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Efinaconazole

Class: Azoles
ATC Class: D01AC03
VA Class: DE102
Chemical Name: (αR,βR) - α - (2,4 - Difluorophenyl) - β - methyl - 4 - methylene - α - (1H - 1,2,4 - triazol - 1 - ylmethyl) - 1 - piperidineethanol
Molecular Formula: C18H22F2N4O
CAS Number: 164650-44-6
Brands: Jublia

Introduction

Antifungal; azole (triazole derivative).1 3

Uses for Efinaconazole

Onychomycosis

Topical treatment of onychomycosis of the toenails (tinea unguium, ringworm of the nail) caused by Trichophyton rubrum or T. mentagrophytes.1

Efinaconazole Dosage and Administration

Administration

Topical Administration

Apply 10% solution topically to affected toenails using flow-through brush applicator supplied by the manufacturer.1

Do not administer orally or intravaginally;1 do not apply topically to eyes.1

Clean and dry toenails prior to application; do not apply until ≥10 minutes after showering, bathing, or washing.1

Using the integrated flow-through brush applicator supplied by the manufacturer on the bottle, place 1 drop of solution on each affected toenail.1 Use attached brush applicator to gently spread solution evenly over entire toenail surface, including cuticle, folds of skin next to sides of toenail, toenail bed, hyponychium (thickened epidermis underneath toenail tip), and undersurface of toenail tip.1 For the big toenail, apply second drop at the end of the toenail.1 Do not squeeze applicator bottle while spreading solution over toenails.1

Allow solution to dry on the toenails.1

Wash hands with soap and water after applying the drug.1

Avoid pedicures and use of nail polish and other cosmetic nail products during efinaconazole treatment.1

Dosage

Adults

Onychomycosis
Topical

Apply 10% solution to affected toenails once daily for 48 weeks.1 Use amount sufficient to cover entire toenail surface and under toenail tip.1 (See Topical Administration under Dosage and Administration.)

Special Populations

No special population dosage recommendations.1

Cautions for Efinaconazole

Contraindications

  • Manufacturer states none.1

Warnings/Precautions

Sensitivity Reactions

May cause application site irritation (e.g., redness, swelling, burning, itching, blisters);1 no evidence that the drug causes contact sensitization.13 17

Administration Precautions

For topical use only.1 Do not use orally or intravaginally;1 do not apply to eyes.1

Selection and Use of Antifungals

Prior to treatment of onychomycosis, confirm diagnosis by direct microscopic examination of scrapings from infected toenails mounted in potassium hydroxide (KOH) or by culture.8 9 10 11 12

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether distributed into human milk following topical application;1 distributed into milk of rats after sub-Q administration.1 Use with caution in nursing women.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

No overall differences in safety and efficacy in older adults relative to younger adults observed in clinical trials, but greater sensitivity of some older individuals cannot be ruled out.1

Common Adverse Effects

Application site dermatitis,1 ingrown toenail,1 application site vesicles,1 application site pain.1

Interactions for Efinaconazole

Does not inhibit CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 and does not induce CYP1A2 or 3A4 in vitro at concentrations expected clinically.1

No formal drug interaction studies to date.13 Clinically important interactions with CYP inhibitors or inducers unlikely because systemic exposure is low following topical application of efinaconazole to toenails.13

Efinaconazole Pharmacokinetics

Absorption

Bioavailability

Following topical application of efinaconazole 10% solution to toenails, low concentrations are absorbed systemically.1 13 15

Mean peak plasma concentration was 0.67 ng/mL after 28 consecutive days of once-daily topical administration of the 10% solution to all 10 toenails and up to 0.5 cm of skin surrounding each toenail.1 13 15 Plasma concentrations of the drug still detectable in some patients 2 weeks after last dose.15

Steady-state concentrations achieved after about 14 days of once-daily topical application.13 15

Elimination

Metabolism

Following systemic absorption, efinaconazole undergoes oxidative metabolism via multiple CYP isoenzymes, principally CYP2C19 and 3A4.13 Major metabolite (H3) is inactive.13

Half-life

Plasma half-life of 29.9 hours reported following 7 consecutive days of once-daily topical application to all 10 toenails in a study in healthy adults.1

Stability

Storage

Topical

Solution

20–25°C (may be exposed to 15–30°C). 1 Do not freeze.1

The 10% solution contains alcohol and is flammable;1 do not store or use near heat or open flame.1

Keep bottle tightly closed.1

Actions and Spectrum

  • Triazole-derivative azole antifungal.1 3

  • Presumably exerts antifungal activity by altering cellular membranes, resulting in increased membrane permeability and growth inhibition.3 13 14

  • Mechanism of action similar to that of other azole antifungals.1 3 13 14 May involve inhibition of 14-α-demethylase in susceptible fungi, which leads to accumulation of C-14-methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol in fungal cell membranes.1 3 13 14 Depletion of ergosterol affects cell membrane integrity and function and leads to fungal cell death.3 13 14

  • Spectrum of antifungal activity includes dermatophytes, yeasts, and some other fungi.1 3 14 16

  • Dermatophytes: Active in vitro against Trichophyton mentagrophytes,1 3 14 16 T. rubrum,1 14 16 Epidermophyton floccosum,16 Microsporum canis,16 and M. gypseum.16

  • Other fungi: Active in vitro against Candida albicans,3 14 16 Acremonium,16 Aspergillus,16 and Scopulariopsis.16

  • In vitro, appears to be as active or more active than ciclopirox, itraconazole, and terbinafine against T. mentagrophytes and T. rubrum.3 14 16

  • Antifungal activity not affected by presence of keratin.14 18 In vitro studies suggest efinaconazole has low binding affinity for keratin and is readily released from keratinized nail plates; this may increase availability at site of nail fungal infection and increase penetration through the nail plate.6 14 18

  • No evidence to date that T. mentagrophytes or T. rubrum develops resistance to efinaconazole following long-term topical treatment of onychomycosis caused by these dermatophytes.14 16 Although clinical importance unclear, T. mentagrophytes, T. rubrum, and C. albicans with reduced susceptibility to efinaconazole reported in in vitro serial passage resistance studies using subgrowth inhibitory concentrations of the drug.1 14

Advice to Patients

  • Importance of using efinaconazole topical solution only for the condition prescribed.1

  • Advise patients that efinaconazole topical solution is for external use only and to avoid contact with eyes, mouth, or vagina.1

  • Advise patients to clean and dry toenails prior to application of the drug;1 importance of applying the topical solution once daily using the integrated flow-through brush applicator provided with the bottle.1

  • Importance of avoiding pedicures, nail polish, and other cosmetic nail products during efinaconazole treatment.1

  • Advise patients to wash hands with soap and water following application of the drug.1

  • Advise patients that efinaconazole topical solution is flammable and should not be stored or used near heat or an open flame.1

  • Importance of informing clinician if area of application shows signs of persistent irritation (e.g., redness, itching, swelling).1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Efinaconazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Solution

10%

Jublia

Valeant

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Valeant Pharmaceuticals. Jublia (efinaconazole) topical solution 10% prescribing information. Bridgewater, NJ; 2014 Jun.

2. Elewski BE, Rich P, Pollak R et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013; 68:600-8. [PubMed 23177180]

3. Tatsumi Y, Nagashima M, Shibanushi T et al. Mechanism of action of efinaconazole, a novel triazole antifungal agent. Antimicrob Agents Chemother. 2013; 57:2405-9. [PubMed 23459486]

6. Del Rosso JQ. The role of topical antifungal therapy for onychomycosis and the emergence of newer agents. J Clin Aesthet Dermatol. 2014; 7:10-8. [PubMed 25053979]

7. Hay RJ. Dermatophytosis and other superficial mycoses. In: Mandell GL, Bennett, JE, Dolin R, eds. Mandell, Douglas, and Bennett's: principles and practice of infectious diseases. Vol 2. 7th ed. Philadelphia: Elsevier; 2010: 3345-55.

8. Hainer BL. Dermatophyte infections. Am Fam Physician. 2003; 67:101-8. [PubMed 12537173]

9. de Berker D. Clinical practice. Fungal nail disease. N Engl J Med. 2009; 360:2108-16. [PubMed 19439745]

10. Westerberg DP, Voyack MJ. Onychomycosis: Current trends in diagnosis and treatment. Am Fam Physician. 2013; 88:762-70. [PubMed 24364524]

11. Thomas J, Jacobson GA, Narkowicz CK et al. Toenail onychomycosis: an important global disease burden. J Clin Pharm Ther. 2010; 35:497-519. [PubMed 20831675]

12. Roberts DT, Taylor WD, Boyle J et al. Guidelines for treatment of onychomycosis. Br J Dermatol. 2003; 148:402-10. [PubMed 12653730]

13. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number203567 Orig1s000: medical review. From FDA website.

14. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number203567Orig1s000: microbiology/virology review(s). From FDA website.

15. Jarratt M, Siu WJ, Yamakawa E et al. Safety and pharmacokinetics of efinaconazole 10% solution in healthy volunteers and patients with severe onychomycosis. J Drugs Dermatol. 2013; 12:1010-6. [PubMed 24002148]

16. Jo Siu WJ, Tatsumi Y, Senda H et al. Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis. Antimicrob Agents Chemother. 2013; 57:1610-6. [PubMed 23318803]

17. Del Rosso JQ, Reece B, Smith K et al. Efinaconazole 10% solution: a new topical treatment for onychomycosis: contact sensitization and skin irritation potential. J Clin Aesthet Dermatol. 2013; 6:20-4. [PubMed 23556032]

18. Sugiura K, Sugimoto N, Hosaka S et al. The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment. Antimicrob Agents Chemother. 2014; 58:3837-42. [PubMed 24752277]

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