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Itraconazole

A Reappraisal of its Pharmacological Properties and Therapeutic Use in the Management of Superficial Fungal Infections

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An Erratum to this article was published on 01 August 1996

Abstract

Synopsis

Itraconazole is an orally administered triazole antifungal agent Its spectrum of activity includes dermatophyte, dimorphic and dematiaceous fungi, yeasts, and some moulds. In clinical trials, mycological cure was attained in approximately 70 to 80, />-70 and />-80% of patients with, respectively, fingernail and toenail onychomycosis (200 mg/day for 3 months), dermatophytosis (100 mg/day for 2 to 4 weeks) and vaginal candidiasis (400 mg/day for 1 day or 200 mg/day for 3 days). Approximately 20 to 30% of patients with onychomycosis may relapse after completion of therapy; relapse rate data are limited for the other indications.

Recently developed intermittent regimens of itraconazole (400 mg/day for 1 week per month for 3 to 4 months) appear to have similar efficacy to standard regimens in the treatment of onychomycosis. Shorter, higher dosage itraconazole treatment regimens (200 or 400 mg/day for 1 week) are also beneficial in dermatomycoses.

Discrepancies and limitations of study design hamper conclusions about efficacy relative to other antifungal drugs. Newer intermittent and short course higher dosage itraconazole regimens have also not been evaluated in comparative studies. Available studies show that the efficacy of itraconazole appears to be greater than that of griseofulvin, but similar to or lower than that of terbinafine in patients with dermatophyte onychomycosis or cutaneous fungal infections. Moreover, the efficacy of itraconazole may be similar to or lower than that of fluconazole in the treatment of cutaneous mycoses. Comparative data from patients with acute vaginal candidiasis suggest that itraconazole is at least as effective as intravaginal clotrimazole and oral fluconazole, and superior to intravaginal econazole. These results require confirmation.

Prescription-event monitoring data indicate that itraconazole is generally well tolerated. Gastrointestinal disturbances, dizziness and headache occur most commonly; liver toxicity has been rarely described. Its usefulness in some clinical situations may be limited because of its ability to interact with various therapeutic agents.

In conclusion, itraconazole along with other established agents should be considered a first-line treatment for patients with extensive or recalcitrant cutaneous fungal infections, mixed dermatophyte and Candida onychomycosis or vaginal candidiasis. It is currently considered a second-line drug for dermatophyte onychomycosis; the use of newer intermittent itraconazole treatment regimens may, however, extend its role in the management of this condition. Although itraconazole offers greater benefit than conventional therapies (griseofulvin and ketoconazole) in terms of efficacy and tolerability, wider clinical experience is required to determine its merits relative to the newer agents, terbinafine and fluconazole.

Pharmacodynamic Properties

Itraconazole is a triazole antifungal derivative. It acts primarily by inhibiting biosynthesis of ergosterol, an essential component of fungal cell membranes. At clinically achievable serum concentrations, itraconazole is fungistatic. The drug binds more avidly to fungal cytochrome P450 than does ketoconazole and, unlike ketoconazole, has little effect on mammalian cytochrome P450 enzyme systems.

In vitro susceptibility tests (using broth dilution techniques) indicate that itraconazole has a wide spectrum of activity against dermatophytes (e.g. Trichophyton, Epidermophyton and Microsporum species), yeasts (e.g. Candida spp. and Cryptococcus neoformans), dimorphic and dematiaceous fungi, and some moulds such as Aspergillus. These results may not, however, reflect or predict in vivo efficacy, since correlations between in vitro tests and clinical outcomes have not been fully established yet.

Pharmacokinetic Properties

Although oral itraconazole is well absorbed when administered after food, wide interpatient variation is evident. Drug absorption is dose-dependent.

Itraconazole is widely distributed, with an apparent volume of distribution of 10.7 L/kg after intravenous administration. The drug accumulates slowly in the vaginal mucosa, the stratum corneum and nails, and may be detected in skin and nails for up to 1 and 6 months, respectively, after completion of therapy. Itraconazole is highly bound (99.8%) to plasma proteins.

Itraconazole undergoes extensive hepatic metabolism. The drug has a plasma elimination half-life of 64 hours after multiple-dose oral administration. Total plasma clearance of itraconazole is 22.9 L/h following intravenous administration; 35 and 54% of an oral dose may be excreted via urine and faeces, respectively, 1 week after administration. At clinically relevant dosages, the elimination process of itraconazole may become saturated.

Preliminary findings suggest that patients with hepatic impairment may eliminate itraconazole more slowly than healthy volunteers. Drug disposition was, however, unaffected in patients with renal impairment; dialysis appears to have a negligible effect on itraconazole clearance. The extent of itraconazole absorption is greatly reduced in immunocompromised patients with AIDS or acute leukaemia.

Therapeutic Efficacy

Onychomycosis. Early noncomparative and placebo-controlled trials evaluated the efficacy of itraconazole at dosages of 100 mg/day administered for up to 12 months in patients with dermatophyte or Candida onychomycosis; cure (resolution of clinical symptoms and negative mycology) was achieved in 4 to 73% of affected toenails and 50 to 82% of fingernails.

Improved efficacy is observed at higher itraconazole dosages. At currently recommended dosages (200 mg/day for 3 months), approximately 70 to 80% of patients with fingernail and toenail infections attain mycological cure. Despite extensive therapy, approximately 20 to 30% of patients with ‘cured’ nails relapse after treatment cessation. Similar cure rates have also been reported with intermittent itraconazole therapy (400 mg/day for 1 week per month for 3 to 4 months), currently under investigation.

Limited comparisons with other oral antifungal agents suggest that itraconazole 100 mg/day may have greater efficacy than griseofulvin 500 to 1000 mg/day in the treatment of dermatophyte onychomycosis; treatment durations ranged from 3 to 18 months. At dosages of 200 mg/day administered for 3 months, itraconazole appears to have efficacy similar to or lower than that of terbinafine 250 mg/day. These conflicting results require investigation in future studies. As expected, itraconazole was superior to topical miconazole 2% cream. Direct comparisons assessing the efficacy of intermittent itraconazole therapy with other established antifungals are currently unavailable.

Pharmacoeconomic data from a multinational payer-perspective study suggest that terbinafine is more cost effective (lower cost per disease-free day) than itraconazole, griseofulvin and ketoconazole. Intermittent itraconazole therapy is, however, likely to be more cost effective than terbinafine.

Cutaneous fungal infections. Results from noncomparative studies using itraconazole 100 mg/day demonstrate that 2-week treatment courses generally produce clinical and mycological cure/marked improvement in />-80% of patients with dermatophyte infections affecting body areas, groin, and interdigital areas of the hand and foot; complete healing (clinical cure and negative mycology) may be observed in ≈ 50 to 80% of patients. Longer (4-week) regimens are required for palmar and plantar infections to achieve similar cure rates. Higher itraconazole dosages (200 or 400 mg/day) given for 1 week also produce similar cure rates, but a more rapid response is seen. The drug has shown efficacy against infections of the scalp and against pityriasis versicolor.

Taken together, the results of comparative studies indicate that itraconazole 100 mg/day administered for 2 to 4 weeks appears to have greater efficacy than griseofulvin 500 mg/day in various tinea infections. Preliminary results also show that the efficacy of itraconazole 100 mg/day may be similar to or lower than that of terbinafine 250 mg/day or fluconazole 50 to 100 mg/day when given for up to 1 month. Future studies using comparable dosage regimens (including short term, higher dosage schedules) are required to confirm these trends.

Vaginal candidiasis. Early dose-finding studies indicate that total itraconazole doses of 400 to 600mg are required for adequate treatment response (mycological cure />- 80%) in women with acute vaginal candidiasis. Prophylactic therapy (e.g. 200mg once a month or 200mg twice weekly) may be beneficial in recurrent infection.

Comparative studies in patients with acute vaginal candidiasis suggest that itraconazole is at least as effective as intravaginal clotrimazole and oral fluconazole, but superior to intravaginal econazole. Patients preferred itraconazole therapy to the intravaginal comparator agent.

Tolerability

Findings from >15 000 patients demonstrate that gastrointestinal disturbances, dizziness, pruritus and headache occur most commonly during therapy with itraconazole. A greater incidence of adverse events occurred with treatment periods />- 1 month (17.7 vs 7%), with a resulting withdrawal rate of 4.7%. A similar adverse event profile has been reported in patients receiving intermittent therapy. Prescription-event monitoring data from 13 645 patients indicate that itraconazole is generally well tolerated. The drug has a similar adverse event profile to fluconazole. Additionally, patients receiving prolonged therapy for onychomycosis over several months did so without untoward effects.

Mild, transient increases in hepatic enzymes normalised in 1 to 7% of patients after discontinuation of therapy. Liver toxicity has been rarely described. Hypokalaemia may occur in up to 6% of patients. The drug does not appear to induce functional changes on the pituitary-testicular-adrenal axis.

Clinically significant drug interactions may occur when itraconazole is given concomitantly with antihistamines (terfenadine or astemizole), cyclosporin, tacrolimus, digoxin, isoniazid, rifampicin (rifampin), drugs that raise gastric pH (e.g. antacids, ranitidine, omeprazole or didanosine), antiepileptics [e.g. phenobarbital (phenobarbitone), phenytoin or carbamazepine], cisapride, midazolam, triazolam, oral hypoglycaemics, HMG-CoA reductase inhibitors or warfarin.

Dosage and Administration

The following oral dosages of itraconazole are recommended for superficial mycoses:

  1. •

    Onychomycosis. 200mg once daily for 3 months. Alternatively, an intermittent regimen may be used: 200mg twice daily for 1 week per month for 3 consecutive months for toenails and 2 consecutive months for fingernails.

  2. •

    Dermatomycoses. 100mg once daily for 15 days or 200mg once daily for 7 days.

  3. •

    Plantar tinea pedis and palmar tinea manuum. 100mg once daily for 30 days or 200mg twice daily for 7 days.

  4. •

    Pityriasis versicolor. 200mg once daily for 7 days.

  5. •

    Vulvovaginal candidiasis. 200mg twice daily for 1 day or 200mg once daily for 3 days.

Capsules must be swallowed whole immediately after food. Itraconazole is not recommended for use in children or in the elderly.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Malini Haria, Harriet M. Bryson & Karen L. Goa

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  1. Malini Haria
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Various sections of the manuscript reviewed by: R. Arenas, Department of Dermatology, Hospital General ‘Dr Manuel gea Gonzalez’, Tlalpan, Mexico; C. Carbon, Service de Médecine Interne, CHU Bichat-Claude Bernard, Paris, France; Y.M. Clayton, St John’s Institute of Dermatology, St Thomas’ Hospital, London, England; M. Coel, Department of Dermatology, Centre Hospitalier, Brussels, Belgium; J. Delescluse, Department of Dermatology, Centre Hospitalier, Brussels, Belgium; W.E. Dismukes, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; A. Espinel-lngroff, Division of Infectious Diseases, Medical College of Virginia, Richmond, Virginia, USA; V. Harindra, St Mary’s Hospital, Portsmouth, England; D. Parent, Department of Genitourinary Medicine; Hopital Erasme, Brussels, Belgium; T. Roberts, Department of Dermatology, Southern General Hospital, Glasgow, Scotland; A.S. Sekhon, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada; M. Schäfer-Korting, Institut Pharmazic II, Freie Universität Berlin, Berlin, Germany; G.E. Stein, Division of Infectious Diseases, Department of Medicine, Michigan State University, East Lansing, Michigan, USA; J.M. Tobin, St Mary’s Hospital, Portsmouth, England; J.M. Wishart, Auckland, New Zealand; P. Woolley, Department of Genitourinary Medicine, Withington Hospital, Manchester, England.

An erratum to this article is available at http://dx.doi.org/10.1007/BF03257493.

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Haria, M., Bryson, H.M. & Goa, K.L. Itraconazole. Drugs 51, 585–620 (1996). https://doi.org/10.2165/00003495-199651040-00006

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