● Vaginal candidiasis (vaginal yeast infections due to Candida).
● Oropharyngeal and esophageal candidiasis. Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia.
● Cryptococcal meningitis.
● Indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy.
● Maintenance therapy to prevent relapse of cryptococcal disease in patients with acquired immunodeficiency syndrome (AIDS).\
● Dermatomycosis, including tinea corporis, tinea cruris, tinea pedis, tinea unguium (onychomycosis) and dermal candida infections.
Pharmacology:
Mechanism of Action:
Fluconazole is a highly selective inhibitor of fungal cytochrome P 450 dependent enzyme lanosterol 14-α-demethylase.This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition Activity. In Vitro and In Clinical Infections Fluconazole has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.
● Candida albicans
● Candida glabrata (Many strains are intermediately susceptible)
● Candida parapsilosis
● Candida tropicalis
● Cryptococcus neoformans.
Pharmacokinetics:
The bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20–50 hours) after oral administration. The Cmax and AUC data from a food-effect study involving administration of Fluconazole tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food. Therefore, fluconazole may be taken without regard to meals. Steady-state concentrations are reached within 5–10 days following oral doses of 50–400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11–12%). Following either single- or multiple oral doses for up to 14 days.
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.
The pharmacokinetics of fluconazole is markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of fluconazole may need to be reduced in patients with impaired renal function. A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%.
Drug Resistance:
Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination of these mechanisms.
The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR genes) and those of the ATP-binding cassette super family (encoded by CDR genes). Up regulation of the MDR gene leads to fluconazole resistance, whereas, up regulation of CDR genes may lead to resistance to multiple azoles.
In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to fluconazole in vivo than in vitro.
Fluconazole administered orally and/or intravenously was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Activity has been demonstrated against fungal infections caused by Aspergillus flavus and Aspergillus fumigatus in normal mice.
Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis.
Contraindications:
Contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients.
There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents.
Caution should be used in prescribing to patients with hypersensitivity to other azoles.
Co-administration of terfenadine is contraindicated in patients receiving( fluconazole) at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study.
Co-administration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, pimozide, and quinidine are contraindicated in patients receiving fluconazole.
Drug Interactions:
Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 co-administered with fluconazole. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored.
Clinically or potentially significant drug interactions between fluconazole and the following agents/classes have been observed. These are described in greater detail below:
Oral hypoglycemic, Coumarin-type anticoagulants, Phenytoin, Cyclosporine, Rifampin, Theophylline, Terfenadine, Cisapride, Astemizole, Rifabutin, Voriconazole, Tacrolimus
Short-acting benzodiazepines: Triazolam, Oral Contraceptives, Pimozide, Hydrochlorothiazide, Alfentanil, Amitriptyline, nortriptyline, Amphotericin B, Azithromycin, Carbamazepine, Calcium Channel Blockers, Celecoxib, CyclophosphamideFentanyl, Halofantrine, HMG-CoA reductase inhibitors, Losartan, Methadone, Non-steroidal anti-inflammatory drugs, Prednisone, Saquinavir. Sirolimus, Vinca Alkaloids, Vitamin A, Zidovudine Fluconazole reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When fluconazole is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary.
Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving concomitant fluconazole and coumarin-type anticoagulants. In postmarketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin-type anticoagulants is recommended.
Adjustment of warfarin may be necessary.
Fluconazole increases the plasma concentrations of phenytoin, cyclosporine, theophylline, rifabutin ,tacrolimus, amitriptyline and nortriptyline, carbmazepine, Calcium Channel Blockers, celecoxib, halofantrine, Methadone, NSAIDS, sirolimus, zidovudine, Careful monitoring of phenytoin concentrations in patients receiving fluconazole and phenytoin is recommended.
Rifampin: Rifampin enhances the metabolism of concurrently administered fluconazole. Depending on clinical circumstances, consideration should be given to increasing the dose of fluconazole when it is administered with rifampin.
Cisapride: There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were coadministered.
Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Co-administration of fluconazole and astemizole is contraindicated.
Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is started within 24 h after the last dose of fluconazole.
Hydrochlorothiazide: increases plasma concentration of fluconazole by 40 %
Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. It should be given with caution to patients with hepatic disorder and renal dysfunction. Although skin rashes are very rare but if patients develop rashes during treatment with fluconazole should be monitored closely and the drug discontinued if lesions progress. Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4 should be monitored.When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or seizures may occur.
Warning and Precautions:
Pregnancy and Lactation:
Caution should be exercised while administering the drug to nursing woman and pregnant women due to inadequate data.
Pediatric Use:
The use of fluconazole in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small non comparative pediatric clinical studies in addition to pharmacokinetic studies in children. Efficacy is not established in children below 1 year of age.
Geriatric Use:
Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function.
Undesirable Effects:
Fluconazole is generally well tolerated. In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. The most common treatment-related adverse events reported in the patients headache, nausea, abdominal pain, diarrhea, dyspepsia, dizziness, and taste perversion. Most of the reported side effects were mild to moderate in severity. In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported.QT prolongation, torsade de pointes., Leukopenia, including neutropenia and agranulocytosis,thrombocytopenia, Hypercholesterolemia, hypertriglyceridemia, hypokalemia, Taste perversion.
Over Dosage:
There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behavior. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted. Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma levels by approximately 50%.