A CME/CE CERTIFIED SUPPLEMENT TO SUPPLEMENT 3 VOL. 34, NO. 3S JUNE 2015

EDITORS

Kenneth A. Arndt, MD Philip E. LeBoit, MD Bruce U. Wintroub, MD

Managing Onychomycosis: New and Emerging Treatments and Recurrence Prevention Strategies GUEST EDITORS

David M. Pariser, MD, Chair Nathaniel J. Jellinek, MD Phoebe Rich, MD Melodie S. Young, MSN, RN, A/GNP-c



Introduction S45

Efficacy and Safety of Onychomycosis Treatments: S46 An Evidence-Based Overview

Understanding Onychomycosis Treatment: S51 Mechanisms of Action and Formulation



Management Strategies for Onychomycosis S54 in Special Patient Populations



Making Strides in Preventing S56 Onychomycosis Recurrence



Post-Test and Evaluation Form S60

Managing Onychomycosis: New and Emerging Treatments and Recurrence Prevention Strategies Original Release Date: June 2015 Most Recent Review Date: June 2015 Expiration Date: June 30, 2017 Estimated Time to Complete Activity: 2.5 hours Participants should read the activity information, review the activity in its entirety, and complete the online post-test and evaluation. Upon completing this activity as designed and achieving a passing score on the post-test you will be directed to a Web page that will allow you to receive your certificate of credit via email or you may print it out at that time. The online post-test and evaluation can be accessed at http://tinyurl.com/onycho15. Inquiries may be directed to Global Academy for Medical Education [email protected] or (973) 290-8225.

Accreditation Statements

Physicians: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of The University of Louisville and Global Academy for Medical Education, LLC.  The University of Louisville is accredited by the ACCME to provide continuing medical education for physicians. The University of Louisville Office of Continuing Medical Education & Professional Development designates this enduring material for a maximum of 2.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurses: This program has been approved by the Kentucky Board of Nursing for 3.0 contact hours through the University of Louisville Hospital, provider number 4-0068-7-16-820. The Kentucky Board of Nursing approval of an individual nursing education provider does not constitute endorsement of program content. Participants must complete the entire activity, provide license, and complete the evaluation to receive contact hours.

Target Audience

This educational activity is designed for dermatologists, family practitioners, internists, nurse practitioners, physician assistants, and other clinicians who treat patients with onychomycosis.

Educational Needs

With the introduction of more effective treatments—particularly the recently approved topical agents—clinicians in dermatology as well as other specialties and general primary care have a renewed interest in diagnosing and treating onychomycosis, an infection that is now recognized as clinically important but was once considered largely a cosmetic problem with minimal or no medical implications. However, although efficacy with some treatments is good, the medications must be used consistently and correctly for several months before clinical evidence of improvement appears, and before patients perceive that treatment is working. Treatment options currently approved in the United States for onychomycosis include topical and oral agents, as well as laser therapy. Oral agents must be chosen for their activity against the involved pathogens (dermatophytes, nondermatophytes, or yeast species, or combination infections). The currently approved systemic agents generally are safe for most patients, but concerns remain with respect to systemic side effects (for example, hepatotoxicity), particularly in pediatric patients, the elderly, and others with underlying medical conditions such as diabetes. The three agents currently approved for topical therapy are ciclopirox gel 0.77%, approved in 1999, and efinaconazole 10% topical solution and tavaborole topical solution, 5%, both approved in 2014. Other classes of topical antifungals are being evaluated both here and abroad. Clinicians must be able to effectively and safely use the currently approved agents, and must be prepared to evaluate the emerging data on medications now being investigated. Several laser devices are approved, and other types of lasers as well as other modalities (including photodynamic therapy) are being tested in clinical trials. This supplement focuses on the efficacy and safety of onychomycosis treatments, particularly those recently approved, and provides an overview of emerging therapies. Mechanisms of action of drugs and devices also are presented to help clinicians tailor therapy according to individual patient clinical profiles. Management strategies for challenging patient populations are offered, and practical approaches to preventing recurrence are addressed— in particular, strategies for enhancing patient adherence to medication use and avoidance of sources of reinfection.

Jointly provided by and

Learning Objectives

As a result of participating in this activity, participants should be able to: • Explain the benefits of early diagnosis and treatment of onychomycosis and the potential sequelae if this infection is untreated or is inadequately treated. • Establish or improve practice protocols for identifying patients with onychomycosis, particularly in special populations (for example, the elderly, pediatric patients, immunocompromised patients, patients with psoriasis, and those with diabetes mellitus). • Identify the mechanism of action for the currently available therapeutic options, including differences in formulation and associated efficacy, and use this knowledge to more effectively tailor treatment choices to individual patients. • Incorporate or enhance monitoring for onychomycosis in patients in special, at-risk, or difficult-to-manage populations (for example, the elderly, pediatric patients, immunocompromised patients, patients with psoriasis, and those with diabetes mellitus). • More effectively use currently available oral and topical medications to treat various patient populations. • Discuss techniques, including obtaining good culture specimens, that permit more accurate diagnosis of the infecting organisms and the most appropriate choice of therapy. • Review and, if necessary, improve patient education materials and teaching plans regarding the patient’s role in the treatment of onychomycosis and the prevention of recurrence to increase the chances of effective long-term management of this disease. • Evaluate the results of clinical studies on new and emerging and available treatments for onychomycosis.

Disclosure Declarations

As a provider accredited by the ACCME, the Office of CME & PD, School of Medicine, University of Louisville must ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All planners, faculty, reviewers, and other persons that affected the content of this CME activity were required to submit a financial disclosure form from which relevant conflicts of interest were determined. The persons below disclosed the following: David M.Pariser,MD, Consultant: Anacor Pharmaceuticals,Inc.,DUSA Pharmaceuticals, Inc., LEO Pharma Inc., and Valeant Pharmaceuticals North America LLC. Nathaniel J. Jellinek, MD, Advisory Board: Valeant Pharmaceuticals. Phoebe Rich, MD, Grant/Research: Anacor, Meiji Seika Pharma Co., Ltd., Topica Pharmaceuticals, Inc., and Valeant Pharmaceuticals. Melodie S.Young, MSN, RN,A/GNP-c, has no relevant financial relationships to disclose. CME Reviewer: Cindy England Owen, MD, Assistant Professor, Division of Dermatology, University of Louisville School of Medicine, has no relevant financial relationships to disclose. The CME & PD Staff and Advisory Board have nothing to disclose with the exception of Dr. Douglas Coldwell, Speaker: Sirtex, Inc. and Consultant: DFine, Inc. Global Academy for Medical Education Staff: Sylvia H. Reitman, MBA, DipEd; Shirley V. Jones, MBA; and Joanne Still, BA have no relevant financial relationships to disclose.

Off-Label/Investigational Use Disclosure

This CME/CE activity discusses the off-label use of fluconazole for the treatment of onychomycosis and unapproved dosing schedules for itraconazole and terbinafine. Also discussed is the use in pediatric patients of medications approved for the treatment of onychomycosis in adults; currently, no medication is approved for the treatment of onychomycosis in pediatric patients. This continuing education supplement was developed from interviews with the faculty.The Guest Editors acknowledge the editorial assistance of Global Academy for Medical Education and Joanne Still, medical writer, in the development of this supplement.The manuscript was reviewed and approved by the Guest Editors as well as the Editors of Seminars in Cutaneous Medicine and Surgery. The ideas and opinions expressed in this supplement are those of the Guest Editors and do not necessarily reflect the views of the supporters, Global Academy for Medical Education, the University of Louisville, or the Publisher.

Supported by an educational grant from

Valeant Pharmaceuticals North America LLC.

STATEMENT OF PURPOSE Seminars in Cutaneous Medicine and Surgery presents well-rounded and authoritative discussions of important clinical areas, especially those undergoing rapid change in the specialty. Each issue, under the direction of the Editors and Guest Editors selected because of their expertise in the subject area, includes the most current information on the diagnosis and management of specific disorders of the skin, as well as the application of the latest scientific findings to patient care. Seminars in Cutaneous Medicine and Surgery (ISSN 1085-5629) is published quarterly by Frontline Medical Communications Inc., 7 Century Drive, Suite 302, Parsippany, NJ 07054-4609. Months of issue are April, June, September, and December. Periodicals postage paid at Parsippany, NJ, and additional mailing offices. POSTMASTER: Send address changes to Seminars in Cutaneous Medicine and Surgery, Subscription Services, 151 Fairchild Ave, Suite 2, Plainview, NY 11803-1709. RECIPIENT: To change your address, contact Subscription Services at 1-800-480-4851.

EDITORS Kenneth A. Arndt, MD Clinical Professor of Dermatology, Emeritus Harvard Medical School Adjunct Professor of Surgery Dartmouth Medical School Hanover, New Hampshire Adjunct Professor of Dermatology Brown Medical School Providence, Rhode Island

Philip E. LeBoit, MD Professor of Clinical Dermatology University of California, San Francisco San Francisco, California

Bruce U. Wintroub, MD Associate Dean Professor and Chair of Dermatology School of Medicine University of California, San Francisco San Francisco, California

Editorial correspondence should be addressed to Kenneth A. Arndt, MD, Skincare Physicians of Chestnut Hill, 1244 Boylston St, Suite 302, Chestnut Hill, MA 02467. Correspondence regarding subscriptions or change of address should be directed to the Publisher, Subscription Services, 151 Fairchild Ave, Suite 2, Plainview, NY 11803-1709, 1-800-480-4851. Yearly subscription rate: $258.00 per year. Prices are subject to change without notice. Current prices are in effect for back volumes and back issues. Single issues, both current and back, exist in limited quantities and are offered for sale subject to availability. Back issues sold in conjunction with a subscription are on a prorated basis. Copyright © 2015 by Frontline Medical Communications Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Advertising representative: Sally Cioci, 7 Century Drive, Suite 302, Parsippany, NJ 07054-4609. Phone: 973-206-3434; Fax: 973-206-9378; e-mail: [email protected] Publication of an advertisement in Seminars in Cutaneous Medicine and Surgery does not imply endorsement of its claims by the Editor(s) or Publisher of the journal. The ideas and opinions expressed in Seminars in Cutaneous Medicine and Surgery do not necessarily reflect those of the Editors or Publisher. Publication of an advertisement or other product mention in Seminars in Cutaneous Medicine and Surgery should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with any questions about the features or limitations of the products mentioned. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other health care professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Seminars in Cutaneous Medicine and Surgery is indexed in Index Medicus/ MEDLINE and EMBASE/Excerpta Medica.

June 2015, Vol. 34, No. 3S

TABLE OF CONTENTS

Managing Onychomycosis: New and Emerging Treatments and Recurrence Prevention Strategies S45 Introduction S46 Efficacy and Safety of Onychomycosis Treatments: An Evidence-Based Overview David M. Pariser, MD Nathaniel J. Jellinek, MD Phoebe Rich, MD

S51 Understanding Onychomycosis Treatment: Mechanisms of Action and Formulation Nathaniel J. Jellinek, MD Phoebe Rich, MD David M. Pariser, MD

S54 Management Strategies for Onychomycosis in Special Patient Populations Phoebe Rich, MD Nathaniel J. Jellinek, MD David M. Pariser, MD

S56 Making Strides in Preventing Onychomycosis Recurrence Melodie S. Young, MSN, RN, A/GNP-c David M. Pariser, MD Phoebe Rich, MD Nathaniel J. Jellinek, MD

S60 Post-Test and Evaluation Form

GUEST EDITORS David M. Pariser, MD, Chair

Nathaniel J. Jellinek, MD

Phoebe Rich, MD

Melodie S.Young, MSN, RN, A/GNP-c

Professor of Dermatology Eastern Virginia Medical School Department of Dermatology Pariser Dermatology Norfolk, Virginia

Clinical Adjunct Professor of Dermatology Oregon Health Science University Portland, Oregon

Assistant Clinical Professor Department of Dermatology Warren Alpert Medical School Brown University Adjunct Assistant Clinical Professor Division of Dermatology University of Massachusetts Medical School Fellowship Director, Procedural Dermatology Dermatology Professionals, Inc. East Greenwich, Rhode Island

Modern Dermatology A Baylor Health Texas Affiliate Dallas, Texas

Vol. 34, No. 3S, June 2015

INTRODUCTION

U

ntil relatively recently, onychomycosis generally was not recognized as an infection that warranted serious clinical consideration. This was due, in part, to the fact that prior to the introduction of oral terbinafine, effective therapy was not available. With the approval by the US Food and Drug Administration (FDA) of terbinafine in 1996 and the subsequent approval of the topical agent ciclopirox in 1999, interest in diagnosing and treating onychomycosis increased. However, although these new medications were effective in many cases, the achievement of a mycologic cure and cosmetic clearance of the infection were elusive goals for many other patients. Moreover, even after the introduction of these medications, patients typically sought attention for onychomycosis only when pain or other symptoms had progressed to the point at which the infection could no longer be ignored. Early cases of this fungal infection were not commonly identified by either patients or clinicians, and the importance of early treatment was not appreciated. Finally, recurrence was the rule rather than the exception. Within the past decade, research regarding the pathogenesis of onychomycosis has led to a better understanding of the underlying infectious organisms, the introduction in 2014 of two new topical agents, and, as a result, a resurgence of interest in the diagnosis and treatment of both onychomycosis and a commonly related cutaneous infection, tinea pedis. In this supplement, the faculty provides an overview of the state of the art in onychomycosis diagnosis and treatment, with a particular focus on the efficacy and safety data from clinical studies of the newer and emerging medications and devices. Also, a discussion of the mechanisms of action of these modalities is presented, to help clinicians tailor therapy according to individual patient profiles. In addition, management strategies for challenging patient populations are offered, as well as some practical approaches for improving treatment results and reducing the risk for recurrence of infection. The goal of this educational activity is to provide clinicians with up-to-date information on the diagnosis and treatment of onychomycosis that will support their efforts to work with patients to manage or, when possible, eradicate this infection.

David M. Pariser, MD

Professor of Dermatology Eastern Virginia Medical School Department of Dermatology 
Pariser Dermatology Norfolk, Virginia

Journal Supplement Chair

Publication of this CME/CE article was jointly provided by the University of Louisville School of Medicine Continuing Medical Education and Global Academy for Medical Education, LLC, and is supported by an educational grant from Valeant Pharmaceuticals North America LLC. Dr Pariser has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Joanne Still, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article. David M. Pariser, Consultant: Anacor Pharmaceuticals, Inc., DUSA Pharmaceuticals, Inc., LEO Pharma Inc., and Valeant Pharmaceuticals. Address reprint requests to: David M. Pariser, MD, Professor of Dermatology, Eastern Virginia Medical School, Department of Dermatology, Pariser Dermatology, 601 Medical Tower, Norfolk, VA 23507; [email protected] 1085-5629/13/$-see front matter © 2015 Frontline Medical Communications doi:10.12788/j.sder.2015.0147

Vol. 34, No. 3S, June 2015, Seminars in Cutaneous Medicine and Surgery S45

Efficacy and Safety of Onychomycosis Treatments: An Evidence-Based Overview David M. Pariser, MD,* Nathaniel J. Jellinek, MD,† and Phoebe Rich, MD‡ ■ Abstract Three systemic agents commonly are used for the treatment of onychomycosis. Until the introduction of ciclopirox in 1999, these were the only FDA-approved therapeutic options for managing these infections.With the recent approval of two new topical antifungal agents—efinaconazole in the azole class, and tavaborole, a unique boron-containing medication— clinicians and patients have an improved roster of medications for managing onychomycosis. Semin Cutan Med Surg 34(supp3):S46-S50 © 2015 published by Frontline Medical Communications

■ Keywords Ciclopirox; dermatophyte infections; efinaconazole; fluconazole; itraconazole; laser therapy; onychomycosis; tavaborole; terbinafine

S

ince the introduction of oral terbinafine in 1996, interest in onychomycosis diagnosis and treatment has increased; the availability of newer medications and devices both reflects and is a result of that increasing interest. This article provides an evidence-based overview of drug therapy (including systemic and topical antifungal agents and over-the-counter herbal and homeopathic topical remedies), laser treatments, and mechanical modalities.

Drug Therapy: Oral Antifungal Agents For most cases of onychomycosis seen in the United States, the causative organism is a dermatophyte, most commonly, Trichophyton rubrum. Three oral agents typically are used: fluconazole (not approved by the US Food and Drug Administration [FDA] for this indication), itraconazole, and terbinafine (both of * Professor of Dermatology, Eastern Virginia Medical School, Department of Dermatology, Pariser Dermatology, Norfolk, Virginia † Assistant Clinical Professor, Department of Dermatology, Warren Alpert Medical School at Brown University, Adjunct Assistant Clinical Professor, Division of Dermatology, University of Massachusetts Medical School, Fellowship Director, Procedural Dermatology, Dermatology Professionals, Inc., East Greenwich, Rhode Island ‡ Clinical Adjunct Professor of Dermatology, Oregon Health Science University, Portland, Oregon Publication of this CME/CE article was jointly provided by the University of Louisville School of Medicine Continuing Medical Education and Global Academy for Medical Education, LLC, and is supported by an educational grant from Valeant Pharmaceuticals North America LLC. Dr Pariser, Dr Jellinek, and Dr Rich have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Joanne Still, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

which are FDA-approved for the treatment of onychomycosis). The Table summarizes the cure rates reported for the agents discussed below. Fluconazole

Fluconazole, a triazole, was introduced in 1990 for the treatment and prophylaxis of both localized and systemic Candida albicans infections. For several decades, it also has been studied and used throughout the world for treating onychomycosis. Although fluconazole is approved in other countries for onychomycosis, it is not FDA-approved for this indication. This agent has not been rigorously examined in large, randomized, double-blind, placebo-controlled trials for onychomycosis, but several studies of fluconazole suggest that this agent is effective for many patients with onychomycosis. In a multicenter, double-blind study of 362 patients, Scher and colleagues1 tested three dosages of fluconazole in patients with onychomycosis: 150, 300, and 450 mg/week for up to 9 months or until the nail was determined to be clear. The investigators reported clinical cures in 37% of patients who received 150 mg/week, in 46% of patients who received 300 mg/week, and in 48% of patients who received 450 mg/week. More recently, a group from Poland published the results of a study of fluconazole pulse therapy in 50 patients with laboratoryconfirmed dermatophyte infections (in most cases, the infecting organism was T. rubrum).2 Patients were given one 400-mg dose of fluconazole once weekly, for a maximum of 12 months. Thirty-three patients (66%) completed the trial, which included a 2-month follow-up period. Of the 17 patients who did not complete the trial, 11 (22%) withdrew (4 cited lack of therapeutic effect; 7 gave no reason) and 6 (12%) were excluded because of drug-related adverse effects (including gastrointestinal symptoms, a transient increase in liver enzyme levels, and skin lesions). Among the 33 patients who completed the treatment and followup protocol, 22 (66.7%) had a complete clinical and mycologic cure; 7 (21.2%) had mycologic eradication but not a clinical cure; and 4 (12.1%) had neither clinical nor mycologic cure. The median duration of treatment was 9 months in the group of patients who had complete clinical and mycologic cures. The investigators also noted that the patients with more extensive disease (a greater number of nails and more nail surface involved) and/or longer duration of infection required a longer course of treatment.2 In this study, the relapse rate was low—the investigators reported that only one patient (4.6%) experienced a relapse during the 2-month follow-up period after ending treatment (ie, within 2 months after the achievement of clinical and mycologic cure).2 Among the oral antifungals, fluconazole’s main advantages are once-weekly dosing, few drug-drug interactions, and a relatively low incidence of adverse effects. Itraconazole

Address reprint requests to: David M. Pariser, MD, Professor of Dermatology, Eastern Virginia Medical School, Department of Dermatology, Pariser Dermatology, 601 Medical Tower, Norfolk, VA 23507; [email protected]

The FDA-approved regimen for itraconazole treatment of toenail onychomycosis is 200 mg/day continuously for 3 months; according to the prescribing information for this drug, the cure rate with this regimen in the pivotal clinical trials was 14%.3 However, a pulsed-dose regimen—400 mg/day for 7 days for 1 week/month for 4 months—has been shown to be more effective (pulsed dosing is FDA-approved for treating fingernail but not toenail onychomycosis). In a study comparing continuous terbinafine with intermittent (pulsed-dose) itraconazole in almost 500 patients with toenail fungus, Evans and colleagues4

S46 Seminars in Cutaneous Medicine and Surgery, Vol. 34, No. 3S, June 2015

© 2015 Frontline Medical Communications 1085-5629/13/$-see front matter doi:10.12788/j.sder.2015.0148

David M. Pariser, MD, Consultant: Anacor Pharmaceuticals, Inc., DUSA Pharmaceuticals, Inc., LEO Pharma Inc., and Valeant Pharmaceuticals. Nathaniel J. Jellinek, MD, Advisory Board: Valeant Pharmaceuticals. Phoebe Rich, MD, Grant/Research: Anacor, Meiji Seika Pharma Co., Ltd., Topica Pharmaceuticals, Inc., and Valeant Pharmaceuticals.

David M. Pariser, MD, Nathaniel J. Jellinek, MD, and Phoebe Rich, MD reported complete cure (both clinical and mycologic cure) in 25 of 107 patients (23%) after three cycles of intermittent itraconazole and in 28 of 108 patients (26%) after four cycles. Similar to fluconazole, itraconazole is generally well tolerated; Scher reported adverse effects in approximately 3% of patients.5 The more commonly reported adverse effects were headache, gastrointestinal effects (including diarrhea, dyspepsia, nausea, and abdominal pain), and cutaneous symptoms including rash, pruritus, and urticaria. Acute generalized exanthematous pustulosis has been reported as a rare adverse event that resolves almost completely within a few weeks of cessation of the drug and use of corticosteroids.6 Gupta and Shear reported liver enzyme elevations in 0.3% to 0.5% of patients treated with itraconazole.7 The use of itraconazole for onychomycosis is contraindicated in patients with congestive heart failure (CHF) or a history of CHF or evidence of other types of ventricular dysfunction. Also, because itraconazole is a potent inhibitor of cytochrome p450 3A4, it can elevate plasma concentrations of some medications, resulting in serious cardiovascular events. Simultaneous use of itraconazole with these medications (such as cisapride, quinidine, and simvastatin) is contraindicated.3 In addition, Ahmad and colleagues8 reported that itraconazole has a negative inotropic effect on the heart in healthy individuals. Because of itraconazole’s greater risk for adverse effects compared to terbinafine, itraconazole is considered a second-line agent. It is an option in patients who have failed treatment with

■ TABLE Efficacy of Antifungals in Onychomycosis:

Complete Cure Rates Reported in Selected Clinical Trials*

Oral Antifungal Agents Medication and Regimen

Complete Cure Rates

Fluconazole1 150 mg/week

37%

300 mg/week

46%

450 mg/week

48%

Itraconazole 200 mg/day x 12 weeks3 400 mg/day for 1 Repeated for 3 pulses Repeated for 4 pulses

14%

week/month4 23% 26%

Terbinafine 250 mg/day x 12 weeks10

38%

250 mg/day for 1 week/month4 Repeated for 3 pulses Repeated for 4 pulses

49% 54%

Topical Antifungal Agents Ciclopirox 8%12

5.5% to 8.5%

Efinaconazole16

15% and 18%

(in two phase III trials, respectively)

Tavaborole17

(in two phase III trials, respectively)

6.5% and 9.1%

*The dosage regimens shown are not necessarily FDA-approved. Itraconazole is not FDA-approved for intermittent dosing for the treatment of toenail onychomycosis.

or cannot tolerate terbinafine, or when culture and sensitivity testing indicates that the infecting organisms are more susceptible to itraconazole. Terbinafine

Terbinafine’s FDA-approved toenail onychomycosis regimen is 250 mg/day for 12 weeks.9 Drake and colleagues10 reported a complete cure rate of 38% with terbinafine 250 mg/day for 3 months and no significant difference in response between 12-week and 24-week treatment courses. In the Lamisil® vs Itraconazole in ONychomycosis (LION) study of 496 patients,4 a complete cure was seen in 49% of patients with a 12-week course of terbinafine; 54% of patients had a complete cure with a 16-week regimen. Tosti and colleagues11 examined the relapse rates of patients who had mycologic cures with terbinafine compared to those who had mycologic cures with itraconazole in an open, randomized study. The investigators followed 47 patients with T. rubrum infections who had been treated with intermittent itraconazole or continuous or intermittent terbinafine. From the point at which they ended treatment, patients were examined every 3 months for up to 3 years; evaluations included direct microscopy and cultures. Of the 36 patients who completed the study, 8 (22.2%) experienced a relapse by the end of the 36-month follow-up period: two patients who had received 250 mg/day of terbinafine continuously for 12 weeks, two patients who had been treated with 500 mg/day of terbinafine for 1 week of each month for 3 months, and four patients treated with itraconazole, 400 mg/day for 1 week of each month for 3 months. The investigators reported that pulse-dosed itraconazole was more commonly associated with relapse (4 out of 11 patients) than continuous (2 out of 12 patients) or pulse-dosed terbinafine (2 out of 13 patients), although the differences in relapse among the three groups was not statistically significant. (Pulseddose therapy with terbinafine is not FDA-approved at this time.)

Drug Therapy: Topical Antifungal Agents Three medications are FDA-approved for the topical treatment of onychomycosis. Ciclopirox, FDA-approved in 1999, was the first of these to be introduced. Efinaconazole and tavaborole were both FDA-approved in 2014. Ciclopirox

Ciclopirox 8% solution is a lacquer formulation indicated for use in immunocompetent patients with mild to moderate onychomycosis without involvement of the lunula and due to T. rubrum. Its use requires regular debridement consisting of removal by a health care professional (as frequently as once a month) of unattached, infected nails, along with trimming and filing affected nails. In addition, the treatment protocol requires patients to remove the lacquer with alcohol every 7 days, to keep nails trimmed, and to use an emery board to file away loose nail material. Ciclopirox is associated with complete cure rates ranging from 5.5% to 8.5%, as part of the management protocol (with frequent nail debridement) described above.12 In controlled clinical trials, the reported mycologic cure rate is 29% to 36%, and the clinical cure rate (clear or almost clear nails) ranges from 6% to 9%.13 Ciclopirox has also been investigated as an adjunct to improve the efficacy of systemic therapy. In one such study, Avner and colleagues14 compared oral terbinafine monotherapy with oral terbinafine plus ciclopirox and found that the combination yielded a complete cure rate of 68% and a mycologic cure rate of 88%, whereas the oral agent alone was associated with a complete cure rate of 50% and a mycologic cure rate of 65%. The adverse effects associated with the use of ciclopirox generally are mild, including burning, itching, and stinging at the application site.15 Efinaconazole

Efinaconazole solution, which does not require removal each week, is a topical triazole antifungal FDA-approved for once-daily Vol. 34, No. 3S, June 2015, Seminars in Cutaneous Medicine and Surgery S47

■ ❚ ❙ Efficacy and Safety of Onychomycosis Treatments: An Evidence-Based Overview application for 48 weeks. Application instructions specify that the medication must completely cover the toenail folds and bed, the hyponychium, and the undersurface of the nail plate. In two identical multicenter, randomized, double-blind, vehiclecontrolled studies, Elewski and colleagues16 evaluated the efficacy and safety of efinaconazole 10% solution versus placebo in a total pool of 1,655 subjects. To be included in the studies, subjects were required to be between 18 and 70 years of age and have a clinical diagnosis of distal lateral subungual (DLS) onychomycosis of at least one great toenail, with 20% to 50% clinical involvement. Women with childbearing potential were required to use birth control during the study. Other eligibility requirements included 3 mm or more of uninfected nail on the target toenail from the proximal nail fold, evidence of toenail growth, a positive result on potassium hydroxide (KOH) microscopy, and a culture demonstrating the presence of dermatophyte or mixed dermatophyte and Candida organisms 42 days or less before beginning the study. Excluded from participation were individuals with a history of immunosuppression and/or clinical signs that indicated possible immunosuppression, HIV infection, uncontrolled diabetes mellitus, the presence of toenail infection with organisms other than dermatophytes, the presence of severe moccasin-type tinea pedis at screening or baseline, previous surgery involving the target toenail, or any disease or condition that might have resulted in toenail abnormalities or interfered with clinical evaluation. In study 1, 870 patients were randomized to receive either efinaconazole (n=656) or vehicle (n=214); in study 2, 785 patients were randomized to receive either the study medication (n=583) or vehicle (n=202). Subjects applied the medication or vehicle to the target toenail once daily for 48 weeks. The primary end point for efficacy was the proportion of patients who achieved a complete cure, as evaluated at week 52—ie, 4 weeks after the final application. Cure was defined as complete clinical clearance of the target toenail and mycologic cure demonstrated by a negative result on potassium hydroxide examination and negative culture. A total of 1,436 patients completed the 48-week treatment period, and 1,420 (85.5%) completed through the 4-week follow-up at week 52. Early discontinuations—235 patients— were due to patient request (98 patients; 41.7%), lost to follow-up (78 patients; 33.2%); adverse events (33 patients; 14.0%); protocol violation (7 patients; 3.0%); worsening condition (1 patient; 0.5%), and pregnancy (1 patient; 0.5%). The other discontinuations (17 patients; 7.2%) were for other reasons. At the follow-up evaluation at week 52, 17.8% of patients in study 1 and 15.2% of patients in study 2 had a complete cure with efinaconazole compared to 3.3% and 5.5% of patients in the vehicle groups in study 1 and study 2, respectively. The differences in both studies were significant (P