ULTRAVATE

1 INDICATIONS AND USAGE ULTRAVATE lotion is indicated for the topical treatment of plaque psoriasis in patients 12 years of age and older. ULTRAVATE lotion is a corticosteroid indicated for the topical treatment of plaque psoriasis in patients 12 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Apply a thin layer of ULTRAVATE lotion to the affected skin twice daily for up to two weeks. Rub in gently. Discontinue therapy when control is achieved. If no improvement is seen within two weeks, reassessment of diagnosis may be necessary. Treatment beyond two weeks is not recommended and the total dosage should not exceed 50 grams (50 ml) per week because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis {see Warnings and Precautions 5.1].Do not use with occlusive dressings unless directed by a physician. ULTRAVATE lotion is for external use only. Avoid use on the face, scalp, groin, or axillae. ULTRAVATE lotion is not for ophthalmic, oral, or intravaginal use. Apply a thin layer to the affected areas twice daily. (2) Limit use to 50 g/week. (2) Discontinue treatment when control is achieved. (2) If no improvement is seen within 2 weeks, reassess diagnosis. (2) Treatment beyond 2 consecutive weeks is not recommended. (2) Do not use with occlusive dressings unless directed by a physician. (2) Avoid use on the face, scalp, groin, or axillae. (2) Not for ophthalmic, oral, or intravaginal use. (2)

4 CONTRAINDICATIONS None. None.

5 WARNINGS AND PRECAUTIONS Reversible hypothalamic-pituitary-adrenal (HPA) axis suppression may occur, with the potential for glucocorticosteroid insufficiency during or after treatment. Systemic absorption may require evaluation for HPA axis suppression. (5.1) Systemic effects of topical corticosteroids may also include Cushing's syndrome, hyperglycemia, and glucosuria. Use of potent corticosteroids on large areas, for prolonged durations, under occlusive dressings, or on an altered skin barrier may increase systemic exposure. (5.1) Children may be more susceptible to systemic toxicity when treated with topical corticosteroids. (5.1, 8.4) Local adverse reactions with topical steroids may include atrophy, striae, irritation, acneiform eruptions, hypopigmentation, and allergic contact dermatitis. Adverse reactions may be more likely to occur with occlusive use or more potent corticosteroids. (5.2, 5.5) Topical corticosteroids may increase the risk of cataract and glaucoma formation. If visual symptoms occur, consider referral to an ophthalmologist tor evaluation. (5.3) Initiate appropriate therapy if concomitant skin infections develop. (5.4) 5.1 Effects on Endocrine System ULTRAVATE lotion has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis.Systemic effects of topical corticosteroids may include reversible HPA axis suppression, with the potential for glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of treatment of the topical corticosteroid.The potential for hypothalamic-pituitary adrenal (HPA) suppression with ULTRAVATE lotion was evaluated in the following studies: In a study of 20 adult subjects with moderate to severe plaque psoriasis involving 􀃙20% of their body surtace area. ULTRAVATE lotion produced HPA axis suppression when used twice daily for two weeks in 5 out of 20 (25%) adult subjects with plaque psoriasis. The effects of HPA axis suppression were reversible on discontinuation of the treatment [see Clinical Pharmacology (12.2)] . In another clinical study, 16 adolescent subjects (12 to less than 17 years old) with moderate to severe plaque psoriasis involving 10% or more of their body surtace area applied a maximum of approximately 50 grams of ULTRAVATE lotion to affected areas twice daily for two weeks. Of the 14 subjects evaluated for HPA axis suppression, adrenal suppression occurred in 1 subject (7%) which recovered upon retest [see Clinical Pharmacology (12.2)] . Because of the potential for systemic absorption, use of topical corticosteroids, including ULTRAVATE lotion, may require that patients be evaluated periodically for evidence of HPA axis suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of more potent corticosteroids, use over large surtace areas, prolonged use, occlusive use, use on an altered skin barrier, concomitant use of multiple corticosteroid-containing products, liver failure, and young age. An ACTH stimulation test may be helpful in evaluating patients for HPA axis suppression.If HPA axis suppression is documented, attempt to gradually withdraw the drug, reduce the frequency of application, or 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.Systemic effects of topical corticosteroids may also include Cushing's syndrome, hyperglycemia, and glucosuria. Use of more than one corticosteroid-containing product at the same time may increase the total systemic exposure to topical corticosteroids. Pediatric patients may be more susceptible than adults to systemic toxicity from the use of topical corticosteroids due to their larger surtace-to-body mass ratios [see Use in Specific Populations (8.4)]. 5.2 Local Adverse Reactions 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 ULTRAVATE lotion. Some local adverse reactions may be irreversible. 5.3 Ophthalmic Adverse Reactions Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported in postmarketing experience with the use of topical corticosteroid products. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation. 5.4 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 ULTRAVATE lotion until the infection has been adequately treated. 5.5 Allergic Contact Dermatitis Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation. Consider confirmation of a clinical diagnosis of allergic contact dermatitis by appropriate patch testing. Discontinue ULTRAVATE lotion if allergic contact dermatitis is established.

6 ADVERSE REACTIONS The most commonly reported adverse reactions (≥1%) are telangiectasia, application site atrophy, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact LAcer Pharma, LLC at 1-888-403-8874 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, 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. During randomized, controlled, blinded clinical trials 277 adults with plaque psoriasis were treated with ULTRAVATE lotion twice daily for up to two weeks (up to approximately 50 grams/week). Table 1 presents adverse reactions that occured in at least 1% of subjects treated with ULTRAVATE lotion twice daily for up to two weeks, and more frequently than in vehicle-treated subjects. Table 1: Adverse Reactions Occurring in ≥ 1% of Subjects Treated with ULTRAVATE Lotion for up to Two Weeks ULTRAVATE Lotion (N=277) Vehicle Lotion (N=259) Adverse Reaction % % Telangiectasia 1% 0% Application site atrophy 1% <1% Headache 1% <1% Less common dverse reactions (incidence less than 1% but greater than 0.1%) that occured in subjects treated with ULTRAVATE lotion included application site discoloration, herpes zoster, influenza, nasopharyngitis, otitis media acute, throat infection, wound, and increased blood pressure.

8.1 Pregnancy There are no available data on Ultravate lotion use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published data report an increased risk of low birthweight with the use of greater than 300 grams of potent or very potent topical corticosteroid during pregnancy. In animal reproduction studies, halobetasol propionate administered systemically during organogenesis to pregnant rats at 13 and 33 times the human topical dose and to pregnant rabbits at 3 times the human topical dose resulted in teratogenic and embryotoxic effects [see Data]. The clinical relevance of the animal findings is not clear. The background risk of major birth defects and miscarriage for the indicated population are unknown. 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 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. Animal Data Halobetasol propionate has been shown to be teratogenic in rats and rabbits when given systemically during organogenesis at doses of 0.04 to 0.1 mg/kg/day in rats and 0.01 mg/kg/day in rabbits. These doses are approximately 13, 33, and 3 times, respectively, the human topical dose of halobetasol propionate, 0.05%. Halobetasol propionate was embryotoxic in rabbits but not in rats.Cleft palate was observed in both rats and rabbits. Omphalocele was seen in rats, but not in rabbits.