ZORYVE

ZORYVE (roflumilast) cream is a white to off-white cream for topical use. The active ingredient, roflumilast, is a phosphodiesterase 4 (PDE4) inhibitor. Roflumilast is described chemically as 3-cyclopropylmethoxy- N -(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide. The empirical formula is C 17 H 14 Cl 2 F 2 N 2 O 3, and the molecular weight is 403.21. The structural formula is represented below: Roflumilast is practically insoluble in water and hexane, sparingly soluble in ethanol, and freely soluble in acetone. Each gram of cream, 0.05%, 0.15%, or 0.3%, contains 0.5 mg, 1.5 mg, or 3 mg of roflumilast, respectively, in a cream base containing ceteareth-10 phosphate, cetearyl phosphate, cetostearyl alcohol, diethylene glycol monoethyl ether, hexylene glycol, isopropyl palmitate, methylparaben, propylparaben, purified water, sodium hydroxide, and white petrolatum. Hydrochloric acid may have been added to adjust pH. Chemical Structure

ZORYVE cream is a phosphodiesterase 4 inhibitor: Plaque Psoriasis ZORYVE cream, 0.3%, is indicated for the topical treatment of plaque psoriasis, including intertriginous areas, in adult and pediatric patients 6 years of age and older. ( 1.1 ) Atopic Dermatitis ZORYVE cream, 0.15%, is indicated for the topical treatment of mild to moderate atopic dermatitis in adult and pediatric patients 6 years of age and older. ( 1.2 ) ZORYVE cream, 0.05%, is indicated for the topical treatment of mild to moderate atopic dermatitis in pediatric patients 2 to 5 years of age. ( 1.2 ) 1.1 Plaque Psoriasis ZORYVE ® cream, 0.3%, is indicated for topical treatment of plaque psoriasis, including intertriginous areas, in adult and pediatric patients 6 years of age and older. 1.2 Atopic Dermatitis ZORYVE cream, 0.15%, is indicated for topical treatment of mild to moderate atopic dermatitis in adult and pediatric patients 6 years of age and older. ZORYVE cream, 0.05%, is indicated for topical treatment of mild to moderate atopic dermatitis in pediatric patients 2 to 5 years of age.

Plaque Psoriasis Use ZORYVE cream, 0.3%, for the treatment of plaque psoriasis in adult and pediatric patients 6 years of age and older. Atopic Dermatitis Use ZORYVE cream, 0.15%, for the treatment of mild to moderate atopic dermatitis in adult and pediatric patients 6 years of age and older. Use ZORYVE cream, 0.05%, for the treatment of mild to moderate atopic dermatitis in pediatric patients 2 to 5 years of age. Administration Instructions Apply ZORYVE cream to affected areas once daily and rub in completely. Wash hands after application. ZORYVE cream is for topical use only and not for ophthalmic, oral, or intravaginal use. For topical use only. ( 2 ) Not for ophthalmic, oral, or intravaginal use. ( 2 ) Plaque Psoriasis Apply ZORYVE cream, 0.3%, once daily to affected areas. ( 2 ) Atopic Dermatitis Adult and Pediatric Patients 6 Years of Age and Older Apply ZORYVE cream, 0.15%, once daily to affected areas. ( 2 ) Pediatric Patients 2 to 5 Years of Age Apply ZORYVE cream, 0.05%, once daily to affected areas. ( 2 )

ZORYVE cream is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C) [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . Moderate to severe liver impairment (Child-Pugh B or C). ( 4 )

The most common adverse reactions (reported in ≥1% of subjects) are: Plaque Psoriasis: diarrhea, headache, insomnia, nausea, application site pain, upper respiratory tract infection, and urinary tract infection. ( 6.1 ) Atopic Dermatitis: headache, nausea, application site pain, diarrhea, vomiting, upper respiratory tract infection, rhinitis, and conjunctivitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Arcutis Biotherapeutics, Inc. at 1-844-692-6729 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. Plaque Psoriasis Adult and Pediatric Subjects 6 Years of Age and Older In two multicenter, randomized, double-blind, vehicle-controlled trials (DERMIS-1 and DERMIS-2), 881 adult and pediatric subjects 6 years of age or older with plaque psoriasis were treated with ZORYVE cream, 0.3%, or vehicle cream once daily for 8 weeks [see Clinical Studies (14.1) ] . The proportion of subjects who discontinued treatment due to an adverse reaction was 1.0% for subjects treated with ZORYVE cream, 0.3%, and 1.3% for subjects treated with vehicle cream. The most common adverse reaction that led to discontinuation of ZORYVE cream, 0.3%, was application site urticaria (0.3%). Table 1 presents adverse reactions that occurred in at least 1% of subjects treated with ZORYVE cream, 0.3%, and for which the rate exceeded the rate for vehicle cream. Table 1: Adverse Reactions Reported in ≥1% of Adult and Pediatric Subjects 6 Years of Age and Older with Plaque Psoriasis Treated with ZORYVE Cream, 0.3%, (and More Frequently than Vehicle Cream) for 8 Weeks in Trials DERMIS-1 and DERMIS-2 Adverse Reaction ZORYVE Cream, 0.3% (N=576) n (%) Vehicle Cream (N=305) n (%) Diarrhea 18 (3.1) 0 (0.0) Headache 14 (2.4) 3 (1.0) Insomnia 8 (1.4) 2 (0.7) Nausea 7 (1.2) 1 (0.3) Application site pain 6 (1.0) 1 (0.3) Upper respiratory tract infection 6 (1.0) 1 (0.3) Urinary tract infection 6 (1.0) 2 (0.7) In 594 subjects with plaque psoriasis who continued treatment with ZORYVE cream, 0.3%, for up to 64 weeks in open-label extension trials, the adverse reaction profile was consistent with that observed in vehicle-controlled trials. Atopic Dermatitis Adult and Pediatric Subjects 6 Years of Age and Older In two multicenter, randomized, double-blind, vehicle-controlled trials (INTEGUMENT-1 and INTEGUMENT-2), 1336 adult and pediatric subjects 6 years of age or older with mild to moderate atopic dermatitis were treated with ZORYVE cream, 0.15%, or vehicle cream once daily for 4 weeks [see Clinical Studies (14.2) ] . The proportion of subjects who discontinued treatment due to an adverse reaction was 1.6% for subjects treated with ZORYVE cream, 0.15%, and 1.1% for subjects treated with vehicle cream. Table 2 presents adverse reactions that occurred in at least 1% of subjects treated with ZORYVE cream, 0.15%, and for which the rate exceeded the rate for vehicle cream. Table 2: Adverse Reactions Reported in ≥1% of Adult and Pediatric Subjects 6 Years of Age and Older with Atopic Dermatitis Treated with ZORYVE Cream, 0.15%, (and More Frequently than Vehicle Cream) for 4 Weeks in Trials INTEGUMENT-1 and INTEGUMENT-2 Adverse Reaction ZORYVE Cream, 0.15% (N=885) n (%) Vehicle Cream (N=451) n (%) Headache 26 (2.9) 4 (0.9) Nausea 17 (1.9) 2 (0.4) Application site pain 13 (1.5) 3 (0.7) Diarrhea 13 (1.5) 2 (0.4) Vomiting 13 (1.5) 2 (0.4) The adverse reaction of insomnia was reported in fewer than 1% of subjects treated with ZORYVE cream, 0.15%. Pediatric Subjects 2 to 5 Years of Age In a multicenter, randomized, double-blind, vehicle-controlled trial (INTEGUMENT-PED), 652 pediatric subjects 2 to 5 years of age with mild to moderate atopic dermatitis were treated with ZORYVE cream, 0.05%, or vehicle cream once daily for 4 weeks [see Clinical Studies (14.2) ] . Table 3 presents adverse reactions that occurred in at least 1% of subjects treated with ZORYVE cream, 0.05%, and for which the rate exceeded the rate for vehicle cream. Table 3: Adverse Reactions Reported in ≥1% of Pediatric Subjects 2 to 5 Years of Age with Atopic Dermatitis Treated with ZORYVE Cream, 0.05%, (and More Frequently than Vehicle) for 4 Weeks in Trial INTEGUMENT-PED Adverse Reaction ZORYVE Cream, 0.05% N=437 n (%) Vehicle Cream N=215 n (%) Upper respiratory tract infection 18 (4.1) 3 (1.4) Diarrhea 11 (2.5) 1 (0.5) Vomiting 9 (2.1) 0 Rhinitis 7 (1.6) 0 Conjunctivitis 6 (1.4) 0 Headache 5 (1.1) 0 Adult and Pediatric Subjects 2 Years of Age and Older The long-term safety of ZORYVE cream, 0.15%, and ZORYVE cream, 0.05%, was assessed in an open-label extension trial of 1219 subjects 2 years of age and older with mild to moderate atopic dermatitis who had completed one of the 4-week vehicle-controlled trials. The safety profile observed in the open-label extension trial was generally consistent with the safety profile observed at Week 4.

Co-administration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously may increase roflumilast systemic exposure and may result in increased adverse reactions. If these products are co-administered with ZORYVE cream, weigh the potential for increased adverse reactions against benefit. ( 7.1 ) Co-administration of roflumilast with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased adverse reactions. If these products are co-administered with ZORYVE cream, weigh the potential for increased adverse reactions against benefit. ( 7.1 ) 7.1 Effects of Other Drugs on ZORYVE Cream Drugs that Inhibit Cytochrome P450 (CYP) Enzymes No formal drug-drug interaction studies were conducted with ZORYVE cream; however, the co-administration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously may increase roflumilast systemic exposure and may result in increased adverse reactions. If these products are co-administered with ZORYVE cream, weigh the potential for increased adverse reactions against benefit [see Clinical Pharmacology (12.3) ] . Oral Contraceptives Containing Gestodene and Ethinyl Estradiol The co-administration of roflumilast with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased adverse reactions. If these products are co-administered with ZORYVE cream, weigh the potential for increased adverse reactions against benefit [see Clinical Pharmacology (12.3) ] .

Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature]