JUBLIA

JUBLIA- efinaconazole solution
Valeant Pharmaceuticals North America LLC

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 pre-natal pup mortality, reduced live litter sizes and increased post-natal 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 post-natal 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 Chemical Structure
(click image for full-size original)

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.

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