Efinaconazole

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Anti infectives for systemic use -> Antibacterials for systemic use

Breast Feeding; Lactation; Anti-Infective Agents; Antifungal Agents;

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Warning

H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 3 reports by companies from 3 notifications to the ECHA C&L Inventory.

Warning

H361: Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

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.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

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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.

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.

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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.

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.

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).

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).

/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).

/LABORATORY ANIMALS: Acute Exposure/ Assessments of efinaconazole acute toxicity were conducted in rat via dermal and subcutaneous (SC) administration, in mice via intraperitoneal administration, and in dog via dermal administration. Efinaconazole was well tolerated in both genders of all 3 species, with all LD50 values higher than 0.5 to 2 grams/kg.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In 13 week dermal toxicity in mice, the systemic exposure to efinaconazole was much higher as compared to minipig. In this study an increase in liver weight and minimal to mild panlobular hepatocellular hypertrophy was observed 30% IDP-108, the local application of IDP-108 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 of 10% and 30% IDP-108 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. The NOAEL, established by the 30% strength which had an exposure of 700 folds or more for efinaconazole as compared to human exposure levels.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Efinaconazole 10% solution is a new triazole antifungal agent developed for the topical treatment of fungal infections of the nails. The current study examined the effect of intratympanic application of efinaconazole 10% solution in the guinea pig ear. Sixteen male Hartley guinea pigs (weight 501-620 g) were divided into 3 groups to be treated with efinaconazole 10% solution, gentamicin (50 mg/mL), or saline solution. Topical solutions of 0.2 mL were applied through a small hole made at the tympanic bulla once daily for 7 consecutive days. Post-intervention auditory brainstem responses were obtained 7 days after the last treatment. The extent of middle ear damage and hair cell loss was investigated. The efinaconazole- and gentamicin-treated groups showed severe deterioration in auditory brainstem response threshold. Middle ear examination revealed extensive changes in the efinaconazole-treated group and medium changes in the gentamicin-treated group. Hair cells were preserved in the efinaconazole- and saline-treated groups, but severe damage was seen in the gentamicin group. In conclusion, efinaconazole 10% solution applied intratympanically to the guinea pig middle ear caused significant middle ear inflammation and hearing impairment.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Efinaconazole was generally well tolerated in rats with repeated daily doses of up to 30 (males) and 40 (females) mg/kg. The high doses were the maximum tolerated doses, based on increased frequency of severe injection site reactions and a 17% average lower body weight in males compared to controls. No target organs of toxicity were identified at any dose level. Administration of the propylene glycol vehicle at 2 mL/kg over 6 months was not well tolerated and resulted in mortalities in all groups. Vehicle-related effects included severe dermal clinical signs, and gross and microscopic pathology findings at the injection sites. Early death in several efinaconazole-treated rats was attributed to spinal cord necrosis and urinary tract disease; these lesions also were noted in control rats and were attributed to the spread of injection site reactions (necrosis, abscessation). The NOAEL was determined to be 10 mg/kg/day in both male and female rats which had an exposure of 70 folds or more for efinaconazole and metabolite H3 as compared to human exposure levels.

For more Non-Human Toxicity Excerpts (Complete) data for Efinaconazole (12 total), please visit the HSDB record page.

/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/

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.

D - Dermatologicals

QD - Dermatologicals

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.

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 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.

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EFINACONAZOLE

Established Pharmacologic Class [EPC] - Azole Antifungal

Chemical Structure [CS] - Azoles

Efinaconazole is an Azole Antifungal.

EFINACONAZOLE

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.

Antifungal Agents

MEDICATION

A new synthetic route, the shortest reported to date, to access a key intermediate for the synthesis of various triazole antifungal agents was developed. The elusive tetrasubstituted stereogenic center that is essential in advanced triazole antifungal agents was constructed via the catalytic asymmetric cyanosilylation of a ketone. The subsequent transformations were performed in two one-pot operations, enhancing the overall synthetic efficiency toward the intermediate. This streamlined synthetic approach was successfully applied to efficient enantioselective syntheses of efinaconazole (Jublia) ... .

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.