Efinaconazole

348.3902864

348.39

1592732-453-0

J82SB7FXWB

DTXSID40167787

C97998

D - Dermatologicals

54.2

2

1.26±0.1 g/cm3(Predicted)

512.2±60.0 °C(Predicted)

263.6±32.9 °C

1.590

In water, 321.6 mg/L at 25 °C (est)

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).|Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature -20 °C.

1.57X10-9 mm Hg at 25 °C (est)

Henry's Law constant = 1.83X10-13 atm-cu m/mol at 25 °C (est)

Hydroxyl radical reaction rate constant = 2.17X10-12 cu cm/molecule-sec at 25 °C (est)|Ozone radical reaction rate constant = 1.2X10-17 cu cm/molecule-sec at 25 °C (est)

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong oxidizing agents.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including efinaconazole, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]|P201, P202, P281, P308+P313, P405, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory.|H361: Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: impervious clothing. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Jublia is flammable; keep away from heat or flame.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.|Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.|Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed.|Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

IDENTIFICATION AND USE: Efinaconazole is used as antifungal agent. It is indicated for the topical treatment of onychomycosis of the toenail(s) due to Trichophyton rubrum and Trichophyton mentagrophytes. HUMAN EXPOSURE AND TOXICITY: Efinaconazole 10% solution did not cause contact sensitization and induced only minimal skin irritation in human studies. ANIMAL STUDIES: Efinaconazole was generally well tolerated in rats with repeated daily doses of up to 30 (males) and 40 (females) mg/kg. In 13 week dermal toxicity in mice, an increase in liver weight and minimal to mild panlobular hepatocellular hypertrophy was observed, the local application of the drug and/or the vehicle alone resulted in higher incidences of hyperkeratosis, epidermal hyperplasia, and mononuclear infiltrates in the treated skin. Higher concentration of the test article were associated with higher severity of these cutaneous changes compared to controls, and a low incidence of the formation of erosion/ulcers at the treated site. Efinaconazole 10% solution applied intratympanically to the guinea pig middle ear caused significant middle ear inflammation and hearing impairment. In dermal toxicity studies, efinaconazole was well tolerated in minipigs at doses up to 150-200 mg /kg/day. Slight to moderate skin reactions were noted macroscopically and microscopically in all test article groups and vehicle control and consisted of hyperkeratosis, acanthosis and localized inflammation. These skin effects were attributed to the vehicle and were not considered adverse due to the mild severity of changes. 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). 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). 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). 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).

Indicated in the treatment of fungal infection of the nail, known as onychomycosis.|FDA Label|Treatment of onychomycosis

Antifungal Agents|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. /Included in US product label/|We sought to evaluate the efficacy of efinaconazole topical solution, 10%, in patients with onychomycosis and coexisting tinea pedis. We analyzed 1,655 patients, aged 18 to 70 years, randomized (3:1) to receive efinaconazole topical solution, 10%, or vehicle from two identical multicenter, double-blind, vehicle-controlled 48-week studies evaluating safety and efficacy. The primary end point was complete cure rate (0% clinical involvement of the target toenail and negative potassium hydroxide examination and fungal culture findings) at week 52. Three groups were compared: patients with onychomycosis and coexisting interdigital tinea pedis on-study (treated or left untreated) and those with no coexisting tinea pedis. Treatment with efinaconazole topical solution, 10%, was significantly more effective than vehicle use irrespective of the coexistence of tinea pedis or its treatment. Overall, 352 patients with onychomycosis (21.3%) had coexisting interdigital tinea pedis, with 215 of these patients (61.1%) receiving investigator-approved topical antifungal agents for their tinea pedis in addition to their randomized onychomycosis treatment. At week 52, efinaconazole complete cure rates of 29.4% were reported in patients with onychomycosis when coexisting tinea pedis was treated compared with 16.1% when coexisting tinea pedis was not treated. Both cure rates were significant compared with vehicle (p = 0.003 and 0.045, respectively), and in the latter subgroup, no patients treated with vehicle achieved a complete cure. Treatment of coexisting tinea pedis in patients with onychomycosis enhances the efficacy of once-daily topical treatment with efinaconazole topical solution, 10%.|A number of comorbidities and risk factors complicate the successful management of onychomycosis. Underlying conditions and patient characteristics, such as tinea pedis, age, and obesity, contribute to risk, whereas comorbidities, such as diabetes and psoriasis, can increase susceptibility to the disease. There are limited data on treatment effectiveness in these patients. Here, the authors review post hoc analyses of efinaconazole topical solution, 10%, in mild-to-moderate onychomycosis and present new data in terms of age and obesity. The only post hoc analysis to report significant differences so far is gender, where female patients do much better; however, the reasons are unclear. The authors report significant differences in terms of efficacy in obese patients who do not respond as well as those with normal body mass index (p=0.05) and in patients who have their co-existing tinea pedis treated compared to those in whom co-existing tinea pedis was not treated (p=0.025). Although there is a trend to reduced efficacy in older patients and those with co-existing diabetes, differences were not significant. More research is needed in onychomycosis patients with these important risk factors and comorbidities to fully evaluate the treatment challenges and possible solutions.|Onychomycosis is a common fungal infection of the nail unit that results in discoloration, subungual debris, thickening, onycholysis, and often pain and impairment of mobility. Dermatophytomas are characterized by a thick fungal mass within and under the nail plate and are especially resistant to treatment. Here we report a case of a patient with a dermatophytoma who had failed oral terbinafine but was successfully treated with efinaconazole 10% topical solution.

Adverse effects reported in at least 1% of adults treated with efinaconazole 10% topical solution and more frequently than with topical vehicle solution include application site dermatitis, ingrown toenail, application site vesicles, and application site pain.|Prior to treatment of onychomycosis, the diagnosis should be confirmed by direct microscopic examination of scrapings from infected toenails mounted in potassium hydroxide (KOH) or by culture.|Efinaconazole 10% solution is for topical use only. The topical solution should not be used orally or intravaginally, and should not be applied to the eyes.|Efinaconazole 10% topical solution may cause application site irritation (e.g., redness, swelling, burning, itching, blisters); there is no evidence to date that the solution causes contact sensitization.|For more Drug Warnings (Complete) data for Efinaconazole (10 total), please visit the HSDB record page.

mean ± SD plasma Cmax on Day 28 of treatment: 0.67 ± 0.37 ng/mL. mean ± SD AUC was 12.15 ± 6.91 ng*h/mL.

Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues. (See all compounds classified as Antifungal Agents.)

Administration of Jublia by the topical route leads to low systemic efinaconazole concentrations. Systemic absorption of efinaconazole in 18 patients with severe onychomycosis was determined after application of Jublia once daily for 28 days to patients' 10 toenails and 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 plasma Cmax on Day 28 was 0.67 ng/mL. The mean plasma concentration versus time profile was generally flat over the course of treatment. In onychomycosis patients, the steady state plasma concentration range was 0.1-1.5 ng/mL for efinaconazole and 0.2-7.5 ng/mL for H3 metabolite.|/MILK/ Efinaconazole and or its metabolites were excreted in milk from lactating rats. The radioactivity concentration in milk was higher than that in plasma concentration for 24 hours after the administration of 14C-efinaconazole to lactating rats. However, the elimination half-life of the milk radioactivity was about one half of that of the plasma radioactivity, suggesting that efinaconazole or its metabolites was not retained in milk.|/MILK/ It is not known whether efinaconazole is excreted in human milk.|Efinaconazole penetrates through nails in vitro after Jublia administration, suggesting drug penetrations to the site of fungal infection in the nail and the nail bed, though clinical relevance is unknown. The penetration of Jublia was evaluated in an in vitro investigation after daily application of radiolabelled efinaconazole (10%) to human nails for 28 days at 55.1 uL/sq cm. After 28 days, the cumulative radioactivity in the receptor fluid and in the nail plate, on a percent basis of total administered radioactivity, was 0.03% and 0.16% (3.11 mg eq/g), respectively. The flux rate was relatively constant from Days 18 to 28, mean 1.40 ug eq/sq cm/day, suggesting steady state attainment.|For more Absorption, Distribution and Excretion (Complete) data for Efinaconazole (8 total), please visit the HSDB record page.

Efinaconazole is extensively metabolized. It is oxidatively metabolized, cleaved and conjugated to glucuronic acid. The studies have identified 5 metabolites (H1, H2, H3, H4 and H5) of efinaconazole. In rats and minipigs, H3 was the major efinaconazole plasma metabolite, and its levels usually equaled or exceeded those of parent drug. The in vitro and in vivo metabolite profiles in nonclinical species were similar to human with no unique human metabolite(s).|Jublia (efinaconazole) is extensively metabolized through oxidative/reductive processes, with the potential of additional metabolite glucuronidation. Analysis of human plasma confirmed that H3 is the only major efinaconazole metabolite.|Efinaconazole metabolites, but not parent drug, were excreted in the bile and urine of rats and dogs which suggests complete metabolism of efinaconazole prior to excretion. Most of the absorbed radioactivity was eliminated during the first 72 hours after dermal and SC dosing in urine and feces.

29.9 hours in healthy patients.|In a ... study of healthy volunteers, the plasma half-life of Jublia at day 10 following repeat treatment applications repeated to all 10 toenails was 29.9 hours.

Efinaconazole is an azole antifungal. Efinaconazole inhibits fungal lanosterol 14α-demethylase involved in the biosynthesis of ergosterol, a constituent of fungal cell membranes.|Efinaconazole is a triazole antifungal agent. Efinaconazole inhibits fungal lanosterol 14alpha-demethylase involved in ergosterol biosynthesis. The accumulation of 14alpha-methyl sterols and subsequent loss of ergosterol in the fungi cell wall may be responsible for the fungistatic and fungicidal activity of efinaconazole. Efinaconazole is shown in vitro to be substantially adsorbed to keratin but keratin binding is weak. Efinaconazole's low keratin affinity is expected to result in increased availability of free drug to the nail infection site.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ Onychomycosis is a chronic condition that often requires long-term management to eradicate the causative fungus, allow a healthy nail to grow, and prevent relapse. As a successful outcome depends highly on patient adherence with treatment, a low risk of periungual skin irritation with topical medication is clinically relevant. /The purpose of this research was/ to study the potential for efinaconazole 10% solution and its corresponding vehicle to induce delayed contact skin sensitization and evaluate its skin irritation potential. Efinaconazole 10% solution and its vehicle were studied in 239 healthy volunteers for the potential to induce contact skin sensitization. This included a series of induction, challenge, and re-challenge phases. An additional 21-day cumulative irritation study was undertaken in 35 healthy volunteers to compare three concentrations of efinaconazole (1%, 5%, and 10%), vehicle, and positive/negative controls. There was no evidence of induced contact sensitization under occlusive, semi-occlusive, and open (open rub-in) applications of efinaconazole 10% solution. Efinaconazole 1%, 5%, and 10% solutions have mean cumulative irritancy indices of 1.12, 1.26, and 1.18, respectively, where a range of >0 to =1 is classified as "mildly irritating." Results were comparable to vehicle (1.04). Efinaconazole 10% solution did not cause contact sensitization and induced only minimal skin irritation in the studies completed.|/ALTERNATIVE and IN VITRO TESTS/ Efinaconazole and the major human plasma metabolite, H3, have negligible or no potential to increase QT interval based on in vitro hERG inhibition. This hERG inhibition model used electrophysiological assessment of IKr potassium current in human cells transfected with human hERG cDNA. The H3 metabolite was inactive on hERG-mediated current at 100 uM (22500 ng/mL) and lower concentrations while efinaconazole produced slight inhibition, 17%, at the maximal soluble concentration of 10 uM (3480 ng/mL).

efinaconazole

For the topical treatment of onychomycosis, efinaconazole is commercially available as a 10% solution. The clear colorless to pale yellow solution contains efinaconazole in an alcohol-based vehicle. The topical solution also contains anhydrous citric acid, butylated hydroxytoluene, C12-15 alkyl lactate, cyclomethicone, diiospropyl adipate, disodium edetate, and purified water.|Topical: Solution, 10%, (Jublia) Valeant.

Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients