`
`Risk Factors and Comorbidities
`for Onychomycosis
`Implications for Treatment with Topical Therapy
`
`aBONI E. ELEWSKI, MD; bANTONELLA TOSTI, MD
`aDepartment of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama;
`bDepartment of Dermatology & Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, Florida
`
`ABSTRACT
`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 challengse and possible solutions.
`(J Clin Aesthet Dermatol. 2015;8(11):38–42.)
`
`Onychomycosis is a common problem in dermatology
`
`practice that can result in significant morbidity.1,2
`Successful treatment has been difficult because of
`slow growth of the nail; patient comorbidities, such as
`diabetes, peripheral vascular disease, and psoriasis; and
`reluctance of prescribers and patients to prescribe or take
`oral medications because of “perceived” toxicity issues.
`The disease can have a major impact on the individual
`and other family members.3–5 Dystrophic nails can cause
`embarrassment, affecting a patient’s self-esteem, and may
`have a greater impact on quality of life (QoL) than the
`severity of the disease itself.6 Thickened nails can also be
`painful, causing discomfort in walking and affecting other
`aspects of daily living.3
`A number of underlying conditions, such as tinea pedis,
`nail damage, and nail psoriasis can contribute to risk as
`well as characteristics such as age and obesity. Underlying
`cancer,7,9
`comorbidities,
`such
`as
`diabetes,7,8
`immunodeficiency,10 or peripheral arterial disease,11 can
`
`increase susceptibility to onychomycosis.7 An inherited
`genetic predisposition to
`infection has also been
`identified.12
`Clinical trials provide guidance on likely treatment
`outcomes in these patients at risk. However, some
`comorbid conditions (i.e., peripheral vascular disease) can
`be exclusion criteria, many trials were not set up to
`specifically study certain comorbidities, and
`the
`demographics and disposition of patients who visit
`dermatology and podiatry practices can be very different
`from those enrolled in clinical trials.
`Recently, a number of post hoc analyses have been
`published on the use of efinaconazole topical solution,
`10%, in the treatment of mild-to-moderate onychomycosis.
`Where data exist, it is the authors’ intention to review the
`findings in terms of the implications for successful
`treatment outcomes. In addition, they present new data
`with efinaconazole in terms of age and obesity.
`Aging is the most common risk factor for onychomycosis,
`
`DISCLOSURE: Drs. Elewski and Tosti were advisors to Valeant Pharmaceuticals. Dr. Elewski was a principal investigator in one of the pivotal Phase
`3 studies with efinaconazole topical solution, 10%.
`ADDRESS CORRESPONDENCE TO: Boni E. Elewski, MD, Department of Dermatology, University of Alabama at Birmingham School of Medicine,
`Birmingham, AL; E-mail: beelewski@aol.com
`
`38
`
`[ N o v e m b e r 2 0 1 5 • V o l u m e 8 • N u m b e r 1 1 ]
`
`38
`
`Page 1 of 5
`
`ACRUX DDS PTY LTD. et al.
`
`EXHIBIT 1518
`
`IPR Petition for
`
`U.S. Patent No. 7,214,506
`
`
`
`[ R E V I E W ]
`
`Risk Factors and Comorbidities
`for Onychomycosis
`Implications for Treatment with Topical Therapy
`
`aBONI E. ELEWSKI, MD; bANTONELLA TOSTI, MD
`aDepartment of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama;
`bDepartment of Dermatology & Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, Florida
`
`ABSTRACT
`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 challengse and possible solutions.
`(J Clin Aesthet Dermatol. 2015;8(11):38–42.)
`
`Onychomycosis is a common problem in dermatology
`
`practice that can result in significant morbidity.1,2
`Successful treatment has been difficult because of
`slow growth of the nail; patient comorbidities, such as
`diabetes, peripheral vascular disease, and psoriasis; and
`reluctance of prescribers and patients to prescribe or take
`oral medications because of “perceived” toxicity issues.
`The disease can have a major impact on the individual
`and other family members.3–5 Dystrophic nails can cause
`embarrassment, affecting a patient’s self-esteem, and may
`have a greater impact on quality of life (QoL) than the
`severity of the disease itself.6 Thickened nails can also be
`painful, causing discomfort in walking and affecting other
`aspects of daily living.3
`A number of underlying conditions, such as tinea pedis,
`nail damage, and nail psoriasis can contribute to risk as
`well as characteristics such as age and obesity. Underlying
`cancer,7,9
`comorbidities,
`such
`as
`diabetes,7,8
`immunodeficiency,10 or peripheral arterial disease,11 can
`
`increase susceptibility to onychomycosis.7 An inherited
`genetic predisposition to
`infection has also been
`identified.12
`Clinical trials provide guidance on likely treatment
`outcomes in these patients at risk. However, some
`comorbid conditions (i.e., peripheral vascular disease) can
`be exclusion criteria, many trials were not set up to
`specifically study certain comorbidities, and
`the
`demographics and disposition of patients who visit
`dermatology and podiatry practices can be very different
`from those enrolled in clinical trials.
`Recently, a number of post hoc analyses have been
`published on the use of efinaconazole topical solution,
`10%, in the treatment of mild-to-moderate onychomycosis.
`Where data exist, it is the authors’ intention to review the
`findings in terms of the implications for successful
`treatment outcomes. In addition, they present new data
`with efinaconazole in terms of age and obesity.
`Aging is the most common risk factor for onychomycosis,
`
`DISCLOSURE: Drs. Elewski and Tosti were advisors to Valeant Pharmaceuticals. Dr. Elewski was a principal investigator in one of the pivotal Phase
`3 studies with efinaconazole topical solution, 10%.
`ADDRESS CORRESPONDENCE TO: Boni E. Elewski, MD, Department of Dermatology, University of Alabama at Birmingham School of Medicine,
`Birmingham, AL; E-mail: beelewski@aol.com
`
`38
`
`[ N o v e m b e r 2 0 1 5 • V o l u m e 8 • N u m b e r 1 1 ]
`
`38
`
`Page 1 of 5
`
`
`
`most likely due to poor peripheral circulation, longer
`exposure to pathogenic fungi, repeated nail trauma,
`suboptimal immune function, and slower nail growth.13 In
`addition, various medical conditions more common in the
`elderly increase the risk of comorbid onychomycosis.
`Surveys suggest that overall the incidence is much higher in
`adults than in children, afflicting 0.6 percent of children
`under the age of 18 years, approximately 10 to 20 percent of
`adults and 15 to 40 percent of elderly people.14–16 However,
`prevalence rates do not necessarily correlate with
`consultations. Not all of the patients we see with
`onychomycosis are elderly. This could be attributed to the
`fact that onychomycosis may be considered a cosmetic
`problem by the younger patients who are more conscious of
`their appearance coming forward for therapy. The increased
`incidence in the younger population could also be due to
`their exposure to occupation-related trauma predisposing
`them to onychomycosis or the more common use of
`occlusive footwear.
`
`PATIENT CHARACTERISTICS
`Treatment of mild-to-moderate onychomycosis with
`efinaconazole topical solution, 10%, does not seem to be
`influenced by patient age. Although there was a trend of
`younger patients (<40 years of age) doing better, this was
`not significant (Figure 1). Complete cure rates ranged
`from 16.7 percent in those patients over 65 years of age, to
`23.4 percent
`in the younger patients. In elderly
`onychomycosis patients, it is likely that other factors, such
`as whether they can actually reach their toenails or have
`the manual dexterity to apply a topical product, will
`influence utilization of this treatment.
`Obesity, with a body mass index (BMI) of 30kg/m2 or
`greater has significantly
`increased among the US
`population over the past 30 years.17 Approximately 119
`million Americans, nearly two thirds of the adult
`population, are either overweight or obese.18 Despite being
`recognized as a major public health problem, little is known
`about
`its
`impact on onychomycosis prevalence or
`outcomes. Significant increases have been observed in the
`incidence of onychomycosis in obese inpatient clinic
`attendees examined dermatologically for the presence of
`disease compared to normal controls.19 In a study of more
`than 1,000 patients randomly invited to have an additional
`examination of their feet, obesity (with vascular disease
`and diabetes) was one of the three most prevalent
`predisposing factors among patients found to have fungal
`nail disease.20
`In the two pivotal studies, efinaconazole topical
`solution, 10%, appears to be less effective in patients who
`are overweight or obese, and differences between obese
`patients and those with “normal” BMIs were significant
`(P=0.05, Figure 2). Almost three out of four patients
`(73.5%) with onychomycosis in the studies were either
`overweight (39.1%) or obese (34.4%). Complete cure rates
`at Week 52 ranged from 15.9 percent in the obese patients
`to 22.0 percent in patients who had a normal BMI. Other
`post hoc analyses have shown that female patients do
`
`Figure 1. Influence of age on complete cure rates with
`efinaconazole at Week 52 (ITT subjects, pooled observed case data)
`
`Figure 2. Influence of obesity on complete cure rates with
`efinaconazole at Week 52 (ITT subjects, pooled observed case data)
`
`significantly better when treated with efinaconazole,
`compared to the males enrolled in the studies.21 Although
`the reasons are not clear, this observation may have some
`impact on complete cure rates in the cohort with a BMI of
`<25kg/m2; however, there was a greater proportion of
`males in the overweight group (84.6%) compared to those
`classified as obese (76.9%). Reasons why efinaconazole
`may be less effective in obese onychomycosis patients is
`less clear. Comorbid conditions could be a confounder;
`also, it is possible their disease could be more severe.
`Adherence may be impacted through some obese patients
`having difficulty reaching their feet to apply a topical
`treatment, or overall nail cleanliness may be compromised
`in obese patients who have difficulty showering. There was
`no significant difference in terms of age across the three
`groups, with the obese patients being the youngest (mean
`age 50.8 years). Given both the increasing prevalence of
`onychomycosis and the rise in obesity, this under-
`researched area warrants further investigation.
`
`UNDERLYING CONDITIONS
`The need to evaluate and treat onychomycosis and
`coexisting tinea pedis
`is critical
`if the
`long-term
`
`[ N o v e m b e r 2 0 1 5 • V o l u m e 8 • N u m b e r 1 1 ]
`
`3939
`
`Page 2 of 5
`
`
`
`(16.1%, P=0.025, Figure 3). This important area also
`warrants further study with a larger cohort of patients.
`
`UNDERLYING COMORBIDITIES
`in
`Diabetes
`is a very
`important comorbidity
`onychomycosis patients. Almost a third of patients with
`diabetes suffer with onychomycosis,25 and it is a significant
`limb-threatening infection if left untreated.26 Patients who
`are human immunodeficiency virus (HIV) positive are also
`predisposed to the development of infections including
`onychomycosis and tinea pedis. Onychomycosis has been
`found in 1 in 4 HIV-positive individuals.27 The impact of
`vascular abnormalities on the prevalence of onychomycosis
`is less clear. A recent study demonstrated a significant
`relationship between onychomycosis and venous
`insufficiency, but not peripheral artery disease.28 It has been
`suggested that peripheral artery disease might be an
`independent predictor of onychomycosis,29 and more
`recently in a small study that onychomycosis might act as
`an independent predictor of peripheral artery disease risk.11
`Despite the importance of diabetes as an underlying
`comorbidity, few studies have looked at the treatment of
`onychomycosis in a diabetic population.30 It has been
`suggested
`that people with diabetes who have
`onychomycosis may be more resistant to treatment due to
`hyperglycemia or poor foot hygiene.31 Although the number
`of patients with coexisting diabetes in the efinaconazole
`studies was relatively small, it was still the largest cohort of
`diabetic patients with onychomycosis reported to date and
`supported earlier studies that had suggested similar
`efficacy in both cohorts.32 Complete cure rates in the
`diabetic patients with onychomycosis were 13.0 percent
`compared with 18.8 percent in the nondiabetic population,
`although differences were not significant (Figure 4).32
`
`CONCLUDING REMARKS
`A number of underlying conditions, characteristics, and
`comorbidities can
`lead
`to an
`increased risk of
`onychomycosis, and yet clinical data in these patients are
`lacking.
`The authors’ review suggests that two patient
`characteristics can influence the efficacy of efinaconazole,
`namely gender21 and obesity. In females, more than 27
`percent of patients were complete cures at Week 52 with
`efinaconazole (P=0.001 versus the male population).21 The
`reasons are not clear; male patients may have generally
`more severe disease, thicker toenails, or are less adherent.
`It may be that male patients just require a longer treatment
`course. There may be differences between the US and
`Japanese male populations in the two pivotal studies, as
`shorter people tend to have shorter toenails that would
`take less time to grow out, although these subpopulations
`have not been studied. Our data are the first to report
`treatment differences in onychomycosis patients relating
`to their BMI levels. Complete cure rate in those patients
`with a normal BMI was 22 percent, but again reasons why
`efinaconazole may be
`less effective
`in obese
`onychomycosis patients are not clear.
`
`Figure 3. Influence of tinea pedis and its treatment on-study on
`complete cure rates with efinaconazole at Week 52 (ITT subjects,
`pooled observed case data)
`
`Figure 4. Influence of co-existing diabetes on complete cure
`rates with efinaconazole at Week 52 (ITT subjects, pooled
`observed case data)
`
`management of onychomycosis is to be successful and the
`risk
`of
`recurrence
`or
`re-infection minimized.
`Onychomycosis has been found to be significantly more
`likely to be diagnosed in the context of tinea pedis
`(P<0.001);22 a history of tinea pedis more than doubles the
`onychomycosis risk.9 Interdigital tinea pedis (the most
`common subtype noted) was reported to coexist in 22.1
`percent of onychomycosis patients in a large patient
`survey.2 Finding the two diseases in the same patient is
`more common in men and noted in more than 1 in 4 elderly
`patients.23
`A post hoc analysis of the efinaconazole studies of those
`patients where both diseases co-existed has recently been
`reported.24 Interdigital tinea pedis was reported in 21.3
`percent of patients on-study, a similar level to that
`recorded in previous surveys.2 In efinaconazole-treated
`onychomycosis patients where coexisting tinea pedis was
`also treated on-study (with the physician’s preferred
`treatment), complete cure rates (29.4%) were almost
`twice those when coexisting tinea pedis was not treated
`
`40
`
`[ N o v e m b e r 2 0 1 5 • V o l u m e 8 • N u m b e r 1 1 ]
`
`40
`
`Page 3 of 5
`
`
`
`in an
`The presence of coexisting tinea pedis
`onychomycosis population is an important consideration
`for an effective treatment strategy. The need to diagnose
`and treat coexisting tinea pedis is well-recognized, but the
`data reviewed here are the first to show the significance in
`terms of patient outcomes. In those onychomycosis
`patients who had coexisting tinea pedis treated on-study,
`the complete cure rate was 29.4 percent.
`Data in onychomycosis patients with underlying
`comorbidites are limited, in some cases because of
`exclusion criteria within clinical trial programs. To the
`authors’ knowledge no, studies have specifically looked at
`treatment outcomes
`in diabetic patients with
`onychomycosis, or those onychomycosis patients suffering
`from HIV or peripheral artery disease. Data reviewed here
`in
`the subpopulation of diabetic patients with
`onychomycosis treated with efinaconazole supports other
`small subpopulations suggesting that in this important
`group, complete cure rates are statistically comparable to a
`normal onychomycosis population.
`New topical agents for onychomycosis are now available
`(i.e., efinaconazole and tavaborole). Efinaconazole topical
`solution, 10%, has been shown to be effective in mild-to-
`moderate onychomycosis.33 Data on tavaborole remains
`unpublished, but it is hoped they will provide additional
`insights into treating this important disease.
`Large clinical trials can afford us the opportunity
`through post hoc analyses to provide important insights
`into the management of onychomycosis, but there are
`limitations, and trials that look specifically at the impact of
`risk factors and longer term treatment outcomes are
`needed. Onychomycosis remains a common, progressive
`and difficult disease to manage successfully, and one where
`early diagnosis and treatment is important irrespective of
`risk factors or comorbidities.
`Data the authors have been able to review from previous
`post hoc analyses, and new data presented here on age and
`obesity, support the view that efinaconazole topical
`solution, 10%, should provide a useful option in the
`treatment of mild-to-moderate onychomycosis, particularly
`in female patients.
`
`ACKNOWLEDGMENT
`The authors acknowledge Brian Bulley, MSc, of Inergy
`Limited
`for medical writing
`support. Valeant
`Pharmaceuticals North America LLC funded Inergy’s
`activities pertaining to this manuscript.
`
`REFERENCES
`1.
`Gupta AK, Jain HC, Lynde CW, et al. Prevalence and
`epidemiology of onychomycosis
`in patients visiting
`physicians’ offices: a multicenter canadian survey of 15,000
`patients. J Am Acad Dermatol. 2000;43:244–248.
`Szepietowski JC, Reich A, Garlowska E, et al. Factors
`influencing coexistence of toenail onychomycosis with tinea
`pedis and other dermatomycoses: a survey of 2761 patients.
`Arch Dermatol. 2006;142:1279–1284.
`Schein JR, Gause D, Stier DM, et al. Onychomycosis: baseline
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12.
`
`13.
`
`results of an observational study. J Am Pod Med Ass.
`1997;87:512–519.
`Scher RK. Onychomycosis: a significant medical disorder. J
`Am Acad Dermatol. 1996;35(3 Pt 2):S2–S5.
`Milobratovic D, Jankovic S, Vukicevic J, et al. Quality of life in
`patients with toenail onychomycosis. Mycoses. Epub 2013
`Mar 18.
`Belyayeva E, Gregoriou S, Chalikias J, et al. The impact of nail
`disorders on quality of life. Eur J Dermatol. 2013;23:336–
`371.
`Tosti A, Hay R, Arenas-Guzman R. Patients at risk of
`onychomycosis—risk
`factor
`identification and active
`prevention. J Eur Acad Dermatol Venereol. 2005;19(Suppl
`1):13–16.
`Sigurgeirsson B, Steingrímsson O. Risk factors associated
`with onychomycosis. J Eur Acad Dermatol Venereol.
`2004;18:48–51.
`Winston JA, Miller JA. Treatment of onychomycosis in
`diabetic patients. Clin Diabet. 2006;24:60–166.
`García-Romero TM, Lopez-Aguilar E, Arenas R.
`Onychomycosis in immunosuppressed children receiving
`chemotherapy. Pediatr Dermatol. 2013;30:316–322.
`Fukunaga A, Washio K, Ogura K, et al. Onychomycosis as a
`warning sign for peripheral arterial disease. Acta Derm
`Venereol. 2013;93:747–748.
`Zaias N, Tosti A, Rebell G, et al. Autosomal dominant pattern
`of distal subungualonychomycosis caused by Trichophyton
`rubrum. J Am Acad Dermatol. 1996;34:302–304.
`Elewski BE, Charif MA. Prevalence of onychomycosis in
`patients attending a dermatology clinic in Northeastern Ohio
`for other conditions. Arch Dermatol. 1997;133:1172–1173.
`14. Haneke E. Achilles foot-screening project: background,
`objectives and design. J Eur Acad Dermatol Venereol.
`1999;12(suppl 1):S2–S5.
`Levy LA. Epidemiology of onychomycosis in special-risk
`populations. J Am Podiatr Med Assoc. 1997;87:546–550.
`Tosti A, Piraccini BM, Mariani R, et al. Are local and systemic
`conditions important for the development of onychomycosis?
`Eur J Dermatol. 1998;8:41–44.
`Baskin ML, Ard J, Franklin F, et al. Prevalence of obesity in
`the United States. Obes Rev. 2005;6:5–7.
`F as in fat: how obesity policies are failing in America 2005.
`Trust for America’s Health. Available at: http://healthyamer
`icans.org/reports/obesity2005/. Accessed August 30, 2005.
`19. Doner N, Yasar S, Ekmekci TR. Evaluation of obesity-
`associated dermatoses in obese and overweight individuals.
`Turkderm. 2011;45:146–151.
`Chan MK, Chong LY. A prospective epidemiology survey of
`foot disease in Hong Kong. J Am Podiatr Med Assoc.
`2002;92:450–456.
`Rosen T. Evaluation of gender as a clinically relevant outcome
`variable
`in
`the
`treatment of onychomycosis with
`efinaconazole topical solution 10%. Cutis. 2015;96(3):
`197–201.
`22. Walling HW, Sniezek PJ. Distribution of toenail dystrophy
`predicts histologic diagnosis of onychomycosis. J Am Acad
`Dermatol. 2007;56:945–948.
`Pierard G. Onychomycosis and other superficial fungal
`
`15.
`
`16.
`
`17.
`
`18.
`
`20.
`
`21.
`
`23.
`
`[ N o v e m b e r 2 0 1 5 • V o l u m e 8 • N u m b e r 1 1 ]
`
`41
`
`Page 4 of 5
`
`
`
`25.
`
`infections of the foot in the elderly: a pan-European survey.
`Dermatology. 2001;202:220–224.
`24. Markinson B, Caldwell B. Efinaconazole topical solution, 10%:
`efficacy in onychomycosis patients with co-existing tinea
`pedis. J Am Podiatr Med Assoc. Epub 2015 April 13.
`Gupta A, Konnikov N, MacDonald P, et al. Prevalence and
`epidemiology of toenail onychomycosis in diabetic subjects: a
`multicenter study. Br J Dermatol. 1998;139:665–671.
`Papini M, Cicoletti M, Fabrizi V, et al. Skin and nail mycoses
`in patients with diabetic foot. G Ital Dermatol Venereol.
`2013;148:603–608.
`Gupta AK, Taborda P, Taborda V, et al. Epidemiology and
`prevalence of onychomycosis in HIV-positive individuals. Int
`J Dermatol. 2000;39:746–753.
`28. Ozkan F, Ozturk P, Ozjurt K, et al. Frequency of peripheral
`arterial disease and venous
`insufficiemcy
`in toenail
`onychomycosis. J Dermatol. 2013;40:107–110.
`
`26.
`
`27.
`
`29.
`
`Gupta AK, Gupta MA, Summerbell RC, et al. The
`epidemiology of onychomycosis: possible role of smoking and
`peripheral arterial disease. J Eur Acad Dermatol Venereol.
`2000;14:466–469.
`30. Matricciani L, Talbot K, Jones S. Safety and efficacy of tinea
`pedis and onychomycosis treatment in people with diabetes:
`a systematic review. J Foot Ankle Res. 2011;4:26.
`Tan J, Joseph W. Common fungal infections of the feet in
`patients with diabetes mellitus. Drugs Ageing. 2004;21:101–
`112.
`Vlahovic TC, Joseph WS. Efinaconazole topical, 10% for the
`treatment of toenail onychomycosis in patients with diabetes.
`J Drugs Dermatol. 2014;13:1186–1190.
`Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10%
`solution in the treatment of toenail onychomycosis: two
`phase 3 multicenter, randomized, double-blind studies. J Am
`Acad Dermatol. 2013;68:600–608.
`
`31.
`
`32.
`
`33.
`
`42
`
`[ N o v e m b e r 2 0 1 5 • V o l u m e 8 • N u m b e r 1 1 ]
`
`Page 5 of 5
`
`