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.

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

8.1 Pregnancy

Risk Summary

There are no available human data for the use of JUBLIA during pregnancy to inform any drug associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies, efinaconazole did not cause malformations or any harm to the fetus when administered to pregnant rabbits and rats during the period of organogenesis at subcutaneous doses up to 112 and 154 times, respectively, the Maximum Recommended Human Dose (MRHD) based on Area Under the Curve (AUC) comparisons. Embryolethality was observed only in rats in the presence of maternal toxicity at systemic exposures 559 times the MRHD based on AUC comparisons. Subcutaneous efinaconazole administration to pregnant rats from the beginning of organogenesis through the end of lactation did not cause embryofetal toxicity or developmental effects at systemic exposures 17 times the MRHD based on AUC comparisons (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies.

Data

Animal Data

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 MRHD based on 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 postnatal 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).

8.2 Lactation

Risk Summary

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.

The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for JUBLIA, and any potential adverse effects on the breastfed infant from JUBLIA.

8.4 Pediatric Use

The safety and effectiveness of JUBLIA were established in patients 6 years and older. Use of JUBLIA in these age groups is supported by evidence from well-controlled trials in adults with additional data from an open-label safety study in 60 pediatric subjects ages 6 to 17 (including a pharmacokinetic study in 17 subjects 12 years to less than 17 years old) [see Clinical Pharmacology (12.3)]. Safety and effectiveness of JUBLIA in pediatric subjects under 6 years of age 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.

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.

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 Cmax and AUC0-24 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.

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 mcg/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.

13.1 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).

Storage and Handling Conditions:

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

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Solution is flammable; keep away from heat or flame.

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Protect from freezing.

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Keep out of reach of children.

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Keep bottle tightly closed.

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Store in upright position.