Update on the safety of itraconazole pulse therapy in onychomycosis and dermatomycoses

ARTICLE

The use of oral antifungal agents for the treatment of superficial fungal infections is well documented [1-5]. The older oral agents such as griseofulvin and ketoconazole are generally unsatisfactory therapies due to the prolonged duration of treatment, poor response rates and the potential for severe side effects, especially when treating onychomycosis of the toes [6, 7].

The advent of a new generation of oral antifungal drugs, including itraconazole, terbinafine and fluconazole, has improved the outlook for patients with fungal nail infections. Itraconazole and fluconazole are novel triazole antifungals which selectively inhibit fungal cytochrome P450 (CYP450), via an interaction with C-14 alpha demethylase, by impairing sterol synthesis in fungal cell membranes [8, 9]. Terbinafine is an allylamine antifungal agent which acts via the inhibition of squalene epoxidase. Itraconazole has broad-spectrum activity with important coverage against dermatophytes, yeasts, and moulds [10]. With fluconazole there is relatively less data concerning its activity against onychomycosis caused by Candida species and non-dermatophyte moulds. Terbinafine may be less effective against Candida species compared to its activity against dermatophytes.

A breakthrough in the development of antifungal regimens has been the correlation of tissue pharmacokinetics at specific body sites with dosage, duration of therapy and efficacy. In particular, a "reservoir effect" is found with many of the new antifungal agents, in that they persist in the stratum corneum for many weeks after the discontinuation of treatment. This "reservoir effect" means that high cure rates can be achieved with much shorter courses of treatment [11, 12].

Pharmacokinetic studies have shown that itraconazole has a high affinity for skin and nails [13] with concentrations in the stratum corneum up to 10 times higher than in serum. The active agent persists for 3-4 weeks in the stratum corneum and for 6-12 months in the nail [14, 15]. The pharmacokinetic profile of itraconazole has permitted the development of a pulse regimen for the treatment of onychomycosis and cutaneous dermatomycoses [16, 17]. The therapeutic reservoir only occurs in the target tissues, not in the systemic circulation, since itraconazole is cleared rapidly from the blood within 7-10 days. Pulse dosing regimens (typically, itraconazole 400 mg 1 week on therapy, 3 weeks off therapy) are as effective as, if not more effective than, continuous dosing [18]. Pulse dosing reduces the duration of itraconazole therapy, as well as the total drug exposure.

To date, the safety of itraconazole given for short periods of time has not been extensively appraised and reported. Therefore, in order to assess the overall safety profile of pulse itraconazole, the safety and tolerability of a range of doses were compared with terbinafine and fluconazole from common practice and clinical trials.

Safety of itraconazole in common practice

Itraconazole has been in use worldwide for approximately 15 years. In the past 13 years, more than 50 million patients have received treatment; therefore, the safety profile of itraconazole is well defined. Of these patients, approximately 77% were treated for skin and nail infections (including pulse dosing regimens) and 23% were treated for systemic fungal infections. These patients received more than 8 million months of itraconazole treatment at an average daily dose of 300 mg. The overall tolerability of itraconazole has been excellent. Although drug interactions have been observed, these are well known in terms of pharmacokinetic and consequent pharmacodynamic effects, and therefore are predictable and easily managed. There has been a discussion of drug interactions in several recent comprehensive reviews [19-21].

A prescription event monitoring (PEM) report has shown that among 13,645 patients (including 282 patients > 70 years) who received itraconazole between April 1989 and April 1990, the drug was well tolerated [22]. The dose and duration of treatment with itraconazole depended upon the indication with the most prolonged treatment being for onychomycosis. There were no deaths attributable to itraconazole treatment and the most frequent adverse events (mean rates per 1,000 patients in first month) in itraconazole treated patients were abdominal pain (3.9%), nausea (3.4%) and rash (3.2%). The pattern of adverse events was compared with data obtained from other PEM studies evaluating 33 drugs in a total population of 332,402 patients. A comparison of the adverse events seen following treatment with itraconazole, fluconazole and the mean of 33 other drugs is shown in Table I [22]. Both drugs were well tolerated, with similar adverse events profiles.

A recent review of the safety of new oral antifungal agents [23] confirmed that the most common side effects seen with itraconazole, terbinafine and fluconazole were gastrointestinal disorders (nausea, vomiting, diarrhoea, dyspepsia and abdominal pain). Neurological effects, including headache, dizziness, fatigue, somnolence and malaise have also been reported following treatment with these agents.

Safety of itraconazole in clinical trials

Safety of itraconazole in dermatomycoses

Safety data from several studies, which included a total of 1,246 patients with dermatomycoses (tinea pedis and tinea corporis) have been assessed to compare the safety of short regimens of itraconazole, terbinafine and placebo [24-26]. All doses were well tolerated, with the incidence of adverse events being generally lower for the shorter duration of treatment with itraconazole. The frequencies of headache (0-5%) and gastrointestinal disorders (2-4%) were similar to those seen for placebo at all doses of itraconazole, with the incidence of gastrointestinal disorders in patients treated with 250 mg/day terbinafine being 7%. The incidence of adverse events observed for the 400 mg 1-week pulse regimen was similar to placebo (Table II).

Itraconazole has shown excellent tolerability in 1,197 patients with pityriasis versicolor treated with 200 mg for 1 week, with an overall incidence of adverse events of 6.3% [27]. The most common adverse events seen were headache (2% of patients) and gastrointestinal intolerance (3% of patients). Placebo adverse events were reported by 5% of patients.

Safety of itraconazole in onychomycosis

Pulse versus continuous therapy:

In a worldwide safety review, a total of 27 trials were used to examine the safety of pulse itraconazole compared to continuous therapy for toenail onychomycosis. These studies included 2,867 patients treated with three pulses of itraconazole (200 mg bid for 1 week out of 4 in the month) and 1,845 patients receiving 12 weeks of continuous itraconazole (200 mg daily) from 20 trials [28].

Overall, adverse events were experienced by 18.8% of 2,867 patients receiving pulse therapy compared to 20% of 1,845 patients receiving continuous treatment. Only 2.2% of 2,867 patients receiving pulse therapy withdrew from treatment due to adverse events, compared to 5% of 1,845 patients treated with continuous itraconazole. The review also showed that 1.9% of patients treated with pulse therapy experienced abnormal liver function tests and this was similar to the frequency observed in patients receiving continuous itraconazole therapy (3%). The increases in liver enzyme levels were reversible and the incidence was comparable to that observed in the general population. For example, a survey in the United Kingdom suggested that 6% of an apparently healthy population had at least one abnormal liver function test [29]. Further studies have reported similar rates of liver enzyme elevations with placebo in patients receiving either continuous [30] or pulse itraconazole [31].

The frequencies of the most common adverse events observed with pulse (400 mg/day) and continuous (100 mg/day and 200 mg/day) dosing regimens of itraconazole are shown in Table III. The incidence of adverse events was lowest in the group of patients treated with 400 mg daily for 1 week, with the most common side effects being gastrointestinal (4.3%) and headache (1.1%).

The adverse event profiles of pulse and continuous itraconazole have also been compared in placebo-controlled studies [31]. In both analyses, similar rates of adverse events were seen for itraconazole and placebo-treated patients (Figs. 1 and 2). Among patients who reported an adverse event, the most frequently-reported events during pulse therapy were: headache, gastrointestinal disorders and skin reactions (15%, 8% and 15%, respectively), compared to rates of 15%, 19% and 7%, respectively, for patients receiving continuous therapy.

Comparative safety:

The safety profile of 400 mg pulse itraconazole has also been compared with terbinafine and placebo in the treatment of onychomycosis (Table IV). The overall incidence of adverse events seen in the treatment phase of the studies was similar for the 400 mg pulse dose of itraconazole, terbinafine and placebo in patients with onychomycosis.

A double-blind study has also been performed which compared continuous therapy with itraconazole (200 mg/day) and continuous therapy with terbinafine (250 mg/day) in the treatment of onychomycosis [32]. The overall incidence of adverse events was similar in both treatment groups (22% and 23%, respectively). The numbers of patients with a code 4 laboratory abnormality (baseline value is not pathological; at least two values [or the last one during observation period] are pathological) were also similar for itraconazole (15/146: 10%) and terbinafine (17/146: 12%). The numbers of patients with severe adverse events was 7/146 [4.8%] in the terbinafine group and 2/146 [1.4%] in the itraconazole group. The number of patients who discontinued treatment due to adverse events in the terbinafine group was 8% compared with 1% patients treated with itraconazole.

In an analysis of pooled data, adverse events were reported in 32% of 1,248 patients receiving continuous terbinafine treatment (250 mg/day) for 12 weeks [33]. Overall, 4.6% of terbinafine treated patients withdrew from treatment.

In another comparative study between continuous terbinafine and pulse itraconazole for onychomycosis, the number of patients reporting at least one adverse event was similar for terbinafine (47.5%) versus itraconazole (47.6%) [34]. No significant adverse events were noted in either group. The most commonly reported adverse events were nausea, headache, upper respiratory tract infection, chest infection, back pain, flu-like symptoms, bronchitis and fever. Most were mild to moderate in severity and considered by the investigators not to be related to the study medications.

Specific safety issues

Cutaneous adverse reactions

Cutaneous reactions have also been reported following treatment with all three new antifungal agents [23]. From a review of published literature, the rate of skin toxicity caused by itraconazole ranged from 2.7 to 3.7%; a similar range was noted for terbinafine [23, 28, 35]. In the case of itraconazole, the most common cutaneous events have been eruption and pruritus. Generalised exanthematous pustulosis and urticaria were also seen on rare occasions [23]. The cutaneous reactions seen following therapy with terbinafine have a similar spectrum. Rarely, erythema multiforme [36], toxic epidermal necrosis [37] and Stevens-Johnson syndrome [38] have been reported. Should a severe eruption occur the patient should be counselled about discontinuing therapy and the need to seek further medical advice at the onset of a cutaneous eruption [36]. Severe cutaneous reactions have also been seen following exposure to fluconazole, including Stevens-Johnson syndrome [39], although these are uncommon [23, 39].

Hepatic safety

Increases in liver enzymes (transaminases and alkaline phosphatase) and bilirubin have been reported following therapy with itraconazole, fluconazole and terbinafine. From a review of the published literature, itraconazole causes mild transient increases in hepatic enzymes in approximately 1-5% of patients following continuous therapy [40]. In patients receiving pulse itraconazole an increase in liver enzymes has been reported in 1.7-2% of patients [33]. These increases generally return to normal either spontaneously or following discontinuation of treatment [23]. Symptomatic drug-associated hepatitis has been described rarely for itraconazole [41], with the symptoms usually resolving several weeks to months after discontinuation of treatment. Liver monitoring is recommended for patients receiving continuous itraconazole, but not for those receiving pulse therapy.

From published literature, terbinafine has been associated with elevated liver function tests in approximately 3-7% of patients [23, 42]. Rarely, some patients treated with terbinafine have experienced hepatitis, which is thought to be idiosyncratic [23, 43]. Patients have generally recovered within weeks to months of discontinuation of therapy; in some cases prolonged (> 3 months) elevated liver enzymes have been observed [23, 44]. There is a recommendation that hepatic enzyme levels in serum should be monitored in patients receiving terbinafine for more than 6 weeks [43].

Fluconazole also induces liver test and other hepatic abnormalities, which are usually asymptomatic, reversible increases in transaminases. The incidence of hepatotoxicity is low [45], although severe jaundice and fatal hepatic necrosis has been reported in patients with AIDS.

Sensory and neurological disturbances [46-50]

Sensory disturbances such as taste loss (ageusia) have been observed following treatment with terbinafine. For example, taste disturbance has been reported in 2.8% of the terbinafine-treated patients, with complete loss of taste in a proportion of the patients [23, 35]. The taste disturbance usually recovers within several weeks of discontinuing the drug; however, in one patient the taste loss was reported to last for a period exceeding 3 years [47].

Changes in the ocular lens and retina have also been reported in patients receiving terbinafine as well as the placebo [23]. The clinical significance of these changes is unknown.

Haematological adverse reactions [51-59]

Both terbinafine [56, 58] and fluconazole [59] have been associated with reversible agranulocytosis in patients being treated for superficial mycoses. A serum sickness-like reaction has been reported with itraconazole [57].

CONCLUSION

Overall, itraconazole has an excellent safety profile, demonstrated by the low incidence of adverse events reported in common use and in clinical studies, as well as by the low rate of withdrawals due to adverse events. Both continuous and pulse regimens of itraconazole have shown similar rates of adverse events compared with placebo.

The most frequently-reported adverse events following treatment with itraconazole are headache, gastrointestinal disorders and skin reactions. Increasing the daily dose of itraconazole to 400 mg in the pulse regimen has no effect on the incidence of adverse events. In a worldwide safety review, fewer adverse events were seen following 3 pulses of 400 mg/day itraconazole (18.8%), compared with 12 weeks of continuous therapy with 200 mg itraconazole daily (20%). Furthermore, the incidence of withdrawals due to adverse events was lower for pulse therapy (2.2%) than for continuous therapy (5%).

The incidence of abnormal liver function tests observed in the worldwide review was low and similar for continuous therapy (3%) and pulse therapy (1.9%). The rate of abnormal liver function tests observed following treatment with pulse itraconazole therapy was comparable to that seen in the general population. No specific recommendations in terms of liver monitoring were therefore required with the 1-week itraconazole pulse. This reduces cost and improves patient compliance.

Worldwide safety data confirms that pulse and continuous regimens of itraconazole are well tolerated. Overall, pulse therapy appears to have some safety advantages compared with continuous itraconazole or alternative antifungal therapy. Although drug interactions are known to occur with itraconazole, these are known and are therefore predictable and manageable.

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