Hydrocortisone Butyrate 1 mg/g Cream

8 USE IN SPECIFIC POPULATIONS

8.1Pregnancy Risk Summary There are no controlled or large-scale epidemiologic studies with Hydrocortisone Butyrate Cream (lipid), 0.1% use in pregnant women, and available data on hydrocortisone butyrate use in pregnant women have not identified a drug-associated risk for major birth defects, miscarriages or adverse maternal or fetal outcomes. In animal reproduction studies, when administered subcutaneously or topically to pregnant rats, rabbits, and mice, hydrocortisone butyrate induced adverse reproductive and developmental outcomes, including abortion, fetal death, malformation, delayed ossification, decrease in fetal weight, and delay in sexual maturation (see Data) .

The available data do not allow the calculation of relevant comparisons between the systemic exposure of hydrocortisone butyrate observed in animal studies and the systemic exposure that would be expected in humans after topical use of Hydrocortisone Butyrate Cream (lipid), 0.1%. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of 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 Animal Data 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 included increased ossification variations and unossified sternebra. No treatment-related embryofetal toxicity or malformation were noted at doses of 5.4 and 1.8 mg/kg/day, 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.

Increased abortion was noted at 0.3 mg/kg/day. In the absence of maternal toxicity, a dose-dependent decrease in fetal body weight was noted at doses ≥0.1 mg/kg/day. Embryofetal toxicities (reduction in litter size, decreased number of viable fetuses, and increased post-implantation loss) were noted at doses ≥0.2 mg/kg/day.

Additional fetal effects included delayed ossification noted at doses ≥0.1 mg/kg/day and increased fetal malformations (primarily skeletal malformations) noted at doses ≥0.2 mg/kg/day. A dose at which no embryofetal toxicity or malformation was 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 death and fetal resorption and an increase in ossification of caudal vertebrae were noted at 9 mg/kg/day. No treatment-related embryofetal toxicity or malformation was noted at 0.1 mg/kg/day.

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 1 mg/kg/day. No treatment-related embryofetal toxicity or malformation was noted at 1 and 0.2 mg/kg/day.

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 resorption was noted in rabbits and fetal resorptions were noted in rats at the…

8.1Pregnancy Risk Summary There are no controlled or large-scale epidemiologic studies with Hydrocortisone Butyrate Cream (lipid), 0.1% use in pregnant women, and available data on hydrocortisone butyrate use in pregnant women have not identified a drug-associated risk for major birth defects, miscarriages or adverse maternal or fetal outcomes. In animal reproduction studies, when administered subcutaneously or topically to pregnant rats, rabbits, and mice, hydrocortisone butyrate induced adverse reproductive and developmental outcomes, including abortion, fetal death, malformation, delayed ossification, decrease in fetal weight, and delay in sexual maturation (see Data) .

The available data do not allow the calculation of relevant comparisons between the systemic exposure of hydrocortisone butyrate observed in animal studies and the systemic exposure that would be expected in humans after topical use of Hydrocortisone Butyrate Cream (lipid), 0.1%. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of 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 Animal Data 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 included increased ossification variations and unossified sternebra. No treatment-related embryofetal toxicity or malformation were noted at doses of 5.4 and 1.8 mg/kg/day, 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.

Increased abortion was noted at 0.3 mg/kg/day. In the absence of maternal toxicity, a dose-dependent decrease in fetal body weight was noted at doses ≥0.1 mg/kg/day. Embryofetal toxicities (reduction in litter size, decreased number of viable fetuses, and increased post-implantation loss) were noted at doses ≥0.2 mg/kg/day.

Additional fetal effects included delayed ossification noted at doses ≥0.1 mg/kg/day and increased fetal malformations (primarily skeletal malformations) noted at doses ≥0.2 mg/kg/day. A dose at which no embryofetal toxicity or malformation was 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 death and fetal resorption and an increase in ossification of caudal vertebrae were noted at 9 mg/kg/day. No treatment-related embryofetal toxicity or malformation was noted at 0.1 mg/kg/day.

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 1 mg/kg/day. No treatment-related embryofetal toxicity or malformation was noted at 1 and 0.2 mg/kg/day.

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 resorption was noted in rabbits and fetal resorptions were noted in rats at the 10% hydrocortisone butyrate oi…

8.4Pediatric Use Corticosteroid-Responsive Dermatoses The safety and efficacy of Hydrocortisone Butyrate Cream (lipid), 0.1% for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses have not been established in pediatric patients. Atopic Dermatitis The safety and effectiveness of Hydrocortisone Butyrate Cream (lipid), 0.1% for the topical treatment of mild to moderate atopic dermatitis have been established in pediatric patients 3 months of age and older. Use of Hydrocortisone Butyrate Cream (lipid), 0.1% for this indication is supported by evidence from a multicenter, randomized, vehicle-controlled trial of 264 pediatric subjects 3 months of age and older [see Clinical Studies ( 14 )] .

The safety and efficacy of Hydrocortisone Butyrate Cream (lipid), 0.1% for the topical treatment of mild to moderate atopic dermatitis have not been established in pediatric patients younger than 3 months of age. Endocrine Adverse Reactions Eighty-six (86) 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 Hydrocortisone Butyrate Cream (lipid), 0.1% 3 times daily for up to 4 weeks were assessed for HPA-axis suppression in two separate studies.

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 ≤18 mcg/dL after cosyntropin stimulation. At the first follow-up visit, approximately 1 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 [see Clinical Pharmacology ( 12.2 )] .

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 [see Warnings and Precautions ( 5.1 )] . They are therefore also at a greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing’s syndrome while on treatment. Manifestations of adrenal suppression in pediatric patients include low plasma cortisol levels in response to ACTH stimulation.

Linear growth retardation, delayed weight gain, and intracranial hypertension have also been reported in pediatric patients receiving topical corticosteroids. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

8.5Geriatric Use Clinical trials of Hydrocortisone Butyrate Cream (lipid), 0.1% did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects.