Roflumilast

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.

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 )

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 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 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) ] .

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 should be considered along with the mother's clinical need for ZORYVE cream and any potential adverse effects on the breastfed infant from ZORYVE cream or from the underlying maternal condition. Clinical Considerations To minimize potential exposure to the breastfed infant via breast milk, use ZORYVE cream on the smallest area of skin and for the shortest duration possible while breastfeeding. To avoid direct infant exposure, advise breastfeeding women not to apply ZORYVE cream directly to the nipple or areola. If applied to the patient's chest, avoid exposure via direct contact with the infant's skin. Data Animal Data Roflumilast and/or its metabolite concentrations measured 8 hours after an oral dose of 1 mg/kg given to lactating rats were 0.32 and 0.02 mcg/g in the milk and pup liver, respectively. The concentration of roflumilast in animal milk does not necessarily predict the concentration of drug in human milk.

8.3 Females and Males of Reproductive Potential Infertility In a human spermatogenesis study, oral roflumilast 500 mcg had no effects on semen parameters or reproductive hormones during the 3-month treatment period and the following 3-month off-treatment period.

8.4 Pediatric Use Plaque Psoriasis The safety and effectiveness of ZORYVE cream, 0.3%, for the topical treatment of plaque psoriasis, including intertriginous areas, have been established in pediatric patients 2 years of age and older. Use of ZORYVE cream, 0.3%, for this indication is supported by data from: Two 8-week, vehicle-controlled, safety and efficacy trials in adults and 18 subjects 6 to 17 years of age, of whom 11 received ZORYVE cream, 0.3%; One open-label, safety trial in 21 pediatric subjects 2 to 5 years of age with up to 25% BSA involvement who applied ZORYVE cream, 0.3%, up to 24 weeks; With additional safety and pharmacokinetic (PK) data from: Open-label trials of 2- and 24-weeks duration which included 25 subjects 12 to 17 years of age treated with ZORYVE cream, 0.3%; Two 4-week, open-label, safety and PK studies which included 20 pediatric subjects 6 to 11 years of age and 10 pediatric subjects 2 to 5 years of age, treated with ZORYVE cream, 0.3% [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.1) ] . The safety and effectiveness of ZORYVE cream, 0.3%, have not been established in pediatric patients younger than 2 years of age. Atopic Dermatitis ZORYVE Cream, 0.15% The safety and effectiveness of ZORYVE cream, 0.15%, for the topical treatment of mild to moderate atopic dermatitis have been established in pediatric patients 6 years of age and older. Use of ZORYVE cream, 0.15%, in this age group is supported by data from two 4-week, vehicle-controlled, safety and efficacy trials which included 615 subjects 6 to 17 years of age, of whom 406 received ZORYVE cream, 0.15%, [see Clinical Pharmacology (12.3) , Clinical Studies (14.2) ] . Use of ZORYVE cream, 0.15%, in pediatric patients 6 years of age and older is also supported by data from 481 pediatric subjects treated with ZORYVE cream, 0.15%, in open-label trials, of which 104 were treated for 52 weeks. In an open-label PK trial in 36 pediatric subjects 2 to 16 years of age, following topical administration of roflumilast cream, 0.15%, once daily for 2 weeks, mean systemic exposure of roflumilast and roflumilast N-oxide in subjects 2 to 5 years of age was approximately 3.2-fold and 5.2-fold higher, respectively, compared to subjects 12 to 16 years of age, and approximately 2-fold and 2.3-fold higher, respectively, compared to subjects 6 to 11 years of age. The safety and effectiveness of ZORYVE cream, 0.15%, have not been established in pediatric patients younger than 6 years of age. ZORYVE Cream, 0.05% The safety and effectiveness of ZORYVE cream, 0.05%, for the topical treatment of mild to moderate atopic dermatitis have been established in pediatric patients 2 to 5 years of age. […]

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.