Efinaconazole

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# Overview
Efinaconazole is a azole antifungal that is FDA approved for the treatment of onychomycosis of the toenail(s).   Common adverse reactions include ingrown toenails, application site dermatitis, application site vesicles, and application site pain.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Indications
- 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.

### Dosage
- 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.

### DOSAGE FORMS AND STRENGTHS
- JUBLIA (efinaconazole) topical solution, 10% contains 100 mg of efinaconazole in each gram of clear, colorless to pale yellow solution.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Efinaconazole in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Efinaconazole in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Efinaconazole in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Efinaconazole in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Efinaconazole in pediatric patients.

# Contraindications
- None

# Warnings
There is limited information regarding Efinaconazole Warnings' in the drug label.

# Adverse Reactions

## 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.

## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Efinaconazole in the drug label.

# Drug Interactions
- In vitro studies have shown that JUBLIA, at therapeutic concentrations, neither inhibits nor induces cytochrome P450 (CYP450) enzymes.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 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 . 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).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Efinaconazole in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Efinaconazole during labor and delivery.

### 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.

### Pediatric Use
- Safety and effectiveness of JUBLIA in pediatric subjects have not been established.

### Geriatic 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.

### Gender
There is no FDA guidance on the use of Efinaconazole with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Efinaconazole with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Efinaconazole in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Efinaconazole in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Efinaconazole in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Efinaconazole in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- topical

### Monitoring
There is limited information regarding Monitoring of Efinaconazole in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Efinaconazole in the drug label.

# Overdosage
There is limited information regarding Overdose of Efinaconazole in the drug label.

# Pharmacology

## Mechanism of Action
- Efinaconazole is an azole antifungal. Efinaconazole inhibits fungal lanosterol 14-demethylase involved in the biosynthesis of ergosterol, a constituent of fungal cell membranes.

## Structure
- 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.

## Pharmacodynamics
- The pharmacodynamics of JUBLIA is unknown.

## 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.
- 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.
- 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 g/mL or less against most (90%) isolates of the following microorganisms:
- Trichophyton rubrum
- Trichophyton mentagrophytes
- 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.

## Nonclinical Toxicology
- 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).

# 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.

# How Supplied
- 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:

## Storage
- Store at 20C - 25C (68F - 77F); excursions permitted to 15C - 30C (59F - 86F) .
- 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

# Images

## Drug Images

## Package and Label Display Panel

### PRINCIPAL DISPLAY PANEL

### Ingredients and Appearance

# Patient Counseling 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.

### PATIENT PACKAGE INSERT

### INSTRUCTIONS FOR USE

# Precautions with Alcohol
Alcohol-Efinaconazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Jublia

# Look-Alike Drug Names
There is limited information regarding Efinaconazole Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price