ZORYVE

Indications and Usage, Plaque Psoriasis ( 1.1 ) 6/2026 Indications and Usage, Atopic Dermatitis ( 1.2 ) 10/2025 Dosage and Administration ( 2 ) 6/2026

1 INDICATIONS AND USAGE 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 2 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 2 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.

2 DOSAGE AND ADMINISTRATION Plaque Psoriasis Use ZORYVE cream, 0.3%, for the treatment of plaque psoriasis in adult and pediatric patients 2 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 )

3 DOSAGE FORMS AND STRENGTHS Cream, 0.3%: 3 mg of roflumilast per gram of white to off-white cream in 60-gram tubes. Cream, 0.15%: 1.5 mg of roflumilast per gram of white to off-white cream in 60-gram tubes. Cream, 0.05%: 0.5 mg of roflumilast per gram of white to off-white cream in 60-gram tubes. Cream, 0.3%: 3 mg of roflumilast per gram in 60-gram tubes. ( 3 ) Cream, 0.15%: 1.5 mg of roflumilast per gram in 60-gram tubes. ( 3 ) Cream, 0.05%: 0.5 mg of roflumilast per gram in 60-gram tubes. ( 3 )

4 CONTRAINDICATIONS 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 )

6 ADVERSE REACTIONS 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 644 subjects 6 years of age and older 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. Pediatric Subjects 2 to 5 Years of Age The safety of ZORYVE cream, 0.3%, once daily was assessed in an open-label trial for up to 24 weeks. The adverse reaction profile in pediatric subjects 2 years to 5 years of age with plaque psoriasis was consistent with that observed in adult and pediatric subjects 6 years of age and older. 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 1 …

7 DRUG INTERACTIONS 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) ] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are insufficient data available on the use of ZORYVE cream in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, roflumilast administered orally to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities at doses up to 36 and 31 times the maximum recommended human dose (MRHD), respectively. Roflumilast induced post-implantation loss in rats at oral doses greater than or equal to 12 times the MRHD. Roflumilast induced stillbirth and decreased pup viability in mice at oral doses 19 and 59 times the MRHD, respectively. Roflumilast has been shown to adversely affect pup post-natal development when dams were treated with an oral dose 59 times the MRHD during pregnancy and lactation periods in mice ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. 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. Clinical Considerations Labor or Delivery Avoid using ZORYVE cream during labor and delivery. There are no human studies that have investigated effects of ZORYVE cream on preterm labor or labor at term; however, animal studies showed that oral roflumilast disrupted the labor and delivery process in mice. Data Animal Data In an embryo-fetal development study, pregnant rats were dosed orally during the period of organogenesis with up to 1.8 mg/kg/day roflumilast (36 times the MRHD on a mg/m 2 basis). No evidence of structural abnormalities or effects on survival rates were observed. Roflumilast did not affect embryo-fetal development at a maternal oral dose of 0.2 mg/kg/day (4 times the MRHD on a mg/m 2 basis). In a fertility and embryo-fetal development study, male rats were dosed orally with up to 1.8 mg/kg/day roflumilast for 10 weeks and females for 2 weeks prior to pairing and throughout the organogenesis period. Roflumilast induced pre- and post-implantation loss at maternal oral doses greater than or equal to 0.6 mg/kg/day (12 times the MRHD on a mg/m 2 basis). Roflumilast did not cause fetal structural abnormalities at maternal oral doses up to 1.8 mg/kg/day (35 times the MRHD on a mg/m 2 basis). In an embryo-fetal development study in rabbits, pregnant does were dosed orally with 0.8 mg/kg/day roflumilast during the period of organogenesis. Roflumilast did not cause fetal structural abnormalities at the maternal oral doses of 0.8 mg/kg/day (31 times the MRHD on a mg/m 2 basis). In pre- and post-natal developmental studies in mice, dams were dosed orally with up to 12 mg/kg/day roflumilast during the period of organogenesis and lactation. Roflumilast induced stillbirth and decreased pup viability at maternal oral doses greater than 2 mg/kg/day and 6 mg/kg/day, respectively (19 and 59 times the MRHD on a mg/m 2 basis, respectively). Roflumilast induced delivery retardation in pregnant mice at maternal oral doses greater than 2 mg/kg/day (19 times the MRHD on a mg/m 2 basis). Roflumilast decreased pup rearing frequencies at a maternal oral dose of 6 mg/kg/day during pregnancy and lactation (59 times the MRHD on a mg/m 2 basis). Roflumilast also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at a maternal oral dose of 12 mg/kg/day (116 times the MRHD on a mg/m 2 basis). 8.2 Lactation Risk Summary There are no data on the presence of roflumilast or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. Roflumilast and/or its metabolites are excreted into the milk of lactating rats ( see Data ). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding s …

12.1 Mechanism of Action Roflumilast and its active metabolite (roflumilast N-oxide) are inhibitors of PDE4. Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic 3′,5′-adenosine monophosphate [cyclic AMP] metabolizing enzyme) activity leads to accumulation of intracellular cyclic AMP. The specific mechanism(s) by which roflumilast exerts its therapeutic action is not well defined.

11 DESCRIPTION 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

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ZORYVE (roflumilast) cream is a white to off-white cream supplied as follows: Cream, 0.3%: 3 mg of roflumilast per gram supplied in 60-gram aluminum tubes (NDC 80610-130-60). Cream, 0.15%: 1.5 mg of roflumilast per gram supplied in 60-gram aluminum tubes (NDC 80610-115-60). Cream, 0.05%: 0.5 mg of roflumilast per gram supplied in 60-gram aluminum tubes (NDC 80610-105-60). 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]