ARTICLE
The treatment of dermatomycosis (dermatophytic infection of the skin)
and onychomycosis (fungal infection of the nail plate) has improved dramatically
in recent years with the introduction of a new generation of oral antifungal
agents, the allylamine terbinafine and the triazoles fluconazole and itraconazole.
Itraconazole has been on the market for more than 10 years and has been
used in the treatment of more than 34 million patients, approximately
two-thirds of whom had dermatological (skin and nail) infections. Consequently,
an extensive database on the safety of itraconazole in the treatment of
dermatomycosis and onychomycosis has been compiled from controlled clinical
trials and post-marketing surveillance. We have drawn on this database
to review the safety of various continuous itraconazole regimens used
in the treatment of these conditions.
To evaluate the safety of a drug objectively, the incidence of adverse
events must be compared with that observed with a placebo in a similar
study population under the same conditions and during the same study period.
This shows the extent to which the reported adverse event relates to the
intake of the drug (i.e. the attributable risk). Pharmacovigilance
during the post-marketing period provides additional qualitative information
on new adverse events that are revealed only after extensive use of the
drug in a large patient population. In contrast to prospective studies,
post-marketing surveillance data do not provide precise quantitative information
on the incidence of these adverse events.
Safety in controlled clinical
trials
Adverse events
The clinical trials used as data sources for this review are summarized
in Table I [1-4] (unpublished
data). The overall incidence of adverse events in patients who received
continuous itraconazole treatment for onychomycosis or dermatomycosis
(20.4%) differed little from that in patients who received either topical
miconazole or oral placebo (18.4%), representing an attributable risk
of 2% (Table I). In addition,
the attributable risk of adverse events with itraconazole did not exceed
1% for any body system.
The most frequently reported adverse events in all treatment groups
were gastrointestinal disorders, headache and skin disorders (Table
I), although most skin disorders were related directly to the
underlying fungal disease. Serious adverse events that could reasonably
be attributed to itraconazole treatment were rare and were limited to
allergic reactions (anaphylaxis, rash, urticaria), abnormal liver function
test results, hepatitis and drug interactions.
The absolute incidence of adverse events in all treatment groups was
higher in patients with onychomycosis than in patients with dermatomycoses.
This difference was probably due to the longer duration of treatment for
onychomycosis (3 months compared with a maximum of 1 month for dermatomycosis).
For onychomycosis, the incidence of adverse events in both the itraconazole
group and the control group was higher in the US trials [2] (unpublished
data) than in the German trial [3], which may reflect differences in reporting
practices.
Laboratory abnormalities
In general, blood and urine samples were taken before treatment and
at weeks 4, 8 and 12 of treatment in patients treated for onychomycosis
or weeks 2 and 4 of treatment in patients treated for dermatomycoses.
In some patients, blood and urine samples were taken up to 4 months after
treatment.
Laboratory data have been analysed for 554 itraconazole-treated patients
and 378 placebo-treated patients from the 19 placebo-controlled studies
in onychomycosis and dermatomycosis performed in the USA [2] (unpublished
data). No pattern of abnormalities emerged that could be attributed to
itraconazole and no significant differences between itraconazole and placebo
were recorded, with the exception of elevated liver function test values
and leucocyte count. Laboratory data from the German onychomycosis study
showed that the incidence of clinically important laboratory abnormalities
was 7.0% (n = 1,143) with itraconazole and 4.2% (n = 379)
with oral placebo plus topical miconazole, an attributable risk of 2.8%
[3].
Liver and biliary system
Itraconazole therapy has been associated with a low incidence of elevated
liver function test values, most of which were transient and rarely clinically
significant; very rarely, itraconazole therapy was associated with an
idiosyncratic hepatitis that was reversed on discontinuation of treatment
[5, 6]. Symptomatic hepatitis has been reported extremely rarely in association
with itraconazole when it is used to treat onychomycosis and other dermatomycoses,
with an estimated frequency of one in 500,000. In the studies analysed
here, liver and biliary system disorders were almost always in the form
of asymptomatic liver enzyme elevations and were recorded in 1.5% of patients
who received continuous itraconazole treatment and in 0.7% of patients
who received a placebo or miconazole, giving an overall attributable risk
of 0.8%. The incidence of hepatobiliary adverse events was slightly higher
in patients receiving itraconazole treatment for onychomycosis (1.7%)
than in those receiving itraconazole treatment for dermatomycoses (1.3%).
In the placebo-controlled studies in the USA [2] (unpublished data),
liver function test values were increased slightly more frequently in
the itraconazole groups than in the placebo groups for each indication
and more frequently in the onychomycosis trials than in the dermatomycosis
trials (Table II).
In the German onychomycosis study [3], elevations in liver function
test values were addressed specifically. The incidence of elevated alanine
aminotransferase (ALT) concentrations was extremely low in the itraconazole
group and was not statistically significantly higher than in the group
receiving topical treatment with miconazole (Table
II).
Hepatic monitoring
When itraconazole is used as continuous therapy at 200 mg/day for 4
weeks or longer, it is suggested that liver function tests should be performed
4 weeks after the start of therapy.
Post-marketing surveillance
Prescribing information on itraconazole has been updated to reflect
the safety data from post-marketing surveillance. Post-marketing data
from approximately 34 million patients, accumulated between the introduction
of itraconazole and 1997, have confirmed the data from clinical trials.
Most serious adverse events reported during post-marketing surveillance
were associated with defined underlying risk factors or the use of concomitant
medication or were considered unlikely to be related to itraconazole.
Although a relationship with itraconazole could not be ruled out, no pattern
or frequency of adverse events emerged to support any significant hazard,
contra-indication or warning beyond those already cited in the package
insert.
Safety in diabetic patients
Effective treatment of onychomycosis and dermatomycosis is particularly
important in patients with underlying chronic disease such as diabetes,
in whom these conditions may lead to serious complications [7]. Existing
clinical trials and extensive post-marketing surveillance reports have
not identified any adverse events associated with itraconazole that would
pose an additional risk in patients with diabetes nor have they suggested
important interactions between itraconazole and oral hypoglycaemic agents.
Moreover, interaction of itraconazole with antidiabetic drugs is unlikely
because insulin is not metabolized by cytochrome P450 enzymes and no evidence
has been found to indicate that oral antidiabetics are metabolized by
the same P450 subfamily as itraconazole (CYP 3A4).
Potential for further improvements
in safety
Pharmacokinetic studies have shown that itraconazole has a high affinity
for the stratum corneum and persists in this tissue for up to 4 weeks
after discontinuation of therapy [8-10]. In addition, nail matrix kinetics
have shown that itraconazole can be found in the distal part of the nail
within 1 week of the start of treatment with itraconazole, which suggests
that itraconazole penetrates the nail not only through the nail matrix
but also through the nail bed [10, 11]. Furthermore, therapeutic concentrations
of itraconazole have been shown to persist in fingernails for 3 months
after treatment and in toenails for up to 6 months after treatment [12].
These findings have led to the development of shorter itraconazole treatment
schedules for the treatment of dermatomycosis and onychomycosis. For dermatomycosis,
itraconazole regimens of 200 and 400 mg/day for 1 week have been introduced
for the treatment of tinea corporis/cruris and tinea pedis/manus, respectively.
These schedules have been shown to be at least as effective as conventional
longer-term itraconazole regimens [13, 14].
In addition, a new concept has emerged in the treatment of onychomycosis,
namely short-term, intermittent therapy with itraconazole 200 mg twice
daily (total dose 400 mg/day) for 1 week, followed by a 3-week drug-free
period, repeated for 3 months [15]. The efficacy of this novel intermittent
itraconazole schedule in the treatment of onychomycosis has been found
to be similar to that of the conventional continuous itraconazole schedule
(200 mg/day for 3 months) in a multicentre, double-blind, randomized,
parallel-group, phase III trial [16]. A meta-analysis of studies in which
itraconazole has been used to treat onychomycosis suggests that the intermittent
regimen may have higher efficacy than the continuous regimen in the treatment
of toenail onychomycosis (mycological cure rate 76% ± 9.3% versus
66.4% ± 6.1%, respectively) [17].
Although some of these short-term itraconazole regimens involve a daily
dose of 400 mg, the safety profile of itraconazole does not appear to
be affected adversely [18-20]. Moreover, short-term treatment may offer
advantages over continuous treatment in terms of safety. For example,
in a 3-month treatment period, use of the intermittent itraconazole 1-week
regimen required exactly half the amount of active drug compared to continuous
treatment, 84 instead of 168 (2 x 84)/100 mg capsules itraconazole. Intermittent
treatment may also promote patient compliance. The intermittent regimen
has now become the preferred regimen over continuous itraconazole therapy
for the management of onychomycosis and other dermatomycoses. There are
no monitoring guidelines for intermittent itraconazole therapy.
CONCLUSION Close
monitoring of adverse events and laboratory variables in controlled clinical
trials and extensive post-marketing surveillance have indicated that itraconazole
is well tolerated at a dose of 50-200 mg/day for 1-4 weeks to treat dermatomycoses
or 200 mg/day for 12 weeks to treat onychomycosis. Appropriate precautions
must be taken with respect to patient selection, monitoring of liver function
test values when the treatment is continuous (> 1 month) and concomitant
medication. Itraconazole can also be used safely in the treatment of onychomycosis
or dermatomycosis in diabetic patients. Recently developed short-term and
intermittent itraconazole regimens may provide additional benefits in terms
of patient safety, compliance and cost.REFERENCES
1. Boonk W, de Geer D, de Kreek E, Remme J, van Huystee B. Itraconazole
in the treatment of tinea corporis and tinea cruris: comparison of two
treatment schedules. Mycoses 1999 (in press).
2. Elewski BE, Scher RK, Aly R, Daniel III R, Jones HE, Odom RB, Zaias
N, Jacko ML. Double-blind, randomized comparison of itraconazole capsules
vs placebo in the treatment of toenail onychomycosis. Cutis
1997; 59: 217-20.
3. Haneke E, Tajerbashi M, De Doncker P, Heremans A. Itraconazole in
the treatment of onychomycosis: a double-blind comparison with miconazole.
Dermatology 1998; 196: 323-9.
4. Schuller J, Remme JJ, Rampen FHJ, Van Neer FCJ. Itraconazole in the
treatment of tinea pedis and tinea manus: comparison of two treatment
schedules. Mycoses 1999 (in press).
5. Sugar AM. Fluconazole and itraconazole: current status and prospects
for antifungal therapy [review]. Curr Clin Top Infect Dis 1993;
13: 74-98.
6. Hay RJ. Risk/benefit ratio of modern antifungal therapy: focus on
hepatic reactions [review]. J Am Acad Dermatol 1993; 29: S50-S4.
7. Karchmer AW, Gibbons GW. Foot infections in diabetes: evaluation
and management. Curr Clin Top Infect Dis 1994; 14: 1-22.
8. Heykants J, Michiels M, Meuldermans W, Monbaliu J, Lavrijsen K, van
Peer A, Levron JC, Woestenborghs R, Cauwenbergh G. The pharmacokinetics
of itraconazole in animals and man: an overview. In: Recent trends
in the discovery, development and evaluation of antifungal agents.
Fromtling RA, ed. Barcelona, Spain: JR Prous Science Publishers, 1987:
223-49.
9. Larosa E, Cauwenbergh G, Cilli P, Woestenborghs R, Heykants J. Itraconazole
pharmacokinetics in the female genital tract: plasma and tissue levels
in patients undergoing hysterectomy after a single dose of 200 mg of itraconazole.
Eur J Obstet Gynecol Reprod Biol 1986; 23: 85-9.
10. Cauwenbergh G, Degreef H, Heykants J, Woestenborghs R, Van Rooy
P, Haeverans K. Pharmacokinetic profile of orally administered itraconazole
in human skin. J Am Acad Dermatol 1988; 18: 263-8.
11. Matthieu L, De Doncker P, Cauwenbergh G, Woestenborghs R, van de
Velde V, Janssen PAJ, Dockx P. Itraconazole penetrates the nail via
the nail matrix and the nail bed an investigation in onychomycosis.
Clin Exp Dermatol 1991; 16: 374-6.
12. Willemsen M, De Doncker P, Willems J, Woestenborghs R, Van de Velde
V, Heykants J, Van Cutsem J, Cauwenbergh G, Roseeuw D. Posttreatment itraconazole
levels in the nail. New implications for treatment in onychomycosis. J
Am Acad Dermatol 1992; 26: 731-5.
13. Parent D, Decroix J, Heenen M. Clinical experience with short schedules
of itraconazole in the treatment of tinea corporis and/or tinea cruris.
Dermatology 1994; 189: 378-81.
14. Gupta AK, De Doncker P, Heremans A, Stoffels P, Piérard GE,
Decroix J, Heenen M, Degreef H. Itraconazole for the treatment of tinea
pedis: a dosage of 400 mg/day given for 1 week is similar in efficacy
to 100 or 200 mg/day given for 2 to 4 weeks. J Am Acad Dermatol
1997; 36: 789-92.
15. Roseeuw D, De Doncker P. New therapeutic concepts for the treatment
of onychomycosis. J Eur Acad Dermatol Venereol 1993; 2 (suppl.
1):
34-8.
16. Havu V, Brandt H, Heikkila H, Hollmen A, Oksman R, Rantanen T, Saari
S, Stubb S, Turjanmaa K, Piepponen T. A double-blind, randomized study
comparing itraconazole pulse therapy with continuous dosing for the treatment
of toe-nail onychomycosis. Br J Dermatol 1997; 136: 230-4.
17. Gupta AK. Pharmacoeconomic analysis of oral antifungal therapies
used to treat dermatophyte onychomycosis of the toenails: a US analysis.
Pharmacoeconomics 1998; 13: 243-56.
18. De Doncker P, Decroix J, Piérard GE, Roelant D, Woestenborghs
R, Jacqmin P, Odds F, Heremans A, Dockx P, Roseeuw D. Antifungal pulse
therapy for onychomycosis. A pharmacokinetic and pharmacodynamic investigation
of monthly cycles of 1-week pulse therapy with itraconazole. Arch Dermatol
1996; 132: 34-41.
19. De Doncker P, Gupta AK, Marynissen G, Stoffels P, Heremans A. Itraconazole
pulse therapy for onychomycosis and dermatomycosis: an overview. J
Am Acad Dermatol 1997; 37: 969-74.
20. Gupta AK, De Doncker P, Scher RK, Haneke E, Daniel III CR, André
J, Baran R. Itraconazole for the treatment of onychomycosis. Int J
Dermatol 1998; 37: 303-8.
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