Efinaconazole

1 INDICATIONS AND USAGE JUBLIA (efinaconazole) topical solution, 10% is an azole antifungal indicated for the topical treatment of onychomycosis of the toenail(s) due to Trichophyton rubrum and Trichophyton mentagrophytes . JUBLIA is an azole antifungal indicated for the topical treatment of onychomycosis of the toenail(s) due to Trichophyton rubrum and Trichophyton mentagrophytes . (1)

2 DOSAGE AND ADMINISTRATION Apply JUBLIA to affected toenails once daily for 48 weeks, using the integrated flow-through brush applicator. When applying JUBLIA, ensure the toenail, the toenail folds, toenail bed, hyponychium, and the undersurface of the toenail plate, are completely covered. JUBLIA is for topical use only and not for oral, ophthalmic, or intravaginal use. • Apply JUBLIA to affected toenails once daily for 48 weeks using the integrated flow-through brush applicator. (2) • When applying JUBLIA, ensure the toenail, the toenail folds, toenail bed, hyponychium, and the undersurface of the toenail plate, are completely covered. (2) • For topical use only. Not for oral, ophthalmic, or intravaginal use. (2)

6 ADVERSE REACTIONS The most common adverse reactions (incidence >1%) were ingrown toenails, application site dermatitis, application site vesicles, and application site pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 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. In two clinical trials, 1227 subjects were treated with JUBLIA, 1161 for at least 24 weeks and 780 for 48 weeks. Adverse reactions reported within 48 weeks of treatment and in at least 1% of subjects treated with JUBLIA and those reported in subjects treated with the vehicle are presented in Table 1 . Table 1: Adverse Reactions Reported by at Least 1% of Subjects Treated for up to 48 Weeks Adverse Event, n (%) JUBLIA (N=1,227) Vehicle (N=413) Ingrown toenail 28 (2.3%) 3 (0.7%) Application site dermatitis 27 (2.2%) 1 (0.2%) Application site vesicles 20 (1.6%) 0 (0.0%) Application site pain 13 (1.1%) 1 (0.2%) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of JUBLIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. General Disorders and Administration Site Conditions: Application site erythema and exfoliation Skin and Subcutaneous Tissue Disorders: Onychomadesis, Nail discoloration

12.3 Pharmacokinetics Systemic absorption of efinaconazole in 18 adult subjects with severe onychomycosis was determined after application of JUBLIA once daily for 28 days to patients’ 10 toenails and 0.5 cm adjacent skin. The concentration of efinaconazole in plasma was determined at multiple time points over the course of 24-hour periods on days 1, 14, and 28. Efinaconazole mean ± SD plasma C max on Day 28 was 0.67 ± 0.37 ng/mL and the mean ± SD AUC was 12.15 ± 6.91 ng*h/mL. The plasma concentration versus time profile at steady state was generally flat over a 24-hour dosing interval. In a separate study of healthy volunteers, the plasma half-life of efinaconazole following daily applications when applied to all 10 toenails for 7 days was 29.9 hours. Specific Populations Pediatric patients PK of efinaconazole was assessed in 17 pediatric subjects 12 to <17 years of age with moderate to severe onychomycosis following application of JUBLIA once daily to all 10 toenails for 28 days. The plasma concentrations of efinaconazole in pediatric subjects were relatively flat over a 24-hour dosing interval. The mean ± SD plasma C max and AUC 0-24 for efinaconazole on Day 28 were 0.55±0.38 ng/mL and 11.4±7.68 h•ng/mL, respectively. Drug Interactions JUBLIA is considered a non-inhibitor of the CYP450 enzyme family. In in vitro studies using human liver microsomes, efinaconazole did not inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2PE1 and CYP3A4 enzyme activities at expected clinical systemic concentrations. In vitro studies in human primary hepatocytes showed that efinaconazole did not induce CYP1A2 or CYP3A4 activities.