Hydrocortisone Butyrate

1 INDICATIONS AND USAGE Hydrocortisone butyrate lotion, 0.1% is indicated for the topical treatment of mild to moderate atopic dermatitis in patients 3 months of age and older. Hydrocortisone butyrate lotion, 0.1% is a corticosteroid indicated for the topical treatment of mild to moderate atopic dermatitis in patients 3 months of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Apply a thin layer to the affected skin areas two times daily, and rub in gently. Do not apply hydrocortisone butyrate lotion, 0.1% in the diaper area unless directed by a physician. Discontinue therapy 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 hydrocortisone butyrate lotion, 0.1% has not been established beyond 4 weeks of use [see WARNINGS AND PRECAUTIONS (5.1) ] . Do not use hydrocortisone butyrate lotion, 0.1% with occlusive dressings unless directed by a physician. Avoid use in the diaper area, as diapers or plastic pants may constitute occlusive dressings. Hydrocortisone butyrate lotion, 0.1% is not for oral, ophthalmic, or intravaginal use. Apply a thin layer to the affected skin two times daily. ( 2 ) Rub in gently. ( 2 ) Discontinue hydrocortisone butyrate lotion, 0.1% when control is achieved. ( 2 ) Reassess diagnosis if no improvement is seen within 2 weeks. 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. Safety and efficacy of hydrocortisone butyrate lotion, 0.1% has not been established beyond 4 weeks of use. ( 2 ) Avoid use under occlusion or in the diaper area. ( 2 ) Hydrocortisone butyrate lotion, 0.1% is not for oral, ophthalmic, or intravaginal use. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Lotion, 0.1%. Each gram of hydrocortisone butyrate lotion, 0.1% contains 1 mg of hydrocortisone butyrate USP in a white to off white lotion base. Hydrocortisone butyrate lotion, 0.1% is supplied in bottles of 2 fl. oz. and 4 fl. oz. Lotion, 0.1% (1 mg/g), supplied in bottles of 2 fl. oz. and 4 fl. oz. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS 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 hydrocortisone butyrate lotion [ see WARNINGS AND PRECAUTIONS (5.1) and USE IN SPECIFIC POPULATIONS (8.4) ] Concomitant skin infections [see WARNINGS AND PRECAUTIONS (5.2) ] Allergic contact dermatitis [ see WARNINGS AND PRECAUTIONS (5.3) ] The most common adverse reactions (>1%) are application site reactions. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 and/or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. The safety data derived from hydrocortisone butyrate lotion clinical trials reflect exposure to hydrocortisone butyrate lotion twice daily for up to four weeks in separate clinical trials involving pediatric subjects 3 months to 18 years of age and adult subjects 18 years of age and older 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 hydrocortisone butyrate lotion. Although the rates of application site reactions in the vehicle group were greater than those in the hydrocortisone butyrate lotion group in both studies, these rates are included in the tables (Table 1 and Table 2) because skin irritation is a known adverse reaction of topical corticosteroids. TABLE 1. Frequency of adverse reactions in pediatric subjects with mild to moderate atopic dermatitis Hydrocortisone Butyrate Lotion ( n=139) n (%) Vehicle ( n=145) n (%) Application site reactions, including application site burning, pruritus, dermatitis, erythema, eczema, inflammation, or irritation 2 (1) 20 (14) Infantile acne 1 (1) 0 (0) Skin depigmentation 1 (1) 0 (0) TABLE 2. Frequency of adverse reactions in adult subjects with mild to moderate atopic dermatitis Hydrocortisone Butyrate Lotion ( n=151) n (%) Vehicle ( n=150) n (%) Application site reactions, including application site burning, dermatitis, eczema, erythema, or pruritus 5 (3) 7 (5) 6.2 Postmarketing Experience Because adverse 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 additional local adverse reactions have been reported infrequently with topical corticosteroids, and they may occur more frequently with the use of occlusive dressings and higher potency corticosteroids. These reactions included: irritation, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, miliaria and telangiectasia.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no controlled or large-scale epidemiologic studies with Hydrocortisone Butyrate Lotion 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 Lotion. 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 2-4% and 15-20%, 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 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 lotion. 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 ointment dose. No …

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 atopic dermatitis is unknown.

11 DESCRIPTION Hydrocortisone Butyrate Lotion, 0.1% contains hydrocortisone butyrate, a non-fluorinated hydrocortisone ester, for topical use. Hydrocortisone butyrate is a corticosteroid. The chemical name of hydrocortisone butyrate is Pregn-4-ene-3,20-dione, 11,21-dihydroxy-17-[(1-oxobutyl)oxy(11β)-]. It has the following structural formula: Hydrocortisone butyrate is a white to off-white powder with a molecular weight of 432.56, and a molecular formula of C 25 H 36 O 6 . It is practically insoluble in water, slightly soluble in ether, soluble in methanol, alcohol, and acetone, and freely soluble in chloroform. Each gram of Hydrocortisone Butyrate Lotion contains 1 mg of hydrocortisone butyrate in a white to off-white lotion base consisting of anhydrous citric acid, ceteth-20, cetostearyl alcohol, butylated hydroxytoluene (BHT), butylparaben, light mineral oil, propylparaben, purified water, sodium citrate, and white petrolatum. Structural formula

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Hydrocortisone Butyrate Lotion, 0.1% is white to off-white in color and supplied in: 2 fl. oz. bottle: NDC 72162-2630-2 4 fl. oz. bottle: NDC 72162-2630-4 Storage and Handling Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from freezing. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504