Difamilast

1 INDICATIONS & USAGE ADQUEY is indicated for the topical treatment of adults and pediatric patients 2 years of age and older with mild to moderate atopic dermatitis. ADQUEY is a phosphodiesterase 4 inhibitor indicated for the topical treatment of adults and pediatric patients 2 years of age and older with mild to moderate atopic dermatitis. (1)

2 DOSAGE & ADMINISTRATION ADQUEY is for topical use only and not for ophthalmic, oral, or intravaginal use. Apply a thin layer of ADQUEY twice daily to affected areas and rub in completely. Wash hands after application. Avoid areas of the skin that are infected when applying ADQUEY. For topical use only. Not for ophthalmic, oral, or intravaginal use. (2) Apply a thin layer of ADQUEY twice daily to affected areas and rub in completely. (2)

4 CONTRAINDICATIONS None. None. (4)

6 ADVERSE REACTIONS The most common adverse reaction occurring in ≥1% of subjects is nasopharyngitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Acrotech Biopharma Inc. at 1-888-292-9617 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. The safety of ADQUEY was assessed in two double-blind, vehicle-controlled clinical trials (Trial 2 and Trial 3) that enrolled 532 adult and pediatric subjects 2 years of age and older in Japan with mild to moderate atopic dermatitis (AD). Subjects applied ADQUEY or vehicle ointment topically twice daily for 4 weeks [ see Clinical Studies (14) ]. Adverse reactions reported by ≥1% of ADQUEY-treated subjects and more frequently than in subjects receiving vehicle are listed in Table 1. Table 1: Adverse Reactions Occurring in ≥1% of Adult and Pediatric Subjects 2 Years of Age and Older Treated with ADQUEY for Mild to Moderate Atopic Dermatitis (and Greater than Vehicle) through Week 4 in Trials 2 and 3 Adverse Reaction ADQUEY (N=267) n (%) Vehicle (N=265) n (%) Nasopharyngitis 16(6) 10(4) Less common (<1%) adverse reactions in subjects treated with ADQUEY in Trials 2 and 3 included application site folliculitis, contact dermatitis, application site rash, and molluscum contagiosum. In Trial 1, a vehicle-controlled dose ranging trial, 43 subjects 10 years of age and older in the United States, Australia, and Poland received ADQUEY topically twice daily for 8 weeks and the safety profile was consistent with Trials 2 and 3. In two additional vehicle-controlled dose ranging trials (Trial 4 and Trial 5), 92 subjects 2 years of age and older in Japan received ADQUEY topically twice daily for 4 weeks (Trial 4) and twice daily for 8 weeks (Trial 5) and the safety profile was consistent with Trials 2 and 3. In open-label trials of both Japanese and United States (US) subjects, 857 adult and pediatric subjects continued twice-daily treatment with ADQUEY for up to 52 weeks. The following application site adverse reactions occurred that led to drug discontinuation: pain, pruritus, vesicles, blistering, erythema, burning and contact dermatitis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ADQUEY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General disorders and administration site condition : application site swelling.

8.1 Pregnancy Risk Summary The available data on the use of topical difamilast during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, difamilast administered subcutaneously to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities at doses up to 30 and 3 times the maximum recommended human dose (MRHD), respectively. Difamilast induced increased post-implantation loss, decreased fetal weight, retarded ossification and increased visceral abnormalities in rats at subcutaneous dose 263 times the MRHD. Difamilast induced increased skeletal variations in rabbits at subcutaneous doses 14 times the MRHD ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, and other adverse outcomes. 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. Data Animal Data In an embryo-fetal development study, pregnant rats were dosed subcutaneously during the period of organogenesis with up to 100 mg/kg/day difamilast (263 times the MRHD based on AUC comparison). Increased post-implantation loss, decreased fetal weight, retarded ossification, and increased visceral abnormalities (membranous ventricular septum defect) were noted at 100 mg/kg/day (263 times the MRHD based on AUC comparison). No embryo-fetal toxicity was observed at 10 mg/kg/day (30 times the MRHD based on AUC comparison). In an embryo-fetal development study in rabbits, pregnant does were dosed subcutaneously during the period of organogenesis with up to 3 mg/kg/day difamilast (14 times the MRHD based on AUC comparison). Increased skeletal variations (increased supernumerary lumbar vertebra) were observed at 3 mg/kg/day (14 times the MRHD based on AUC comparison). No embryo-fetal toxicity was observed at 1 mg/kg/day (3 times the MRHD based on AUC comparison). In a pre- and post-natal development study in rats, dams were dosed subcutaneously with up to 3 mg/kg/day difamilast during the periods of organogenesis and lactation. No treatment-related adverse effects on reproductive functions of dams, or pre- and post-natal development of offspring were observed at 3 mg/kg/day (13 times the MRHD based on AUC comparison).