Ala-Cort

Ala-Cort (hydrocortisone butyrate) ® is a topical corticosteroid indicated for:

Relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in adults.

The topical treatment of mild to moderate atopic dermatitis in pediatric patients 3 months to 18 years of age.

PANDEL^® (hydrocortisone probutate) Cream, 0.1% is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 18 years of age or older.

Ala-Cort (hydrocortisone butyrate) is not for oral, ophthalmic, or intravaginal use.

Therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary. Before prescribing for more than 2 weeks, any additional benefits of extending treatment to 4 weeks should be weighed against the risk of HPA axis suppression and local adverse events. The safety and efficacy of Locoid Lipocream has not been established beyond 4 weeks of use.

Corticosteroid-Responsive Dermatoses in Adults

Apply a thin film to the affected skin areas two or three times daily, depending on the severity of the condition. Rub in gently.

Atopic Dermatitis in Patients From 3 Month to 18 Years

Apply a thin film to the affected skin areas two times daily. Rub in gently.

Ala-Cort (hydrocortisone butyrate) should not be used with occlusive dressings or applied in the diaper area unless directed by a physician.

Apply a thin film of PANDEL to the affected area once or twice a day depending on the severity of the condition. Massage gently until the medication disappears.

Occlusive dressings may be used for the management of refractory lesions of psoriasis and other deep-seated dermatoses, such as localized neurodermatitis (lichen simplex chronicus).

Discontinue PANDEL when control is achieved. If no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary.

Do not use PANDEL with occlusive dressings unless directed by the physician. Do not apply PANDEL in the diaper area, as diapers or plastic pants may constitute occlusive dressings.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypothalamic-pituitary-adrenal (HPA) Axis Suppression

Systemic effects of topical corticosteroids may include reversible HPA axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria.

Studies conducted in pediatric subjects demonstrated reversible HPA axis suppression after use of Ala-Cort (hydrocortisone butyrate). Pediatric patients may be more susceptible than adults to systemic toxicity from equivalent doses of Ala-Cort (hydrocortisone butyrate) due to their larger skin surface-to-body-mass ratios.

Patients applying a topical corticosteroid to a large surface area or to areas under occlusion should be considered for periodic evaluation of the HPA axis. This may be done by using cosyntropin (ACTH1-24) stimulation testing (CST).

If HPA axis suppression is noted, the frequency of application should be reduced or the drug should be withdrawn, or a less potent corticosteroid should be substituted. Signs and symptoms of glucocorticosteroid insufficiency may occur, requiring supplemental systemic corticosteroids.

Concomitant Skin Infections

If skin infections are present or develop, an appropriate antifungal, antibacterial or antiviral agent should be used. If a favorable response does not occur promptly, use of Ala-Cort (hydrocortisone butyrate) should be discontinued until the infection has been adequately controlled.

Skin Irritation

Ala-Cort (hydrocortisone butyrate) may cause local skin adverse reactions.

If irritation develops, Ala-Cort (hydrocortisone butyrate) should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing a failure to heal rather than noticing a clinical exacerbation. Such an observation should be corroborated with appropriate patch testing.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies were conducted to determine the photoco-carcinogenic or dermal carcinogenic potential of Ala-Cort.

Hydrocortisone butyrate revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames test and L5178Y/TK+ mouse lymphoma assay) and one in vivo genotoxicity test (mouse micronucleus assay).

No evidence of impairment of fertility or effect on mating performance was observed in a fertility and general reproductive performance study conducted in male and female rats at subcutaneous doses up to and including 1.8 mg/kg/day (0.7X MTHD). Mild effects on maternal animals, such as reduced food consumption and a subsequent reduction in body weight gain, were seen at doses ≥ 0.6 mg/kg/day (0.2X MTHD).

Use In Specific Populations

Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Therefore, Ala-Cort (hydrocortisone butyrate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.

Note: The animal multiples of human exposure calculations in this label were based on body surface area comparisons for an adult (i.e., mg/m²/day dose comparisons) assuming 100% human percutaneous absorption of a maximum topical human dose (MTHD) for hydrocortisone butyrate cream (25 g).

Systemic embryofetal development studies were conducted in rats and rabbits. Subcutaneous doses of 0.6, 1.8 and 5.4 mg/kg/day hydrocortisone butyrate were administered to pregnant female rats during gestation days 6 – 17. In the presence of maternal toxicity, fetal effects noted at 5.4 mg/kg/day (2X MTHD) included an increased incidence of ossification variations and unossified sternebra. No treatment related effects on embryofetal toxicity or teratogenicity were noted at doses of 5.4 mg/kg/day and 1.8 mg/kg/day, respectively (2X MTHD and 0.7X MTHD, respectively).

Subcutaneous doses of 0.1, 0.2 and 0.3 mg/kg/day hydrocortisone butyrate were administered to pregnant female rabbits during gestation days 7 – 20. An increased incidence of abortion was noted at 0.3 mg/kg/day (0.2X MTHD). In the absence of maternal toxicity, a dose dependent decrease in fetal body weight was noted at doses ≥ 0.1 mg/kg/day (0.1X MTHD). Additional indicators of embyrofetal toxicity (reduction in litter size, decreased number of viable fetuses, increased post-implantation loss) were noted at doses ≥ 0.2 mg/kg/day (0.2X MTHD). Additional fetal effects noted in this study included delayed ossification noted at doses ≥ 0.1 mg/kg/day and an increased incidence of fetal malformations (primarily skeletal malformations) noted at doses ≥ 0.2 mg/kg/day. A dose at which no treatment related effects on embryofetal toxicity or teratogenicity were observed was not established in this study.

Additional systemic embryofetal development studies were conducted in rats and mice. Subcutaneous doses of 0.1 and 9 mg/kg/day hydrocortisone butyrate were administered to pregnant female rats during gestation days 9 – 15. In the presence of maternal toxicity, an increase in fetal deaths and fetal resorptions and an increase in the number of ossifications in caudal vertebrae were noted at a dose of 9 mg/kg/day (3X MTHD). No treatment related effects on embryofetal toxicity or teratogenicity were noted at 0.1 mg/kg/day (0.1X MTHD).

Subcutaneous doses of 0.2 and 1 mg/kg/day hydrocortisone butyrate were administered to pregnant female mice during gestation days 7 – 13. In the absence of maternal toxicity, an increased number of cervical ribs and one fetus with clubbed legs were noted at a dose of 1 mg/kg/day (0.2X MTHD). No treatment related effects on embryofetal toxicity or teratogenicity were noted at doses of 1 and 0.2 mg/kg/day, respectively (0.2X MTHD and 0.1X MTHD, respectively).

No topical embryofetal development studies were conducted with hydrocortisone butyrate cream. However, topical embryofetal development studies were conducted in rats and rabbits with a hydrocortisone butyrate ointment formulation. Topical doses of 1% and 10% hydrocortisone butyrate ointment were administered to pregnant female rats during gestation days 6 – 15 or pregnant female rabbits during gestation days 6 – 18. A dose-dependent increase in fetal resorptions was noted in rabbits (0.2 – 2X MTHD) and fetal resorptions were noted in rats at the 10% hydrocortisone butyrate ointment dose (80X MTHD). No treatment related effects on embyrofetal toxicity were noted at the 1% hydrocortisone butyrate ointment dose in rats (8 MTHD). A dose at which no treatment related effects on embryofetal toxicity were observed in rabbits after topical administration of hydrocortisone butyrate ointment was not established in this study. No treatment related effects on teratogenicity were noted at a dose of 10% hydrocortisone butyrate ointment in rats or rabbits (80X MTHD and 2X MTHD, respectively).

A peri- and post-natal development study was conducted in rats. Subcutaneous doses of 0.6, 1.8 and 5.4 mg/kg/day hydrocortisone butyrate were administered to pregnant female rats from gestation day 6 – lactation day 20. In the presence of maternal toxicity, a dose dependent decrease in fetal weight was noted at doses ≥ 1.8 mg/kg/day (0.7X MTHD). No treatment related effects on fetal toxicity were noted at 0.6 mg/kg/day (0.2X MTHD). A delay in sexual maturation was noted at 5.4 mg/kg/day (2X MTHD). No treatment related effects on sexual maturation were noted at 1.8 mg/kg/day. No treatment related effects on behavioral development or subsequent reproductive performance were noted at 5.4 mg/kg/day.

Nursing Mothers

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 corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ala-Cort (hydrocortisone butyrate) is administered to a nursing woman.

Pediatric Use

Safety and efficacy in pediatric patients below 3 months of age have not been established.

Because of higher skin surface-to-body-mass ratios, pediatric patients are at a greater risk than adults of HPA axis suppression when they are treated with topical corticosteroids. They are therefore also at a greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing's syndrome while on treatment.

Eighty-six (86) pediatric subjects (between 5 months and 18 years of age) with moderate to severe atopic dermatitis affecting at least 25% of body surface area (BSA) treated with Ala-Cort (hydrocortisone butyrate) three times daily for up to 4 weeks were assessed for HPA axis suppression in two separate studies. The disease severity (moderate to severe atopic dermatitis) and the dosing regimen (three times daily) in these HPA axis studies were different from the subject population (mild to moderate atopic dermatitis) and the dosing regimen (two times daily) for which Ala-Cort (hydrocortisone butyrate) is indicated in this population. Five of the 82 evaluable subjects (6.1%) demonstrated evidence of suppression, where the criterion for defining HPA axis suppression was a serum cortisol level of less than or equal to 18 micrograms per deciliter after cosyntropin stimulation. Suppressed subjects ranged in age from 5 months to 16 years and, at the time of enrollment, had 25% to 95% BSA involvement. These subjects did not demonstrate any clinical signs or symptoms despite evidence of HPA axis suppression. At the first follow up visit, approximately one month after the conclusion of treatment, cosyntropin stimulation results of all subjects had returned to normal, with the exception of one subject. This last subject recovered adrenal function by 65 days post-treatment.

Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have also been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include low plasma cortisol levels to an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

Geriatric Use

Clinical studies of Ala-Cort (hydrocortisone butyrate) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

WARNINGS

No information provided.

PRECAUTIONS

General: Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment.Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical cor-ticosteroids while on treatment.

Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA-axis suppression. This may be done by using the ACTH stimulation, A.M.plasma cortisol or urinary free cortisol tests.

If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corti-costeroids. For information on systemic supplementation, see prescribing information for those products.

Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. (See PRECAUTIONS-Pediatric Use). If irritation develops, Pandel (hydrocortisone probutate cream) Cream, 0.1% should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing a failure to heal rather than noting a clinical exacerbation, as observed with most topical products not containing corticosteroids.

If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of Pandel (hydrocortisone probutate cream) Cream, 0.1% should be discontinued until the infection has been adequately controlled.

Laboratory Tests

The following tests may be helpful in evaluating if HPA axis suppression does occur:

ACTH stimulation test
A.M.plasma cortisol test
Urinary free cortisol test

Carcinogenesis, Mutagenesis and Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids.

In two mutagenicity experiments using hydrocortisone probutate, negative responses were observed in the occurrence of micronuclei in the bone marrow of mice and in the Ames reverse mutation test bacterial assay - with and without metabolic activation.

Pregnancy

Teratogenic Effects - Pregnancy Category C. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application to laboratory animals.

Hydrocortisone probutate has not been tested for teratogenicity when applied topically; however, it is absorbed percutaneously, and studies in Wistar rats using the subcutaneous route resulted in teratogenicity at dose levels equal to or greater than 1 mg/kg. This dose is approximately 12 times the human average topical dose of Pandel (hydrocortisone probutate cream) Cream, 0.1% assuming 3% absorption and an application of 30 g/day on a 70 kg individual. Abnormalities seen included delayed ossification of the caudal vertebrae and other skeletal variations, cleft palate, umbilical hernia, edema, and exencephalia.

In rabbits, hydrocortisone probutate given by the subcutaneous route was teratogenic at doses equal to or greater than 0.1 mg/kg. This dose is approximately 2 times the human average topical dose of Pandel (hydrocortisone probutate cream) Cream, 0.1% assuming 3% absorption and an application of 30 g/day on a 70 kg individual. Abnormalities seen included delayed ossification of the cau-dal vertebrae and other skeletal abnormalities, cleft palate and increased fetal mortality.

The differences between the doses used in animal studies and the proposed human dose may not fully predict the human outcome. The animals received a bolus subcutaneous dose, whereas humans receive a dermal application, where absorption is lower and highly dependent on various factors (e.g., vehicle, integrity of epidermal barrier, occlusion).

There are no adequate and well-controlled studies of the teratogenic potential of hydrocortisone probutate in pregnant women. Although human epidemiological studies do not indicate an increased incidence of teratogenicity with the use of topical corticosteroids, Pandel (hydrocortisone probutate cream) Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mother

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 corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Pandel (hydrocortisone probutate cream) Cream, 0.1% is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. 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 a greater risk of adrenal 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.

Hypothalamic-pituitary-adrenal (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.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• HPA axis suppression. This has been observed in pediatric subjects using Ala-Cort
• Concomitant skin infections
• Skin irritation

Clinical Trials Experience: Adults

The following additional local adverse reactions have been reported infrequently with topical corticosteroids but may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, drying, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae and miliaria.

Clinical Trials Experience: Pediatrics

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. The safety data derived from Ala-Cort (hydrocortisone butyrate) clinical trials reflect exposure to Locoid Lipocream twice daily for up to four weeks in separate clinical trials involving pediatric subjects 3 months to 18 years of age with mild to moderate atopic dermatitis.

Adverse reactions shown in the tables below include those for which there is some basis to believe there is a causal relationship to Ala-Cort (hydrocortisone butyrate).

Table 1 : Frequency of adverse reactions in pediatric subjects with mild to moderate atopic dermatitis

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Ala-Cort (hydrocortisone butyrate). 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.

Skin: Erythema, Rash and Application site irritation.

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.

The most frequent adverse reactions reported for PANDEL during clinical trials were application site reactions, including burning in 4, stinging in 2, and moderate paresthesia in 1 out of 226 subjects.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of PANDEL because these reactions were 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.

These adverse reactions are as follows:

Skin and Subcutaneous Tissue Disorders:rash, papulovesicular rash

Application Site Reactions: dryness, erythema, pruritus, allergic contact dermatitis.

The following local adverse reactions are reported with topical corticosteroids, and they may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infections, skin atrophy, striae, and miliaria.

No information provided.

No Information Provided