Am J Clin Dermatol (2014) 15:17–36
DOI 10.1007/s40257-013-0056-2
EVIDENCE-BASED REVIEW
Oral Therapy for Onychomycosis: An Evidence-Based Review
Daniel Coelho de Sá • Ana Paula Botto Lamas •
Antonella Tosti
Published online: 19 December 2013
 Springer International Publishing Switzerland 2013
Abstract
Introduction Onychomycosis is a very common fungal
infection of the nail apparatus; however, it is very hard to
treat, even when the causative agent is identified, and
usually requires prolonged systemic antifungal therapy.
Until the 1990s, oral treatment options included only
griseofulvin and ketoconazole, and the cure rate was very
low. New generations of antimycotics, such as fluconazole,
itraconazole and terbinafine have improved treatment
success.
Methods Literature was identified by performing a Pub-
Med Ovid MEDLINE, Ovid EMBASE, EBSCO CINAHL,
and Literatura Latino-Americana e do Caribe em Ciências
da Saúde (LILACS) search. Prospective and randomized
clinical trials were chosen to be included in this review.
Forty-six trials were included.
Results Fluconazole, itraconazole and terbinafine are
effective in the treatment of onychomycosis and have a
good safety profile. When a dermatophyte is the pathogen,
terbinafine produces the best results. For Candida and
Electronic supplementary material The online version of this
article (doi:10.1007/s40257-013-0056-2) contains supplementary
material, which is available to authorized users.
D. C. de Sá
Department of Dermatology, Faculdade de Medicina da
Universidade de São Paulo, São Paulo, SP, Brazil
e-mail: sa-coelho@ig.com.br
A. P. B. Lamas
Aracaju, SE, Brazil
A. Tosti (&)
Department of Dermatology and Cutaneous Surgery, Miller
School of Medicine, University of Miami, Miami, FL, USA
e-mail: atosti@med.miami.edu
nondermatophyte infections, the azoles, mainly itraconaz-
ole, are the recommended therapy.
Conclusion In the majority of the studies, terbinafine
treatment showed a higher cure ratio than the other drugs
for dermatophyte onychomycosis.
1 Introduction
Onychomycosis is a very common fungal infection of the
nail apparatus, with a prevalence ranging from 2 to 40 % in
different studies [1–5]. Many factors can affect this prev-
alence and justify this wide variability, such as age, gender,
diabetes, peripheral arterial disease, occlusive footwear,
trauma, HIV infection, and hyperhidrosis [5–9]. The
elderly have a higher prevalence, whereas in children it is
rarely found [5, 6, 10]. This may be due to the lack of
predisposing factors and the faster nail growth in children
[11].
Onychomycosis is several times more common in toe-
nails due to their slower growth rate compared with fin-
gernails [11]. Many times, onychomycosis is seen as an
aesthetical problem, but in advanced stages, it can cause
discomfort, pain, and physical and occupational limita-
tions, and it may interfere with quality of life [12, 13].
Besides the cosmetic problem, onychomycosis should be
treated to avoid the risk of contamination of other nails in
the same patient or contamination of other healthy people,
since infected patients can act as a reservoir for family
contacts and can contaminate communal bathing places.
Erysipelas, cellulitis and ingrown nail are some compli-
cations of untreated onychomycosis [14–17].
Different types of fungi can cause this disease, which
varies from one geographic area to another primarily
because of different climatic conditions. The most frequent
18
are the dermatophytes (approximately 90 % in toenails),
with Trichophyton rubrum being the most prevalent
(60 %). Nondermatophytic molds (Scytalidium, Scopular-
iopsis, Aspergillus) are less common agents [18–20].
Onychomycosis may be subdivided into five major clinical
forms: distal and lateral subungual onychomycosis
(DLSO), proximal subungual onychomycosis (PSO),
superficial white onychomycosis (SWO), endonyx, and
total dystrophic onychomycosis (TDO) [21].
Onychomycosis is a difficult infection to treat as a cure
is not always achieved and relapses are very common [22,
23]. Until the 1990s, oral treatment options included only
griseofulvin and ketoconazole, and the cure rate was very
low. New generations of antimycotics, such as fluconazole,
itraconazole and terbinafine have improved treatment
success.
2 Methods
Criteria for considering studies for this review:
– Types of studies:
• Randomized controlled trials (RCTs).
• Case reports and review articles were excluded.
– Types of participants:
• People of either sex, any age and undergoing oral
treatment for onychomycosis, with drugs like
terbinafine, itraconazole, fluconazole, posaconaz-
ole, ketoconazole and griseofulvin.
– Types of interventions:
• Oral administration of a drug compared with
another drug, no intervention or placebo.
• All dosages, durations and routes of administration
used in each study were considered. For the
purposes of this review, all RCTs about oral
treatment of onychomycosis were considered.
– Types of outcome measures:
Primary outcomes:
• Clinical cure
• Mycological cure
Search methods for identification of studies:
– Electronic search:
• A literature search was conducted through January
2013 using PubMed Ovid MEDLINE, Ovid EM-
BASE, EBSCO CINAHL, and Literatura Latino-
Americana e do Caribe em Ciências da Saúde
(LILACS) to identify clinical trials that evaluated
D. C. de Sá et al.
oral therapies for onychomycosis. Research was
performed with no date limits. (See Online
Resource 1 for more search details.)
– Key search terms:
• Onychomycosis 9 oral treatment;
• Onychomycosis 9 fluconazole 9 oral treatment;
• Itraconazole 9 onychomycosis 9 oral treatment;
• Terbinafine 9 onychomycosis 9 oral treatment;
• Posaconazole 9 onychomycosis 9 oral treatment;
• Ketoconazole 9 onychomycosis 9 oral treatment;
• Griseofulvin 9 onychomycosis 9 oral treatment.
All the abstracts were read, and case reports and review
articles were excluded. Potentially eligible papers were
read in full and all relevant papers were kept and included
in this review.
3 Results and Discussion
From a total of 824 studies, 46 articles were selected by the
inclusion criteria for this evidence-based review (Fig 1).
The variation in the designs of the studies precludes the use
of statistical analysis between them. Although only studies
that evaluated clinical or mycological cure were included
in this review, there were considerable variations between
them regarding the definition of clinical cure and the length
of follow-up after completion of treatment to assess out-
comes, which may explain the differences found in results
between the studies (Table 1).
3.1 Terbinafine
Terbinafine is an antifungal agent of the allylamine group
with activity against fungi, dermatophytes and some yeast
[24, 25]. It inhibits the activity of the squalene epoxidase,
leading to a deficient synthesis of ergosterol, one of the
components of the fungal cell membrane [26]. It has been
approved for the treatment of onychomycosis, and it is now
one of the most used drugs in Europe and the USA.
Terbinafine can be used in a dosage of 250 mg/day as
shown by Baudraz-Rosselet et al. [27] in 1992. Terbinafine
was used for up to 6 months, with a cure rate of 77 % for
toenails and 100 % for fingernails. These patients were
again evaluated after 6 months post-treatment and 90.9 and
85.7 %, respectively, remained free of recurrence [27].
Finlay [28] showed that the drug rapidly reaches the nail
plate and remains for weeks after the treatment has stop-
ped. In this study, 12 patients received 250 mg/day for
48 weeks. After 3–18 weeks, nail clippings already
detected the drug in the same concentrations in affected
and unaffected nails. However, in some infected nails, the
Oral Therapy for Onychomycosis
Fig. 1 Article selection flow
diagram
changed anatomy can result in areas the drug does not
reach, resulting in persistence or recurrence of the infec-
tion. The author suggests that other trials comparing a
shorter use of terbinafine should be conducted [28].
Goodfield [29] performed a trial with 85 patients with
mycologically proven dermatophyte infectious using ter-
binafine 250 mg/day for 3 months. The toenail cure rate
was 82 %, while in the fingernail it was 71 %. This study
showed that a 3-month treatment with 250 mg daily is a
safe, effective and well tolerated regimen to treat derma-
tophyte onychomycosis [29].
Watson et al. [30] evaluated the efficacy and safety of
terbinafine used in a new regimen. Patients were divided
into two groups, and both used the drugs for 12 weeks. One
of them received 250 mg/day of oral terbinafine and the
19
other group placebo. At week 28, patients who did not
respond to the treatment at week 24 were offered 12 weeks
of terbinafine therapy. The patients who responded were
just observed. At week 48, effectiveness evaluation was
performed. From 111 patients, 88 % treated with terbina-
fine and 29 % of the placebo group had negative myco-
logical culture at week 24; 57 % of the terbinafine group
and 6 % of the placebo group were responders. By week
48, the mycological cure rate in the terbinafine group was
94 %, while in the placebo plus terbinafine group it was
38 % [30].
Alpsoy et al. [31] evaluated pulsed treatment (group 2—
500 mg/day, 7 days a month) compared with daily treat-
ment (group 1—250 mg/day), both for 3 months, and
found similar results in both groups. All patients were

Table 1 Studies evaluating oral therapy for the treatment of onychomycosis
TERBINAFINE
Baudraz-Rosselet
et al. [27]
Finlay [28]
Goodfield [29]
Watson et al. [30]
Alpsoy et al. [31]
Drake et al. [32]
Billstein et al. [33]
Farkas et al. [34]
Warshaw et al. [35]
Therapeutic regimen
Terbinafine 250 mg/day for 6 months for toenail
and fingernail onychomycosis
Terbinafine 250 mg/day for up to 48 weeks
Terbinafine 250 mg/day for 3 months for toenail
and fingernail onychomycosis
Twelve weeks of terbinafine (250 mg daily)
followed by 12 weeks of observation for
toenail onychomycosis. Responders—no
further treatment; nonresponders—offered 12
weeks of terbinafine (250 mg daily) from week
28
Terbinafine in dermatophyte toe onychomycosis:
Group 1—250 mg/day for 3 months. Group
2— 500 mg/day for 7 days/month for 3 months
Terbinafine 250 mg/day for 12 or 24 weeks for
patients with toenail onychomycosis
Twelve, 16 or 24 weeks of oral terbinafine 250
mg/day
Twelve weeks of terbinafine 250 mg daily for
diabetic patients with toenail onychomycosis
Terbinafine, 250 mg daily for 3 months
(continuous) or terbinafine, 500 mg daily for 1
week per month for 3 months (pulse) for
treatment of toenail onychomycosis
Results
Toenails: cure rate of 77 %; recurrence-free rate of
90.9 % after 6 months of follow-up.
Fingernails: cure rate of 100 %; recurrence-free rate of
85.7 % after 6 months of follow-up
Drug was first detectable 3-18 weeks after starting
therapy. A level of 0.25-0.55 ng/mg was quickly
achieved and remained stable
Toenail mycological cure rate with active treatment was
82 %; no patient taking placebo maintained
mycological cure. In fingernail patients treated with
active drug, 71 % achieved mycological cure
88 % of the patients given terbinafine and 29 % given
placebo had a negative mycological culture at week
24; 57 % of the terbinafine group and 6 % of the
placebo group were responders at week 48; the overall
mycological cure rate for the patients given
terbinafine was 94 %, and for placebo ? terbinafine it
was 38 %
Cure rate was 79.2 % in group 1 and 73.9 % in group 2;
this difference was not significant
A total of 74 % of patients achieved a successful
clinical outcome regardless the time of use
In weeks 48 and 72, patients were evaluated and showed
significant rates of mycological and clinical cure
compared with placebo
Mycological cure rate of 73 %; clinical cure and
complete cure were 57 and 48 %; no hypoglycemic
episode was reported
Superiority of continuous-dose terbinafine for
mycological cure (70.9 vs. 58.7 %), clinical cure (44.6
vs. 29.3 %), complete cure (40.5 vs. 28.0 %), and the
complete cure of all ten toenails (25.2 vs. 14.7 %)
20
Conclusion
Medication is safe, effective, with few
side effects
Concentrations of terbinafine in distal
clippings of unaffected nails were
similar to those in affected nails. In
some cases, the abnormal anatomy of
the infected nail may result in protected
áreas that can lead to persistence and
recurrence of the infecction
Three-month treatment with terbinafine is
effective
Mycologic cure rates can be achieved
with terbinafine by this treatment
regimen
Intermittent therapy with terbinafine is as
effective as 3-month treatment in
dermatophyte toe onychomycosis
Oral terbinafine is a safe and effective
therapy for the treatment of
onychomycosis
Patients treated with terbinafine showed
higher clinical and mycological cure
statistically superior to placebo. The
12-week treatment with terbinafine
showed similar efficacy rates to the
longer treatment courses
Terbinafine should be a drug of choice for
the treatment of toenail onychomycosis
in diabetic patients using multiple
medications
This study demonstrated the superiority of
continuous- over pulse-dose terbinafine
D. C. de Sá et al.
Table 1 continued
Therapeutic regimen
Takahata et al. [36] Pulse therapy with terbinafine 500 mg/day 1
week/month in patients with dermatophytic
onychomycosis (3 pulses). Topical terbinafine
was applied daily during the entire treatment
period and after it finished until the final
evaluation
FLUCONAZOLE
Assaf and Elewski [37] Eight patients took fluconazole 300 mg weekly,
one patient 200 mg weekly, and two received
100 or 200 mg on alternate days for moderate
and severe onychomycosis
Scher et al. [38] Fluconazole (150, 300, and 450 mg) given orally
once weekly in the treatment of distal
subungual onychomycosis of the toenail caused
by dermatophytes
Ling et al. [39] Fluconazole 450 mg once weekly for 4, 6 or 9
months in the treatment of onychomycosis of
the toenail caused by dermatophytes.
Drake et al. [40] Fluconazole 150, 300 or 450 mg once weekly in
the treatment of distal subungual
onychomycosis of the fingernail caused by
dermatophytes
Savin et al. [41] Once-weekly fluconazole (150, 300 or 450 mg)
in the treatment of distal subungual
onychomycosis of the fingernails caused by
dermatophytes
Chen et al. [42] Once-weekly fluconazole (100, 150 or 300 mg)
with a once-a-day topical application of 1 %
ketoconazole cream in the treatment of
onychomycosis
Results
Efficacy was assessed on the basis of both clinical and
mycological examinations. Complete cure in 41
patients (74.5 %), marked improvement in three
patients (5.6 %), slight improvement in three patients
(5.6 %) and drop out in six patients (10.7 %). Two
patients (3.6 %) discontinued terbinafine because of
gastrointestinal disturbance
Patients with toenails involved were clinically cured
after 6 months, and patients with fingernails involved
were cured after 3.7 months
86–89 % of patients in the fluconazole treatment group
achieved clinical successes compared with 8 % of
placebo group. Clinical cure (completely healthy nail)
was achieved in 28–36 % of the fluconazole groups
compared with 3 % of the placebo group. Mycological
eradication rates of 47–62 % were seen in the fluconazole
groups compared with 14 % in the placebo group. There
were no significant differences between the fluconazole
groups on these efficacy measures
All groups taking fluconazole achieved superior clinical
and mycological results compared with placebo at the
end of treatment and until 6 months’ follow-up.
Patients who received therapy for 9 months had
clinical and mycological responses significantly
superior compared with those who received
fluconazole for 4 or 6 months
Clinical cure and mycological eradication were
achieved at 6-month follow-up in 78 % of patients
treated with fluconazole 150 mg, 84 % with 300 mg,
and 91 % with 450 mg, compared with 3 % of patients
treated with placebo. Clinical relapse in cured patients
during the 6 months of follow- up was 1.5–3.3 %
After two weekly doses, 30–33 % of steady- state
concentrations had been achieved in healthy nails and
22–29 % in affected nails. Steady state was achieved
in 3–5 months. Fluconazole concentrations fell slowly
after drug discontinuation and were still detectable 4
months after end of treatment
Marked improvement or better was achieved in 55, 60
and 67 % in the groups taking 100, 150 and 300 mg,
respectively
Conclusion
Regimen of three pulses of terbinafine
therapy in combination with topical
terbinafine is safe and effective in
treating dermatophytic onychomycosis
and offers advantages in convenience
and cost-effectiveness compared with
continuous dosing
Oral Therapy for Onychomycosis
Intermittent fluconazole, taken once
weekly or on alternate days, is well
tolerated and efficacious
Doses between 150–450 mg weekly for 6
months were clinically and
mycologically effective as well as safe
and well tolerated
Fluconazole is effective and safe in the
treatment of distal subungual
onychomycosis of the toenail
Fluconazole administered once weekly is
safe and effective in eradicating distal
subungual onychomycosis of the
fingernail caused by dermatophytes
Fluconazole concentrations in nails are
significantly related to successful
treatment of onychomycosis
The regimen of 150 mg once weekly for 6
months is recommended considering
efficacy, compliance and economy
21

Table 1 continued
Therapeutic regimen
ITRACONAZOLE
Odom et al. [43] Itraconazole 200 mg once daily for 12 weeks in
the treatment of toenail onychomycosis
Odom et al. [44] Itraconazole 200 mg twice daily for the first
week of each month for 2 consecutive months
in fingernail onychomycosis
De Doncker et al. [45] Continuous itraconazole (200 mg/day for 6 or 12
weeks or 100 mg/day for 20 weeks) or a pulse
schedule (200 mg twice a day for 1 week/
month in two or four cycles), for patients with
onychomycosis caused by nondermatophyte
mold alone or in conjunction with a
dermatophyte
Chen et al. [46] Itraconazole 100 mg daily or intermittent pulse
therapies with 200, 300 or 400 mg daily for 1
week/month. The time of treatment was 3
months for fingernail onychomycosis and 4
months for toenail infection. Non-cured
patients were treated with a further one week
intermittent treatment with 400 mg/day
Hiruma et al. [47] Monthly pulse regimen with itraconazole 200 mg
daily for 7 days. The number of pulses was
determined in accordance with improvements
or the patients’ requests
Gupta et al. [48] Itraconazole pulse therapy (400mg/day for one
week each month) for 2 months in fingernails
and for 3 months in toenails onychomycosis
caused by Candida.
Avner et al. [49] Two different regimens of itraconazole for
toenail onychomycosis: 200 mg/day for 1
week/month for 3 months followed by a single
course of 200 mg/day for 1 week after 3
months; the other group received three pulses
of 200 mg/day for 1 week with an interval of 5
weeks without treatment, followed by an
additional single course (200 mg twice daily
for 7 days) after 3 months
Results
Clinical and mycological success was significantly
improved in itraconazole-treated patients when
compared with the placebo group. 16 % of the patients
in the itraconazole group had no changes at week 48
after the beginning of the therapy, versus 74 % in the
placebo group
Clinical success, mycological cure and an overall
success of 77, 73 and 68 %, respectively, in the
itraconazole group, with statistical significance
compared with placebo
It was achieved 88 % of complete cure in mold
infections and 84 % of clinical cure and 68 % of
mycological cure in mixed infections
Nine months after the end of the therapy, cure rates
were 78.4 % in the group receiving the 100 mg/day
continuous regimen, and 91.3, 76.2 and 28.6 % in the
groups receiving 400, 300 and 200 mg weekly,
respectively
Mycological and complete clinical cure rates at the end
of the follow-up (12 months) were 68 and 62 %,
respectively
Mycological cure rate for fingernail onychomycosis was
100 % and for toenail onychomycosis was 90.6 %.
Complete cure was 53.1 and 83.3 % for toenail and
fingernail onychomycosis, respectively
Clinical and mycological cure rates at the end of follow-
up were 59.5 % for the first group and 76.3 % for the
second, but were without statistical difference
22
Conclusion
Itraconazole 200 mg taken once daily for
12 weeks is effective therapy for
onychomycosis
Short-term itraconazole pulse therapy for
fingernail onychomycosis is effective
and well tolerated
Itraconazole appears to be effective and
safe for the treatment of toenail
onychomycosis caused by some
nondermatophyte molds alone or in
combination with dermatophytes
Itraconazole is effective in the treatment
of tinea of both toenails and fingernails,
and intermittent pulse therapy can be
superior to continuous dose
administration
The duration of the disease, the number of
affected nails, and severity of
thickening had statistical influence on
treatment results
Itraconazole administered for two and
three pulses is an effective and safe
treatment for fingernail and toenail
onychomycosis, respectively, caused by
Candida albicans and other Candida
species
These two regimens are acceptable
alternatives to the treatment of
onychomycosis
D. C. de Sá et al.
Table 1 continued
Therapeutic regimen Results Conclusion

FLUCONAZOLE AND
TERBINAFINE
Havu et al. [50] Terbinafine 250 mg daily for 12 weeks or At completion of the study (week 60), the mycological Terbinafine 250 mg daily for 12 weeks is
fluconazole 150 mg once weekly for 12 or 24 cure rate was higher in the terbinafine group than in significantly more effective in the
weeks the fluconazole groups: 89 vs. 51 and 49 %, treatment of onychomycosis than
respectively. Complete clinical cure was 67 % in the fluconazole 150 mg once weekly for
terbinafine group, compared with 21 and32 % in the either 12 or 24 weeks
Oral Therapy for Onychomycosis

fluconazole groups, respectively

FLUCONAZOLE,
ITRACONAZOLE
AND TERBINAFINE
Arca et al. [51] Fluconazole, itraconazole and terbinafine in
patients with distal subungual toenail
onychomycosis. Fluconazole 150mg/week,
itraconazole 200mg 2x/day during first week
each month and terbinafine 250mg/day, during
3 months
ITRACONAZOLE AND
TERBINAFINE
Bräutigam et al. [52] Terbinafine 250 mg/day or itraconazole 200 mg/
day during 12 weeks in the treatment of toenail
tinea unguium
Tosti et al. [53] Three groups of therapy: terbinafine 250 mg/day;
terbinafine 500 mg/day 7 days/month;
itraconazole 400 mg daily 7 days/month. For
toenail onychomycosis, treatment duration was
4 months; for fingernail onychomycosis, it was
2 months
De Backer et al. [54] Terbinafine 250 mg/day or itraconazole 200 mg/
day during 12 weeks, for dermatophyte
onychomycosis
Sigurgeirsson et al. [55] Four treatment regimens in patients with
dermatophyte toenail onychomycosis:
terbinafine 250 mg/day for 12 or 16 weeks, and
itraconazole 400 mg/day for 1 week in every 4
for 12 or 16 weeks
At the end of the follow-up period (6 months), clinical
cure and mycological cure proportions were 81.3 and
75 % in the terbinafine group, 77.8 and 61.1 % in the
itraconazole group, and 37.5 and 31.2 % in the
fluconazole group
At the end of the study, mycological cure rates were
81 % (70 out of 86) for terbinafine and 63 % (53 out of
84) for itraconazole. Negative culture was achieved in
92 % (79 out of 86) in the terbinafine group and 67 %
(56 out of 84) in the itraconazole group
Sixteen of 17 patients (94.1 %) in the terbinafine 250
mg group achieved mycological cure, as did 16 of 20
(80 %) in the terbinafine 500 mg/day group and 15 of
20 (75 %) in the itraconazole group
Statistically significantly greater percentage in the
terbinafine group than in the itraconazole group when
comparing mycological cure (73 % vs 45.8 %) and
also when comparing patients with clinical cure or
with minimal symptoms at the end of the study
(76.2 % vs 58.1 %).
At week 72, complete cure rates were 45.8 and 55.1 %
for patients treated with terbinafine for 12 and 16
weeks, respectively, and 23.4 and 25.9 % for those
treated with itraconazole for 12 and 16 weeks,
respectively
Fluconazole, at these doses and treatment
durations, was the least effective. With
regard to cost-effectiveness, side effects
and cure rates, terbinafine could be the
drug of choice in the short-term
treatment of toenail onychomycosis
Terbinafine is more effective than
itraconazole in the treatment of toenail
tinea infection
The percentage of patients cured with
continuous terbinafine was higher than
that in the group that used intermittent
terbinafine and in the itraconazole
group, but was not statistically
significant
Terbinafine produced higher rates of
clinical and mycological cure than
itraconazole
Continuous terbinafine is significantly
more effective than intermittent
itraconazole in the treatment of toenail
dermatophyte onychomycosis
23

Table 1 continued
Therapeutic regimen
Bahadir et al. [56] Pulse itraconazole (100 mg twice a day during
the first week of 3 consecutive months) or
continuous terbinafine (250mg/day for 3
months)
Gupta et al. [57] One pulse of itraconazole (200 mg twice daily
for 1 week) followed by 3-week stop and later
by a pulse of terbinafine (250 mg twice daily
for 1 week)
Gupta et al. [58] Group 1: two pulses of itraconazole (400 mg/day
7 days/month) followed by one or two pulses
of terbinafine (500 mg/day 7 days/month)
Group 2: three or four pulses of terbinafine
Heikkilä and Stubb [59] Four treatment regimens in patients with
dermatophyte toenail onychomycosis:
terbinafine 250 mg/day for 12 or 16 weeks, and
itraconazole 400 mg/day for 1 week in every 4
for 12 or 16 weeks
Sigurgeirsson et al. [60] Four treatment regimens in patients with
dermatophyte toenail onychomycosis:
terbinafine 250 mg/day for 12 or 16 weeks, and
itraconazole 400 mg/day for 1 week in every 4
for 12 or 16 weeks. Patients who had
therapeutic failure, relapse or re-infection
received a new course of terbinafine 250 mg/
day for 12 weeks
Warshaw et al. [61] Oral terbinafine or pulse itraconazole for toenail
onychomycosis caused by Candida
Mishra et al. [62] Itraconazole or terbinafine pulse therapies for 4
months in patients with fingernail and/or
toenail onychomycosis: one group took
itraconazole 200 mg/day for 1 week every
month and the other received terbinafine 250
mg twice daily for 1 week every month
Results
After 24 weeks of follow-up, healing rates of 60 % in
the itraconazole group and 68.57 % in the terbinafine
group were observed, but there was no statistical
difference between therapies
At week 39–48, mycological cure, clinical cure and
complete cure were achieved in all 20 patients
At week 72, in the group 1 versus group 2, the
mycological cure rate was 54 of 75 (72.0 %) versus 44
of 90 (48.9 %), clinical cure rate was 42 of 75
(56.0 %) versus 35 of 90 (38.9 %), effective therapy
rate was 49 of 75 (65.3 %) versus 41 of 90 (45.6 %),
and complete cure rate was 39 of 75 (52.0 %) versus
29 of 90 (32.2 %), respectively
Complete clinical and mycological cure rate with
terbinafine for 4 months was 78 %, compared with
35 % with terbinafine for 3 months, 24 % with
itraconazole for 4 months and 28 % with itraconazole
for 3 months
Analyzing patients who did not need a second
treatment, the complete cure rates at the end of the
study were 26 % in the terbinafine group and 11 % in
the itraconazole group. Patients originally treated with
itraconazole and patients originally treated with
terbinafine achieved the same complete cure rate of
72 % after the second treatment with terbinafine
No patients in either group achieved complete cure of
the target toenail. Mycological cure rates of the target
toenail: 42.9 % (pulse itraconazole) and 44.4 %
(terbinafine)
Itraconazole was more effective in onychomycosis
caused by molds and Candida. Complete cure among
the nondermatophyte mold in the itraconazole group
was observed in 62 % cases and in the terbinafine
group in 44 %. For Candida species, itraconazole was
more effective than terbinafine, 92 vs. 40 %. Both
agents achieved similar cure rates for dermatophytes
24
Conclusion
Continuous terbinafine appears to be more
effective than pulse itraconazole in the
treatment of onychomycosis. However,
the results did not reach statistical
significance and a high success rate was
achieved with both treatments
Regimen effective, safe, with few side
effects, which make this a high-
compliance therapy
Sequential pulse therapy with
itraconazole and terbinafine is effective
and safe for the treatment of
dermatophyte toenail onychomycosis
The initial treatment for onychomycosis
should be a 4-month continuous course
of terbinafine
Continuous terbinafine provided superior
long-term mycological and clinical
efficacy and lower rates of mycological
and clinical relapse compared with
intermittent itraconazole
It is possible that more than 3 months of
oral therapy with terbinafine or
itraconazole is necessary to clear
Candida infections of the toenail in an
elderly population with longstanding
and severe disease. This study had
several limitations
Both oral itraconazole and terbinafine are
effective in the treatment of
onychomycosis when administered in
the pulse dosage form. Terbinafine is
more cost effective, while itraconazole
has a broader spectrum of antimycotic
activity
D. C. de Sá et al.
Table 1 continued
Therapeutic regimen
Gupta et al. [63] Pulse itraconazole (200 mg twice daily, 1 week
on, 3 weeks off, for 12 weeks) vs. continuous
terbinafine (250 mg once daily for 12 weeks) in
the treatment of dermatophyte toenail distal
and lateral subungual onychomycosis in the
diabetic population
Gupta et al. [64] Terbinafine 250 mg/day 1 month, pause 1 month
and repeat 1 month (group 1); terbinafine 250
mg/day for 12 weeks (group 2); itraconazole
pulse of 200 mg twice daily for 7 days on, 21
days off, three pulses given (group 3)
Piraccini et al. [65] Terbinafine 250 mg daily or itraconazole 400 mg
daily for 1 week per month during 3 months or
less
POSACONAZOLE
AND TERBINAFINE
Elewski et al. [67] Patients received one of six regimens:
posaconazole 100, 200 or 400 mg once daily
for 24 weeks; posaconazole 400 mg once daily
for 12 weeks; terbinafine 250 mg once daily for
12 weeks; or placebo for 24 weeks.
FLUCONAZOLE,
GRISEOFULVIN,
ITRACONAZOLE,
KETOCONAZOLE
AND TERBINAFINE
Gupta and Patients received one of five regimens:
Gregurek-Novak [73] griseofulvin 600 mg twice daily for 12 months;
ketoconazole 200 mg daily for 4 months;
itraconazole pulse therapy given for three
pulses, with each pulse consisting of 200 mg
twice daily for 1 week, with 3 weeks off
between successive pulses; terbinafine 250 mg
daily for 12 weeks; and fluconazole 150 mg
daily for 12 weeks.
Results
At week 72, mycological and clinical cure rates in the
terbinafine group were 76 and 69.2 %, respectively,
and 84.2 and 68.4 % in the itraconazole group,
respectively
Mycological cure rates were 36 of 43 (83.7 %), 25 of 32
(78.1 %), and 17 of 30 (56.7 %) for the groups 1, 2
and 3, respectively (p = 0.01 for group 1 vs. group 3).
No significant differences in mycological cure rates
were noted.
Twelve of 73 patients (16.4 %) developed a recurrence
of onychomycosis a mean time of 36 months after
successful treatment. These included five of the 14
patients (35.7 %) who had taken itraconazole and
seven of the 59 (11.9 %) who had taken terbinafine
No differences were statistically significant between any
of the posaconazole regimens and terbinafine,
although patients taking posaconazole 200 mg daily
24 weeks achieved the highest cure rate (54.1 %),
followed by those receiving 400 mg daily 24 weeks
(45.5 %), terbinafine (37 %), posaconazole 100 mg
daily 24 weeks (22.9 %) and 400 mg daily 12 weeks
(20 %)
Complete cure 12 months after the start of the therapy:
griseofulvin (0/11); ketoconazole (8/12); itraconazole
(12/12); terbinafine (11/12); and fluconazole (8/12)
Conclusion
Both continuous terbinafine and
itraconazole pulse therapy are effective
and safe in the management of
dermatophyte toenail onychomycosis in
people with diabetes
Intermittent terbinafine regimen provided
Oral Therapy for Onychomycosis
similar efficacy and safety to the
goldstandard continuous terbinafine
regimen and better effective cure rates
than pulse itraconazole therapy
Administration of systemic terbinafine to
treat the first episode of onychomycosis
may provide better long-term success
than itraconazole in patients with a
complete response
The efficacy and favorable safety profile
of posaconazole suggest a potential new
treatment for onychomycosis. The
availability of low-cost generic
terbinafine may limit posaconazole use
to second-line treatment of infections
refractory to, or patients intolerant of,
terbinafine, or nondermatophyte mold
infections
Itraconazole and terbinafine were the
most effective oral agents with
favorable benefit-risk profile for the
treatment of toe onychomycosis due to
S. brevicaulis. Griseofulvin is
ineffective against toe onychomycosis
caused by S. brevicaulis. Ketoconazole
is not recommended for toe
onychomycosis given its potential for
adverse effects
25

Table 1 continued
Therapeutic regimen
GRISEOFULVIN AND
TERBINAFINE
Haneke et al. [68] Patients with fingernail onychomycosis treated
with terbinafine 250 mg/day or microsized
griseofulvin 500 mg/day during12 weeks.
Placebo was given for 12 more weeks
Faergemann et al. [69] Terbinafine 250mg/day during 16 weeks or
griseofulvin 500mg/day for 52 weeks
Hofmann et al. [70] Terbinafine 250 mg/day for 24 weeks or
microsized griseofulvin 1000 mg/day for 48
weeks
GRISEOFULVIN AND
ITRACONAZOLE
Piepponen et al. [71] Itraconazole100 mg/day or griseofulvin 500 mg/
day during 6–9 months, for patients with
onychomycosis in fingernails and toenails
Korting et al. [72] Ultramicrosized griseofulvin (UMSG) at doses
of 660 and 990 mg/day or itraconazole at 100
mg/day
Results
Six months after the end of the therapy, 76 % of the
group that received terbinafine and 39 % of those that
received griseofulvin were completely cured
In the terbinafine group, 42 % were completely cured
and 84 % mycologically cured. In the griseofulvin
group, 2 % were completely cured and 45 %
mycologically cured. The incidence of adverse events
was lower in the terbinafine group (11 % vs. 29 %)
In 67 % of the patients in the terbinafine group, the
treatment was effective versus 56 % of those treated
with griseofulvin. At a follow-up visit 24 weeks later,
cure rates had decreased to 60 % in the terbinafine
group and to 39 % in the griseofulvin group. The
mycological cure rate was 81 % with terbinafine and
62 % with griseofulvin
At month 6 and 9, both treated groups had a significant
reduction in symptom severity compared with the
beginning of the treatment in all parameters but with
no clinically or statistically significant differences
between the treatment groups. The itraconazole group
kept improving even in the follow-up period. Nineteen
of the 26 itraconazole patients (73 %) remained cured
during the follow-up period and 12 of the 17
griseofulvin patients (71 %)
Cure or partial cure was found in 6 % (UMSG at 660
mg), 14 % (UMSG at 990 mg), and 19 % (itraconazole
at 100 mg) of patients. Most patients had to be treated
for 18 months
26
Conclusion
Short-duration treatment (3 months) for
fingernail dermatophytosis with
terbinafine and griseofulvin is well
tolerated. Terbinafine is associated with
higher cure rate
Terbinafine was more effective and had
fewer adverse events than griseofulvin
in the treatment of toenail
onychomycosis
Long-term therapeutic superiority of
terbinafine over high-dose griseofulvin
in the treatment of toenail mycosis
Both drugs were equally effective in the
treatment of onychomycosis, but the
itraconazole group continued improving
after the end of the therapy
Itraconazole at 100 mg showed better
efficacy and was better tolerated than
griseofulvin
D. C. de Sá et al.
Oral Therapy for Onychomycosis
followed for 48 weeks, with cure rates of 79.1 % (group 1)
and 73.9 % (group 2), with no significant difference [31].
In a North American multicenter trial, Drake et al. [32]
evaluated the mycological and clinical cure rates of terbi-
nafine 250 mg/day for 12 or 24 weeks compared with
placebo. From the 358 patients with toenail onychomyco-
sis, 74 % of patients achieved a successful clinical outcome
regardless of the duration of use. The difference between
the response rates of the two groups treated with terbinafine
was comparable (71 vs. 77 % for 12 and 24 weeks,
respectively). Relapse was observed in 11 % of the patients
who responded to terbinafine and occurred 18–21 months
after cessation of the treatment. This study though suggests
that the treatment should be longer than 12 weeks in
patients with extensive involvement of the halux toenail
[32].
Billstein et al. [33] performed a trial comparing the
efficacy of terbinafine 250 mg/day for 12, 16 and 24 weeks
with placebo. In weeks 48 and 72, patients were evaluated
and showed significant rates of mycological and clinical
cure compared with placebo. The 12-week treatment with
terbinafine showed similar efficacy rates to the longer
treatment courses [33].
Farkas et al. [34] investigated the safety and efficacy of
terbinafine for the treatment of onychomycosis in diabetic
patients using insulin and/or oral antidiabetic agents.
Patients received 250 mg/day of oral terbinafine during
12 weeks. Follow-up was up to 48 weeks, and clinical,
mycological and laboratory investigations were performed.
Glucose levels were also monitored. A mycological cure
rate of 73 % was achieved. Clinical cure and complete cure
rates were 57 and 48 %, respectively. No hypoglycemic
episode was observed. In the study, the authors suggest that
terbinafine should be the drug of choice in diabetic patients
using multiple medications [34].
Warshaw et al. [35] also compared 250 mg daily treat-
ment to 500 mg/day for 1 week/month pulsed therapy.
Superiority of continuous-dose terbinafine for mycological
cure (70.9 vs. 58.7 %), clinical cure (44.6 vs. 29.3 %),
complete cure (40.5 vs. 28.0 %), and the complete cure of
all ten toenails (25.2 vs. 14.7 %) was shown. In both reg-
imens, the complete cure of all ten nails was very low. This
demonstrates the low effectiveness of terbinafine to
achieve this complete cure and suggests that this outcome
should be considered as a new standard outcome measure
for other studies evaluating onychomycosis [35].
Takahata et al. [36] assessed the safety and efficacy of
terbinafine 500 mg/day for 7 days with a 3-week stop; this
regimen was repeated twice. Topical terbinafine was
applied daily during the entire treatment period and after it
finished until the final evaluation (12 months after the
beginning of the treatment). A complete cure was observed
in 41 patients (74.5 %). No patient had abnormal
27
laboratory findings, although three patients quit the treat-
ment because of terbinafine side effects (gastrointestinal
and drug-induced eruption) [36].
Seven studies have been conducted (Baudraz-Rosselet
et al. [27], Billstein et al. [33], Finlay [28], Goodfield [29],
Drake et al. [32], Watson et al. [30], and Farkas et al. [34])
that showed 250 mg/day use of terbinafine is effective for
onychomycosis treatment. A treatment of 500 mg/day
7 days/month was used by Takahata et al. [36] and also
achieved high cure rates. We found two studies comparing
different dosage regimens of terbinafine. Alpsoy et al. [31]
and Warshaw et al. [35] compared the daily dosage of
250 mg with a pulsed regimen of 500 mg/day 7 days/
month. While in the first study no statistical difference was
found, in the Warshaw et al. [35] study, cure rates were
higher in the daily group. Duration of treatment also varied
among the studies. Goodfield [29], Alpsoy et al. [31], and
Takahata et al. [36] performed 3-month duration studies,
Baudraz-Rosselet et al. [27] a 6-month study, and Finlay
[28] a 12-month study. In all of them, significant cure rates
were achieved. Two studies compared different duration of
the therapeutics. Billstein et al. [33] compared daily use of
terbinafine during 12, 16 and 24 weeks. Drake et al. [32]
also compared 250 mg/day for 12 or 24 weeks. In both
studies, similar cure rates were obtained with no statisti-
cally significant difference. Considering efficacy, compli-
ance and economy, the ideal dosage regimen of terbinafine
is 250 mg/day for 12 weeks.
3.2 Fluconazole
Fluconazole is a broad-spectrum antifungal with demon-
strated in vitro activity against dermatophytes, including
Trichophyton, Candida species, and some nondermato-
phyte molds. It has been detected in nails within 2 weeks
of starting therapy and persists in high concentrations for
3–6 months after treatment.
Assaf and Elewski [37] evaluated an intermittent pulse
of fluconazole without nail avulsion in patients with
moderate and severe onychomycosis. Eleven patients were
treated with three different regimens until clinical cure.
Eight received 300 mg once/week, one 200 mg once/week
and two received 100 or 200 mg on alternate days. Patients
with toenails affected achieved cure after a mean treatment
of 6 months, while those with fingernail involvement
achieved a cure after a mean of 3.7 months. The study
concluded that fluconazole is effective when used in once/
week and alternate day regimens [37].
Scher et al. [38] published a study evaluating three
different doses of fluconazole (150, 300 and 450 mg/week
for up to 12 months) in the treatment of distal subungual
onychomycosis of the toenail. All of the fluconazole-trea-
ted patients showed statistically significant improvement
28
compared with placebo when clinical improvement, clini-
cal cure and mycological cure were analyzed at the end of
therapy and until 6 months’ follow-up. Differences
between the fluconazole groups were not significant.
Clinical improvement was achieved in 86–89 % of patients
in the fluconazole treatment groups compared with 8 % of
the placebo group. Clinical cure was 28–36 % in the
fluconazole group and 3 % in the placebo group. The
fluconazole group had mycological eradication rates of
47–62 % compared with 14 % in placebo. The clinical
relapse rate over 6 months of follow-up was low at 4 %
[38].
Ling et al. [39] compared three different durations (4, 6
or 9 months) of 450 mg/week fluconazole treatment for
toenail onychomycosis. All groups taking the antifungal
achieved superior clinical and mycological results com-
pared with placebo at the end of treatment and until
6 months’ follow-up. Patients who received therapy for
9 months had clinical and mycological responses signifi-
cantly superior compared with those who received fluco-
nazole for 4 or 6 months [39].
Drake et al. [40] evaluated fluconazole 150, 300 and
450 mg administered once weekly for up to 9 months in
the treatment of distal subungual onychomycosis of the
fingernail. Clinical cure and mycological eradication were
achieved at 6-month follow-up in 78 % of patients treated
with fluconazole 150 mg, 84 % with 300 mg, and 91 %
with 450 mg, compared with 3 % of patients treated with
placebo. Clinical relapse in cured patients during the 6
months of follow-up was 1.5–3.3 % [40].
Savin et al. [41] performed a study to determine plasma
and fingernail concentrations of fluconazole administered
in once-weekly doses of 150, 300 and 450 mg until cure of
onychomycosis or for a maximum of 9 months. Significant
amounts of fluconazole were found in fingernails 2 weeks
after the beginning of the treatment, and steady state was
achieved in 3–5 months. Fingernail concentrations fell
slowly after drug discontinuation and were still detectable
4 months after the end of treatment. Fingernail concen-
trations were dose proportional over the dose range of
150–450 mg. A statistically significant correlation was
found between affected fingernail steady-state concentra-
tion and clinical response at the end of treatment. The
success rate climbed with increasing concentrations. A
steady-state concentration over 7.5 mg/g, which occurred
with the 300- and 450-mg dosage regimens, was shown to
be more effective [41].
Chen et al. [42] evaluated three groups of patients
receiving 100, 150 or 300 mg/week of fluconazole for a
maximum of 12 months or until a complete cure plus
topical 1 % ketoconazole cream during 12 months. There
was no statistical difference in clinical cure (42, 46 and
48 %, respectively) between the groups [42].
D. C. de Sá et al.
In all studies, fluconazole showed a safety profile of
adverse events that did not significantly change treatment
adherence. All studies used positive potassium hydroxide
(KOH) wet mount and culture for a dermatophyte to con-
firm diagnosis and to evaluate treatment success. Nail
infections for Candida and nondermatophyte were not
analyzed. Patients continued to have improvement when
results at the end of the therapy were compared with those
at the end of the follow-up period in the Scher et al. [38],
Ling et al. [39], and Drake et al. [40] studies, which had a
6-month period of follow-up after the end of the treatment.
Scher et al. [38] and Ling et al. [39] analyzed only toenails.
In the Chen et al. [42] trial, patients with toenail and fin-
gernail onychomycosis were included; the proportion of
each was not reported. Only Drake et al. [40] evaluated
fingernails exclusively, and the results given in the study
showed higher rates of cure of fingernail onychomycosis
than that found in other studies that evaluated only toenails.
Ideal dosage and duration of fluconazole treatment cannot
be determined analyzing the studies, since different treat-
ment regimens were evaluated. In the studies that used a
predetermined duration of treatment, Ling et al. [39] found
that a 450 mg/week fluconazole dose was better when
administered for 9 months than for 6 or 4 months. Scher
et al. [38] found that there was no difference between the
doses (150, 300 or 450 mg/week), and the mean time of
treatment was 9.5–10.2 months, and did not differentiate
the duration between the groups. Chen et al. [42] observed
that treatment duration was significantly higher in the
100-mg group (8.4 ± 5.6 months) than the average dura-
tion in the 150-mg (6.4 ± 3.4) and 300-mg (5.6 ± 3.8)
groups. The total fluconazole dosage was significantly
higher in the 300-mg group. Considering efficacy, com-
pliance and economy, the authors suggested the dosage of
150 mg once weekly for 6 months as the best fluconazole
treatment regimen. In the pharmacokinetic study of Savin
et al. [41], 300- and 450-mg dosage regimens achieved the
best results. Drake et al. [40], evaluating only fingernails,
estimated a median time to cure of 6 months in the 300-
and 450-mg groups and of 7 months in the 150-mg group.
3.3 Itraconazole
Itraconazole is a triazole antifungal, has the broadest
spectrum of activity, and interrupts ergosterol synthesis via
the cytochrome P450 (CYP) enzyme pathway. It rapidly
penetrates the nail plate, and persists for up to 6–9 months
post-treatment.
Odom et al. [43], evaluating 75 patients with toenail
onychomycosis in a treatment regimen of itraconazole
200 mg once a day for 12 weeks, had statistically signifi-
cant results compared with those of the placebo group.
Only 16 % of the patients in the itraconazole group had no
Oral Therapy for Onychomycosis
changes at week 48 after the beginning of the therapy
versus 74 % in the placebo group [43].
Odom et al. [44] evaluated 73 patients with fingernail
onychomycosis caused by dermatophytes taking itraco-
nazole 200 mg twice a day during week 1 for 2 consecutive
months, and found clinical success, mycological cure and
an overall success of 77, 73 and 68 %, respectively, with
statistical significance compared with placebo. No relapses
were related until 19 months after the end of the treatment
[44].
De Doncker et al. [45], in a study with 36 patients with
onychomycosis caused by nondermatophyte mold alone or
in conjunction with a dermatophyte, treating patients with
continuous itraconazole (200 mg/day for 6 or 12 weeks or
100 mg/day for 20 weeks) or with a pulse schedule
(200 mg twice a day for 1 week/month in two or four
cycles), achieved 88 % of complete cure in mold infections
and 84 % of clinical cure and 68 % of mycological cure in
mixed infections [45].
Chen et al. [46] compared itraconazole 100 mg daily
with intermittent pulse regimens of 200, 300 or 400 mg
daily for 1 week per month. The time of treatment was
3 months for fingernail onychomycosis and 4 months for
toenail infection. Nine months after the end of the therapy,
patients treated with the pulse regimen of 400 mg achieved
higher cure rates (91.3 %), against 78.4, 76.2 and 28.6 %
for continuous 100 mg daily, 300-mg pulse regimen and
200-mg pulse treatment, respectively. Patients who had
improvement, but were without cure, were treated for 1
week with 400 mg/day and achieved a marked increase in
cure rate [46].
Hiruma et al. [47] evaluated 63 patients with toe or
fingernail onychomycosis caused by dermatophytes using a
monthly pulse regimen with itraconazole 200 mg daily for
7 days. The average number of pulses was 4.7 ± 3.2, and
was determined in accordance with improvements or the
patients’ requests. Mycological and complete clinical cure
rates at the end of follow-up (12 months) were 68 and
62 %, respectively. The duration of the disease, the number
of affected nails, and severity of thickening had statistical
influence on treatment results [47].
Gupta et al. [48] performed a trial with 44 patients with
onychomycosis caused by Candida albicans and other
Candida species, using itraconazole pulse therapy of
400 mg/day for 7 days. Onychomycosis of the toenails was
treated with three pulses, and onychomycosis of the fin-
gernails with two pulses. The mycological cure rate for
fingernail onychomycosis was 100 % and for toenail ony-
chomycosis was 90.6 % [48].
Avner et al. [49] evaluated two regimens of itraconazole
for toenail onychomycosis. One group of patients used
200 mg 29/day for 1 week/month for 3 months followed
by a single course of 200 mg/day for 1 week after
29
3 months. The other group received three pulses of 200 mg
29/day for 1 week with an interval of 5 weeks without
treatment, followed by an additional single course (200 mg
29/day for 7 days) after 3 months. Patients were followed
up for 24 months from the beginning of treatment, and
clinical and mycological cure rates at the end of follow-up
were 59.5 % for the first group and 76.3 % for the second,
but were without statistical difference. No recurrences were
observed from the end of the treatment until the end of the
follow-up period [49].
Decisions about what is the ideal treatment dosage and
duration of itraconazole are hampered by the different
methodologies used in the studies. Both regimens with
continuous or pulse dosages were effective. The target
nail and the causative agent varied between the studies.
Only in the study from Chen et al. [46] continuous and
pulse therapies were compared, and the best result was
reached by the regimen of 400 mg daily for 1 week/
month during 3 months for fingernail and 4 months for
toenail onychomycosis. In this study, patients were pre-
dominantly infected by dermatophytes, but yeasts and
nondermatophytes infections were also present. De
Doncker et al. [45] also used different regimens with
continuous and pulse therapies, but did not compare the
results between them, and analyzed only toenails infected
with nondermatophyte molds alone or in conjunction with
a dermatophyte. Onychomycosis caused by Candida
species exclusively was assessed in two studies. Gupta
et al. [48] showed an effective treatment schedule with
itraconazole 400 mg/day for 1 week/month for 2 months
in fingernail and for 3 months in toenail onychomycosis.
Toenails infected exclusively by dermatophytes were
assessed for Odom et al. [43] and Avner et al. [49]. In
the first study, a continuous therapy with 200 mg/day for
12 weeks was used, and in the second, two different
pulse therapies regimens were evaluated, with good
results. Fingernails infected exclusively with dermato-
phytes were analyzed only by Odom et al. [44], using a
pulse therapy with 400 mg/day during 1 week/month for
2 months.
3.4 Fluconazole and Terbinafine
Havu et al. [50] compared fluconazole with terbinafine and
demonstrated that terbinafine 250 mg/day for 12 weeks
was significantly more effective in terms of clinical and
mycological cure than fluconazole 150 mg/week for 12 or
24 weeks. In the study, which had a follow-up time of
60 weeks, the length of unaffected nail increased until the
24th week in the group of patients that took fluconazole for
12 weeks, and until the 36th week in group that took it for
24 weeks, but was still increasing in the terbinafine group
at the final visit (60th week) [50].
30
3.5 Fluconazole, Itraconazole and Terbinafine
Arca et al. [51] evaluated 50 patients with toenail ony-
chomycosis divided into the following treatment regimens:
fluconazole 150 mg/week, itraconazole 200 mg 29/day
during first week each month, and terbinafine 250 mg/day
during 3 months. They showed a lower result for fluco-
nazole than terbinafine and itraconazole, and no statisti-
cally significant difference between terbinafine and
itraconazole. At the end of the treatment, the clinical cure
rates were 50 % in the terbinafine group, 44.4 % in the
itraconazole group, and 6.3 % in the fluconazole group. At
the endpoint of the follow-up period (6 months), rates
reached 81.3 % in the terbinafine group, 77.8 % in the
itraconazole group, and 37.5 % in the fluconazole group.
The mycological cure proportions at the end of the treat-
ment were 43.8, 50 and 25 % for patients treated with
terbinafine, itraconazole and fluconazole, respectively, and
at the end of the follow-up were 75, 61.1 and 31.2 %,
respectively [51].
3.6 Itraconazole and Terbinafine
Several studies have compared the efficacy of terbinafine
with other drugs. Most of them showed the superiority of
terbinafine in the treatment of onychomycosis caused by
dermatophytes.
Bräutigam et al. [52] compared the efficacy and tolera-
bility of terbinafine (250 mg/day) and itraconazole
(200 mg/day). One hundred and ninety-five patients with
dermatophyte onychomycosis were selected and followed
up for 40 weeks. In the terbinafine group, 81 % achieved
mycological cure while 63 % in itraconazole group
achieved mycological cure. Negative culture was achieved
by 92 % in the terbinafine group and by 67 % in the itr-
aconazole group [52].
Tosti et al. [53] assessed the efficacy of pulsed therapy
of terbinafine (500 mg/day 7 days/month) and compared
the results with continuous treatment (250 mg/day) and
with itraconazole pulsed regimen (400 mg/day 7 days/
month). For toenail onychomycosis, treatment duration
was 4 months, while for fingernail onychomycosis, it was
2 months. After 6 months of discontinuation, 94 % were
cured in the terbinafine daily group, 80 % in the pulsed
terbinafine group and 75 % in the itraconazole group.
Although the cure rates were higher in the daily terbi-
nafine group, there was no statistical significant differ-
ence between the daily and the pulsed terbinafine groups
[53].
De Backer et al. [54] compared 12 weeks of terbinafine
daily treatment (250 mg) with itraconazole daily (200 mg)
treatment for confirmed dermatophyte onychomycosis.
There was a statistically significantly higher percentage
D. C. de Sá et al.
cure in the terbinafine group than in the itraconazole group
(73 vs. 45.8 %, respectively).
Sigurgeirsson et al. [55] carried out a multicenter study
(LION study) in six European countries, and evaluated four
treatment regimens in 496 patients with dermatophyte
toenail onychomycosis: terbinafine 250 mg/day for 12 or
16 weeks, and itraconazole 400 mg/day for 1 week in
every 4 for 12 or 16 weeks. All treatments were well tol-
erated, with no significant differences in the adverse events
reported. All comparisons of mycological and clinical cure
were statistically in favor of the terbinafine regimens. At
week 72, complete cure rates were 45.8 and 55.1 % for
patients treated with terbinafine for 12 and 16 weeks,
respectively, and 23.4 and 25.9 % for those treated with
itraconazole for 12 and 16 weeks, respectively [55].
A total of 60 patients with toenail or fingernail ony-
chomycosis divided in two groups that received terbinafine
250 mg every day for 3 months or itraconazole 100 mg
twice a day for 1 week/month for 3 months were evaluated
by Bahadir et al. [56]. They found, after 24 weeks of fol-
low-up, healing rates of 60 % in the itraconazole group and
68.57 % in the terbinafine group, but there was no statis-
tical difference between therapies [56].
In 2000, Gupta et al. [57] evaluated the effectiveness
and safety of sequential use of itraconazole and terbinafine
in 20 patients. The therapy consisted of one pulse of itr-
aconazole (200 mg twice daily for 1 week) followed by
3 weeks’ stop and by one pulse of terbinafine (250 mg
twice daily for 1 week) after the stop interval. Four months
from the beginning of the treatment, patients were evalu-
ated. If there was evidence of mycological involvement, a
new course of pulsed itraconazole was offered. At weeks
39–48, mycological cure, clinical cure and complete cure
were achieved. The authors found this regimen effective
and safe, with few side effects, which makes this a high-
compliance therapy [57].
Gupta et al. [58] compared a sequential pulse regimen of
itraconazole and terbinafine with a pulsed regimen of ter-
binafine alone: sequential pulse therapy (IIT) with two
pulses of itraconazole (400 mg/day 7 days/month) fol-
lowed by one or two pulses of terbinafine (500 mg/day
7 days/month) versus three or four pulses of terbinafine
(TTT). After 72 weeks, mycological cure rates were 72 %
(IIT) versus 48.9 % (TTT), clinical cure was 56 versus
38.9 %, effective therapy 65.3 versus 45.6 %, and com-
plete cure 52.0 versus 32.2 %, respectively, with p \ 0.05.
Both treatments were well tolerated with few adverse
effects [58].
Heikkilä and Stubb [59] re-examined clinically and
mycologically the Finnish patients of the original LION
study 4 years after the beginning of treatment. A total of 76
patients participated. The rates of complete cure (clinical
and mycological) were higher at 4 years in comparison
Oral Therapy for Onychomycosis
with those at 72 weeks in the group that received terbina-
fine for 16 weeks (increased from 50 to 78 %). In the other
groups, the results remained almost unchanged or were
worse at 4 years, from 48 to 35 % in the terbinafine
12-week group, from 33 to 28 % in the itraconazole
12-week group, and from 18 to 24 % in the itraconazole
16-week group. However, this study was not able to give
full statistical significance between the groups [59].
In a prospective study of 5 years, Sigurgeirsson et al.
[60] followed up 144 patients from the three Icelandic
centers that were in the LION study. Patients who had
therapeutic failure, relapse or re-infection received a new
course of terbinafine 250 mg/day for 12 weeks. Analyzing
patients who did not need a second treatment, the complete
cure rates at the end of the study were 26 % in the terbi-
nafine group and 11 % in the itraconazole group. Patients
originally treated with itraconazole and patients originally
treated with terbinafine achieved the same complete cure
rate of 72 % after the second treatment with terbinafine.
Terbinafine provided superior efficacy and lower rates of
relapse compared with itraconazole [60].
Warshaw et al. [61] evaluated 16 patients with Candida
toenail onychomycosis, who were treated with terbinafine
or itraconazole for 3 months. At 18 months, no patients in
either group achieved complete cure of the target toenail.
Complete cure of the other nine toenails was achieved in
33.3 and 28.6 % of the patients in the terbinafine and itr-
aconazole groups, respectively. This study had several
limitations such as the small size of the sample and
assumes the limitation of not clearly distinguishing
between pathogenic and nonpathogenic molds [61].
Mishra et al. [62] compared itraconazole and terbinafine
pulse therapies for 4 months in 120 patients with fingernail
and/or toenail onychomycosis. One group took itraconaz-
ole 200 mg 29/day for 1 week every month and the other
received terbinafine 250 mg 29/day for 1 week every
month. Itraconazole was more effective in onychomycosis
caused by molds and Candida. Complete cure among the
nondermatophyte mold in the itraconazole group was
observed in 62 % of cases and in the terbinafine group in
44 %. For Candida species, itraconazole was more effec-
tive than terbinafine: 92 vs. 40 %. Both agents achieved
similar cure rates for dermatophytes. Analyzing all of the
cases, the results were similar, with 90 % in the itraco-
nazole group achieving mycological cure after 1 year of
follow-up, and 87 % in the terbinafine group [62].
Gupta et al. [63] published a study with 64 diabetic
patients with dermatophyte toenail onychomycosis, evalu-
ating the efficacy of the pulse itraconazole (200 mg twice
daily, 1 week on, 3 weeks off, for 12 weeks) versus con-
tinuous terbinafine (250 mg once daily for 12 weeks).
Neither drug was deemed significantly more efficacious
than the other, and both were safe. At week 72,
31
mycological and clinical cure rates in the terbinafine group
were 76 and 69.2 %, respectively, and 84.2 and 68.4 % in
the itraconazole group, respectively [63].
Gupta et al. [64], in 2009, proposed a new regimen of
terbinafine in which a daily dosage of 250 mg for 4 weeks
was followed by a 4-week period without the drug, then 4
more weeks using the drug; this was compared with the
usual 12 weeks of 250 mg/day use of terbinafine and the
pulse regimen of itraconazole 200 mg twice daily for
7 days on, 21 days off (three pulses). No difference has
been found in the cure rates between terbinafine groups, but
patients treated with itraconazole reached lower cure rates
[64].
An important weakness of the majority of the studies is
the short length of follow-up of the groups. For this reason,
Piraccini et al. [65] investigated a group of 73 patients for
7 years. To be included, patients had to have complete
clinical cure 12 months after treatment was completed and
could only have been treated for 3 months or less. Patients
evaluated used terbinafine 250 mg daily (59 patients) or
itraconazole 400 mg daily for 1 week per month (14
patients). In patients treated with terbinafine, 11.9 % of
patients relapsed, as compared with 35.7 % of itraconaz-
ole-treated patients. Although the number of patients in the
terbinafine group was higher, what could strengthen these
conclusions is that this study showed that terbinafine
treatment leads to fewer relapses of onychomycosis [65].
3.7 Posaconazole and Terbinafine
Posaconazole is an extended-spectrum triazole not yet
approved in Europe and the USA for onychomycosis
treatment. It is well tolerated and has a high efficacy
in vitro against dermatophytes. Evaluating nail concentra-
tion during and after oral treatment, Krishna et al. [66]
showed that posaconazole penetrated and reached dose-
related levels in nail plates during treatment, and, similar to
other azoles, remained in high levels even several weeks
after treatment. In a study with 218 patients, Elewski et al.
[67] evaluated posaconazole as an option for toenail ony-
chomycosis treatment. Patients received one of six regi-
mens: posaconazole 100, 200 or 400 mg once daily for
24 weeks; posaconazole 400 mg once daily for 12 weeks;
terbinafine 250 mg once daily for 12 weeks; or placebo for
24 weeks. Statistically significant cure rates at week 48
were obtained in all regimens of posaconazole when
compared with placebo. No differences were statistically
significant between any of the posaconazole regimens and
terbinafine, although patients taking posaconazole 200 mg
daily 24 weeks achieved the highest cure rate (54.1 %),
followed by those receiving 400 mg daily 24 weeks
(45.5 %), terbinafine (37 %), posaconazole 100 mg daily
24 weeks (22.9 %) and 400 mg daily 12 weeks (20 %)
32
[67]. Because of the efficacy and the good safety profile
shown in the study, the authors suggested posaconazole as
a possible second-line treatment for patients with intoler-
ance or refractoriness to terbinafine, or for those with
nondermatophyte mold infections. More studies are needed
to confirm posaconazole’s effectiveness.
3.8 Griseofulvin and Terbinafine
Haneke et al. [68] performed a trial with 180 patients with
fingernail onychomycosis treated with terbinafine 250 mg/
day or microsized griseofulvin 500 mg/day during
12 weeks. Placebo was given for 12 more weeks followed
by a 24-week observation period. At endpoint, 76 % of the
terbinafine and 39 % of the griseofulvin group were com-
pletely cured. The authors concluded that for a 3-month
treatment period, both drugs are well tolerated but terbi-
nafine is more effective [68].
Faergemann et al. [69] compared the use of terbinafine
250 mg/day during 16 weeks with griseofulvin 500 mg/day
for 52 weeks for the treatment of onychomycosis in 89
patients. Those who did not improve at week 16 received
250 mg/day of terbinafine, and follow-up was for 20 weeks.
In the terbinafine group, 42 % were completely cured. In the
griseofulvin group, 2 % were completely cured. The inci-
dence of adverse events was lower in the terbinafine group
(11 vs. 29 %). They found that terbinafine was more
effective and had fewer adverse events than griseofulvin in
the treatment of toenail onychomycosis [69].
Hofmann et al. [70], in a study with 195 patients with
severe dermatophyte infections of the toenails, compared a
24-week treatment with terbinafine (250 mg/day) with a
48-week treatment with microsized griseofulvin
(1,000 mg/day). In 67 % of the patients in the terbinafine
group, the treatment was effective, versus 56 % of those
treated with griseofulvin. At a follow-up visit 24 weeks
later, cure rates had decreased to 60 % in the terbinafine
group and to 39 % in the griseofulvin group. These results
demonstrated the long-term therapeutic superiority of ter-
binafine over high-dose griseofulvin in the treatment of
toenail mycosis [70].
3.9 Griseofulvin and Itraconazole
Piepponen et al. [71] studied 61 patients with onychomy-
cosis in fingernails and toenails treated with itraconazole
100 mg/day or griseofulvin 500 mg/day for 6–9 months. At
month 6 and 9, both treated groups had a significant
reduction in symptom severity but with no clinically or
statistically significant differences. Of the itraconazole
patients, 73 % remained cured during the follow-up period
versus 71 % of the griseofulvin patients. The griseofulvin
group had a great number of drop-outs, making it difficult
D. C. de Sá et al.
to evaluate the real symptom recurrence. The authors
conclude that both drugs were equally effective, but the
itraconazole group continued improving after the end of the
therapy [71].
Korting et al. [72] evaluated 109 patients with tinea
unguium of the toenails, fingernails, or both, treated with
one of the following therapies: ultramicrosized griseofulvin
(UMSG) at doses of 660 or 990 mg/day, and itraconazole
at 100 mg/day. Cure or partial cure was found in 6 %
(UMSG at 660 mg), 14 % (UMSG at 990 mg), and 19 %
(itraconazole at 100 mg) of patients. Most patients had to
be treated for 18 months. Itraconazole showed better effi-
cacy results with fewer adverse events [72].
3.10 Fluconazole, Griseofulvin, Itraconazole,
Ketoconazole and Terbinafine
Gupta and Gregurek-Novak [73] evaluated 59 patients with
toenail onychomycosis caused by Scopulariopsis brevi-
caulis treated with one of five oral antifungal agents:
griseofulvin 600 mg twice daily for 12 months; ketocona-
zole 200 mg daily for 4 months; itraconazole pulse therapy
given for three pulses, with each pulse consisting of
200 mg twice daily for 1 week, with 3 weeks off between
successive pulses; terbinafine 250 mg daily for 12 weeks;
and fluconazole 150 mg daily for 12 weeks. Complete cure
results 12 months after the start of the therapy were as
follows: griseofulvin (0/11); ketoconazole (8/12); itraco-
nazole (12/12); terbinafine (11/12); and fluconazole (8/12).
The authors suggested itraconazole and terbinafine were
the most effective oral agents with favorable benefit-to-risk
profiles for the treatment of toenail onychomycosis due to
S. brevicaulis [73].
3.11 Side Effects of Oral Therapy
Several studies have examined the safety profile of dif-
ferent oral antifungal drugs for treating onychomycosis
[74–77]. In the majority of these studies, oral antifungal
therapy was well tolerated and safe, with low incidences of
adverse reactions (5–10 %) [24, 78] and a low risk of
discontinuing the treatment because of these reactions
[79–81].
Oral griseofulvin and ketoconazole were, in the past, the
agents of choice for treatment. Because of their low cure
rates, these agents have been substituted by newer systemic
compounds with higher cure rates and lower incidences of
side effects [82].
Griseofulvin has a narrow spectrum of activity (only
dermatophytes) and low affinity for keratin, and thus
requires long-term therapy [83–85]. Because of this long
duration of therapy and griseofulvin’s interactions with
other drugs, it is rarely used today for onychomycosis
Oral Therapy for Onychomycosis
treatment. Severe adverse effects are very rare. Most
adverse events are very mild and include nausea and
headache. Less common symptoms are photosensitivity,
hepatotoxicity and hematological effects such as leukope-
nia, neutropenia and monocytosis [85].
Ketoconazole has a high affinity for keratins, with high
tissue levels, and this is what made ketoconazole a prom-
ising agent to treat onychomycosis [86]. Asymptomatic
elevation in liver biochemical tests can be found in some
patients [87], but serious adverse reactions occurred in some
patients treated with this drug, such as an idiosyncratic form
of drug-induced hepatitis, limiting its use to severe systemic
or incapacitating disorders in those not responsive to other
agents [88–90]. There are some case reports of fulminant
liver failure after ketoconazole therapy [88, 89, 91, 92]. The
incidence of these events is higher in women, in those on
therapy longer than 2 weeks, in those who have had previ-
ous therapy with oral griseofulvin, in those with preexisting
liver disease and in individuals with alcoholism [93]. Other
adverse effects and drug interactions include nausea, vom-
iting, allergic rash, hormone imbalance, menstrual distur-
bances, fluid retention, teratogenicity and inhibition of the
metabolism of other drugs [86].
Fluconazole is used primarily to treat mucosal or sys-
temic candidiasis and has a potential for drug interactions
and needs to be given as long-term treatment [94]. Adverse
effects are very mild, including gastrointestinal disturbance
(nausea, abdominal pain, diarrhea), headache, and insom-
nia. This drug can also cause elevation in liver function
tests, and this is an indication for discontinuation of ther-
apy [78, 95].
Itraconazole was approved in 1995 for the treatment of
onychomycosis and has a low incidence of adverse effects,
with the most common adverse effects being gastrointes-
tinal disturbance (nausea, abdominal pain, diarrhea) and
headache. Itraconazole can also cause elevation in liver
function tests. There have been no reports of hepatitis in
patients using the pulse regimen, thus itraconazole pulse
therapy for onychomycosis appears to be safe. No papers
have suggested there is a requirement for liver function
monitoring for the pulse regimen; however, such moni-
toring is recommended when there is a history of altered
liver function tests or hepatic dysfunction before the
beginning of therapy. However, in patients on continuous
therapy over a month, some authors do suggest testing [78,
93, 96, 97].
Terbinafine has mild adverse effects reported, such as
nausea, diarrhea, mild abdominal pain, taste change and
taste loss [98–102]. Hepatotoxicity can be seen in a few
cases, with a prodrome of asthenia, anorexia and abdomi-
nal pain. Pale stools and dark urine can be seen 1 week
after the onset and can progress to hepatocellular and
cholestatic dysfunction. Thus, it is recommended that
33
patients on terbinafine therapy have liver function tests
performed pretreatment and at 4–6 weeks [78, 103].
3.12 Cost-Effectiveness
Treatment costs of onychomycosis are high. Medication is
often not covered by health insurance or by the govern-
ment, which can become a concern to the patient. Some
studies evaluated the costs of the different therapies for
onychomycosis. Most studies found that terbinafine was
the most effective therapy in relation to cost (lowest cost-
effectiveness ratio) [104, 105]. Griseofulvin has the lowest
acquisition cost of all, but requires long-term use [106].
Although terbinafine is more cost effective, itraconazole
has a broader spectrum of antimicrobial activity. Thus, it
should be considered in the management of infections
caused by molds and/or Candida [45]. Warshaw et al. [61]
found that a combination of pulsed itraconazole and pulsed
terbinafine was the most cost-effective regimen [107].
4 Conclusions
Many studies about onychomycosis treatment have been
performed over the last couple of decades. In the majority
of the studies, terbinafine has proven its superiority in the
treatment of onychomycosis. In these studies, the identified
pathogens were dermatophytes.
The efficacy of terbinafine in Candida infections is
questionable. Some studies showed little efficacy, while
others suggested that a longer duration of treatment is
necessary. When other pathogens were isolated, itraco-
nazole and other azoles have proven to be more effective
than terbinafine because of their broader antimicrobial
coverage for Candida and nondermatophyte molds. Based
on this difference, confirmation and identification of
infection through positive cultures are therefore very
important.
Terbinafine can be used in different dosage regimens.
No statistical difference was found between 12 and
24 months treatment. Only one study showed that contin-
uous therapy is superior to pulsed regimen. Pulsed therapy
regimen may be used with less cost and fewer adverse
effects. Sequential pulsed therapy of itraconazole and ter-
binafine also can be an option.
Itraconazole can be used in pulse or continuous sche-
dule, with different dosages, and the duration of therapy
can vary from 2 to 4 months. Considering cost benefit,
pulsed regimen (200 mg twice a day for 1 week/month)
can be considered a good choice of therapy.
The ideal dosage and duration of fluconazole treatment
could not be determined by analyzing the studies, since
different treatment regimens were evaluated. Dosage
34
regimens of 150, 300 and 450 mg weekly during
6–10 months can be used.
Acknowledgments No sources of funding were used to prepare this
article. The authors have no conflicts of interest that are directly
relevant to the content of this review.
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