Efinaconazole (DB09040): A Comprehensive Monograph on its Pharmacology, Clinical Efficacy, and Therapeutic Application in Onychomycosis

Executive Summary

Efinaconazole is a topical triazole antifungal agent specifically developed and approved for the treatment of onychomycosis, a common and persistent fungal infection of the toenails. Marketed under the brand names Jublia® and Clenafin®, among others, it is indicated for infections caused by the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. The primary mechanism of action involves the potent and specific inhibition of fungal lanosterol 14α-demethylase, an essential enzyme in the ergosterol biosynthesis pathway. The disruption of this pathway leads to the depletion of ergosterol, a critical component of the fungal cell membrane, and the accumulation of toxic sterol precursors, resulting in fungicidal activity.

A defining characteristic of efinaconazole is its formulation as a 10% topical solution with physicochemical properties optimized for nail penetration. Its low affinity for keratin and low surface tension allow it to permeate the dense nail plate and reach the site of infection in the nail bed and matrix, a significant advantage over older topical agents that were often sequestered in the superficial nail layers. This enhanced delivery mechanism is central to its clinical efficacy.

The clinical efficacy of efinaconazole was established in two large, pivotal Phase III, randomized, double-blind, vehicle-controlled trials. After a 48-week daily treatment regimen, efinaconazole demonstrated statistically significant superiority over the vehicle across all primary and secondary endpoints. Complete cure rates, defined as a completely clear nail with mycological eradication, were approximately 15-18% for efinaconazole compared to 3-6% for the vehicle. Mycological cure rates exceeded 50%, underscoring the drug's potent antifungal activity, while the lower complete cure rates reflect the slow process of healthy nail regrowth.

The safety profile of efinaconazole is exceptionally favorable, a direct consequence of its topical administration and minimal systemic absorption. Plasma concentrations are negligible, which virtually eliminates the risk of systemic adverse events and drug-drug interactions commonly associated with oral azole antifungals. The most frequently reported adverse reactions are mild and localized to the application site, including ingrown toenail and application site dermatitis. This robust safety profile makes efinaconazole a first-line therapeutic option for mild-to-moderate onychomycosis, particularly in patients with contraindications to systemic therapy, such as those with hepatic impairment or polypharmacy, and in the approved pediatric population (ages 6 and older). The primary challenges to its use are the long 48-week treatment duration, which necessitates strong patient adherence, and its high cost in certain markets.

Molecular Identification and Physicochemical Profile

This section details the fundamental chemical and physical identity of efinaconazole, providing the necessary foundation for understanding its pharmacological behavior and clinical application. The molecule's unique properties are directly linked to its formulation as an effective topical treatment for onychomycosis.

Nomenclature and Identifiers

Efinaconazole is identified globally through a standardized set of names and registry numbers, ensuring its unambiguous recognition in scientific literature, regulatory filings, and clinical practice.

• Generic Name: Efinaconazole [1]
• Brand Names: The most common brand name is Jublia®, used in the United States, Canada, Puerto Rico, South Korea, and Taiwan. Other international brand names include Clenafin® in Japan, Fungo nail® in Argentina, and Efirush® in South Korea.[1]
• Systematic Identifiers:
• DrugBank ID: DB09040 [1]
• CAS Number: 164650-44-6 [3]
• UNII (Unique Ingredient Identifier): J82SB7FXWB [3]
• ATC (Anatomical Therapeutic Chemical) Code: D01AC19 [4]
• ChEBI ID: CHEBI:82718 [3]
• KEGG ID: D10021 [3]
• Developmental Codes: During its development, efinaconazole was also known by the codes KP-103 and IDP-108.[1]

Chemical Structure and Properties

Efinaconazole's chemical structure defines its classification as a triazole antifungal and is responsible for its specific interaction with its molecular target.

• Chemical Class: Efinaconazole is a small molecule classified as a triazole antifungal, a subset of the broader azole antifungal class.[5] Structurally, it is a complex organic compound also described as an organofluorine compound, an olefinic compound, a member of piperidines, a tertiary alcohol, and a tertiary amino compound.[5]
• IUPAC Name: The systematic name for the molecule is (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.[3]
• Molecular Formula:  [3]
• Molecular Weight: 348.39 g·mol⁻¹ [3]
• Structural Representations: For computational chemistry and database interoperability, its structure is represented by:
• SMILES: C[C@H]([C@](CN1C=NC=N1)(C2=C(C=C(C=C2)F)F)O)N3CCC(=C)CC3 [5]
• InChIKey: NFEZZTICAUWDHU-RDTXWAMCSA-N [5]

Physicochemical Characteristics and Clinical Relevance

The clinical utility of efinaconazole as a topical agent for onychomycosis is profoundly influenced by its specific physicochemical properties. These characteristics govern its formulation, stability, and, most importantly, its ability to penetrate the dense keratin structure of the nail plate to reach the site of infection.

• Appearance: In its pure form, efinaconazole is a white to beige powder.[9] As a final medicinal product, it is formulated as a 10% clear, colorless to pale yellow topical solution.[8]
• Solubility and Lipophilicity: The molecule is sparingly soluble in water, with a reported solubility of 0.61 mg/mL.[1] Its partition coefficient (logP) values range from 1.49 to 2.24, indicating a moderate lipophilicity.[1] This balance between hydrophilicity and lipophilicity is advantageous for traversing the complex aqueous and lipid environments of the skin and nail unit.
• Ionization Properties: Efinaconazole has a strongest acidic  of 12.7 and a strongest basic  of 7.45, indicating it will be positively charged at physiological pH.[1]
• Formulation and Nail Penetration: The therapeutic success of efinaconazole is not merely a function of its antifungal potency but is critically enabled by its formulation and physicochemical profile. Onychomycosis has historically been challenging to treat topically because the nail plate acts as a formidable barrier, preventing most drugs from reaching the pathogens residing in the nail bed and matrix.[10] Many older topical antifungals, such as ciclopirox and amorolfine, exhibit high affinity for keratin, the primary protein component of the nail. This high affinity causes the drug molecules to become tightly bound to the superficial layers of the nail plate, effectively sequestering them and preventing deeper penetration.[12]

Efinaconazole was designed to overcome this fundamental challenge. Its molecular structure results in a significantly lower affinity for keratin. In vitro studies have quantified this advantage, showing that the concentration of free, unbound efinaconazole in a keratin suspension was 14.3%, compared to just 0.7% for ciclopirox and 1.9% for amorolfine.[12] This low binding affinity means that more of the active drug is available to diffuse through the nail plate rather than being trapped within it.

Furthermore, the vehicle solution is formulated to have low surface tension, which enhances its ability to spread across the nail surface and wick into small crevices, such as the subungual space (underneath the nail) and the lateral nail folds.[10] This combination of low keratin binding and an optimized delivery vehicle facilitates superior transungual penetration, allowing therapeutic concentrations of efinaconazole to reach the site of infection. This direct link between its physicochemical properties and its ability to overcome the nail barrier is the principal reason for its improved clinical performance compared to previous topical therapies.

Table 1: Efinaconazole Identification and Physicochemical Properties

Property	Value	Source(s)
Identifiers
CAS Number	164650-44-6	3
DrugBank ID	DB09040	1
ATC Code	D01AC19	4
Chemical Properties
Molecular Formula		3
Molecular Weight	348.39 g·mol⁻¹	3
Physicochemical Properties
Water Solubility	0.61 mg/mL	1
logP (Lipophilicity)	1.49 - 2.24	1
pKa (Strongest Acidic)	12.7	1
pKa (Strongest Basic)	7.45	1
Polar Surface Area	54.18 Ų	1
Keratin Affinity	Low (14.3% free drug in suspension)	12

Comprehensive Pharmacological Profile

This section provides an in-depth analysis of the pharmacological actions of efinaconazole, covering its molecular mechanism, spectrum of activity against fungal pathogens, and its behavior within the human body (pharmacokinetics). This profile establishes the scientific rationale for its therapeutic use and its favorable safety characteristics.

Mechanism of Action (Pharmacodynamics)

Efinaconazole exerts its antifungal effect through a well-defined molecular mechanism characteristic of the azole class of antifungals.

• Molecular Target: The primary target of efinaconazole is the fungal cytochrome P450 enzyme lanosterol 14α-demethylase (also referred to as sterol 14α-demethylase or CYP51).[1] This enzyme plays a pivotal role in the biosynthesis of ergosterol, the main sterol component of fungal cell membranes.[1]
• Biochemical Pathway Disruption: By binding to and inhibiting lanosterol 14α-demethylase, efinaconazole effectively blocks the conversion of lanosterol into ergosterol.[2] Ergosterol is essential for maintaining the structural integrity, fluidity, and proper function of the fungal plasma membrane, performing a role analogous to that of cholesterol in mammalian cells.[1]
• Cellular Consequences: The inhibition of this enzymatic step has two major detrimental effects on the fungal cell. First, the depletion of ergosterol compromises the cell membrane, leading to increased permeability and disruption of membrane-bound enzyme activities. Second, the blockage causes an intracellular accumulation of 14α-methylated sterol precursors, such as lanosterol, which are toxic to the cell and further disrupt membrane architecture.[7] The combined effect of ergosterol depletion and toxic precursor accumulation leads to the cessation of fungal growth (fungistatic effect) and, at sufficient concentrations, fungal cell death (fungicidal effect).[2]
• Morphological Effects: At therapeutic concentrations, the biochemical disruption manifests as visible damage to the fungal structure. In vitro studies have shown that exposure to efinaconazole causes distinct degenerative changes in the hyphae of Trichophyton mentagrophytes, including a shortening of the distance between septa, flattening and nonuniform widths of the hyphae, globular swelling, and a separation of the plasma membrane from the cell wall.[10]

Antimicrobial Spectrum

Efinaconazole possesses a broad spectrum of activity against a wide range of fungi implicated in human disease, with particular potency against the dermatophytes responsible for onychomycosis.

• Primary Clinical Targets: The approved indication for efinaconazole is for onychomycosis caused by the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes.[3] It demonstrates potent activity against these organisms, with in vitro minimum inhibitory concentrations (MICs) of 0.06 μg/mL or less against 90% or more of clinical isolates.[8]
• Broad-Spectrum Activity: Beyond its primary targets, efinaconazole is active against a wider array of pathogenic fungi. This includes other dermatophytes such as Microsporum species and Epidermophyton floccosum; yeasts, including Candida albicans and other Candida species; and certain non-dermatophyte molds like Scopulariopsis, Aspergillus, and Acremonium.[1]
• Comparative Potency: When compared in vitro to other antifungal agents used for onychomycosis, efinaconazole often demonstrates superior potency. Studies have shown it to have lower MICs (indicating greater activity) than terbinafine, ciclopirox, itraconazole, and amorolfine against key pathogens like T. rubrum, T. mentagrophytes, and C. albicans.[12] A crucial feature is that its antifungal activity is not diminished by the presence of keratin, which is vital for its effectiveness within the nail environment.[7]

Pharmacokinetics and Systemic Exposure

The pharmacokinetic profile of efinaconazole is a cornerstone of its clinical safety. Designed for topical application, its formulation ensures high local concentrations at the site of infection while keeping systemic absorption and exposure extremely low.

• Absorption: Following the recommended topical application to toenails, systemic absorption of efinaconazole is minimal.[2] A key pharmacokinetic study was conducted in 18 adult subjects with severe onychomycosis who applied the 10% solution to all ten toenails and adjacent skin daily for 28 days. The plasma concentrations measured at steady state (Day 28) were very low:
• Mean Peak Plasma Concentration (): The average maximum concentration reached in the blood was  ng/mL.[1]
• Mean Area Under the Curve (): The average total drug exposure over a 24-hour period was  ng*h/mL.[1]
• Distribution: At steady state, the plasma concentration of efinaconazole remains relatively constant and flat over the 24-hour dosing interval, indicating a slow, continuous, and very low level of absorption.[8]
• Elimination Half-life: In a separate study involving healthy volunteers who applied the solution daily for 7 days, the plasma elimination half-life () was determined to be 29.9 hours.[2]
• Pediatric Pharmacokinetics: A study in pediatric patients aged 12 to 16 years confirmed that systemic exposure to efinaconazole was comparable to that observed in the adult population, supporting its safety in this younger age group.[15]

The extremely low systemic exposure is a deliberate and highly advantageous feature. Oral antifungal agents used for onychomycosis, such as terbinafine and itraconazole, achieve high systemic concentrations to reach the nail bed, but this comes with risks of systemic side effects, notably hepatotoxicity and significant drug-drug interactions.[7] Efinaconazole's design—a topical solution engineered for local delivery—effectively uncouples local efficacy from systemic risk. This "safety by design" principle makes it an invaluable therapeutic option, particularly for patients who are poor candidates for oral therapy due to comorbidities, concurrent medications, or a history of liver disease. This is especially relevant in the elderly population, which has a high prevalence of both onychomycosis and polypharmacy.

Table 2: Summary of Efinaconazole Pharmacokinetic Parameters (Adults, Day 28)

Parameter	Mean Value (± Standard Deviation)	Source(s)
Peak Plasma Concentration ()	ng/mL	1
Area Under the Curve ()	ng*h/mL	1
Elimination Half-life ()	29.9 hours	2

Drug Interaction Potential

The potential for efinaconazole to cause clinically significant drug-drug interactions is negligible, a direct result of its minimal systemic absorption.

• Cytochrome P450 (CYP) Enzyme Studies: The primary mechanism for drug interactions with azole antifungals is the inhibition or induction of CYP450 enzymes in the liver. Extensive in vitro studies were conducted to assess this risk. Using human liver microsomes and primary hepatocytes, researchers found that efinaconazole, at concentrations far exceeding those observed clinically, did not inhibit the major CYP enzymes (including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2PE1, and CYP3A4).[7] Furthermore, it did not induce the activity of CYP1A2 or CYP3A4.[7]
• Clinical Conclusion: Given the combination of extremely low systemic exposure and the lack of interaction with CYP enzymes in vitro, clinically relevant drug-drug interactions are not expected.[2] Consequently, no formal clinical drug interaction studies have been conducted, and none are deemed necessary. This lack of interaction potential is a major safety advantage over systemic azole antifungals like itraconazole.

Clinical Efficacy and Performance in Onychomycosis

This section provides a critical evaluation of the clinical evidence supporting the use of efinaconazole for onychomycosis. The analysis focuses on the design and outcomes of the pivotal Phase III trials that formed the basis for its regulatory approval, as well as data from long-term and pediatric studies.

Pivotal Phase III Trial Analysis (Studies P3-01 & P3-02)

The clinical efficacy of efinaconazole was rigorously established in two large, identically designed, Phase III, multi-center, randomized, double-blind, vehicle-controlled superiority trials.[17] These studies, designated P3-01 (N=870) and P3-02 (N=785), represent the highest level of clinical evidence for the drug's effectiveness.

• Study Design: The trials were designed to demonstrate the superiority of efinaconazole 10% topical solution over its vehicle (the solution without the active drug). Patients were randomized in a 3:1 ratio to receive either efinaconazole or the vehicle. The treatment was self-applied once daily for 48 consecutive weeks. A key feature of the study design was the absence of any concomitant nail debridement (physical removal of the diseased nail), meaning the observed efficacy is attributable to the drug alone.[17]
• Patient Population: The trials enrolled adults between 18 and 70 years of age with a clinical diagnosis of mild-to-moderate distal lateral subungual onychomycosis (DLSO). The severity was defined as 20% to 50% clinical involvement of the target great toenail, without involvement of the nail matrix (lunula).[17] To ensure the infection was caused by a susceptible pathogen, all participants were required to have a diagnosis confirmed by both a positive potassium hydroxide (KOH) microscopic examination and a positive dermatophyte culture.[17] Patients with severe disease, uncontrolled diabetes, or known immunosuppression were excluded.[17]
• Treatment and Follow-up: The total duration of each study was 52 weeks, comprising the 48-week active treatment period and a subsequent 4-week treatment-free follow-up period, during which the primary efficacy endpoints were assessed.[17]

Efficacy Endpoints and Outcomes at Week 52

The trials employed stringent, FDA-accepted endpoints to evaluate treatment success. Across both studies, efinaconazole demonstrated a consistent and statistically significant superiority over the vehicle for all primary and major secondary endpoints, with p-values of less than 0.001 for these comparisons.[17]

• Primary Endpoint - Complete Cure: This was the most rigorous endpoint, defined as the achievement of both 0% clinical involvement of the target toenail (a completely clear nail) and mycological cure (a negative KOH test and a negative fungal culture) at week 52.
• Results: In Trial 1, 17.8% of patients in the efinaconazole group achieved a complete cure, compared to 3.3% in the vehicle group. In Trial 2, the rates were 15.2% for efinaconazole versus 5.5% for the vehicle.[3]
• Key Secondary Endpoint - Mycological Cure: This endpoint measured the drug's fundamental ability to eradicate the fungal pathogen, irrespective of the nail's cosmetic appearance.
• Results: Efinaconazole was highly effective at eliminating the fungus, with mycological cure rates of 55.2% in Trial 1 and 53.4% in Trial 2. These were substantially higher than the rates in the vehicle groups, which were 16.8% and 16.9%, respectively.[13]
• Other Clinically Relevant Secondary Endpoints:
• Complete or Almost Complete Cure: Defined as ≤5% nail involvement plus mycological cure, this endpoint captures a cosmetically acceptable outcome. The rates were 26.4% (Trial 1) and 23.4% (Trial 2) for efinaconazole, compared to just 7.0% and 7.5% for the vehicle.[3]
• Treatment Success: Defined as <10% of the target toenail area being affected at week 52. The rates were 35.7% (Trial 1) and 31.0% (Trial 2) for efinaconazole, versus 11.7% and 11.9% for the vehicle.[17]

A critical analysis of these results reveals a notable gap between the high mycological cure rates (over 50%) and the more modest complete cure rates (under 20%). This discrepancy is not indicative of a failure of the drug's antifungal action. Rather, it highlights a fundamental aspect of onychomycosis pathology. The drug is very effective at killing the fungus. However, the complete cure endpoint requires the nail to be 100% visually clear. Toenails grow very slowly, and years of fungal infection can cause long-lasting or even permanent nail dystrophy, such as thickening and discoloration. Therefore, even after the pathogen is completely eradicated, the damaged portion of the nail must grow out and be replaced by healthy nail, a process that can take 12 to 18 months or longer. The lower complete cure rate at 52 weeks reflects the biological limitations of nail growth and the persistence of pre-existing damage, not a lack of pharmacological efficacy. This understanding is crucial for managing patient expectations; therapeutic success should be primarily defined by the eradication of the infection to prevent pain and transmission, with cosmetic improvement being a secondary and more gradual outcome.

Table 3: Efficacy Outcomes of Pivotal Phase III Trials at Week 52

Efficacy Endpoint	Trial 1 (P3-01)	Trial 2 (P3-02)
	Efinaconazole (N=655)	Vehicle (N=215)
Complete Cure (Primary)	17.8%	3.3%*
Mycological Cure	55.2%	16.8%*
Complete or Almost Complete Cure (≤5% Involvement + Mycological Cure)	26.4%	7.0%*
Treatment Success (<10% Involvement)	35.7%	11.7%*
*P < 0.001 for the comparison between efinaconazole and vehicle.
Data sourced from.3

Long-Term and Pediatric Efficacy

Clinical research has also explored the efficacy of efinaconazole beyond the initial 52-week trial period and in younger patient populations.

• Long-Term Use: An open-label extension study followed patients treated for 72 weeks. The results showed continued improvement with longer treatment duration, with the complete cure rate rising to 31%, the mycological cure rate to 62%, and the treatment success rate to 57%.[19] Another study extending to 48 months suggested that after an initial period of daily use, an intermittent maintenance regimen (2–3 times per week) could be effective in sustaining the cure and providing prophylaxis against relapse.[20]
• Pediatric Efficacy: The drug's approval was expanded to include children aged 6 years and older based on a Phase IV, open-label, single-arm study involving 62 pediatric patients with mild-to-severe onychomycosis. The study demonstrated both safety and efficacy in this population, with 65% of patients achieving mycological cure by week 52.[3]

Subgroup Analysis and Performance

An analysis of the pivotal trial data by the FDA revealed some demographic trends in treatment response, although these should be interpreted with caution due to varying subgroup sizes.

• Sex: A greater trend towards efficacy was observed in female subjects compared to their male counterparts.[21]
• Race: Asian subjects showed a greater trend towards efficacy when compared to White or Black/African American subjects.[21]
• Age: The effectiveness of efinaconazole was found to be similar in patients above and below the age of 65.[21]

Clinical Application: Dosage, Administration, and Patient Management

This section provides practical guidance for the clinical use of efinaconazole, translating trial protocols and regulatory labeling into actionable information for healthcare providers and patients. Proper administration and patient adherence are paramount to achieving therapeutic success.

Approved Indications and Dosage Forms

• Indication: Efinaconazole is indicated for the topical treatment of onychomycosis of the toenail(s) caused by the dermatophyte fungi Trichophyton rubrum and Trichophyton mentagrophytes.[3]
• Patient Population: The drug is approved for use in adults and in pediatric patients 6 years of age and older.[2]
• Dosage Form: Efinaconazole is supplied as a 10% ( mg/g) topical solution. It is available in 4 mL and 8 mL bottles that feature a unique integrated flow-through brush applicator designed to facilitate proper application.[2]

Regimen and Method of Administration

Adherence to the correct dosage and application technique is critical for the drug to penetrate the nail and exert its antifungal effect.

• Dosage Regimen: The recommended regimen is to apply the solution to the affected toenail(s) once daily for 48 weeks.[8]
• Application Technique: Patients should be carefully instructed on the following steps to ensure optimal drug delivery:

1. Preparation: The affected toenails must be clean and completely dry before application. It is recommended to wait at least 10 minutes after showering, bathing, or washing the feet.[23]
2. Applicator Priming: Remove the cap, hold the bottle upside down over the toenail, and gently squeeze the bottle to moisten the brush tip with the solution.[24]
3. Comprehensive Coverage: Using the moistened brush, spread the solution over the entire surface of the toenail. Crucially, the application must also cover the surrounding and underlying structures: the cuticle, the lateral and proximal nail folds (the skin along the sides and base of the nail), the hyponychium (the skin just under the free edge of the nail), and the undersurface of the nail plate itself.[8]
4. Big Toe Application: For the great toenail, it is recommended to apply a second drop of the solution to the tip of the nail and spread it as described above.[24]
5. Drying: Allow the treated area(s) to dry completely before covering with socks, shoes, or bedding.[24]
6. Post-Application: Replace the cap tightly and wash hands with soap and water.[2]

Patient Counseling and Adherence

Effective patient counseling is essential to manage expectations and promote the long-term adherence required for successful treatment.

• Treatment Duration and Adherence: The single greatest barrier to achieving real-world success with efinaconazole is the demanding 48-week daily regimen. While clinical trials demonstrate efficacy under controlled conditions, patient adherence in typical clinical practice may be lower. Onychomycosis is often cosmetically driven and may lack severe symptoms, which can reduce a patient's motivation for such a prolonged treatment course. Healthcare providers must stress that completing the full 48-week therapy is absolutely necessary, even if the nail's appearance begins to improve earlier. Fungal infections of the nail are notoriously slow to resolve, and premature discontinuation is a leading cause of treatment failure and relapse.[16] Providers can suggest strategies to improve adherence, such as linking the application to another daily routine (e.g., before bed) or using calendar or phone reminders.[25]
• Missed Doses: Patients should be instructed to apply a missed dose as soon as they remember. However, if it is nearly time for the next scheduled dose, they should skip the missed one and resume their normal schedule. They should not apply a double dose to make up for a missed one.[16]
• General Precautions:
• Flammability: The solution contains alcohol and is flammable. Patients must be warned to avoid proximity to heat, open flames, and to refrain from smoking during and immediately after application.[16]
• External Use Only: Reinforce that the medication is strictly for external use on the toenails and surrounding skin. It must be kept away from the eyes, mouth, and vagina.[16]
• Nail Cosmetics: The use of pedicures, nail polish, or other cosmetic nail products (e.g., gel or acrylic nails) on the treated nails should be avoided throughout the 48-week treatment period, as their impact on drug penetration and efficacy has not been evaluated.[14]
• Storage: The medication should be stored in its original container, kept tightly closed, and in an upright position. It should be kept at room temperature (20°C to 25°C, or 68°F to 77°F) and away from heat, open flames, and the reach of children. The solution should not be frozen.[16]

Safety, Tolerability, and Risk Profile

This section provides a comprehensive assessment of the safety and tolerability of efinaconazole. Its favorable risk-benefit profile, characterized by minimal systemic exposure and primarily localized, mild adverse effects, is a key attribute that distinguishes it from systemic treatment options.

Adverse Reactions

The safety of efinaconazole has been well-established in large clinical trials. The overwhelming majority of adverse events are mild to moderate in severity and are confined to the site of application.

• Most Common Adverse Reactions: In a pooled analysis of clinical trials involving 1227 subjects treated with efinaconazole, the following adverse reactions were reported in at least 1% of patients and occurred more frequently than in the vehicle-treated group:
• Ingrown toenail: 2.3%
• Application site dermatitis (including redness, itching, and swelling): 2.2%
• Application site vesicles (blisters): 1.6%
• Application site pain (including burning or stinging): 1.1%

[2]

• Clinical Management: Patients should be counseled about the possibility of these local reactions. If irritation at the application site becomes severe or persistent, they should be advised to contact their healthcare provider.[2]

Table 4: Incidence of Adverse Reactions (≥1%) in Clinical Trials

Adverse Event	Efinaconazole 10% Solution (N=1227)	Vehicle Solution (N=413)
Ingrown toenail	2.3%	0.7%
Application site dermatitis	2.2%	0.2%
Application site vesicles	1.6%	0.0%
Application site pain	1.1%	0.2%
Data derived from product labeling based on pooled 48-week clinical trial data.21

Contraindications, Warnings, and Precautions

Efinaconazole has a very clean safety profile with few absolute restrictions.

• Contraindications: The U.S. manufacturer's labeling lists no contraindications for the use of efinaconazole.[2] The Canadian labeling, however, lists known hypersensitivity to efinaconazole or any component of the formulation as a contraindication.[2] As a standard precaution, any patient who has experienced an allergic reaction to the drug or its ingredients should not use it.[16]
• Warnings and Precautions:
• Route of Administration: The product is strictly for topical use on toenails and the immediately surrounding skin. It is not intended for oral, ophthalmic, or intravaginal administration.[2]
• Flammability: The solution is flammable due to its alcohol content. Patients must be counseled to keep it away from heat and open flames.[16]

Use in Specific Populations

The safety and efficacy of efinaconazole have been considered for various patient populations.

• Pediatric Use: Safety and effectiveness have been established in children aged 6 years and older. The use of efinaconazole in children younger than 6 years has not been studied and is therefore not recommended.[2]
• Geriatric Use: Clinical studies included a sufficient number of subjects aged 65 and over to determine that there are no overall differences in safety or efficacy compared to younger subjects. Systemic exposure is similarly low in the geriatric population.[21]
• Pregnancy: There is a lack of adequate and well-controlled studies in pregnant women. It is classified as Pregnancy Category C.[7] In animal reproduction studies, subcutaneous administration of efinaconazole to pregnant rats and rabbits during organogenesis at doses resulting in systemic exposures many times higher than the maximum recommended human dose (MRHD) did not cause harm to the fetus. However, because animal studies are not always predictive of human response, efinaconazole should be used during pregnancy only if the potential benefit clearly justifies the potential risk to the fetus. If antifungal treatment is deemed necessary during pregnancy, topical therapy is generally preferred over systemic options.[2]
• Lactation: It is unknown whether efinaconazole is excreted in human milk following topical application. After subcutaneous administration to nursing rats, the drug was detected in their milk. A decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the clinical need for the therapy in the mother and the potential benefits of breastfeeding.[16]

Nonclinical Toxicology

A standard battery of nonclinical toxicology studies was conducted to assess the long-term risks of efinaconazole.

• Carcinogenicity: A 2-year dermal carcinogenicity study was conducted in mice. While severe skin irritation from the vehicle confounded the interpretation at the highest dose, there was no evidence of drug-related neoplasms at doses resulting in exposures up to 248 times the MRHD.[8]
• Genotoxicity: Efinaconazole showed no evidence of mutagenic or clastogenic potential in a series of in vitro (Ames assay, Chinese hamster lung cell chromosome aberration assay) and in vivo (mouse peripheral reticulocyte micronucleus assay) genotoxicity tests.[8]

Regulatory Status and Commercial Landscape

This section outlines the regulatory journey of efinaconazole, its market presence under various brand names, and the economic factors influencing its accessibility.

Global Regulatory Approvals and History

Efinaconazole has been approved in several major markets, primarily in North America and Japan.

• Initial Approval: The first global approval for efinaconazole 10% solution was granted in Canada in October 2013 for the treatment of onychomycosis.[28]
• U.S. FDA Approval: The U.S. Food and Drug Administration (FDA) approved the New Drug Application (NDA #203567) for Jublia® on June 6, 2014, for use in adults aged 18 and older.[3]
• Japanese Approval: Approval in Japan for Clenafin® followed in July 2014.[5]
• Pediatric Label Expansion: On April 29, 2020, the FDA approved a supplemental New Drug Application (sNDA) that expanded the approved age range for Jublia® to include pediatric patients aged 6 years and older, based on the results of a dedicated Phase IV study.[3]
• Regulatory Status in Australia: There is no evidence that efinaconazole (either as Jublia® or a generic equivalent) has been approved by the Therapeutic Goods Administration (TGA) for marketing in Australia. A search of the Australian Register of Therapeutic Goods (ARTG) does not show a listing for the product.[30]

This lack of approval in Australia, despite the drug's availability in other developed markets, highlights the complex interplay of factors that drive global pharmaceutical strategy. An interesting paradox exists: an Australian-based company, Acrux, was the first to receive FDA approval for a generic version of Jublia® for the lucrative U.S. market.[33] This situation demonstrates that a company's strategic decisions are based not only on a drug's clinical merit but also on market size, pricing structures, and patent law. The U.S. market, with its high prices and established Paragraph IV pathway for challenging patents, presents a more attractive opportunity for a generic manufacturer than the smaller, price-controlled Australian market, which operates under the Pharmaceutical Benefits Scheme (PBS). Consequently, it can be more profitable for an Australian company to develop a generic for export to the U.S. than for the brand-name holder to seek registration and reimbursement within Australia itself.

Table 5: International Brand Names and Regulatory Approvals

Region/Country	Brand Name(s)	Approval Status	Initial Approval Date
United States	Jublia®	Approved	June 6, 2014
Canada	Jublia®	Approved	October 2013
Japan	Clenafin®	Approved	July 2014
South Korea	Jublia®, Efirush®	Approved	Not specified
Argentina	Fungo nail®	Approved	Not specified
Puerto Rico	Jublia®	Approved	Not specified
Taiwan	Jublia®	Approved	Not specified
Australia	N/A	Not Approved	N/A
Europe	N/A	Not Approved	N/A
Data sourced from.1

Brand Names and Generic Availability

• Brand Holder: The drug was developed by Kaken Pharmaceutical Co. in Japan. Valeant Pharmaceuticals International Inc. (now Bausch Health Companies Inc.) acquired the rights for North America and markets the product as Jublia®.[1]
• Generic Status: While generic availability is still limited, the pathway has been opened. In June 2021, the FDA granted approval for the first Abbreviated New Drug Application (ANDA) for a generic efinaconazole 10% topical solution to Acrux Limited. The commercial launch date of this generic product is subject to the terms of a confidential patent litigation settlement agreement.[33]

Economic Considerations

The cost of treatment with efinaconazole is a significant factor in its accessibility and varies dramatically between countries.

• United States: The cost of a full 48-week course of treatment in the U.S. can be substantial. In 2015, reports cited a cost of approximately US$2,307 per nail.[3] The brand manufacturer offers co-pay assistance programs to reduce out-of-pocket costs for commercially insured patients.[25]
• Canada: In contrast, a 2019 analysis by the Canadian Agency for Drugs and Technologies in Health found the cost to be much lower, estimating a 48-week course at approximately $178 for a big toe and $89 for a smaller toe.[3] This stark difference reflects the different drug pricing and reimbursement systems in the two countries.

Expert Analysis and Concluding Perspectives

This final section synthesizes the comprehensive data presented in this monograph to provide a nuanced expert opinion on efinaconazole's clinical value, its specific role in the therapeutic armamentarium against onychomycosis, and potential future directions for its use.

Clinical Value Proposition and Place in Therapy

Efinaconazole represents a significant and valuable addition to the treatment options for onychomycosis, occupying a crucial niche between older, less effective topicals and more effective but riskier systemic therapies. Its clinical value is best understood by weighing its distinct strengths and weaknesses.

• Strengths:
• Exceptional Safety Profile: The paramount advantage of efinaconazole is its safety. By design, its topical application and formulation for minimal systemic absorption virtually eliminate the risk of systemic adverse events, such as the hepatotoxicity associated with oral azole antifungals, and the potential for systemic drug-drug interactions.[7] This makes it an ideal and often first-line choice for patients with contraindications to oral therapy, including those with liver disease, the elderly on multiple medications, or patients who simply wish to avoid systemic drug exposure.
• Optimized Topical Delivery: The molecule's low affinity for keratin is a key pharmaceutical innovation that allows for enhanced penetration through the nail plate, a barrier that has limited the efficacy of previous generations of topical agents.[12] This represents a tangible advancement in the topical treatment of this disease.
• Evidence-Based Efficacy: While the absolute cure rates may appear modest, efinaconazole has demonstrated statistically significant and clinically meaningful superiority over vehicle in large, well-designed, pivotal Phase III trials. It provides a reliable, evidence-based, non-systemic treatment option where few existed before.[3]
• Weaknesses:
• Modest Absolute Efficacy: The complete cure rates of 15-18% are lower than those reported for the gold-standard oral agent, terbinafine (approximately 38%).[10] This positions efinaconazole as most appropriate for mild-to-moderate disease and necessitates careful patient selection and management of therapeutic expectations.
• Demanding Treatment Regimen: The requirement for once-daily application for 48 consecutive weeks is a significant undertaking for any patient. This long duration poses a substantial challenge to adherence, which is the rate-limiting step to achieving successful outcomes in real-world clinical practice.[8]
• High Cost: In certain markets, particularly the United States, the high cost of the branded product can be a significant barrier to access for many patients, limiting its widespread use.[3]
• Place in Therapy: Efinaconazole is firmly established as a first-line therapeutic option for mild-to-moderate toenail onychomycosis, particularly in patient populations where systemic therapy is undesirable or contraindicated. It effectively fills the therapeutic gap between older, less potent topicals and more potent but potentially toxic oral agents. Its approval for use in children aged 6 and older also provides a much-needed, safe option for this younger population.

Future Directions

The unique profile of efinaconazole opens several avenues for future research and potential expansion of its clinical role.

• Combination Therapy: Its excellent safety profile makes it an ideal candidate for use in combination with other treatment modalities. Studies could explore its use alongside oral antifungals, potentially to increase overall cure rates or to allow for shorter courses of oral therapy. Combination with device-based treatments, such as laser therapy, could also be investigated to see if a synergistic effect exists.[11]
• Prophylaxis and Maintenance Therapy: Preliminary long-term data suggests that intermittent use of efinaconazole may be effective in preventing the recurrence of onychomycosis after an initial cure has been achieved.[20] Further research could formally establish its role as a "closer" therapy to be used after an initial course of oral treatment, or as a long-term maintenance drug to sustain mycological cure and prevent relapse, which is common in this chronic disease.[11]
• Use in High-Risk Populations: While it is already a preferred agent in many high-risk groups due to its safety, more dedicated research would be beneficial. A clinical trial was initiated to specifically evaluate its efficacy and safety in patients with diabetes mellitus (NCT03168841), a population with a high prevalence of onychomycosis and associated complications.[35] Further studies in other specific populations, such as immunocompromised patients, would also be valuable to better define its role and optimize outcomes in these challenging cases.

Works cited

1. Efinaconazole: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 30, 2025, https://go.drugbank.com/drugs/DB09040
2. Efinaconazole | Drug Lookup | Pediatric Care Online, accessed September 30, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/6267/Efinaconazole
3. Efinaconazole - Wikipedia, accessed September 30, 2025, https://en.wikipedia.org/wiki/Efinaconazole
4. Efinaconazole - brand name list from Drugs.com, accessed September 30, 2025, https://www.drugs.com/ingredient/efinaconazole.html
5. Efinaconazole | C18H22F2N4O | CID 489181 - PubChem, accessed September 30, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Efinaconazole
6. healthy.kaiserpermanente.org, accessed September 30, 2025, https://healthy.kaiserpermanente.org/health-wellness/drug-encyclopedia/drug.efinaconazole-10-topical-solution-with-applicator.581743#:~:text=This%20medication%20is%20used%20to,drugs%20known%20as%20azole%20antifungals.
7. Efinaconazole Monograph for Professionals - Drugs.com, accessed September 30, 2025, https://www.drugs.com/monograph/efinaconazole.html
8. Jublia - accessdata.fda.gov, accessed September 30, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203567s000lbl.pdf
9. Efinaconazole = 98 HPLC 164650-44-6 - Sigma-Aldrich, accessed September 30, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/sml1244
10. Efinaconazole in the treatment of onychomycosis - PMC, accessed September 30, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4459619/
11. How effective is efinaconazole in the management of onychomycosis? - PubMed, accessed September 30, 2025, https://pubmed.ncbi.nlm.nih.gov/26809447/
12. CHEBI:82718 - efinaconazole - EMBL-EBI, accessed September 30, 2025, https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:82718
13. Efinaconazole (Jublia) for the treatment of onychomycosis - PubMed, accessed September 30, 2025, https://pubmed.ncbi.nlm.nih.gov/24850511/
14. Efinaconazole topical Uses, Side Effects & Warnings - Drugs.com, accessed September 30, 2025, https://www.drugs.com/mtm/efinaconazole-topical.html
15. FDA Approves Ortho Dermatologics' Labeling For JUBLIA® (efinaconazole) Topical Solution, 10%, In Patients As Young As Six Years Old - Bausch Health, accessed September 30, 2025, https://ir.bauschhealth.com/news-releases/2020/04-29-2020-120230152
16. Efinaconazole Topical Solution - Cleveland Clinic, accessed September 30, 2025, https://my.clevelandclinic.org/health/drugs/20094-efinaconazole-topical-solution
17. Results - Clinical Review Report: Efinaconazole (Jublia) - NCBI ..., accessed September 30, 2025, https://www.ncbi.nlm.nih.gov/books/NBK543983/
18. Clinical Trial Designs for Topical Antifungal Treatments of Onychomycosis and Implications on Clinical Practice, accessed September 30, 2025, https://cdn.mdedge.com/files/s3fs-public/Document/October-2017/CT100004259.PDF
19. JUBLIA—Cure rates with long-term treatment 1, accessed September 30, 2025, https://www.jubliarx.com/hcp/efficacy/long-term-treatment/
20. Safety and Efficacy of a 48-Month Efinaconazole 10% Solution Treatment/Maintenance Regimen: 24-Month Daily Use Followed by 24-Month Intermittent Use - MDPI, accessed September 30, 2025, https://www.mdpi.com/2036-7449/17/1/7
21. More Information for Jublia (efinaconazole) - FDA, accessed September 30, 2025, https://www.fda.gov/drugs/drug-approvals-and-databases/more-information-jublia-efinaconazole
22. JUBLIA® (efinaconazole): For the treatment of toenail fungus, accessed September 30, 2025, https://www.jubliarx.com/
23. Efinaconazole (topical application route) - Side effects & dosage - Mayo Clinic, accessed September 30, 2025, https://www.mayoclinic.org/drugs-supplements/efinaconazole-topical-application-route/description/drg-20110167
24. Efinaconazole Topical: MedlinePlus Drug Information, accessed September 30, 2025, https://medlineplus.gov/druginfo/meds/a614050.html
25. How to Use (application) | JUBLIA® (efinaconazole), accessed September 30, 2025, https://www.jubliarx.com/using-jublia/
26. Efficacy and side effects | JUBLIA® (efinaconazole), accessed September 30, 2025, https://www.jubliarx.com/efficacy-side-effects/
27. Jublia (efinaconazole) dosing, indications, interactions, adverse effects, and more, accessed September 30, 2025, https://reference.medscape.com/drug/jublia-efinaconazole-999850
28. Efinaconazole: first global approval - PubMed, accessed September 30, 2025, https://pubmed.ncbi.nlm.nih.gov/24249649/
29. Jublia (efinaconazole) FDA Approval History - Drugs.com, accessed September 30, 2025, https://www.drugs.com/history/jublia.html
30. Australian Register of Therapeutic Goods (ARTG), accessed September 30, 2025, https://www.tga.gov.au/products/australian-register-therapeutic-goods-artg
31. Biosimilars approved in Australia, accessed September 30, 2025, https://gabionline.net/es/biosimilares/general/biosimilars-approved-in-australia
32. Efinaconazole | MedPath, accessed September 30, 2025, https://trial.medpath.com/drug/a2e2964f34993adb/efinaconazole
33. Acrux receives approval from the FDA for its generic version of Jublia® - AFR, accessed September 30, 2025, https://company-announcements.afr.com/asx/acr/14f224a6-d2ea-11eb-b908-9ef936e04b40.pdf
34. Generic EFINACONAZOLE INN entry, pharmaceutical patent expiry and freedom to operate, accessed September 30, 2025, https://www.drugpatentwatch.com/p/generic/efinaconazole
35. Study Details | NCT03168841 | Efficacy and Safety of Efinaconazole 10% Solution in the Treatment of Onychomycosis in Diabetic Patients | ClinicalTrials.gov, accessed September 30, 2025, https://www.clinicaltrials.gov/study/NCT03168841?intr=EFINACONAZOLE&aggFilters=studyType:int&viewType=Table&rank=2