Difamilast

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)

Ointment: 1% (10 mg of difamilast per gram) of white to off-white ointment. Ointment: 1%. (3)

None. None. (4)

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).

8.2 Lactation Risk Summary There are no data on the presence of difamilast or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Difamilast 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 ADQUEY and any potential adverse effects on the breastfed infant from ADQUEY or from the underlying maternal condition. Clinical Considerations To minimize potential infant exposure, advise breastfeeding women not to apply ADQUEY directly to the nipple or areola. If applied to the patient's chest, avoid exposure via direct contact with the infant's skin. Data When 14 C-difamilast was subcutaneously administered to lactating rats at a single dose of 3 mg/kg, the concentration of radioactivity in milk was higher than that in blood (with milk/blood ratios at C max and AUC∞ of 13.7 and 5.4, respectively). The concentration of difamilast in animal milk does not necessarily predict the concentration of drug in human milk.

8.4 Pediatric Use The safety and effectiveness of ADQUEY for the topical treatment of mild to moderate atopic dermatitis have been established in pediatric patients 2 years of age and older. Use of ADQUEY in this age group is supported by data from five vehicle-controlled trials, which included 236 subjects 2 to less than 17 years of age, of whom 119 received ADQUEY and 117 received vehicle [ see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14) ]. The safety and effectiveness of ADQUEY have not been established in pediatric patients younger than 2 years of age.

8.5 Geriatric Use In clinical trials of ADQUEY in subjects with mild to moderate atopic dermatitis, 2 subjects were 65 years of age or older, and 0 were aged 75 years and older. Clinical trials of ADQUEY did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger adult subjects.

Difamilast is an inhibitor of phosphodiesterase-4 (PDE-4). Difamilast’s inhibition of PDE-4 (a major cyclic adenosine monophosphate (AMP)-metabolizing enzyme) activity leads to accumulation of intracellular cyclic AMP and decreased productions of various cytokines and chemokines. However, the specific mechanism(s) by which difamilast exerts its therapeutic action is not well defined.