Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1708
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Fluconazole (Tablet)
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SPL Patient Package Insert: Since there are many brand names for these medicines, check with your doctor or pharmacist if you have any questions.
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Dosage and Administration in Adults:<br/>Single Dose:<br/>Multiple Dose:<br/>Dosage and Administration in Children:<br/>Dosage In Patients With Impaired Renal Function:<br/>Administration:
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Pharmacokinetics and Metabolism:<br/>Pharmacokinetics in Children:<br/>Pharmacokinetics in Elderly:<br/>Drug Interaction Studies:<br/>Oral contraceptives:<br/>Cimetidine:<br/>Antacid:<br/>Hydrochlorothiazide:<br/>Rifampin:<br/>Warfarin:<br/>Phenytoin:<br/>Cyclosporine:<br/>Zidovudine:<br/>Theophylline:<br/>Terfenadine:<br/>Oral hypoglycemics:<br/>Rifabutin:<br/>Tacrolimus:<br/>Cisapride:<br/>Midazolam:<br/>Azithromycin:<br/>Microbiology: Mechanism of Action Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 dependent enzyme lanosterol 14-��-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-��-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 albicansCandida glabrata (Many strains are intermediately susceptible)*Candida parapsilosisCandida tropicalisCryptococcus neoformans *In a majority of the studies, fluconazole MICvalues against C. glabrata were above the susceptible breakpoint (���16 mcg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 mcg/mL, see Table 1), the highest dose is recommended . For resistant isolates alternative therapy is recommended. The following in vitro data are available, but their clinical significance is unknown. Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 mcg/mL or less against most (���90%) strains of the following microorganisms, however, the safety and effectiveness of fluconazole in treating clinical infections due to these microorganisms have not been established in adequate and well controlled trials. Candida dubliniensisCandida guilliermondiiCandida kefyrCandida lusitaniae Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy. Susceptibility Testing Methods Cryptococcus neoformans and filamentous fungi No interpretive criteria have been established for Cryptococcus neoformans and filamentous fungi. Candida species Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)with standardized inoculum concentrations of fluconazole powder. The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques: Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedurerequires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 25 mcg of fluconazole to test the susceptibility of yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1. The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommended dosage is used. The intermediate category implies that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies. Quality Control Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standardized fluconazole powder and 25 mcg disks should provide the following range of values noted in Table 2. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant. Activity In Vivo Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans. 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. Fluconazole has also been shown to be active in animal models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary infections in normal mice; one model of Coccidioides immitis intracranial infections in normal mice; and several models of Histoplasma capsulatum pulmonary infection in normal and immunosuppressed mice. The clinical significance of results obtained in these studies is unknown. Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis. Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with Asp. fumigatus. The clinical significance of results obtained in these studies is unknown. Drug Resistance Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-��-demethylase), reduced access to the drug target, or some combination of these mechanisms. Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target with decreased affinity for azoles. Overexpression of ERG11 results in the production of high concentrations of the target enzyme, creating the need for higher intracellular drug concentrations to inhibit all of the enzyme molecules in the cell. 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 superfamily (encoded by CDR genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of CDR genes may lead to resistance to multiple azoles. Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to 32 mcg/mL), the highest fluconazole dose is recommended. Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy.
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General:<br/>Single Dose:<br/>Drug Interactions:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Pregnancy:<br/>Teratogenic effects:<br/>Nursing Mothers:<br/>Pediatric Use:<br/>Geriatric Use:
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Fluconazole
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Fluconazole (Tablet)
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In Patients Receiving a Single Dose for Vaginal Candidiasis:<br/>In Patients Receiving Multiple Doses for Other Infections:<br/>Post-Marketing Experience:<br/>Adverse Reactions in Children:
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CLINICAL STUDIES:<br/>Pediatric Studies:
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Fluconazole
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