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Efficacy of Itraconazole in the Prophylactic Treatment of Pityriasis (Tinea) Versicolor
Jan Faergemann, MD, PhD;
A. K. Gupta, MD, FRCPC;
A. Al Mofadi, MD, FRCPC;
A. Abanami, MD, FRCP(Edin);
A. Abu Shareaah, MD;
Greet Marynissen, PhD
Arch Dermatol. 2002;138:69-73.
ABSTRACT
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Background Pityriasis (tinea) versicolor has a high tendency to recur after being
treated successfully. Prophylactic treatment to reduce recurrence is needed.
Objective To determine whether recurrence of pityriasis versicolor could be prevented
by prophylactic itraconazole treatment.
Design Open treatment followed by a randomized, double-blind, placebo-controlled
phase.
Setting Multinational outpatient centers.
Patients A total of 239 consecutive patients were included; 238 started open
treatment. A total of 209 patients started prophylactic treatment: 106 in
the itraconazole group and 103 in the placebo group.
Interventions Open treatment: itraconazole, 200 mg once daily for 7 days. Prophylactic
treatment: itraconazole, 200 mg, or placebo twice daily 1 day per month for
6 consecutive months.
Main Outcome Measures Mycological cure rates at the end of open treatment and at the end of
prophylactic treatment.
Results Mycological cure at the end of open treatment was 92% (205/223). At
the prophylactic treatment end point (6 months), mycological cure was 88%
(90/102) in the itraconazole group and 57% (56/99) in the placebo group (P<.001). In open treatment, 11 patients were not able
to be evaluated for efficacy. In prophylactic treatment, 4 patients in the
itraconazole group and 4 in the placebo group were not able to be evaluated.
Adverse events were reported during open treatment by 26 patients (11%) and
during prophylactic treatment by 17 (16%) in the itraconazole group and 14
(14%) in the placebo group. No patients experienced any serious adverse events.
Conclusions Prophylactic itraconazole treatment is efficacious for pityriasis versicolor
after 6 months, as is itraconazole in the treatment of pityriasis versicolor.
INTRODUCTION
PITYRIASIS (TINEA) versicolor may be treated with topical or oral agents,
with the latter being used especially when the disease is widespread or does
not respond to topical measures. Systemic agents used for treating pityriasis
versicolor include itraconazole, ketoconazole, and fluconazole.1-2
Itraconazole is a triazole antimycotic agent with strong keratophilic
and lipophilic properties.3 Similar to other
azole antifungal agents, the mode of action of itraconazole involves inhibition
of 14- -demethylase, resulting in impaired sterol synthesis in fungal
cell membranes. In vitro, itraconazole is active not only against yeasts such
as Malassezia and Candida
species but also against dermatophytes and nondermatophyte molds.4-5
When itraconazole is used to treat pityriasis versicolor, a suggested
regimen is 200 mg/d for 7 days, with a minimum cumulative dose of at least
1000 mg being required for effective therapy.6-7
Four weeks after the start of therapy, cure rates of 80% to 90% have been
reported.7 Although the fungal organisms may
be nonviable, the color of the affected skin may take several weeks or months
to normalize.
Pityriasis versicolor recurs at a variable rate in treated individuals,
and 60% to 90% of patients relapse within 2 years in some series.8 Therefore, it is important to evaluate a prophylactic
regimen that may be effective and safe in preventing the recurrence of pityriasis
versicolor.
We evaluated the efficacy of treatment with itraconazole, 200 mg once
daily for 1 week, and the efficacy of placebo-controlled prophylactic treatment
with itraconazole, 200 mg taken 12 hours apart 1 day per month for 6 consecutive
months, in terms of clinical and mycological outcome and frequency of recurrence
of pityriasis versicolor. To our knowledge, this is the first study to evaluate
this regimen of itraconazole as a prophylactic measure against pityriasis
versicolor.
PATIENTS AND METHODS
This multicenter, multinational trial was characterized by an open,
active treatment phase with itraconazole, 200 mg once daily for 1 week, followed
by 4 weeks without active therapy. In patients in whom pityriasis versicolor
cleared, active treatment was followed by a double-blind prophylactic treatment
phase with itraconazole, 200 mg, or placebo twice on 1 day per month for 6
consecutive months. Patients were randomly allocated to 1 of the 2 treatments
in the prophylactic phase.
Patients who fulfilled the inclusion and exclusion criteria at the first
visit (baseline) received itraconazole therapy for 7 days (treatment phase).
Five weeks from the start of therapy (ie, 4 weeks after treatment), patients
who were mycologically cured (no hyphae present) were randomized into the
double-blind prophylactic phase to receive either itraconazole or placebo
treatment for 6 months. Inclusion criteria for subjects included those aged
12 to 70 years who had a clinical diagnosis of pityriasis versicolor confirmed
by mycological examination and who provided written informed consent before
inclusion into the trial. Exclusion criteria for subjects included those with
(1) known sensitivity to itraconazole or its excipients, (2) chronic mucocutaneous
candidiasis or systemic fungal infection, (3) immunosuppression caused by
disease or treatment, (4) any other disease or condition that in the investigator's
opinion should exclude the patient from the trial, and those who (5) participated
in an investigational drug trial within 30 days of selection, (6) were pregnant
or breastfeeding, and (7) were women of childbearing potential without adequate
contraception. The following therapies were not allowed: (1) topical antifungal
agents, topical corticosteroids, shampoos with active ingredients against Malassezia, or tar shampoos used within 2 weeks of the
randomization visit or during the trial (topical corticosteroid nasal sprays
or eye ointments were allowed during the trial); (2) systemic corticosteroid
therapy either within 1 month of the randomization visit or during the trial;
(3) systemic antifungal therapy within 2 months of the randomization visit
or during the trial; (4) use of the enzyme-inducing drugs rifampin, phenytoin,
rifabutin, carbamazepine, and isoniazid; and (5) use of some drugs metabolized
by cytochrome P450 3A4 with concomitant increase in their concentrations (eg,
terfenadine, astemizole, cisapride, oral midazolam hydrochloride, triazolam,
quinidine gluconate, pimozide, and 3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors). Other medications known to interact with itraconazole were monitored
if they were being taken concurrently. Because absorption of itraconazole
is impaired when gastric acidity is decreased, acid-neutralizing agents (eg,
aluminum hydroxide) should be administered at least 2 hours after the intake
of itraconazole. Itraconazole should be administered with 2 glasses of a cola
beverage in individuals with achlorhydria or those taking acid secretion suppressors
(eg, H2-antagonists and proton pump inhibitors).
Patients could be withdrawn from the trial if (1) a serious adverse
event occurred or (2) the investigator considered it in the best interest
of the patient for safety reasons. Patients were withdrawn from the trial
if they withdrew their consent or if the randomization code was broken.
METHODS OF ASSIGNING PATIENTS TO TREATMENT GROUPS
All patients admitted to the trial entered the open treatment phase.
Patients who were mycologically cured (no hyphae present) at the end of week
5 from the start of therapy were allocated to one of the treatment groups
in the double-blind prophylactic phase using a predetermined randomization
code generated at a central site. At each participating medical center, medication
numbers were assigned consecutively starting with the lowest available number.
Therefore, the investigator was not aware of the randomization code.
DETERMINATION OF SAMPLE SIZE
The primary variable was the mycological cure rate at the end of open
treatment and at the end of prophylactic treatment. Mycological cure was described
as negative findings on light microscopic examination. Mycological cure was
expected to occur in 85% of patients who underwent itraconazole treatment
in the first treatment phase, in 89% who underwent prophylactic treatment
with itraconazole, and in 71% who underwent placebo prophylaxis. To be able
to detect this difference with a power of 80% at the 5% level of significance,
74 patients are required in each treatment group. Assuming a mycological cure
rate of 85%, 174 patients would be required to start the first treatment phase
to have 148 patients to randomize between the groups receiving placebo and
active therapy in the prophylactic treatment phase of the study. To account
for a dropout rate of approximately 10%, at least 194 patients needed to be
recruited for the trial.
SAFETY ANALYSIS
An evaluation of adverse events was performed on all patients who received
the trial medication at least once. An additional intent-to-treat analysis
was performed on all randomized patients who had at least 1 administration
of the prophylactic treatment medication and who had efficacy data after visit
2.
INITIAL CHARACTERIZATION OF PATIENT SAMPLE
For the open treatment phase, all data were tabulated and were descriptively
presented with 95% confidence intervals. Comparability between treatment groups
was evaluated with respect to the demographic and baseline data. For continuous
data (eg, age), the Van Elteren test was applied. For nominal categorical
data (eg, sex and race), the Cochran-Mantel-Haenszel test for general association
was used. For ordinal categorical data (eg, clinical global evaluation scores),
the Cochran-Mantel-Haenszel row mean scores differences test was used. All
data were analyzed descriptively.
EFFICACY VARIABLES
The primary variable was the mycological cure rate at the end of open
treatment and at the end of prophylactic treatment. Mycological cure was defined
as no hyphae present. Samples for microscopy were always taken from the same
area. The cure rate at the end of the open treatment phase was tabulated.
Itraconazole and placebo prophylaxis were compared at the end of the prophylactic
treatment phase using the Cochran-Mantel-Haenszel test for general association.
Secondary variables included clinical global evaluation scores and signs
and symptoms of disease. All data were analyzed descriptively per time point.
In the open treatment phase, all data were analyzed descriptively only. Changes
from visit 1 (baseline) were analyzed using the Wilcoxon signed rank test
for ordinal and continuous data and the McNemar test for dichotomous data.
In the prophylactic treatment phase, between-group differences for dichotomous
data were investigated using the Cochran-Mantel-Haenszel test for general
association. Groups were compared for ordinal data using the Cochran-Mantel-Haenszel
row mean scores differences test. Comparisons were performed for continuous
data using the Van Elteren test. Within-group changes from randomization visit
2 were analyzed using the Wilcoxon signed rank test for ordinal and continuous
data and the McNemar test for dichotomous data. Time-to-recurrence data were
analyzed using the Mantel-Cox test.
ASSESSMENTS
For efficacy evaluations, patients had to be seen preferably by the
same physician at each trial visit to maintain uniformity across clinical
evaluations.
Primary Efficacy Variable
The primary efficacy variable was the mycological cure rate assessed
at the end of weeks 5 and 29. Mycological cure was defined as negative microscopic
results (negative potassium hydroxide preparation). For mycological evaluation,
skin scrapings were taken from the active border of the lesion.
Secondary Efficacy Variables
Signs and Symptoms.
Hyperpigmentation, hypopigmentation, itching, erythema, and latent desquamation
were assessed according to absence or presence at each visit.
Clinical Global Evaluation.
At each visit, findings from clinical evaluation were rated as follows:
cured (absence of all symptoms vs baseline, except hyperpigmentation or hypopigmentation);
marked improvement (clinical improvement  50% vs baseline); moderate improvement
(clinical improvement >0% to <50% vs baseline); unchanged (no change in
symptoms vs baseline); and deterioration (worsening of symptoms vs baseline).
Patient Compliance.
Compliance was measured by patient self-assessment and by blister card
reconciliation at the end of open treatment and during prophylactic treatment.
Self-assessment consisted of the patient recording in a diary the number of
capsules taken per dose of trial medication, the time of each intake, and
the dates.
RESULTS
PATIENT DISPOSITION
There were 239 patients recruited. One patient withdrew consent and
received no treatment. Therefore, 238 patients entered the open treatment
phase and received itraconazole, 200 mg/d for 7 days. Demographic and other
baseline characteristics of the patients are given in Table 1. Data are presented on an on-protocol basis (ie, having
excluded patients who were characterized as having a major protocol deviation).
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Table 1. Demographic and Other Baseline Characteristics of the Study
Population
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Twenty-nine patients who received treatment in the open phase did not
continue into the double-blind prophylactic phase. Of these, 18 were not cured
and 11 were lost to follow-up or were noncompliant. At the end of open treatment,
mycological cure was recorded in 205 (92%) of 223 patients (Table 2). All patients randomized into the double-blind prophylactic
phase were mycologically negative at the time of randomization. At the end
of the prophylactic phase, 90 (88%) of 102 patients in the itraconazole group
and 56 (57%) of 99 in the placebo group were still mycologically negative
(P<.001) (Table
2).
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Table 2. Results of Open and Prophylactic Treatment With Itraconazole
in Patients With Pityriasis (Tinea) Versicolor
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CLINICAL GLOBAL EVALUATION
Findings were scored as cured, marked improvement, moderate improvement,
unchanged, or deteriorated. Global evaluation scores were significantly better
in the itraconazole group compared with the placebo group when evaluated at
the prophylactic treatment end point (P<.001).
For all variables (erythema, hypopigmentation, desquamation, and itching),
the itraconazole group showed significantly superior changes at the prophylactic
treatment end point compared with the placebo group.
ADVERSE EVENTS
Adverse events were reported by 26 patients (11%) during open treatment
and 31 (15%) during prophylactic treatment (17 patients [16%] in the itraconazole
group and 14 [14%] in the placebo group).
Adverse events considered to be possibly, probably, or very likely drug
related were reported in 10 patients during the open treatment phase and in
2 in the itraconazole group during the prophylactic treatment phase. All these
adverse events were mild to moderate in intensity, except for severe pruritus
in 1 patient. All patients continued in the trial except for 1 in open treatment
who experienced urticaria and was withdrawn. Two patients in open treatment
and 4 in the placebo group of prophylactic treatment were withdrawn from the
trial because of adverse events. Moderate urticaria in 1 patient was the only
adverse event leading to withdrawal that was considered to be very likely
related to trial medication use. No patients experienced a severe adverse
event.
The most common adverse events during open treatment were gastrointestinal
tract complaints, which were reported by 9 patients (4%). There were no reports
of gastrointestinal tract complaints during prophylactic treatment. The most
common adverse events during prophylactic treatment were upper respiratory
tract infection (reported by 4 patients [4%] in the itraconazole group and
4 [4%] in the placebo group) and influenza-like symptoms (reported by 1 patient
[1%] in the itraconazole group and 4 [4%] in the placebo group).
COMMENT
Itraconazole was effective in this study in the treatment of pityriasis
versicolor, with mycological cure in 92% of patients evaluated 5 weeks after
the start of therapy. The efficacy rate was consistent with that reported
in previous studies.9-18
The excellent in vitro activity of itraconazole against Malassezia species and its high lipophilicity and accumulation in sebaceous
glands19 support the high efficacy rates recorded
when patients were evaluated 5 weeks after the start of therapy and for the
placebo prophylactic group at the end of 6 months' follow-up.
The high rate of recurrence, reaching as much as 60% in 1 year and 80%
in 2 years, is an important consideration in pityriasis versicolor.8 Clinical disease manifests itself when there is conversion
of the saprophytic (blastopore) form of Malassezia
species to the mycelial form. In immunocompetent individuals, factors predisposing
to recurrence may be difficult to eradicate, including a tendency toward seborrhea
and heavy sweating in the presence of high temperature and high humidity.
There may be an inherited predisposition to the disease. A permanent cure
may therefore be difficult to achieve, and this may explain the long-term
nature of the disease. Consequently, a prophylactic regimen may help avoid
recurrence of pityriasis versicolor. Prophylactic regimens using ketoconazole
include 200 mg given on 3 consecutive days every month20
or a single dose of 400 mg taken once a month.21-22
Topical therapies have been used as a prophylactic, but patient compliance
is lower, and no controlled studies have been reported in the literature,
to our knowledge.
The present study was designed to determine whether recurrence of pityriasis
versicolor could be prevented by administering prophylactic itraconazole,
400 mg once a month. To our knowledge, such a study has not been reported
previously. Our results demonstrate that prophylactic therapy with itraconazole
was effective in preventing development of the disease during the 6-month
study.
There are no documented studies of topical prophylactic treatment in
the literature, to our knowledge. Compliance with topical treatment is probably
lower because it is more time-consuming and therefore more difficult to convince
the patient to perform than oral treatment. This prophylactic treatment procedure
with 1 treatment day per month with itraconazole could be used primarily in
patients with frequent recurrences. The prophylactic regimen of itraconazole,
400 mg administrated once a month, was not only effective but also safe and
had high compliance.
AUTHOR INFORMATION
Accepted for publication May 23, 2001.
This study was supported by an unrestricted educational grant from Janssen
Pharmaceutica.
We thank the following individuals for recruiting patients for the study:
T. Novak Gregurek (Croatia); H. Eltonsy, A. Farag, N. Saleh, and Z. Tosson
(Egypt); M. Guimaraes and A. Massa (Portugal); A. Abanami and A. Mofadi (Saudi
Arabia); P. Procter, N. Rabobee, W. Sinclair, and J. van Heerden (South Africa);
J. Faergemann (Sweden); and A. Abu Shareeah (United Arab Emirates).
Corresponding author and reprints: Jan Faergemann, MD, PhD, Department
of Dermatology, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden
(e-mail: jan.faergemann{at}derm.gu.se).
From the Department of Dermatology, Sahlgrenska University Hospital,
Gothenburg, Sweden (Dr Faergemann); the Division of Dermatology, Department
of Medicine, Sunnybrook and Women's College, Health Sciences Center, Sunnybrook,
and the University of Toronto, Toronto, Ontario (Dr Gupta); the Division of
Dermatology, King Fahad National Guard Hospital, Riyadh, Saudi Arabia (Dr
Al Mofadi); the Departments of Dermatology, Riyadh Armed Forces Hospital,
Riyadh (Dr Abanami) and Mafraque Hospital, Ministry of Health, Abu Dubai,
United Arab Emirates (Dr Abu Shareaah); and Medisearch International, Mechelen,
Belgium (Dr Marynissen).
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