Difamilast

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. 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.

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. 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 inebilizumab and any potential adverse effects on the breastfed infant from inebilizumab or from the underlying maternal condition.

Clinical Considerations

To minimize potential infant exposure, advise breastfeeding women not to apply inebilizumab directly to the nipple or areola. If applied to the patient's chest, avoid exposure via direct contact with the infant's skin.

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/cm² (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/cm² (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).

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.

The safety of inebilizumab 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 inebilizumab or vehicle ointment topically twice daily for 4 weeks. Adverse reactions reported by ≥1% of inebilizumab-treated subjects and more frequently than in subjects receiving vehicle are listed in the following table.

Adverse Reactions Occurring in ≥1% of Adult and Pediatric Subjects 2 Years of Age and Older Treated with Inebilizumab 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 inebilizumab 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 inebilizumab 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 inebilizumab 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 inebilizumab 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.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of inebilizumab. 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.