Drugs

, Volume 50, Issue 4, pp 658–690 | Cite as

Fluconazole

An Update of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Use in Major Superficial and Systemic Mycoses in Immunocompromised Patients
  • Karen L. Goa
  • Lee B. Barradell
Drug Evaluation

Abstract

Synopsis

Fluconazole is a triazole antifungal agent which is now an established part of therapy in patients with immune deficiencies. It is effective against oropharyngeal/ oesophageal candidiasis (candidosis) when used orally once daily either as treatment or secondary prophylaxis in patients with AIDS or as treatment or primary prophylaxis in neutropenia associated with cancer therapy. Fluconazole also resolves symptoms in up to 60% of patients with cryptococcal meningitis and AIDS. However, in this infection its efficacy as treatment relative to that of amphotericin B is equivocal, and its major role is as the drug of choice for maintenance therapy following amphotericin B induction. In this regard, fluconazole has been proven superior to amphotericin B and to itraconazole 200 mg/day.

Comparisons with other drugs used for the treatment of mucosal candidiasis in patients with AIDS show fluconazole to be superior to nystatin, similar to itraconazole and at least as effective as clotrimazole and ketoconazole; it was more so than the latter azole in 1 study. In patients undergoing chemotherapy or bone marrow transplantation, fluconazole as primary prophylaxis has produced greater clinical benefit than a clotrimazole regimen.

The incidence of adverse events appears to be somewhat higher in patients with AIDS compared with HIV-negative cohorts, but the qualitative pattern of events is similar. The most frequent events are gastrointestinal complaints, headache and skin rash: rare exfoliative skin reactions and isolated instances of clinically overt hepatic dysfunction have occurred in patients with AIDS.

Issues yet to be clarified include: the use of fluconazole in children with AIDS, in whom results have been promising; its efficacy against other fungal infections encountered in immunocompromised patients; whether the drug influences mortality, as has been suggested by one placebo-controlled trial in patients undergoing bone marrow transplant; and the appropriateness of its potential for use as primary prophylaxis against cryptococcal meningitis in patients with AIDS, where it shows efficacy but there is concern over increasing risk of development of secondary resistance.

Notwithstanding these undefined aspects of its clinical profile, fluconazole is now confirmed as an important antifungal drug in the management of fungal infections in patients with immune deficiencies. In patients with AIDS it is the present drug of choice as maintenance therapy against cryptococcal meningitis and is a preferred agent for secondary prophylaxis against candidat infections; it is also a favoured agent for primary prophylaxis in patients at risk because of neutropenia associated with chemotherapy or bone marrow transplantation.

Pharmacodynamic Properties

Fluconazole is fungistatic and acts by obstructing the conversion of fungal lanosterol to ergosterol, thereby inhibiting membrane sterol synthesis and preventing fungal cell replication. Fluconazole is much more selective than ketoconazole for cytochrome P450 enzymes in fungi than in mammalian cells: most evidence argues against a detrimental effect of fluconazole on mammalian steroid hormone production.

While of unproven predictive value clinically, recently improved in vitro susceptibility testing methods for antifungal drugs indicate that fluconazole is active against several of the most common yeasts encountered in immunocompromised patients. Most Candida spp., with the notable exception of C. krusei, are susceptible, as is Cryptococcus neoformans. C. (Torulopsis) glabrata and Histoplasma capsulatum show variable susceptibility. Aspergillus spp. are resistant to fluconazole. In vivo animal models of immunocompromised hosts parallel these findings. In vitro and limited in vivo data suggest that fluconazole lacks deleterious effects on the immune system.

Secondary resistance of Candida spp. to fluconazole appears to be emerging, as evidenced both microbiologically and clinically, but is presently uncommon. It has become most apparent in patients with advanced AIDS in whom C. albicans is the most prevalent progressively resistant strain. Resistance is less well-documented in other immunocompromised patients.

Pharmacokinetic Properties

Pharmacokinetic parameters of fluconazole do not differ substantially between immunocompromised and healthy individuals and are similar for oral and intravenous formulations. Absorption of oral fluconazole formulations is almost complete in patients with AIDS without gastroenteritis. It is unaffected by the presence of hypochlorhydria provoked, for example, by AIDS or by vomiting in patients with malignancies undergoing chemotherapy.

Fluconazole is poorly bound to plasma proteins (12%) and is widely distributed to body tissues and fluids, including CSF. The volume of distribution (50 to 60L) approximates the volume of body water. In contrast to other available azoles, fluconazole is excreted primarily by renal rather than hepatic mechanisms. Its long elimination half-life (t½β) of about 35 hours permits once-daily dosage regimens. Children with immunodeficiencies have a shorter t½β of about 16 to 20 hours and a larger volume of distribution. Conversely, in neonates the t½β is prolonged to up to 88 hours.

Therapeutic Use

Patients with AIDS or HIV infection. About 80 to 100% of patients with oropharyngeal/oesophageal candidiasis (candidosis) and approximately 35 to 60% of those with cryptococcal meningitis respond clinically to treatment with fluconazole in dosages up to 400 mg/day for ≤8 weeks, as evidenced in comparative trials. In patients with oropharyngeal candidiasis, fluconazole produced similar rates of clinical success as itraconazole, was at least as effective as clotrimazole troches and was superior to nystatin mouthwash. In patients with oesophageal candidiasis, the largest comparison with ketoconazole demonstrated superior clinical efficacy for fluconazole. However, previous use of ketoconazole may have influenced the results: several other studies indicate clinical response is similar for both drugs. Fluconazole also displayed equivalent clinical efficacy to amphotericin B plus flucytosine in this indication, although the latter trial was small. Patients with cryptococcal meningitis have responded similarly to fluconazole and amphotericin B in 1 trial, but fluconazole appears to eradicate C. neoformans twice as slowly as the polyene and other results have shown fluconazole to be less effective than amphotericin B.

Fluconazole has an established position as secondary prophylaxis against severe and recurrent candidiasis: for example, only 7% of 99 patients relapsed after 6 months’ therapy. In cryptococcal meningitis fluconazole has a preferred role as maintenance therapy following the discontinuation of several large trials favouring fluconazole over the comparator agent. Recrudescence rates were 10-fold less for fluconazole (1.8%) than for amphotericin B (18%) and 6-fold less when compared with itraconazole 200mg/day (3.8 vs 23.6%). The drug has also shown efficacy when used as primary prevention against invasive and superficial fungal infections, perhaps excluding histoplasmosis, and is superior to clotrimazole troches; however, the important issue of possible secondary resistance is of widespread concern and is likely to preclude the routine adoption of this strategy.

Limited investigations indicate that fluconazole achieves clinical cure in about 90% of children with oropharyngeal candidiasis. Results of trials examining the efficacy of fluconazole against histoplasmosis in adults are equivocal.

Pharmacoeconomic analyses based on results of clinical trials suggest improved cost effectiveness for fluconazole, assuming greater efficacy than ketoconazole in the treatment or maintenance therapy of candidiasis, but when equivalent efficacy is assumed ketoconazole appears slightly more cost effective. A similar assumption of equivalent efficacy but superior tolerability compared with amphotericin B has also implied cost advantages for fluconazole in patients with cryptococcal meningitis. Whether these assumptions are valid is a matter of some dispute.

Patients with cancer. As treatment for oropharyngeal/oesophageal candidiasis, fluconazole produces clinical cure rates of about 75 to 80% and mycological eradication rates in the region of 50 to 60%. Fluconazole appeared to be as effective as ketoconazole or as amphotericin B plus flucytosine. About 20% of patients relapse following fluconazole treatment.

As primary prophylaxis in adult patients becoming neutropenic after chemotherapy or bone marrow transplant, fluconazole reduces the incidence of fungal colonisations and superficial candidal infections and lengthens time to amphotericin B therapy, compared with placebo. Systemic infections have decreased in patients undergoing bone marrow transplant but not in those undergoing chemotherapy. The finding that the probability of death decreased in fluconazole compared with placebo recipients in 1 large study in patients undergoing bone marrow transplant is encouraging but requires further corroboration.

Fluconazole is at least as effective as oral polyenes (amphotericin B or nystatin) in preventing infection, although questions remain over study design, but appears superior to clotrimazole troches. Aspergillus infection during fluconazole prophylaxis is infrequent but persistent. Paediatric patients receiving fluconazole as treatment or prophylaxis have shown a similar response to that seen in adults.

Tolerability

Immunocompromised patients tolerate fluconazole therapy well: the clinical profile of types of adverse reactions resembles that seen in immunocompetent patients. There is some evidence of increased incidence of adverse effects in patients with AIDS, with the manufacturer reporting a frequency of 21% compared with 13% in HIV-negative individuals. Variable figures recorded among clinical trials may not give a true picture because of patient and concomitant disease factors.

Gastrointestinal complaints (nausea and vomiting, abdominal pain, diarrhoea), headache and skin rash are experienced most often. Infrequently, gastrointestinal and dermatological events may be severe enough to halt therapy. Exfoliative skin reactions, while rare, require immediate treatment cessation. Hepatic enzyme levels are estimated to rise in <5% of the general population receiving fluconazole and in isolated instances have been associated with clinical symptoms of hepatotoxicity. Patients with cancer and paediatric patients have also tolerated fluconazole well. As shown in comparative studies the tolerability of fluconazole is better than that of amphotericin B and similar to that of ketoconazole.

Drug Interactions

Several drug interactions are of particular interest in the management of immunocompromised patients. Rifampicin (rifampin), but not rifabutin, accelerates fluconazole elimination which may cause clinical failure of the antifungal drug. On the other hand, fluconazole increases plasma concentrations of rifabutin, zidovudine and cyclosporin. Fluconazole also increases the t½β of warfarin and the plasma concentrations of phenytoin and sulphonylurea drugs, with clinical consequences in some cases (increased bleeding, CNS toxicity and hypoglycaemia, respectively). Patients receiving these medications concomitantly with fluconazole should be monitored carefully for unwanted effects of these agents.

Dosage and Administration

All doses are administered once daily and are interchangeable for oral and intravenous formulations. The manufacturer’s prescribing information recommends dosage adjustment in patients with renal impairment. US guidelines. For patients with oropharyngeal or oesophageal candidiasis, 200mg on day 1 then 100mg daily is given for at least 2 weeks. Patients with oesophageal infection should receive the drug for a minimum of 3 weeks and for 2 weeks following symptom resolution: the maximum dosage is 400 mg/day. A dosage of 400 mg/day has been used for patients with systemic candidiasis in clinical trials.

For patients with cryptococcal meningitis, the dosage is 400mg on day 1 then 200mg daily for 10 to 12 weeks after CSF culture is negative. Patients unresponsive to 200 mg/day may receive 400 mg/day. The recommended maintenance dosage of fluconazole is 200 mg/day.

Recommended dosages have not been established for children.

UK guidelines. For oropharyngeal candidiasis the usual dosage is 50mg daily for 7 to 14 days. Dosage is the same for oesophageal infection but the duration is longer (14 to 30 days). A 100mg dosage may be used in difficult infections. For candidaemia and other invasive candidal infection, the dosage is 400mg on day 1 then 200mg daily.

Patients with cryptococcal infections should receive 400mg on day 1 followed by 200 to 400mg daily for at least 6 to 8 weeks. For maintenance therapy fluconazole 100 to 200 mg/day is given indefinitely.

As prophylaxis in patients at risk of becoming neutropenic due to chemotherapy or radiotherapy, the dosage is 50 to 400mg daily, based on the patient’s risk of developing infection.

Children older than 4 weeks should receive 3 mg/kg/day for mucosal candidiasis, 6 to 12 mg/kg/day for systemic candidiasis and cryptococcal infection and 3 to 12 mg/kg/day for prevention of fungal infections due to neutropenia associated with chemotherapy or radiotherapy. Neonates aged 2 weeks or younger should receive the same dosages but at 72 hour intervals, while in those aged 2 to 4 weeks the interval should be 48 hours.

Keywords

Adis International Limited Fluconazole Itraconazole Candidiasis Ketoconazole 

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Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • Karen L. Goa
    • 1
  • Lee B. Barradell
    • 1
  1. 1.Adis International LimitedAuckland 10New Zealand

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