasoconstrictor Assay

Clobetasol Propionate Cream, 0.025% is in the high range of potency as demonstrated in vasoconstrictor studies in healthy subjects when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression:

HPA axis suppression was evaluated in a clinical trial in adult subjects (N=24) with moderate to severe plaque psoriasis involving a mean BSA of 26.5 +8.6%. Treatment consisted of twice daily application of Clobetasol Propionate Cream, 0.025% for 15 days. Adrenal suppression, as indicated by a 30-minute post-stimulation cortisol level ≤18 mcg/dL, was observed in 3 out of 24 subjects (12.5%) after 15 days.

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 also increase percutaneous absorption. 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.

In a pharmacokinetic study in 24 adult male and female subjects with moderate to severe psoriasis were treated twice daily for 15 days with a mean dose of approximately 3.7 g of Clobetasol Propionate Cream, 0.025% per application to a mean BSA of 26.5 ± 8.6%. On day 15, the mean + SD pre-treatment and post-treatment systemic concentrations of clobetasol propionate were 50.7 ± 96.0 pg/mL and 56.3 ± 104.7 pg/mL, respectively.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

In a 13-week repeat dose toxicity study in rats, topical administration of clobetasol propionate cream, 0.001, 0.005 and 0.025% at corresponding doses of 0.004, 0.02 and 0.1 mg/kg/day resulted in corticosteroid class-related systemic effects such as reductions in body weight gain, reductions in total leukocytes and individual white cells, decrease in weight of adrenals, thymus, spleen, liver and lung. Histologically, there were decreased hematopoiesis in the bone marrow, thymic atrophy and mast cell infiltration of the mesenteric lymph nodes. All these effects were indicative of severe immune suppression consistent with long-term exposure to corticosteroids. A no observable adverse effect level (NOAEL) was determined to be clobetasol propionate cream, 0.001% (0.004 mg/kg/day) in male rats while a NOAEL could not be determined in females. The clinical relevance of the findings in animals to humans is not clear, but sustained glucocorticoid-related immune suppression may increase the risk of infection and possibly the risk of carcinogenesis.

Clobetasol propionate was not mutagenic in three different test systems: the Ames test, the Saccharomyces cerevisiae gene conversion assay, and the E. coli B WP2 fluctuation test.

Fertility studies conducted in the rat following subcutaneous administration of clobetasol propionate at dosage levels up to 0.05 mg/kg/day revealed that 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

Clobetasol Propionate Cream, 0.025% is a white to off-white cream, supplied as follows:
100g aluminum tube NDC 74157-710-10

16.2 Storage

Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature] Do not freeze.