The Safety of Oral Antifungal Treatments for Superficial Dermatophytosis and Onychomycosis: A Meta-analysis

The American Journal of Medicine (2007) 120, 791-798

CLINICAL RESEARCH STUDY

The Safety of Oral Antifungal Treatments for Superficial Dermatophytosis and Onychomycosis: A Meta-analysis Chia-Hsuin Chang, MD, MSc,a,b Yinong Young-Xu, ScD, MS, MA,c Tobias Kurth, MD, ScD,b,d John E. Orav, PhD,b Arnold K. Chan, MD, ScDb,e a

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; bDepartment of Epidemiology, Harvard School of Public Health, Boston, Mass; cEpiPatterns, Haverhill, NH; dDivisions of Preventive Medicine and Aging, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; ei3 Drug Safety, Waltham, Mass. ABSTRACT PURPOSE: We estimated the absolute risks of treatment termination and incidence of adverse liver outcomes among all commonly used oral antifungal treatments for superficial dermatophytosis and onychomycosis. METHODS: MEDLINE, EMBASE, and Cochrane Library were searched to identify randomized and nonrandomized controlled trials, case series, and cohort studies published before December 31, 2005. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. Treatment arms with the same regimen in terms of drug, type (continuous or intermittent), and dosage were combined to estimate the risk of an outcome of interest. RESULTS: We identified 122 studies with approximately 20,000 enrolled patients for planned comparison. The pooled risks (95% confidence intervals) of treatment discontinuation resulting from adverse reactions for continuous therapy were 3.44% (95% confidence interval [CI], 2.28%-4.61%) for terbinafine 250 mg/day; 1.96% (95% CI, 0.35%-3.57%) for itraconazole 100 mg/day; 4.21% (95% CI, 2.33%-6.09%) for itraconazole 200 mg/day; and 1.51% (95% CI, 0%-4.01%) for fluconazole 50 mg/day. For intermittent therapy, the pooled risks were as follows: pulse terbinafine: 2.09% (95% CI, 0%-4.42%); pulse itraconazole: 2.58% (95% CI, 1.15%-4.01%); intermittent fluconazole 150 mg/week: 1.98% (95% CI, 0.05%-3.92%); and intermittent fluconazole 300 to 450 mg/week: 5.76% (95% CI, 2.42%-9.10%). The risk of liver injury requiring termination of treatment ranged from 0.11% (continuous itraconazole 100 mg/day) to 1.22% (continuous fluconazole 50 mg/day). The risk of having asymptomatic elevation of serum transaminase but not requiring treatment discontinuation was less than 2.0% for all treatment regimens evaluated. CONCLUSION: Oral antifungal therapy against superficial dermatophytosis and onychomycosis, including intermittent and continuous terbinafine, itraconazole, and fluconazole, was associated with a low incidence of adverse events in an immunocompetent population. © 2007 Elsevier Inc. All rights reserved. KEYWORDS: Adverse reactions; Antifungal agents; Dermatophytosis; Fluconazole; Harms; Itraconazole; Metaanalysis; Onychomycosis; Terbinafine; Safety; Systematic review

Superficial dermatophytosis and onychomycosis are the 2 most common dermatologic diseases in the United States. It was estimated that up to 20% of the population had derThis study was supported in part by National Institutes of Health grant RO-1 DK62322 and the Harvard Pharmacoepidemiology Program. Requests for reprints should be addressed to Arnold K. Chan, MD, ScD, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Boston MA 02115. E-mail address: [email protected].

0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2007.03.021

matophytic infections and that the prevalence of onychomycosis was 8.7%.1,2 A recent 12-center North American study found a prevalence of confirmed onychomycosis of 13.8%.3 Meanwhile, analyses of office-based physician visits for fungal skin infections recorded in the 1990 to 1994 National Ambulatory Medical Care Survey revealed that during this period there were 4.1 million visits for cutaneous fungal diseases, of which 60% were visits to internists or family physicians.4

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Oral antifungal therapy with newer agents, such as terSelection Criteria for Studies binafine, itraconazole, and fluconazole, is the treatment of We included randomized and nonrandomized controlled choice for onychomycosis and dermatophytosis not retrials, case series, and cohort studies that enrolled patients sponding to topical therapy. Their safety profiles deserve having superficial dermatophytosis (tinea pedis, tinea mascrutiny because a highly favorable risk– benefit ratio is nus, tinea corpora, and tinea cruris) or onychomycosis, aged expected for treating patients with 18 years or more, and receiving common and non–life-threatening oral antifungal therapy for 2 or dermatologic conditions. Adverse more weeks. Only English articles CLINICAL SIGNIFICANCE reactions associated with the use published before December 31, of oral antifungal agents are usu2005, were included. Pharmacoki● Oral terbinafine, itraconazole, and flually mild, transient, and reversible netic studies, studies focusing on conazole were associated with a low inafter discontinuation of therapy. drug– drug interactions, and studcidence of adverse events in patients The most frequently reported adies that enrolled patients with huwith skin and nail fungal infection. verse effects are associated with man immunodeficiency virus ingastrointestinal system, followed ● Pulse therapy was associated with a fection/acquired immunodeficiency by skin complaints and headlower risk of discontinuation because of syndrome, cancer, hematologic aches.5 Although reported cases of malignancy; those who underwent adverse reactions than continuous symptomatic hepatic injury are bone marrow or organ transplantherapy. rare, there have been case reports tation; and those who received im● Fluconazole seemed to have a lower risk of serious liver injuries leading to munosuppressive therapy were of treatment discontinuation because of liver failure, transplantation, or excluded. We also excluded studdeath.6 Although individual readverse events. ies enrolling patients with tinea views examining the safety proversicolor (treatment duration ● The incidence of adverse events infiles of continuous oral antifungal mostly ⬃1 week) and tinea capitis creased as the dosage of antifungal therapy have been reported,7–10 (prevalent in children). We exagents increased. there has been no systematic evalcluded follow-up studies in which uation of safety profiles among patients who completed a full various regimens, including new course of oral antifungal treatment intermittent therapy, which was were evaluated for an additional period of time to assess assumed to have additional advantages of improved patient relapse rate. compliance, lower cost, and reduced risk of systematic Studies including oral continuous or intermittent therapy adverse reactions.11 We conducted a meta-analysis to comof terbinafine, itraconazole, or fluconazole, with or without bine safety information from all published studies of antitopical agents, as one of the treatment arms were included, fungal therapy for superficial dermatophytosis and onychoregardless of antifungal dosage, length of therapy, or conmycosis to obtain absolute risk estimates associated with tinuous or pulse/intermittent therapy. Treatment arms inthese treatment regimens. volving sequential oral antifungal therapy were included only if clear safety end points were reported for each treatment phase of the trials. METHODS We followed the recommendations of the Quality of Reporting of Meta-analyses conference in conducting this systematic review.12

Literature Search Strategy We searched MEDLINE, EMBASE, and Cochrane Library (which includes the Cochrane Database of Systematic Reviews; the Database of Abstracts of Reviews of Effects; and the Cochrane Register of Controlled Trials) for relevant articles. Medical Subjects Heading (MeSH) terms used for keyword and text word searching included antifungals, terbinafine, itraconazole, fluconazole, onychomycosis, and dermatophytosis. The references of 8 systematic review articles on treatment for dermatophytosis and onychomycosis were examined to identify additional studies that were not found in the computerized databases.13–20 Additional reports were identified from reference lists of the identified articles.

Safety Outcomes The primary outcome of interest in this meta-analysis was the cumulative incidence of patients who withdrew from the study because of adverse reactions. The secondary outcomes of interest were the cumulative incidence of patients stopping treatment because of elevation of serum transaminase levels and the cumulative incidence of patients developing elevation of serum transaminase levels during treatment but not requiring discontinuation. We did not define specific cutoff values for serum transaminase levels that warranted treatment termination because different criteria were used in different studies.

Data Extraction Two physician reviewers independently evaluated each identified study and abstracted relevant characteristics, including the quality of the studies. Disagreement on specific

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Safety of Oral Antifungals

studies between the 2 reviewers was resolved through discussion. Abstracted information included study characteristics (author, year the study was published, study design, treatment regimen, dose, and duration), patient characteristics (dermatophytosis or onychomycosis, percentage of males, and mean age), sample size, efficacy outcomes, proportions of patients who withdrew because of adverse events, and more specifically because of elevation of serum transaminase levels, as well as the proportion of patients developing elevation of serum transaminase levels but not requiring treatment discontinuation. For each treatment arm the number of patients who received at least 1 dose of oral antifungal agents was used as the denominator of the cumulative incidence. Studies that did not report this safety outcome information were excluded from analysis. We reported the summary results for regimens with data from 3 or more studies.

Statistical Analysis We anticipated large variations in trial design in terms of dosage, treatment duration, continuous or pulse/intermittent regimen, with or without concomitant topical therapy. Instead of conducting a meta-analysis using relative effect measures, such as risk difference, relative risk, or odds ratio that required the same contrast of comparison in all studies, we used absolute risk as our outcome of interest because it was not restricted by the comparative arms and its interpretation has direct clinical meaning. We used the beta-binomial model to capture the variation across studies and the maximum likelihood method to estimate the mean pooled event risks.21 From all the eligible studies, we combined all treatment arms with the same regimen in terms of type (continuous, intermittent) and dosage and obtained the summary estimates of cumulative incidence and their 95% confidence intervals (CIs). In the situation in which few adverse events occurred and the beta-binomial distribution collapsed to a simple binomial distribution, we calculated the Wald CIs.22 We used the adjusted Wald method to calculate the point estimates and 95% CIs for those risk estimates corresponding to no event.23 For rare outcomes, lower bounds of the CIs were set to be no smaller than zero. The main analytic results were obtained from combining data from randomized controlled trials only. In the auxiliary analysis, we added data from nonrandomized controlled trials, case series, and cohort studies. We also stratified the analysis by disease indication (dermatophytosis or onychomycosis).

RESULTS We identified 299 studies that reported oral antifungal treatment for dermatophytosis or onychomycosis from computerized literature databases and reference lists of systematic reviews and identified articles (Figure 1); 214 of them were reported in English and were retrievable for review. Two physicians independently reviewed all reports. A total of 77 studies were excluded for 1 of the following reasons: age less than 18 years for study subjects; therapies were given for

793 nonsuperficial dermatophytosis or onychomycosis (tinea imbricata, Pityrosporum folliculitis, cutaneous candidiasis, and systematic mycosis); studies of ketoconazole or griseofulvin only; immunocompromised patients or patients with cancer; pharmacokinetic or mycologic studies; same study cohorts or reports for trial follow-up; and treatment duration of less than 2 weeks. Among the remaining studies, relevant safety information was reported in 122 studies, and they were included in the meta-analysis (Appendix). These 122 studies, published from 1987 to 2005 with the number of study subjects ranging from 5 to 1608, included a total of 19,298 patients. Seventyseven of the studies were randomized controlled trials. Most of these trials were head-to-head comparisons of a variety of treatment regimens, and 15 studies included a placebo arm. The characteristics of the randomized controlled trial arms that we evaluated are summarized in Table 1. Most commonly used continuous regimens in the published randomized controlled trials were terbinafine 250 mg/day (41 arms, 3135 patients); itraconazole 100 mg/day (19 arms, 1002 patients) and 200 mg/day (12 arms, 2145 patients); and fluconazole 50 mg/day (3 arms, 235 patients). Terbinafine 500 mg/day (5 arms, 359 patients) or itraconazole 400 mg/day (15 arms, 766 patients) for 1 week and then repeated every month, and intermittent fluconazole 150 mg (7 arms, 514 patients) or 300 to 450 mg (3 arms, 468 patients) once weekly were the most commonly reported intermittent therapy regimens. The mean age of patients enrolled in the trials ranged from 27 to 72 years, and the proportion of male patients ranged from 14% to 100%. There was substantial variability in the reported risk of safety outcomes among study arms receiving the same antifungal regimens. The summarized treatment termination and safety information for all commonly reported regimens of continuous and intermittent oral antifungal therapy are presented in Tables 2 and 3. For continuous oral antifungal therapy, the pooled risks (95% CIs) of treatment discontinuation because of adverse reactions were 3.44% (95% CI, 2.28%-4.61%) for terbinafine 250 mg/day; 1.96% (95% CI, 0.35%-3.57%) for itraconazole 100 mg/day; 4.21% (95% CI, 2.33%6.09%) for itraconazole 200 mg/day; and 1.51% (95% CI, 0%-4.01%) for fluconazole 50 mg/day. For intermittent or pulse therapy, the pooled risks were as follows: pulse terbinafine: 2.09% (95% CI, 0%-4.42%); pulse itraconazole: 2.58% (95% CI, 1.15%-4.01%); intermittent fluconazole 150 mg/week: 1.98% (95% CI, 0.05%-3.92%); and intermittent fluconazole 300 to 450 mg/week: 5.76% (95% CI, 2.42%-9.10%). The incidence of liver injury associated with oral antifungal therapy was less than 2% in general. For the risks of having elevated serum transaminase levels that required treatment termination, the pooled risk estimates for continuous therapy ranged from 0.11% (itraconazole 100 mg/day) to 1.22% (fluconazole 50 mg/day). The pooled risk estimates for pulse therapy ranged from 0.39% (fluconazole 150 mg/week and itraconazole 400 mg/day) to 0.85% (fluconazole 300-450 mg/ week). The pooled risks of developing elevated serum

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Figure 1

Literature search and selection of published reports.

transaminase levels not requiring treatment discontinuation was on the order of 1.5% for continuous regimens and 1% for intermittent regimens evaluated. The pooled probabilities of the 3 safety end points for the placebo arms in double-blind randomized controlled trials (15 arms, 891 patients) were 3.25% (95% CI, 1.48%5.02%), 1.01% (95% CI, 0%-2.19%), and 1.15% (95% CI, 0%-3.46%), respectively. These estimates might be interpreted as inflated estimates for the “background rates” of these events among patients with superficial dermatophytosis or onychomycosis because of the intensive laboratory monitoring in randomized controlled trials. None of the above treatment regimens had an incidence of adverse events substantially higher than these background rates. We stratified the risk estimates according to indication for oral antifungal therapy. Continuous terbinafine 250 mg/ day and intermittent fluconazole 150 mg/week were used in treating both dermatophytosis and onychomycosis. The pooled estimates of discontinuing continuous terbinafine because of adverse reactions were 2.72% (95% CI, 1.02%-

4.42%) for 2 to 6 weeks against dermatophytosis (11 arms, 623 patients) and 3.74% (95% CI, 2.28%-5.21%) for 8 to 48 weeks against onychomycosis (30 arms, 2512 patients). The probabilities of developing elevations of serum transaminase levels that required treatment stopping were 0.31% (95% CI, 0%-0.74%) for 2 to 6 weeks and 0.44% (95% CI, 0.13%-0.76%) for 8 to 48 weeks. For intermittent fluconazole 150 mg/week, the pooled risks of treatment termination attributable to all safety concern and to adverse liver outcomes were 0.31% (95% CI, 0%-0.93%) and 0.59% (95% CI, 0%-1.43%) for 2 to 6 weeks (3 arms, 320 patients), and 4.12% (95% CI, 1.33%-6.92%) and 1.03% (95% CI, 0%-2.45%) for 8 weeks or longer (4 arms, 194 patients). We identified 10 nonrandomized controlled clinical trials and 35 case series or cohort study reports with sufficient safety information reported. In the auxiliary analysis that added data from these studies, the safety profiles of different oral antifungal regimens generally followed the same order as results from the main analysis of randomized controlled trials (Tables 2 and 3).

Chang et al

Characteristics of the Included Randomized Controlled Trial Arms with Commonly Used Oral Antifungal Regimens Range of Patient Demographics

Drug Continuous T T I I I F Intermittent T I F F F Placebo

Range of Reported Safety Outcomes

Treatment Termination Because of Adverse Reaction (%)

Treatment Termination Because of Elevated Serum Transaminase (%)

Transaminase Elevation Did Not Require Treatment Termination (%)

0

0%–2.56% 0%–5.26%

0%–10% 0%–2.15% 0%–4.44% 0%–5.56% 0%–5.91% 0%–4.30%

Dosage

Indication

No. of RCT Arms

No.

Mean Age (y)

Proportion of Males

250 mg/d 250 mg/d 100 mg/d 100 mg/d 200 mg/d 50 mg/d

D O D O O D

11 30 15 4 12 3

18–184 5–186 10–303 10–45 27–1212 19–123

29–47 36–68 27–46 38–48 39–49 39–43

0.58–1.00 0.46–0.97 0.43–0.88 0.26–0.57 0.30–0.74 0.70–0.72

0%–10.00% 0%–12.05% 0%–6.06% 0%–13.89% 0%–7.69% 0%–5.26%

500 mg/d ⫻ 1⁄4wk* 400 mg/d ⫻ 1⁄4wk* 150 mg/wk† 150 mg/wk† 300–450 mg/wk†

O

5

5–153

39–64

0.48–0.96

0%–5.23%

0%–1.05%

0

O

15

12–126

36–71

0.12–0.96

0%–6.35%

0%–3.70%

0%–6.12%

D O O D, O

3 4 3 15

79–122 16–89 88–288 22–104

42 43–49 48 40–72

0.64–0.82 0.32–0.73 0.73 0.58–1.00

0%–0.82% 0%–4.55% 3.47%–10.23% 0%–12.50%

0%–1.47% 0%–1.45% 0%

0 0%–2.27% 0.35%–2.27% 0%–12.50%

Safety of Oral Antifungals

Table 1

0%–0.82% 0%–4.55% NA 0%–13.64%

T ⫽ terbinafine; I: itraconazole; F ⫽ fluconazole; D ⫽ dermatophytosis; O ⫽ onychomycosis; RCT ⫽ randomized controlled trial; NA ⫽ not available. *Administered for 1 week and then repeated every 4 weeks. †Once weekly.

795

796 Table 2

The American Journal of Medicine, Vol 120, No 9, September 2007 Pooled Risk Estimates of Safety Outcomes for Various Regimens of Continuous Oral Antifungal Therapy

Drug

Regimen

Terbinafine

250 mg/d

Itraconazole

100 mg/d

Itraconazole

200 mg/d

Fluconazole

50 mg/d

Treatment Termination Because of Adverse Effects (%)

Transaminase Elevation Required Treatment Termination (%)

Transaminase Elevation Did Not Require Treatment Termination (%)

Study Design

No. of Arms/ Patients Included

Pooled Estimate

95% CI

Pooled Estimate

95% CI

Pooled Estimate

95% CI

RCT All RCT All RCT All RCT All

41/3135 57/3563 19/1002 29/1307 12/2145 14/2183 3/235 5/879

3.44 3.45 1.96 1.91 4.21 3.94 1.51 2.30

2.28–4.61 2.39–4.51 0.35–3.57 0.59–3.23 2.33–6.09 2.17–5.70 0.00–4.01 0.93–3.66

0.34 0.35 0.11 0.08 0.70 0.68 1.22 0.59

0.09–0.60 0.09–0.62 0.00–0.32 0.00–0.25 0.33–1.06 0.33–1.04 0.00–5.30 0.00–1.79

0.70 0.70 1.24 1.21 1.90 1.98 1.63 2.16

0.08–1.32 0.09–1.30 0.00–2.64 0.15–2.28 0.13–3.68 0.36–3.61 0.00–5.02 0.02–4.30

RCT ⫽ randomized controlled trial; CI ⫽ confidence interval; All ⫽ including randomized and nonrandomized controlled trials, case series, and cohort studies; NA ⫽ not available because not reported in the published literature. ⴱAdjusted Wald method for point estimate and CI.

DISCUSSION Several observational studies examined the safety profiles of different oral antifungal agents for treating dermatophytosis or onychomycosis.7,8,10,24 They concluded that the incidence of serious adverse reaction associated with the use of new oral antifungal agents was in a low range. We conducted this meta-analysis to estimate the average cumulative incidences of 3 important safety end points among commonly used oral antifungal regimens from published reports. With regard to both continuous and intermittent therapy, the risk of treatment discontinuation because of adverse reaction ranged from 1.5% (fluconazole 50 mg/day) to 4.2% (itraconazole 200 mg/day). The risk of liver injury

Table 3

requiring or not requiring treatment discontinuation was less than 2.0% for all evaluated treatment regimens. None of the above treatment regimens had risks of adverse events substantially higher than the background risks estimated from the placebo arms in double-blind randomized controlled trials. These findings, in accordance with the results from prior studies, suggested that oral antifungal therapy was well tolerated and safe in a general immunocompetent population. In this systematic review with a comprehensive literature search, we identified approximately 50 studies with a total of 5586 patients, including at least 1 treatment arm of intermittent antifungal therapy. Because of the multiplicity

Pooled Risk Estimates of Safety Outcomes for Various Regimens of Intermittent Oral Antifungal Therapy

Drug

Regimen

Terbinafine

500 mg/d ⫻ 1⁄4wk

Itraconazole

400 mg/d ⫻ 1⁄4wk

Fluconazole

150 mg/wk

Fluconazole

300–450 mg/wk

Study Design

No. of Arms/ Patients Included

Treatment Termination Because of Adverse Effects (%)

Transaminase Elevation Required Treatment Termination (%)

Transaminase Elevation Did Not Require Treatment Termination (%)

Pooled Estimate

95% CI

Pooled Estimate

95% CI

Pooled Estimate

95% CI

RCT

5/359

2.09

0.00–4.42

0.56

0.00–1.33

0.92*

0.00–2.20*

All RCT

6/514 15/766

2.97 2.58

0.69–5.24 1.15–4.01

0.58 0.39

0.00–1.24 0.00–0.93

1.08 1.04

0.00–3.43 0.00–2.27

All RCT All RCT All

25/2856 7/514 13/899 3/468 5/507

2.22 1.98 1.57 5.76 4.99

1.04–3.40 0.05–3.92 0.40–2.73 2.42–9.10 2.21–7.77

0.24 0.39 0.33 0.85 0.79

0.00–0.67 0.00–0.93 0.00–0.71 0.02–1.69 0.02–1.56

0.75 0.81 0.58 NA 0.38

0.07–1.44 0.00–2.05 0.00–1.47 NA 0.00–0.91

RCT ⫽ randomized controlled trial; CI ⫽ confidence interval; All ⫽ including randomized and nonrandomized controlled trials, case series, and cohort studies; NA ⫽ not available because not reported in the published literature. *Adjusted Wald method for point estimate and CI.

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Safety of Oral Antifungals

of the treatment regimens in terms of drug, dosage, and type of therapy, we could not perform 1-to-1 direct comparisons between each of these individual regimens. We found that continuous therapy, particularly itraconazole 200 mg/day, seemed to be associated with a higher risk of discontinuation because of adverse reactions and liver injury. Compared with continuous itraconazole 200 mg/day, pulse itraconazole seemed to be associated with a lower risk of discontinuation and liver toxicity. Furthermore, continuous terbinafine 250 mg/day had a better hepatic safety profile compared with high-dose continuous itraconazole. However, we did not find a reduction of the risk of transaminase elevation for pulse terbinafine therapy. From 10 randomized controlled trials that included fluconazole as one of the treatment arms, we found that fluconazole, in continuous or intermittent use, might have a lower risk of treatment discontinuation because of adverse events compared with other antifungal agents. As for the dose effects, we found that the incidence of adverse events increased markedly as the dosage of continuous itraconazole increased from 100 mg/day to 200 mg/ day and the dosage of intermittent fluconazole increased from 150 mg/day to 300 to 450 mg/day. This finding was consistent with clinical observations that risk became higher during high-dose antifungal treatment. Furthermore, as we stratified our analysis on the indication and compared shorter duration of use of oral antifungal agents for dermatophytosis with longer duration of use for onychomycosis, we did not find strong evidence that longer duration of use was associated with an increased risk of adverse liver outcomes. This was supported by the fact that adverse reactions to oral antifungal agents were idiosyncratic in nature, which tended to occur within the first few weeks of treatment, and their occurrence is nonlinear with time.25 Our main analytic results came from data synthesis of randomized controlled trials, which were supposed to have high quality for reporting safety outcomes. However, randomized controlled trials were different from routine clinical practice because of their highly selected patient population and intensive laboratory monitoring. To obtain estimates that may reflect real-life practice, we attempt to capture more of the heterogeneity of clinical practice through the auxiliary analysis that included case series and cohort studies. Nevertheless, we did not find a substantial change in the results, although most of the pooled estimates decreased and the CIs became narrower, probably because of a less rigorous laboratory monitoring plan adopted in these studies. Liver function of enrolled patients was monitored every 2 weeks for oral antifungal use of 2 to 6 weeks and at monthly intervals for use of 8 weeks or longer in the clinical trials. Because of limited information about the time of occurrence of adverse events in the published reports,26 no conclusive recommendation about the optimal liver function test monitoring schedule could be derived for patients receiving oral antifungal agents. In several articles, abnormal

797 transaminase levels were mostly detected during the interval of week 2 to week 6 after initiation of therapy. In addition, several limitations of our study should be considered. First, we might not have included all published articles because we only searched the MEDLINE, EMBASE, and Cochrane Library databases, and the reference lists of the identified articles and systematic reviews, and limited study enrollment to the English literature. However, we consider it unlikely that the association between treatment with antifungal regimens and adverse outcome differs in non-included studies. Second, monitoring of patients and the quality in reporting the safety outcomes varied among studies with different study designs. Although different trials might use different cutoff points of liver enzyme levels for treatment discontinuation, such discrepancy reflects clinical practice. Third, instead of conducting a formal test of heterogeneity, we explored the variation of the reported outcomes by a priori analysis plan stratifying on treatment regimen, dosage, and indication. However, there was not enough remaining variation in age and gender distribution after stratifying on regimen and indication; thus, we could not further explore whether these 2 factors contribute to the heterogeneity of the reported safety outcomes.

CONCLUSION In this meta-analysis of 122 studies with approximately 20,000 enrolled patients, we found that oral antifungal therapy against superficial dermatophytosis and onychomycosis, including intermittent and continuous terbinafine, itraconazole, and fluconazole, was associated with a low risk of adverse events in an immunocompetent population.

ACKNOWLEDGMENT The authors thank Dr Chia-Yi Lu for review of the antifungal studies.

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APPENDIX Studies Included in Meta-analysis 1. Albanese G, Di Cintio R, Martini C, Nicoletti A. Short therapy for tinea unguium with terbinafine: four different courses of treatment. Mycoses. 1995:38:211-214. 2. Albreski DA, Gross EG. The safety of itraconazole in the diabetic population. J Am Podiatr Med Assoc. 1999:89:339-345. 3. Alpsoy E, Yilmaz E, Basaran E. Intermittent therapy with terbinafine for dermatophyte toe-onychomycosis: a new approach. J Dermatol. 1996:23:259-262. 4. Aman S, Akbar TM, Hussain I, et al. Itraconazole pulse therapy in the treatment of disto-lateral subungual onychomycosis. J Coll Physicians Surg Pak. 2003;13:618-620. 5. Arca, E, Tastan HB, Akar A, et al. An open, randomized, comparative study of oral fluconazole, itraconazole and terbinafine therapy in onychomycosis. J Dermatolog Treat. 2002:13:3-9. 6. Arenas R, Dominguez-Cherit J, Fernandez LM. Open randomized comparison of itraconazole versus terbinafine in onychomycosis. Int J Dermatol. 1995:34:138-143. 7. Arenas R, Fernandez G, Dominguez L. Onychomycosis treated with itraconazole or griseofulvin alone with and without a topical antimycotic or keratolytic agent. Int J Dermatol. 1991;30:586-589. 8. Assaf RR, Elewski BE. Intermittent fluconazole dosing in patients with onychomycosis: results of a pilot study. J Am Acad Dermatol. 1996;35(2 Pt 1):216-219. 9. Avner S, Nir N, Henri T. Combination of oral terbinafine and topical ciclopirox compared to oral terbinafine for the treatment of onychomycosis. J Dermatolog Treat. 2005;16:327-330. 10. Bahadir S, Inaloz HS, Alpay K, et al. Continuous terbinafine or pulse itraconazole: a comparative study on onychomycosis. J Eur Acad Dermatol Venereol. 2000;14:422-423. 11. Baldari U, Righini MG, Raccagni AA, et al. Comparative double blind, double dummy study on the efficacy and safety of fluconazole 100 mg/day versus terbinafine 250 mg/day in the treatment of dermatomycoses. G Ital Dermatol Venereol. 2000;135:229-235. 12. Baran R, Belaich S, Beylot C, et al. Comparative multicentre doubleblind study of terbinafine (250 mg per day) versus griseofulvin (1 g per day) in the treatment of dermatophyte onychomycosis. J Dermatolog Treat. 1997;8:93-97. 13. Baran R, Feuilhade M, Combernale P, et al. A randomized trial of amorolfine 5% solution nail lacquer combined with oral terbinafine compared with terbinafine alone in the treatment of dermatophytic toenail onychomycoses affecting the matrix region. Br J Dermatol. 2000;142:1177-1183. 14. Baudraz-Rosselet F, Rakosi T, Wili PB, Kenzelmann R. Treatment of onychomycosis with terbinafine. Br J Dermatol. 1992;126(Suppl 39):40-46. 15. Bonifaz A, Carrasco-Gerard E, Saul A. Itraconazole in onychomycosis: intermittent dose schedule. Int J Dermatol. 1997;36:70-72. 16. Boonk W, de Geer D, de Kreek E, et al. Itraconazole in the treatment of tinea corporis and tinea cruris: comparison of two treatment schedules. Mycoses. 1998;41:509-514. 17. Bourlond A, Lachapelle JM, Aussems J, et al. Double-blind comparison of itraconazole with griseofulvin in the treatment of tinea corporis and tinea cruris. Int J Dermatol. 1989;28:410-412. 18. Brautigam M, Nolting S, Schopf RE, Weidinger G. Randomised double blind comparison of terbinafine and itraconazole for treatment of toenail tinea infection. Seventh Lamisil German Onychomycosis Study Group. BMJ. 1995;311:919-922. 19. Chen J, Liao W, Wen H, et al. A comparison among four regimens of itraconazole treatment in onychomycosis. Mycoses. 1999;42: 93-96. 20. Chen X, Hiruma M, Shiraki Y, Ogawa H. Combination therapy of once-weekly fluconazole (100, 150, or 300 mg) with topical appli-

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