Topical ifenconazole solution (0.25 to 1%) proved beneficial in treating interdigital tinea pedis and tinea corporis in ten guinea pigs in a dose-dependent manner. Thirty-day and nine-day follow-up investigations revealed that the recurrence rates of tinea corporis and tinea pedis in animals treated with 1% ifenconazole were thirty percent and twenty percent, respectively. Nine out of ten mice were protected against dermatophytosis when a single dosage of 1% ifuconazole was administered to the dorsal skin 48 hours prior to fungal inoculation, suggesting that active ifuconazole remains active after delivery and stays in skin tissue for at least 48 hours[2].

Absorption, Distribution and Excretion
Topical application of Jublia can lead to low systemic Efinaconazolene concentrations. This study treated 18 patients with severe onychomycosis for 28 days, applying Jublia once daily to the nails and surrounding skin of all 10 toenails, and measuring systemic absorption of Efinaconazolene. Plasma Efinaconazolene concentrations were measured at multiple time points within 24 hours on days 1, 14, and 28. The mean peak plasma concentration (Cmax) of Efinaconazolene on day 28 was 0.67 ng/mL. The plasma concentration-time curve was generally stable during treatment. In patients with onychomycosis, the steady-state plasma concentrations of Efinaconazolene ranged from 0.1 to 1.5 ng/mL, and the steady-state plasma concentrations of the H3 metabolite ranged from 0.2 to 7.5 ng/mL. /Breast Milk/ Efinaconazolene and its metabolites are excreted in the milk of lactating rats. Within 24 hours of administration of 14C-efenconazole to lactating rats, the radioactivity concentration in breast milk was higher than that in plasma. However, the elimination half-life of radioactivity in breast milk was approximately half that in plasma, indicating that efenconazole or its metabolites do not remain in breast milk. It is unclear whether efenconazole is excreted from human breast milk. In vitro studies have shown that efenconazole can penetrate the nail after administration of Jublia, suggesting that the drug can penetrate to sites of fungal infection in the nail and nail bed, but its clinical significance is unclear. In an in vitro study, the penetration of Jublia was assessed by applying radiolabeled efenconazole (10%) to human nails daily at a dose of 55.1 μL/cm² for 28 days. After 28 days, the cumulative radioactivity in the recipient fluid and nail plate (percentage of total administered radioactivity) was 0.03% and 0.16% (3.11 mg equivalent/g), respectively. From day 18 to day 28, the drug flux remained relatively stable, averaging 1.40 μg equivalents/cm²/day, indicating that steady state had been reached. For more complete data on absorption, distribution, and excretion of Efinaconazole (8 items), please visit the HSDB record page. Metabolism/Metabolites Efinaconazole is extensively metabolized. It is metabolized via oxidative metabolism, cleavage, and glucuronidation. Five metabolites of Efinaconazole (H1, H2, H3, H4, and H5) have been identified. In rats and miniature pigs, H3 is the major metabolite of Efinaconazole in plasma, with concentrations generally equal to or higher than the parent drug. The in vitro and in vivo metabolite profiles of non-clinical species are similar to those of humans, and no human-specific metabolites have been found. Efinaconazole (Jublia) is primarily metabolized via redox processes, and glucuronidation of other metabolites may occur. Analysis of human plasma confirmed that H3 is the only major Efinaconazole metabolite.
The metabolites of ivermectin (not the parent drug) are excreted in the bile and urine of rats and dogs, indicating that ivermectin is completely metabolized before excretion. Most of the absorbed radioactive material is excreted in urine and feces within the first 72 hours after skin and subcutaneous administration.
Biological half-life
In healthy patients, it is 29.9 hours.
In a study of healthy volunteers, after repeated Jublia treatment on all 10 toenails, the plasma half-life on day 10 was 29.9 hours.

Toxicity Summary
Identification and Use: Ephedrine is an antifungal drug. It is indicated for the topical treatment of onychomycosis caused by Trichophyton rubrum and Trichophyton mentagrophytes. Human Exposure and Toxicity: In human studies, a 10% phedrine solution did not cause contact sensitization, only mild skin irritation. Animal Studies: In rats, phedrine was well tolerated with repeated daily doses up to 30 (male) and 40 (female) mg/kg. In a 13-week mouse dermal toxicity study, increased liver weight and mild to moderate hololobular hepatocyte hypertrophy were observed. Topical application of the drug and/or excipients resulted in a higher incidence of hyperkeratosis, epidermal hyperplasia, and mononuclear cell infiltration at the treatment site. Compared to the control group, higher concentrations of the test drug were associated with greater severity of these skin lesions and a lower incidence of erosion/ulceration at the treatment site. Intratympanic injection of 10% Efinaconazoleline solution into the middle ear of guinea pigs resulted in significant otitis media and hearing impairment. In skin toxicity studies, Efinaconazoleline was well tolerated in miniature pigs at doses up to 150–200 mg/kg/day. Mild to moderate skin reactions, including hyperkeratosis, acanthosis, and localized inflammation, were observed in all investigational drug and excipient control groups. These skin reactions were attributed to the excipients and, due to their mildness, were not considered adverse reactions. A two-year mouse skin carcinogenicity study involved daily topical application of 3%, 10%, and 30% Efinaconazoleline solutions. Severe irritation occurred at treatment sites in all dose groups, attributed to the excipients, and interfered with the interpretation of Efinaconazoleline skin reactions. The high-dose group was discontinued at week 34 due to severe skin reactions. No drug-related tumors were observed at doses up to 10% Efinaconazoleline solution (based on AUC comparisons, equivalent to 248 times the maximum recommended human dose). In a rat prenatal and postnatal development study, efenconazole was administered subcutaneously daily at doses of 1, 5, and 25 mg/kg from the onset of organogenesis (day 6 of gestation) to the end of lactation (day 20 of lactation). In the presence of maternal toxicity, embryotoxicity (increased prenatal pup mortality, reduced live birth count, and increased postnatal pup mortality) was observed in the 25 mg/kg/day dose group. No embryotoxicity was observed in the 5 mg/kg/day dose group (based on AUC comparison, 17 times the maximum recommended human dose). No effects on postnatal development were observed in the 25 mg/kg/day dose group (based on AUC comparison, 89 times the maximum recommended human dose). During organogenesis (days 6–19 of gestation), pregnant female rabbits were subcutaneously administered efenconazole at doses of 1, 5, and 10 mg/kg/day. In the presence of maternal toxicity, no embryotoxicity or malformations were observed in the 10 mg/kg/day dose group (based on AUC comparison, 154 times the maximum recommended human dose). Based on the results of two in vitro genotoxicity studies (Ames test and Chinese hamster lung cell chromosome aberration test) and one in vivo genotoxicity study (mouse peripheral blood reticulocyte micronucleus test), ivenaconazole did not show mutagenicity or chromosome breakage.

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Effects during pregnancy and lactation
◉ Overview of use during lactation
No studies have been conducted on topical use of ivenaconazole during lactation. Because the concentration of the drug in the mother's blood after topical application to the toenail is very low, it is unlikely that measurable amounts of the drug will enter breast milk.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

[1]. Mechanism of action of efinaconazole, a novel triazole antifungal agent. Antimicrob Agents Chemother. 2013 May;57(5):2405-9.

[2]. KP-103, a novel triazole derivative, is effective in preventing relapse and successfully treating experimental interdigital tinea pedis and tinea corporis in guinea pigs. Microbiol Immunol. 2002;46(7):425-32.

Efinaconazole is a triazole compound with the structure but-2-ol, substituted at positions 1, 2, and 3 with 1,2,4-triazol-1-yl, 2,4-difluorophenyl, and 4-methylenepiperidin-1-yl, respectively (2R,3R stereoisomers). It is an antifungal drug used topically to treat onychomycosis (a nail infection primarily caused by dermatophytes). It is an EC 1.14.13.70 (sterol 14α-demethylase) inhibitor. It is an organofluorine compound, olefin compound, piperidine compound, tertiary alcohol, tertiary amino compound, conazole antifungal drug, and triazole antifungal drug. Efinaconazole is a 14α-demethylase inhibitor used to treat nail fungal infections, i.e., onychomycosis. It was approved for marketing in Canada and the United States in 2014 and is marketed by Valeant Pharmaceuticals North America LLC under the brand name Jublia. Efinaconazole is an azole antifungal drug.
Efenconazole is a triazole compound with antifungal activity. After administration, efenconazole targets and binds to 14α-demethylase (a cytochrome P450-dependent enzyme) and inhibits its activity. Inhibition of 14α-demethylase prevents the conversion of lanosterol to ergosterol, an important component of the fungal cell wall. Inhibition of ergosterol synthesis alters the composition and integrity of the fungal cell membrane, changes membrane permeability, and ultimately leads to fungal cell lysis.
Drug Indications
Indications for the treatment of nail fungal infections, i.e., onychomycosis.

FDA Label
Treatment of Onychomycosis
Mechanism of Action
Efenconazole is an azole antifungal drug. Efenconazole inhibits fungal lanosterol 14α-demethylase, an enzyme involved in the biosynthesis of ergosterol (a component of the fungal cell membrane).
Efenconazole is a triazole antifungal drug.
Efinaconazoleline inhibits fungal lanosterol 14α-demethylase, an enzyme involved in the biosynthesis of ergosterol. The accumulation of 14α-methylsterol in the fungal cell wall and subsequent loss of ergosterol may be the reason for the antibacterial and bactericidal activity of Efinaconazoleline. In vitro studies show that Efinaconazoleline is highly adsorbed by keratin, but the binding affinity to keratin is weak. The low affinity of Efinaconazoleline to keratin is expected to increase the effectiveness of free drug reaching the site of onychomycosis infection.

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Therapeutic Use
Antifungal Drug
Jublia (Efinaconazoleline) 10% Topical Solution is an azole antifungal drug indicated for the topical treatment of onychomycosis caused by Trichophyton rubrum and Trichophyton mentagrophytes. /US Product Label Contains/
We aim to evaluate the efficacy of 10% Efinaconazoleline topical solution in treating patients with onychomycosis complicated by tinea pedis. We analyzed 1655 patients aged 18 to 70 years from two identical multicenter, double-blind, excipient-controlled 48-week safety and efficacy studies. These patients were randomized 3:1 to receive either 10% ivermectin topical solution or the excipient. The primary endpoint was complete cure at week 52 (0% clinical involvement of the target toenail, negative potassium hydroxide test and fungal culture results). Three groups of patients were compared: those with onychomycosis and interdigital pedis during the study period (treated or untreated) and those without pedis. Regardless of whether pedis was present or under treatment, the efficacy of 10% ivermectin topical solution was significantly superior to the excipient. Overall, 352 patients with onychomycosis (21.3%) also had interdigital pedis, of whom 215 (61.1%) received investigator-approved topical antifungal medication for pedis concurrently with the randomly assigned onychomycosis treatment. At week 52, the complete cure rate of ivermectin in patients with tinea pedis who received treatment for onychomycosis was 29.4%, compared to 16.1% in patients without tinea pedis. Both cure rates were significantly higher than in the excipient group (p = 0.003 and 0.045, respectively), and no patients in the excipient group achieved complete cure in the latter group. For patients with onychomycosis and tinea pedis, once-daily treatment with 10% ivermectin topical solution enhanced efficacy. Multiple comorbidities and risk factors complicate the successful treatment of onychomycosis. Underlying diseases and patient characteristics, such as tinea pedis, age, and obesity, increase the risk of disease; while comorbidities, such as diabetes and psoriasis, increase susceptibility. Data on treatment efficacy in these patients are currently limited. This article reviews a post-hoc analysis of 10% ivermectin topical solution treatment for mild to moderate onychomycosis and provides new data on age and obesity. To date, the only post-hoc analysis reporting a significant difference was in sex, with female patients showing significantly better efficacy than male patients; however, the reason for this is unclear. The authors reported that obese patients had significantly lower efficacy than those with normal body mass index (p=0.05), and patients with tinea pedis also had significantly lower efficacy than those without (p=0.025). Although there was a trend toward decreased efficacy in elderly patients and those with diabetes, the differences were not significant. Further research is needed on onychomycosis patients with these important risk factors and comorbidities to comprehensively assess treatment challenges and potential solutions. Onychomycosis is a common fungal infection of the nail unit that causes nail discoloration, subungual debris, thickening, and onycholysis, often accompanied by pain and limited mobility. Dermatophytoma is characterized by thick clumps of fungus within and beneath the nail plate and is particularly difficult to treat. This article reports a case of a patient with dermatophytoma who did not respond to oral terbinafine but achieved success with 10% ivermectin topical solution.

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Drug Warnings
Adverse reactions have been reported in at least 1% of adults treated with 10% ivermectin topical solution, and the incidence is higher than with excipient-based topical solutions. These include application site dermatitis, ingrown toenails, application site blisters, and application site pain.
Diagnosis should be confirmed by direct microscopic examination or culture of scrapings of infected toenails fixed in potassium hydroxide (KOH) solution before treatment.
10% ivermectin solution is for external use only. This topical solution should not be taken orally or vaginally, nor should it be applied to the eyes.
10% ivermectin topical solution may cause application site irritation (e.g., redness, swelling, burning, itching, blisters); there is currently no evidence that this solution causes contact sensitization.
For more complete data on drug warnings for ivermectin (10 in total), please visit the HSDB records page.

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Pharmacodynamics
On day 28 of treatment, the mean ± standard deviation of plasma Cmax was 0.67 ± 0.37 ng/mL. The mean ± standard deviation of AUC was 12.15 ± 6.91 ngh/mL.

C18H22F2N4O

348.39

348.176

164650-44-6

Efinaconazole-d4

489181

White to off-white solid powder

1.3±0.1 g/cm3

512.2±60.0 °C at 760 mmHg

263.6±32.9 °C

0.0±1.4 mmHg at 25°C

1.590

3.46

1

6

5

25

470

2

C[C@H]([C@](CN1C=NC=N1)(C2=C(C=C(C=C2)F)F)O)N3CCC(=C)CC3

NFEZZTICAUWDHU-RDTXWAMCSA-N

InChI=1S/C18H22F2N4O/c1-13-5-7-23(8-6-13)14(2)18(25,10-24-12-21-11-22-24)16-4-3-15(19)9-17(16)20/h3-4,9,11-12,14,25H,1,5-8,10H2,2H3/t14-,18-/m1/s1

(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol

AGJ95634; KP103; CTK5J2975; KB145948; AGJ-95634; KP-103; CTK-5J2975; KB-145948; AGJ 95634; KP 103; CTK 5J2975; KB 145948; trade names Jublia; Clenafin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~287.03 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.18 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.18 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)