Get your patient on Difamilast (Adquey)

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).

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.

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.

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.

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

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.

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.

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.

The pharmacodynamics of ADQUEY ointment in the treatment of atopic dermatitis is not known.
Cardiac Electrophysiology
ADQUEY ointment is not expected to cause clinically significant QTc interval prolongation at the recommended dosages.

Absorption
The pharmacokinetics (PK) of ADQUEY were investigated in 31 pediatric subjects 2 years of age and older with moderate to severe atopic dermatitis and a mean ± SD body surface area (BSA) involvement of 44 ± 13% (range 25% to 80%). In this trial, subjects applied an average of approximately 4.3 g of ADQUEY ointment, 1% (dose range was 1.7 to 11.7 g per application) twice daily for 2 weeks.
Plasma concentrations were quantifiable in all the subjects. On Day 15, the mean ± SD maximum plasma concentration (C _max ) and area under the concentration time curve from 0 to 8 hours post dose (AUC _0-8 ) for difamilast were 16.9 ± 21.9 ng/mL and 86.2 ± 79.6 ng•h/mL, respectively. Systemic concentrations of difamilast were at steady state by Day 15, with no evidence of accumulation.
The PK of ADQUEY were investigated in 31 adult subjects with mild to moderate atopic dermatitis and a mean ± SD BSA involvement of 6 ± 3% (range 3% to 19%). Subjects applied an average of approximately 0.9 g of ADQUEY ointment, 1% (dose range was 0.1 to 3.8 g per application) twice daily for 4 weeks. On Day 29, the mean ± SD C _max and AUC _0-12 for difamilast were 0.76 ± 1.16 ng/mL and 6.10 ± 8.85 ng•h/mL, respectively.

Distribution
Difamilast serum protein binding is 99% and is not concentration-dependent, in vitro.

Elimination
Metabolism
Difamilast is substantially metabolized to form three major metabolites in the plasma via CYP3A4-mediated O-deethylation (Metabolite 1), CYP1A2-mediated hydroxylation (Metabolite 2), and enzymatic hydrolysis (Metabolite 3).

Excretion
After both single dosing and twice daily administration of difamilast ointment 1% in healthy Japanese subjects for 2 weeks, difamilast and Metabolite 1 were undetectable in urine. The urinary excretion ratios of all the other metabolites were less than 0.1% of the administered dose.

Specific Populations
No dedicated clinical trials have been conducted to assess the impact of intrinsic factors on the PK of difamilast. Based on cross-study analyses, no substantial differences in the PK of difamilast were observed based on age (2-70 years), sex, race, mild or moderate renal impairment, or mild or moderate hepatic impairment. The effect of severe renal impairment (eGFR < 30 mL/min), or severe (Child-Pugh Class C) hepatic impairment on difamilast PK is unknown.

Pediatric Patients
The plasma difamilast trough concentration corrected by dose in pediatric patients was 1.3 to 1.9 times higher than that in adults (on Day 1 and Day 15, respectively).
Drug Interaction Studies
Clinical Studies
No clinical drug interaction trials have been conducted with topical difamilast.

In Vitro Studies
CYP450 Enzymes: Difamilast is a substrate of CYP3A4 and CYP1A2. Difamilast is not expected to inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 at clinically relevant concentrations. Induction of CYP1A2, CYP2B6, CYP2C9, and CYP3A4 by difamilast is expected to be low at clinically relevant concentrations.
Transporter Systems: Difamilast is a substrate of breast cancer resistance protein (BCRP),but is not a substrate of P-glycoprotein (P-gp), OATP1B1, or OATP1B3. Difamilast is not expected to inhibit P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K at clinically relevant concentrations.

In a 2-year dermal carcinogenicity study in rats, no test article-related neoplastic findings were observed in male or female rats that received difamilast at dermal doses up to 3% ointment applied at 0.008 ml/cm ² (4 times the MRHD based on AUC comparison).
In a 2-year dermal carcinogenicity study in mice, no test article-related neoplastic findings were observed in male or female mice that received difamilast at dermal doses up to 3% ointment applied at 0.008 ml/cm ² (4 times the MRHD based on AUC comparison).
Difamilast was not genotoxic in an in vitro bacterial reverse mutation (Ames) test, an in vitro mammalian cell mutation test in mouse lymphoma cells, or an in vivo rat bone marrow micronucleus test.
In a fertility and early embryonic development study in rats, irregular estrus cycles, sperm abnormalities, increased preimplantation loss, and decreased copulation and fertility indexes were observed at a subcutaneous dose of 100 mg/kg/day difamilast (116 times the MRHD for males and 263 times the MRHD for females, respectively, based on AUC comparison). No treatment-related adverse effects on fertility or early embryonic development were observed at 10 mg/kg/day for males and females (20 times the MRHD for males and 30 times the MRHD for females, respectively, based on AUC comparison).