英文药名：JUBLIA(efinaconazole) topical solution, 10% 中文药名：艾氟康唑外用溶液 10％ 生产厂家：Valeant公司制药北美公司 药品介绍 该药物是FDA在一个月内批准的第二个局部治疗趾甲真菌感染的药物 批准上市日期：2014年7月7日 JUBLIA®（efinaconazole）外用溶液，10％ 局部用 美国初始批准：2014 适应症和用法 JUBLIA是局部治疗，由于红色毛癣菌和须癣毛癣菌的脚趾甲真菌病的指示唑类抗真菌。 用法用量 每日一次申请JUBLIA受影响的脚趾甲，使用集成的流通刷子涂抹48周。 当施加JUBLIA，确保趾甲，趾甲褶皱，趾甲床，hyponychium和趾甲板的下表面，被完全覆盖。 仅适用于局部使用。 不经口，眼，或阴道内使用。 剂型和规格 溶液：10％ 禁忌 无 不良反应 最常见的不良反应（发生率>1％）是嵌甲，施用部位皮炎，施用部位的囊泡，和施用部位的疼痛。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use JUBLIA safely and effectively. See full prescribing information for JUBLIA. JUBLIA ® (efinaconazole) topical solution, 10% For topical use Initial U.S. Approval: 2014 INDICATIONS AND USAGE JUBLIA is an azole antifungal indicated for the topical treatment of onychomycosis of the toenails due to Trichophyton rubrum and Trichophyton mentagrophytes. (1) DOSAGE AND ADMINISTRATION • 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. (2) • Not for oral, ophthalmic, or intravaginal use. (2) DOSAGE FORMS AND STRENGTHS Solution: 10%. (3) CONTRAINDICATIONS None. (4) 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 Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 2/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 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. 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. 3 DOSAGE FORMS AND STRENGTHS JUBLIA (efinaconazole) topical solution, 10% contains 100 mg of efinaconazole in each gram of clear, colorless to pale yellow solution. 4 CONTRAINDICATIONS None. 6 ADVERSE REACTIONS 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 = 1227 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%) 7 DRUG INTERACTIONS In vitro studies have shown that JUBLIA, at therapeutic concentrations, neither inhibits nor induces cytochrome P450 (CYP450) enzymes. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with JUBLIA in pregnant women. JUBLIA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Systemic embryofetal development studies were conducted in rats and rabbits. Subcutaneous doses of 2, 10 and 50 mg/kg/day efinaconazole were administered during the period of organogenesis (gestational days 6-16) to pregnant female rats. In the presence of maternal toxicity, embryofetal toxicity (increased embryofetal deaths, decreased number of live fetuses, and placental effects) was noted at 50 mg/kg/day [559 times the Maximum Recommended Human Dose (MRHD) based on Area Under the Curve (AUC) comparisons]. No embryofetal toxicity was noted at 10 mg/kg/day (112 times the MRHD based on AUC comparisons). No malformations were observed at 50 mg/kg/day (559 times the MRHD based on AUC comparisons). Subcutaneous doses of 1, 5, and 10 mg/kg/day efinaconazole were administered during the period of organogenesis (gestational days 6-19) to pregnant female rabbits. In the presence of maternal toxicity, there was no embryofetal toxicity or malformations at 10 mg/kg/day (154 times the MRHD based on AUC comparisons). In a pre- and post-natal development study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day efinaconazole were administered from the beginning of organogenesis (gestation day 6) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal toxicity (increased prenatal pup mortality, reduced live litter sizes and increased postnatal pup mortality) was noted at 25 mg/kg/day. No embryofetal toxicity was noted at 5 mg/kg/day (17 times the MRHD based on AUC comparisons). No effects on postnatal development were noted at 25 mg/kg/day (89 times the MRHD based on AUC comparisons). 8.3 Nursing Mothers It is not known whether efinaconazole is excreted in human milk. After repeated subcutaneous administration, efinaconazole was detected in milk of nursing rats. Because many drugs are excreted in human milk, caution should be exercised when JUBLIA is administered to nursing women. 8.4 Pediatric Use Safety and effectiveness of JUBLIA in pediatric subjects have not been established. 8.5 Geriatric Use Of the total number of subjects in clinical trials of JUBLIA, 11.3% were 65 and over, while none were 75 and over. No overall differences in safety and effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and the younger subjects, but greater sensitivity of some older individuals cannot be ruled out. 11 DESCRIPTION JUBLIA (efinaconazole) topical solution, 10% is a clear colorless to pale yellow solution for topical use. Each gram of JUBLIA contains 100 mg of efinaconazole. Efinaconazole is an azole antifungal with a chemical name of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol). The structural formula for efinaconazole is represented below: JUBLIA contains the following inactive ingredients: alcohol, anhydrous citric acid, butylated hydroxytoluene, C12-15 alkyl lactate, cyclomethicone, diisopropyl adipate, disodium edetate, and purified water. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action JUBLIA topical solution is an azole antifungal [see Clinical Pharmacology (12.4)]. 12.2 Pharmacodynamics The pharmacodynamics of JUBLIA is unknown. 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 Cmax 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. 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. 12.4 Microbiology Mechanism of Action Efinaconazole is an azole antifungal. Efinaconazole inhibits fungal lanosterol 14α-demethylase involved in the biosynthesis of ergosterol, a constituent of fungal cell membranes. Activity In Vitro and In Vivo Efinaconazole has been shown to be active against isolates of the following microorganisms, both in vitro and in clinical infections. Efinaconazole exhibits in vitro minimum inhibitory concentrations (MICs) of 0.06 µg/mL or less against most (≥90%) isolates of the following microorganisms: Trichophyton rubrum Trichophyton mentagrophytes Mechanism of Resistance Efinaconazole drug resistance development was studied in vitro against T. mentagrophytes, T. rubrum and C. albicans. Serial passage of fungal cultures in the presence of sub-growth inhibitory concentrations of efinaconazole increased the MIC by up to 4-fold. The clinical significance of these in vitro results is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year dermal carcinogenicity study in mice was conducted with daily topical administration of 3%, 10% and 30% efinaconazole solution. Severe irritation was noted at the treatment site in all dose groups, which was attributed to the vehicle and confounded the interpretation of skin effects by efinaconazole. The high dose group was terminated at week 34 due to severe skin reactions. No drug-related neoplasms were noted at doses up to 10% efinaconazole solution (248 times the MRHD based on AUC comparisons). Efinaconazole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster lung cell chromosome aberration assay) and one in vivo genotoxicity test (mouse peripheral reticulocyte micronucleus assay). No effects on fertility were observed in male and female rats that were administered subcutaneous doses up to 25 mg/kg/day efinaconazole (279 times the MRHD based on AUC comparisons) prior to and during early pregnancy. Efinaconazole delayed the estrous cycle in females at 25 mg/kg/day but not at 5 mg/kg/day (56 times MRHD based on AUC comparisons). 14 CLINICAL STUDIES The safety and efficacy of once daily use of JUBLIA for the treatment of onychomycosis of the toenail were assessed in two 52-week prospective, multi-center, randomized, double-blind clinical trials in patients 18 years and older (18 to 70 years of age) with 20% to 50% clinical involvement of the target toenail, without dermatophytomas or lunula (matrix) involvement. The trials compared 48-weeks of treatment with JUBLIA to the vehicle solution. The Complete Cure rate was assessed at Week 52 (4-weeks after completion of therapy). Complete cure was defined as 0% involvement of the target toenail (no clinical evidence of onychomycosis of the target toenail) in addition to Mycologic Cure, defined as both negative fungal culture and negative KOH. Table 2 lists the efficacy results for trials 1 and 2. Table 2: Efficacy Endpoints Trial 1 Trial 2 JUBLIA Vehicle JUBLIA Vehicle N = 656 N = 214 N = 580 N = 201 a Complete cure defined as 0% clinical involvement of the target toenail plus negative KOH and negative culture. b Complete or almost complete cure defined as ≤5% affected target toenail area involved and negative KOH and culture. c Mycologic cure defined as negative KOH and negative culture. Complete Curea 117 17.8% 7 3.3% 88 15.2% 11 5.5% Complete or Almost Complete Cureb 173 26.4% 15 7.0% 136 23.4% 15 7.5% Mycologic Curec 362 55.2% 36 16.8% 310 53.4% 34 16.9% 16 HOW SUPPLIED/STORAGE AND HANDLING JUBLIA (efinaconazole) topical solution, 10% is a clear, colorless to pale yellow solution supplied in a white plastic bottle with an integrated flow-through brush applicator as follows: • 4 mL (NDC 0187-5400-04) • 8 mL (NDC 0187-5400-08) Storage and Handling Conditions: Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP Controlled Room Temperature]. • Solution is flammable; keep away from heat or flame • Protect from freezing • Keep out of the reach of children • Keep bottle tightly closed • Store in upright position 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information) • JUBLIA is for external use only and is not for ophthalmic, oral, or intravaginal use. It is for use on toenails and immediately adjacent skin only. • Apply JUBLIA once daily to clean dry toenails. Wait for at least 10 minutes after showering, bathing, or washing before applying. • Use JUBLIA only on the affected toenails, as directed by your healthcare provider. • Inform a health care professional if the area of application shows signs of persistent irritation (for example, redness, itching, swelling). • The impact of nail polish or other cosmetic nail products on the efficacy of JUBLIA has not been evaluated. • Flammable, avoid use near heat or open flame https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=922d4d25-c530-11e1-9b21-0800200c9a66 甲真菌病又一新药—JUBLIA®（efinaconazole）外用溶液获准上市 2014年6月9日,灰指甲治疗药物Jublia获FDA批准，该药是首个外用型三唑类抗真菌药，用于局部远端侧位甲下甲真菌（DLSO）的治疗。 抗真菌药Jublia（efinaconazole，10%外用溶液）获FDA批准，用于脚趾甲灰指甲（onychomycosis）的治疗，该药是首个外用三唑类（trizole）抗真菌药物。此前，Jublia于2013年11月获加拿大卫生部批准。Valeant计划于2014年第三季度在美国和加拿大推出该药。 灰指甲（onychomycosis）是一种发生在人指（趾）甲上的传染性疾病的俗称，是由一大类称做病原真菌的微生物感染引起，该病目前治疗不足，很大程度上是由于现有治疗药物的局限性。目前，非处方或处方外用药提供的疗效十分有限，在用药的同时往往需要频繁清创，或刮、切割或去除指甲。处方口服药则由于药物相互作用和严重的安全性问题而应用十分有限。 关于Jublia（efinaconazole，10%外用溶液）： Jublia是首个外用三唑类抗真菌药，开发用于局部远端侧位甲下甲真菌（DLSO）的治疗，这是一种最为常见的甲真菌病，致病菌先侵入远端甲下甲床，甲床下角质增生、增厚，甲板可变为白色、棕色至灰褐色，表面凹凸不平，失去光泽，甲板缺失、松脆。 Jublia是一种外用溶液，通过一种独特的内置用量控制型指甲刷进行涂敷，该药能很快干燥，无需出去过量的药物，同时无需顾虑系统性副作用，如药物相互作用或急性肝损伤。