Desoximetasone

6 ADVERSE REACTIONS The most common adverse reactions (≥ 1%) are application site dryness, application site irritation and application site pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Taro Pharmaceuticals, U.S.A., Inc., at 1-866-923-4914 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. In randomized, multicenter, prospective vehicle-controlled clinical trials, subjects with moderate to severe plaque psoriasis of the body applied Desoximetasone Topical Spray or vehicle spray twice daily for 4 weeks. A total of 149 subjects applied Desoximetasone Topical Spray. Adverse reactions that occurred in ≥ 1% of subjects treated with Desoximetasone Topical Spray were application site dryness (2.7%), application site irritation (2.7%) and application site pruritus (2.0%). Another less common adverse reaction (<1% but >0.1%) was folliculitis. Table 1. Number (%) of Subjects with Adverse Reactions Occurring in ≥ 1% Desoximetasone Topical Spray, 0.25% b.i.d. (N = 149) Vehicle spray b.i.d. (N = 135) Number of Subjects with Adverse Reactions 13 (8.7%) 18 (13.3%) Application site dryness 4 (2.7%) 7 (5.2%) Application site irritation 4 (2.7%) 5 (3.7%) Application site pruritus 3 (2.0%) 5 (3.7%)

4 CONTRAINDICATIONS None None ( 4 )

11 DESCRIPTION Desoximetasone Topical Spray, 0.25% contains desoximetasone as the active ingredient. Desoximetasone is a corticosteroid with the chemical name of pregna-1, 4-diene-3, 20-dione, 9-fluoro-11, 21-dihydroxy-16-methyl-, (11β,16α)-. Desoximetasone has the molecular formula of C 22 H 29 FO 4 and a molecular weight of 376.47. The CAS Registry Number is 382-67-2. The structural formula is: Each gram of Desoximetasone Topical Spray contains 2.5 mg of desoximetasone in a clear, colorless liquid with the following inactive ingredients: glyceryl oleate, isopropyl alcohol (23.4%), isopropyl myristate, L-menthol, and mineral oil. Desoximetasone Topical Spray is co-packaged with a manual spray pump for installation by the pharmacist prior to dispensing to patients. Chemical Structure

2 DOSAGE AND ADMINISTRATION Apply Desoximetasone Topical Spray as a thin film to the affected skin areas twice daily. Rub in gently. The treated skin area should not be bandaged or otherwise covered or wrapped unless directed by the physician. Desoximetasone Topical Spray should be discontinued when control is achieved. Treatment beyond 4 weeks is not recommended. Do not use if atrophy is present at the treatment site. Avoid use on the face, axilla or groin. Desoximetasone Topical Spray is for external use only. It is not for oral, ophthalmic, or intravaginal use. Apply a thin film to the affected skin areas twice daily. Rub in gently. ( 2 ) Desoximetasone Topical Spray should be discontinued when control is achieved. ( 2 ) Treatment beyond 4 weeks is not recommended. ( 2 ) Do not use if atrophy is present at the treatment site. ( 2 ) Do not use with occlusive dressings, unless directed by the physician ( 2 ) Avoid use on the face, axilla or groin. ( 2 ) Desoximetasone Topical Spray is not for oral, ophthalmic, or intravaginal use. ( 2 )

10 OVERDOSAGE Desoximetasone Topical Spray can be absorbed in sufficient amounts to produce systemic effects. [ see Warnings and Precautions (5.1) ]

12 CLINICAL PHARMACOLOGY 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 psoriasis is unknown. 12.2 Pharmacodynamics Vasoconstrictor studies performed with Desoximetasone Topical Spray in healthy subjects indicate that it is in the high to super-high range of potency as compared with other topical corticosteroids. The potential for hypothalamic-pituitary-adrenal (HPA) axis suppression was evaluated in a study of 24 adult subjects with moderate to severe plaque psoriasis. Desoximetasone Topical Spray was applied twice a day for 28 days. Twenty-one subjects had evaluable serum cortisol levels. The proportion of subjects demonstrating HPA axis suppression was 8.3% (1 out of 12) in subjects having psoriasis involvement of 10 to 15% of body surface area (BSA), and 22.2% (2 out of 9) in subjects having psoriasis involvement of > 15% of their BSA. In this study HPA axis suppression was defined as serum cortisol level ≤18 mcg/dL 30-min post cosyntropin stimulation. In the 2 subjects with available follow-up values, suppression reversed 28 days after the end of treatment. 12.3 Pharmacokinetics The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. Plasma concentrations of desoximetasone were measured at two single random time points in the HPA axis suppression trial in 24 subjects with psoriasis [ see Clinical Pharmacology (12.2) ]. The mean (% Coefficient of Variation) concentration of desoximetasone was 449 pg/mL (86%) at Day 14 and 678 pg/mL (135%) at Day 28. The concentration time profile following application of Desoximetasone Topical Spray is not known.

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 psoriasis is unknown.

12.2 Pharmacodynamics Vasoconstrictor studies performed with Desoximetasone Topical Spray in healthy subjects indicate that it is in the high to super-high range of potency as compared with other topical corticosteroids. The potential for hypothalamic-pituitary-adrenal (HPA) axis suppression was evaluated in a study of 24 adult subjects with moderate to severe plaque psoriasis. Desoximetasone Topical Spray was applied twice a day for 28 days. Twenty-one subjects had evaluable serum cortisol levels. The proportion of subjects demonstrating HPA axis suppression was 8.3% (1 out of 12) in subjects having psoriasis involvement of 10 to 15% of body surface area (BSA), and 22.2% (2 out of 9) in subjects having psoriasis involvement of > 15% of their BSA. In this study HPA axis suppression was defined as serum cortisol level ≤18 mcg/dL 30-min post cosyntropin stimulation. In the 2 subjects with available follow-up values, suppression reversed 28 days after the end of treatment.

12.3 Pharmacokinetics The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. Plasma concentrations of desoximetasone were measured at two single random time points in the HPA axis suppression trial in 24 subjects with psoriasis [ see Clinical Pharmacology (12.2) ]. The mean (% Coefficient of Variation) concentration of desoximetasone was 449 pg/mL (86%) at Day 14 and 678 pg/mL (135%) at Day 28. The concentration time profile following application of Desoximetasone Topical Spray is not known.

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3

3 DOSAGE FORMS AND STRENGTHS Topical Spray, 0.25%. Each gram of Desoximetasone Topical Spray contains 2.5 mg of desoximetasone in a clear, colorless liquid. Spray, 0.25% w/w ( 3 )

Desoximetasone Desoximetasone GLYCERYL OLEATE ISOPROPYL ALCOHOL ISOPROPYL MYRISTATE LEVOMENTHOL MINERAL OIL DESOXIMETASONE DESOXIMETASONE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of Desoximetasone Topical Spray. In a 13-week repeat-dose toxicity study in rats, topical administration of desoximetasone spray at concentrations of 0.001, 0.005 and 0.02% BID (which corresponds to dose levels of 0.01, 0.05, or 0.2 mg/kg/dose BID, respectively) resulted in a toxicity profile consistent with long-term exposure to corticosteroids, including adrenal atrophy and histopathological changes in several organ systems indicative of severe immune suppression. A no observable adverse effect level (NOAEL) could not be determined in this study. Although the clinical relevance of the findings in animals to humans is not clear, sustained glucocorticoid-related immune suppression may increase the risk of infection and possibly the risk for carcinogenesis. Desoximetasone revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster ovary cell chromosome aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus assay). No evidence of impairment of male or female fertility was observed at subcutaneous desoximetasone doses up to 0.1 mg/kg/day (0.6 mg/m 2 /day) in Sprague-Dawley rats.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of Desoximetasone Topical Spray. In a 13-week repeat-dose toxicity study in rats, topical administration of desoximetasone spray at concentrations of 0.001, 0.005 and 0.02% BID (which corresponds to dose levels of 0.01, 0.05, or 0.2 mg/kg/dose BID, respectively) resulted in a toxicity profile consistent with long-term exposure to corticosteroids, including adrenal atrophy and histopathological changes in several organ systems indicative of severe immune suppression. A no observable adverse effect level (NOAEL) could not be determined in this study. Although the clinical relevance of the findings in animals to humans is not clear, sustained glucocorticoid-related immune suppression may increase the risk of infection and possibly the risk for carcinogenesis. Desoximetasone revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster ovary cell chromosome aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus assay). No evidence of impairment of male or female fertility was observed at subcutaneous desoximetasone doses up to 0.1 mg/kg/day (0.6 mg/m 2 /day) in Sprague-Dawley rats.

NDA204141

Desoximetasone

Desoximetasone

51672-1396

HUMAN PRESCRIPTION DRUG

TOPICAL

PRINCIPAL DISPLAY PANEL - 100 mL Bottle Carton 100 mL NDC 51672-1396-7 Desoximetasone Topical Spray 0.25% For Topical Use Only NOT FOR ORAL, OPHTHALMIC, OR INTRAVAGINAL USE Keep this and all medications out of the reach of children. Rx only TARO PRINCIPAL DISPLAY PANEL - 100 mL Bottle Carton

Mfd. by: Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1 Dist. by: Taro Pharmaceuticals U.S.A., Inc. , Hawthorne, NY 10532 Revised: December 2019 PPK-8767-1 110

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information and Instructions for Use ) Inform patients of the following: Use this medication as directed by the physician. Desoximetasone Topical Spray is for external use only. Avoid use on the face, axilla or groin. Do not to use this medication for any disorder other than that for which it was prescribed. Do not bandage or otherwise cover or wrap the treated skin so as to be occlusive. Report any signs of local or systemic adverse reactions to the physician. Do not use other corticosteroid-containing products with Desoximetasone Topical Spray without first consulting with the physician. Discontinue therapy when control is achieved. If no improvement is seen within 4 weeks, contact the physician. This medication is flammable; avoid heat, flame, or smoking when applying this product. Discard this product 30 days after dispensed by pharmacist.

Instructions for Use Desoximetasone (des ox'' i met' a sone) Topical Spray Important information: Desoximetasone Topical Spray is for use on skin only. Do not get Desoximetasone Topical Spray near or in your mouth, eyes or vagina. Read the Instructions for Use that comes with Desoximetasone Topical Spray before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. Parts of Desoximetasone Topical Spray bottle (See Figure A ) Figure A How to apply Desoximetasone Topical Spray: Step 1: Remove the cap from the pump top. Step 2: Hold the bottle in an upright position while pointing the opening of the pump top in the direction of the affected area. To spray, push down on the pump top. Apply Desoximetasone Topical Spray to the affected area as instructed by your doctor. ( See Figure B ) Figure B Step 3: Spray only enough Desoximetasone Topical Spray to cover the affected area, for example, the elbow (See Figure C ). Rub in Desoximetasone Topical Spray gently. Figure C Repeat Steps 2 and 3 to apply Desoximetasone Topical Spray to other affected areas as instructed by your doctor. Step 4: After applying Desoximetasone Topical Spray, place the cap back onto the pump top. ( See Figure D ) This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Mfd. by: Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1 Dist. by: Taro Pharmaceuticals U.S.A., Inc. , Hawthorne, NY 10532 Issued: April, 2018 PPK-8768-0 167 Figure A Figure B Figure C Figure D

14 CLINICAL STUDIES Two multi-center, randomized, double-blind, vehicle-controlled clinical trials were conducted in 239 subjects aged 18 years and older with moderate to severe plaque psoriasis of the body. In both trials, randomized subjects applied Desoximetasone Topical Spray or vehicle spray to the affected areas twice daily for 4 weeks. Enrolled subjects had a minimum body surface area of involvement of 10%, and a Physician's Global Assessment score (PGA) of 3 (moderate) or 4 (severe). Efficacy was assessed at Week 4 as the proportion of subjects who were considered a Clinical Success ("clear" (0) or "almost clear" (1) according to the PGA scale). Table 2 presents the efficacy results. Table 2. Number of Subjects (%) with Clinical Success (scored as clear or almost clear) at Week 4. Parameter Trial 1 Trial 2 Desoximetasone Vehicle Desoximetasone Vehicle N=59 N=60 N=60 N=60 Clinical Success 18 (30.5%) 3 (5.0%) 32 (53.3%) 11 (18.3%)

8.5 Geriatric Use Clinical studies of Desoximetasone Topical Spray did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.3 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 breast milk. Because many drugs are excreted in human milk, caution should be exercised when Desoximetasone Topical Spray is administered to a nursing woman. If used during lactation, Desoximetasone Topical Spray should not be applied on the chest to avoid accidental ingestion by the infant.

8.4 Pediatric Use Safety and effectiveness of Desoximetasone Topical Spray in patients younger than 18 years of age have not been studied; therefore use in pediatric patients 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 HPA axis suppression and Cushing's syndrome when they are treated with topical corticosteroids. They are therefore at 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. [ see Warnings and Precautions (5.1) ] 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 absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. [ see Warnings and Precautions (5.1) ]

8.1 Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Desoximetasone Topical Spray 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. Desoximetasone has been shown to be teratogenic and embryotoxic in mice, rats, and rabbits when given by subcutaneous or dermal routes of administration at doses 3 to 30 times the human dose of Desoximetasone Topical Spray based on a body surface area comparison.

Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Desoximetasone Topical Spray 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. Desoximetasone has been shown to be teratogenic and embryotoxic in mice, rats, and rabbits when given by subcutaneous or dermal routes of administration at doses 3 to 30 times the human dose of Desoximetasone Topical Spray based on a body surface area comparison.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Desoximetasone Topical Spray 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. Desoximetasone has been shown to be teratogenic and embryotoxic in mice, rats, and rabbits when given by subcutaneous or dermal routes of administration at doses 3 to 30 times the human dose of Desoximetasone Topical Spray based on a body surface area comparison. 8.3 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 breast milk. Because many drugs are excreted in human milk, caution should be exercised when Desoximetasone Topical Spray is administered to a nursing woman. If used during lactation, Desoximetasone Topical Spray should not be applied on the chest to avoid accidental ingestion by the infant. 8.4 Pediatric Use Safety and effectiveness of Desoximetasone Topical Spray in patients younger than 18 years of age have not been studied; therefore use in pediatric patients 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 HPA axis suppression and Cushing's syndrome when they are treated with topical corticosteroids. They are therefore at 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. [ see Warnings and Precautions (5.1) ] 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 absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. [ see Warnings and Precautions (5.1) ] 8.5 Geriatric Use Clinical studies of Desoximetasone Topical Spray did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied/Storage Desoximetasone Topical Spray, 0.25% is a clear colorless liquid supplied in white, opaque bottles with white, opaque screw caps in the following sizes: 30 mL 50 mL 100 mL (2-50 mL bottles) 100 mL (NDC 51672-1396-3) (NDC 51672-1396-4) (NDC 51672-1396-6) (NDC 51672-1396-7) Store at controlled room temperature between 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature] Spray is flammable; avoid heat, flame or smoking when using this product. Each unit is co-packaged with a manual spray pump for installation by the pharmacist. 16.2 Instructions for the Pharmacist Remove the spray pump from the wrapper Remove and discard the cap from the bottle Keeping the bottle vertical, insert the spray pump into the bottle and turn clockwise until well-fastened Dispense the bottle with the spray pump inserted Label the bottle with "discard the product 30 days after dispensing"

Store at controlled room temperature between 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature] Spray is flammable; avoid heat, flame or smoking when using this product. Each unit is co-packaged with a manual spray pump for installation by the pharmacist.