Tavaborole

1 INDICATIONS & USAGE Tavaborole topical solution, 5% is an oxaborole antifungal indicated for the treatment of onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes. Tavaborole topical solution is an oxaborole antifungal indicated for the topical treatment of onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes . ( 1 ) ( 1 )

2 DOSAGE & ADMINISTRATION Apply tavaborole topical solution to affected toenails once daily for 48 weeks. Tavaborole topical solution should be applied to the entire toenail surface and under the tip of each toenail being treated. Tavaborole topical solution is for topical use only and not for oral, ophthalmic, or intravaginal use. Apply tavaborole topical solution to affected toenails once daily for 48 weeks. ( 2 ) Tavaborole topical solution should be applied to the entire toenail surface and under the tip of each toenail being treated. ( 2 ) For topical use only. ( 2 ) Not for oral, ophthalmic, or intravaginal use. ( 2 ) ( 2 )

3 DOSAGE FORMS AND STRENGTHS Tavaborole topical solution, 5% is a clear, colorless alcohol-based solution. Each milliliter of solution contains 43.5 mg (5% w/w) of tavaborole. Solution, 5%. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS Common adverse reactions occurring in ≥1% in subjects treated with tavaborole topical solution included application site exfoliation, ingrown toenail, application site erythema, and application site dermatitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 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, 791 subjects were treated with Tavaborole topical solution. The most commonly reported adverse reactions are listed below (Table 1). Table 1 : Adverse Reactions Occurring in ≥1% of Tavaborole topical solution, 5%-Treated Subjects and at a Greater Frequency than Observed with Vehicle Preferred Term Tavaborole topical solution N= 791 n(%) Vehicle N= 395 n(%) Application site exfoliation 21 (2.7%) 1 (0.3%) Ingrown toenail 20 (2.5%) 1 (0.3%) Application site erythema 13 (1.6%) 0 (0%) Application site dermatitis 10 (1.3%) 0 (0%) 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of Tavaborole topical solution. 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 product exposure: Hypersensitivity; contact allergy

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on tavaborole topical solution use in pregnant women to inform a drug associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. In oral animal reproductive studies, administration of tavaborole during the period of organogenesis resulted in embryofetal toxicity and malformations at 570 times the Maximum Recommended Human Dose (MRHD) based on Area Under the Curve (AUC) comparisons in rats and embryofetal toxicity at 155 times the MRHD based on AUC comparisons in rabbits. Embryofetal toxicity was noted following dermal administration in rabbits up to 36 times the MRHD based on AUC comparisons [see Data]. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies carry some risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects in the U.S. general population is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data Oral administration: In an oral embryofetal development study in rats, oral doses of 30 mg/kg/day, 100 mg/kg/day, and 300 mg/kg/day tavaborole were administered during the period of organogenesis (gestational days 6 to 19) to pregnant female rats. In the presence of maternal toxicity, embryofetal toxicity (increased embryofetal resorption and/or deaths) and drug-related skeletal malformations and variations suggestive of delayed development (i.e., a delay in ossification) were noted in fetuses at 300 mg/kg/day tavaborole [570 times the MRHD based on AUC comparisons]. No developmental toxicity was noted in rats at 100 mg/kg/day tavaborole (26 times the MRHD based on AUC comparisons). In an oral embryofetal development study in rabbits, oral doses of 15 mg/kg/day, 50 mg/kg/day, and 150 mg/kg/day tavaborole were administered during the period of organogenesis (gestational days 7 to 19) to pregnant female rabbits. In the presence of maternal toxicity, excessive embryofetal mortality due to post-implantation loss was noted at 150 mg/kg/day tavaborole. No drug related malformations were noted in rabbits at 150 mg/kg/day tavaborole (155 times the MRHD based on AUC comparisons). No embryofetal mortality was noted in rabbits at 50 mg/kg/day tavaborole (16 times the MRHD based on AUC comparisons). In an oral pre- and post-natal development study in rats, oral doses of 15 mg/kg/day, 60 mg/kg/day, and 100 mg/kg/day tavaborole were administered from the beginning of organogenesis (gestation day 6) through the end of lactation (lactation day 20). In the presence of minimal maternal toxicity, no embryofetal toxicity or effects on postnatal development were noted at 100 mg/kg/day (29 times the MRHD based on AUC comparisons). Topical administration: In a dermal embryofetal development study in rabbits, topical doses of 1%, 5%, and 10% tavaborole solution were administered during the period of organogenesis (gestational days 6 to 28) to pregnant female rabbits. A dose dependent increase in dermal irritation at the treatment site was noted at 5% and 10% tavaborole solution. A decrease in fetal bodyweight was noted at 10% tavaborole solution. No drug related malformations were noted in rabbits at 10% tavaborole solution (36 times the MRHD based on AUC comparisons). No embryofetal toxicity was noted in rabbits at 5% tavaborole solution (26 times the MRHD based on AUC comparisons). 8.2 Lactation Risk Summary There is no information available on the presence of tavaborole topical solution in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production after topical application of tavaborole topical solution to women who are breastfeeding. Tavaborole topical solution is systemically absorbed. The lack of clinical data during lactation precludes a clear determination of the risk of tavaborole topical solution to a breastfed infant. Therefore, …

12.1 Mechanism of Action Tavaborole topical solution is an oxaborole antifungal [see Clinical Pharmacology ( 12.4 ) ].

11 DESCRIPTION Tavaborole topical solution, 5% contains tavaborole, 5% (w/w) in a clear, colorless alcohol-based solution for topical use. The active ingredient, tavaborole, is an oxaborole antifungal with the chemical name of 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole. The chemical formula is C 7 H 6 BFO 2 , the molecular weight is 151.93 and the structural formula is: Tavaborole is a white to off-white powder. It is slightly soluble in water and freely soluble in ethanol and propylene glycol. Each mL of tavaborole topical solution contains 43.5 mg of tavaborole. Inactive ingredients include ethyl alcohol (76.4% v/v), edetate calcium disodium, propylene glycol, and purified water. image description

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tavaborole topical solution, 5% is a clear colorless alcohol-based solution supplied in an amber colored glass bottle with a black screw cap. At initial use, the screw cap is replaced with the dropper assembly. Rubber dropper with glass pipette packed in BOPP pouch printed with "THIS DEVICE CONTAINS DRY NATURAL RUBBER". Tavaborole topical solution, 5% is supplied in the following presentations: NDC 69097-686-37: One bottle containing 10 mL of solution with one glass pointed-tip dropper. NDC 69097-686-34: One bottle containing 4 mL of solution with one glass pointed-tip dropper. 16.2 Storage and Handling 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]. CAUTION: Flammable. Keep away from heat and flame. Discard product within 3 months after insertion of the dropper. Keep bottle tightly closed. Keep out of reach of children.

16.1 How Supplied Tavaborole topical solution, 5% is a clear colorless alcohol-based solution supplied in an amber colored glass bottle with a black screw cap. At initial use, the screw cap is replaced with the dropper assembly. Rubber dropper with glass pipette packed in BOPP pouch printed with "THIS DEVICE CONTAINS DRY NATURAL RUBBER". Tavaborole topical solution, 5% is supplied in the following presentations: NDC 69097-686-37: One bottle containing 10 mL of solution with one glass pointed-tip dropper. NDC 69097-686-34: One bottle containing 4 mL of solution with one glass pointed-tip dropper.