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Fluconazole [Diflucan 50, 100, 150, 200mg]

Generic Name: Fluconazole

Fluconazole, a synthetic triazole derivative, is an azole antifungal agent.

Under what local brands and in what dosages is generic Fluconazole sold in pharmacies of Britain, United States, and Canada?

In pharmacies of the United States, Great Britain and Canada the pharmacists offer you to buy Fluconazole according to your prescription or without a prescription under such brand names and in such strengths and dosage forms:

UK US Canada
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Drug Interactions

While fluconazole can alter the pharmacokinetics of certain drugs that undergo hepatic metabolism, the magnitude of such alterations appears to be less than those associated with ketoconazole; however, comparative studies have not been performed to date. In addition, the possibility that the risk of developing such interactions may be increased at relatively high fluconazole dosages (e.g., 200 mg daily or more) should be considered.

Fluconazole Drug Interactions

Anti-infective Agents

Amphotericin B

Although the clinical importance is unclear, results of in vitro studies evaluating the antifungal effects of amphotericin B used concomitantly with fluconazole or other azole antifungal agents (e.g., clotrimazole, itraconazole, ketoconazole) against Candida albicans, C. pseudotropicalis, C. glabrata, or Aspergillus fumigatus indicate that antagonism can occur with these combinations.

Since amphotericin B exerts its antifungal activity by binding to sterols in the fungal cell membrane and azole antifungal agents act by altering the cell membrane, antagonism is theoretically possible; however, it is unclear whether such antagonism actually would occur in vivo.

Results of studies evaluating combined use of fluconazole and amphotericin B in animal models of aspergillosis, candidiasis, or cryptococcosis have been conflicting. While antagonism occurred in some models (A. fumigatus infection in mice, rabbits, or rats treated with amphotericin B and fluconazole), the combination resulted in additive or indifferent effects in other models (e.g., C. albicans or Cryptococcus neoformans infection in mice or rabbits treated with amphotericin B and fluconazole). In a few studies evaluating the drugs in murine cryptococcosis or candidiasis, sequential use of an initial large dose of amphotericin B followed by an azole antifungal agent (e.g., fluconazole) was uniformly effective in prolonging survival and decreasing fungal burden.

Because further study is needed regarding the interaction between azole antifungal agents and amphotericin B, it has been suggested that concomitant administration of fluconazole and amphotericin B be used with caution, particularly in immunocompromised patients. Results of an in vitro study indicate that the combination of amphotericin B and fluconazole may be synergistic, additive, or indifferent against Pseudallescheria boydii; there was no evidence of antagonism.

Fluconazole Drug Interactions

Flucytosine

In an in vitro study, the combination of fluconazole and flucytosine was synergistic, additive, or indifferent against Cryptococcus neoformans; there was no evidence of antagonism. Synergism generally did not occur if the C. neoformans isolates had fluconazole MICs of 8 mcg/mL or greater. The combination of fluconazole and flucytosine has been synergistic when evaluated in vivo in a murine model of cryptococcal meningitis. It has been suggested that synergism between the drugs may occur because fluconazole damages the fungal cell membrane allowing greater intracellular penetration of flucytosine.

HIV Protease Inhibitors

Concomitant administration of fluconazole (400 mg once daily) and indinavir (1 g mg every 8 hours) for 1 week resulted in a 19% decrease in the AUC of indinavir and no change in the AUC of fluconazole. This pharmacokinetic interaction is considered minor and dosage adjustment of the HIV protease inhibitor probably is unnecessary in patients receiving concomitant fluconazole. Concomitant administration of fluconazole (400 mg on day 1 and 200 mg daily for 4 days) and ritonavir (200 mg every 6 hours for 4 days) resulted in a 12 and 15% increase in the AUC and peak plasma concentration of ritonavir, respectively.

Nonnucleoside Reverse Transcriptase Inhibitors

Concomitant administration of efavirenz (400 mg daily) and fluconazole (200 mg daily) for 7 days in healthy individuals did not result in clinically important changes in the pharmacokinetics of either drug, and dosage adjustments are not necessary in patients receiving the drugs concomitantly. Concomitant administration of delavirdine (300 mg every 8 hours) and fluconazole (400 mg daily) for 2 weeks in patients with human immunodeficiency virus (HIV) infection was well tolerated and did not appear to affect the pharmacokinetics of either drug. Dosage adjustments are not necessary in patients receiving delavirdine and fluconazole concomitantly.

Nucleoside Reverse Transcriptase Inhibitors

Concomitant administration of fluconazole appears to interfere with the metabolism and clearance of zidovudine. In one study in men with HIV infections who received zidovudine (200 mg every 8 hours) alone or in conjunction with fluconazole (400 mg daily), the AUC of zidovudine was increased 74% (range: 20-173%), peak serum zidovudine concentrations were increased 84% (range: -1 to 227%), and the terminal elimination half-life of the drug was increased 128% (range: -4 to 189%) in patients receiving concomitant fluconazole. Although the clinical importance of this effect is unknown, it has been suggested that patients receiving concomitant zidovudine and fluconazole therapy be monitored closely for zidovudine-associated adverse effects. In one limited study in patients with HIV infection receiving oral didanosine (3.-7. mg/kg daily), concomitant administration of oral fluconazole (200 mg every 12 hours for 2 doses then 200 mg once daily for 6 days) did not result in any clinically important differences in the AUC of didanosine, peak serum didanosine concentrations, or time to peak concentrations.

Rifabutin and Rifampin

Concomitant administration of fluconazole (200 mg daily) and rifabutin (300 mg daily) in HIV-infected individuals results in substantially increased plasma concentrations and AUCs of rifabutin and its major metabolite, LM565. This effect presumably occurs via inhibition of cytochrome P-450 (CYP) isoenzymes involved in metabolism of rifabutin and may account in part for the increased incidence of certain adverse effects (e.g., uveitis) reported with concomitant rifabutin/fluconazole therapy.

Concomitant administration of fluconazole and rifampin may affect the pharmacokinetics of both drugs. Administration of a single 200-mg oral dose of fluconazole in health adults receiving rifampin (600 mg daily) resulted in approximately a 25% decrease in the AUC and a 20% decrease in the plasma half-life of fluconazole.

The clinical importance of this possible pharmacokinetic interaction between fluconazole and rifampin is unclear; however, it has been suggested that such an interaction may have contributed to relapse of cryptococcal meningitis in a few patients who were receiving fluconazole concomitantly with rifampin. The manufacturer of fluconazole states that, depending on clinical circumstances, consideration can be given to increasing dosage of fluconazole when the drug is administered concomitantly with rifampin. There also is some evidence that concomitant administration of fluconazole and rifampin results in increased rifampin plasma concentrations compared with administration of rifampin alone.

CNS Agents

Concomitant administration of amitriptyline and fluconazole has resulted in increased serum concentrations of the tricyclic antidepressant, and CNS toxicity has been reported in a few patients receiving the drugs concomitantly. It has been suggested that fluconazole may interfere with metabolism of amitriptyline by inhibition of CYP isoenzymes involved in metabolism of the antidepressant. Amitriptyline and fluconazole should be used concomitantly with caution.

Concomitant administration of carbamazepine and fluconazole has resulted in increased carbamazepine concentrations and associated toxicity, presumably as the result of fluconazole inhibiting CYP isoenzymes involved in metabolism of the anticonvulsant. It has been suggested that carbamazepine concentrations be monitored in patients receiving fluconazole concomitantly. In mechanically ventilated patients sedated with IV midazolam, concomitant administration of IV fluconazole resulted in a 20-300% increase in plasma midazolam concentrations in some patients within 18-48 hours after the first dose of fluconazole. In addition, administration of oral fluconazole to healthy individuals receiving IV midazolam reportedly results in a 50% decrease in clearance of the benzodiazepine. Because of concerns that prolonged sedation may occur if fluconazole were administered to patients sedated with IV midazolam, it has been suggested that a reduction in the infusion rate of midazolam should be considered if there is evidence of increased sedation during concomitant fluconazole therapy.

Coumarin

Anticoagulants Increased prothrombin time has been reported in patients receiving fluconazole concomitantly with a coumarin anticoagulant (e.g., warfarin). In one study in healthy adults receiving 200 mg of fluconazole daily or placebo, area under the prothrombin time versus time (for a 7-day post-warfarin period) curve for a single 15-mg warfarin dose increased by about 12% when concomitant fluconazole versus placebo were compared. Increased prothrombin times also have been reported when lower dosages of fluconazole (100 mg once daily) were administered concomitantly with warfarin sodium. Concomitant administration of fluconazole with nicoumalone (a coumarin anticoagulant not commercially available in the US) resulted in increased prothrombin time and intracranial hemorrhage in at least one patient. Prothrombin times should be monitored carefully when fluconazole is used concomitantly with a coumarin anticoagulant.

Cyclosporine

Concomitant administration of fluconazole and cyclosporine may result in increased plasma cyclosporine concentrations, especially when the drugs are used in renal transplant recipients. In several studies in bone marrow transplant recipients receiving cyclosporine maintenance therapy, administration of 100- or 200-mg oral doses of fluconazole once daily for 14 days resulted in only slight increases in plasma cyclosporine concentrations, which were not considered clinically important.

However, administration of usual oral dosages of fluconazole to renal transplant recipients (with or without impaired renal function) receiving cyclosporine has resulted in increases in the AUC and peak plasma concentrations of the immunosuppressive agent. In one study in renal transplant patients who had received at least 6 months of cyclosporine therapy and had been receiving a stable cyclosporine dosage for at least 6 weeks, administration of fluconazole 200 mg daily for 14 days resulted in a mean increase of 60 or 157% in peak or minimum cyclosporine plasma concentrations, respectively, and a mean decrease of 45% in the apparent oral clearance of the drug. In addition, increased serum creatinine concentrations, which returned to pretreatment levels with dosage reduction of both drugs, have been reported in patients receiving fluconazole and cyclosporine concomitantly.

While the mechanism of this possible interaction is not known, displacement of cyclosporine from protein-binding sites is unlikely since fluconazole is only minimally protein bound. Plasma cyclosporine concentrations and serum creatinine should be monitored carefully in patients receiving fluconazole concomitantly, and dosage adjusted accordingly.

Tacrolimus

Concomitant administration of tacrolimus and fluconazole has resulted in increased serum concentrations of tacrolimus, and nephrotoxicity has been reported in patients receiving the drugs concomitantly. The manufacturer states that patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored.

Astemizole and Terfenadine

Prolongation of the QT interval and QT interval corrected for rate (QTc) and, rarely, serious cardiovascular effects, including arrhythmias (e.g., ventricular tachycardia, atypical ventricular tachycardia [torsades de pointes, ventricular fibrillation]), cardiac arrest, palpitations, hypotension, dizziness, syncope, and death, have been reported in patients receiving recommended dosages of terfenadine or astemizole (neither antihistamine currently is commercially available in the US) concomitantly with another azole antifungal agent, ketoconazole.

Ketoconazole can markedly inhibit the metabolism of astemizole or terfenadine, probably via inhibition of the cytochrome P-450 microsomal enzyme system, resulting in increased plasma concentrations of unchanged drug (to measurable levels) and reduced clearance of the active desmethyl or carboxylic acid metabolite, respectively. Such alterations in the pharmacokinetics of these antihistamines may be associated with prolongation of the QT and QTc intervals.

Similar alterations in the pharmacokinetics of these antihistamines and/or adverse cardiac effects also have been reported in patients receiving the drugs concomitantly with itraconazole, although in vitro data suggest that itraconazole may have a less pronounced effect than ketoconazole on the pharmacokinetics of astemizole. Studies have been performed to determine whether similar interactions occur with concomitant administration of terfenadine and fluconazole. In one study, concomitant administration of terfenadine and fluconazole (at a dosage of 200 mg daily) did not result in prolongation of QT interval; however, use of higher fluconazole dosages (400 or 800 mg daily) in another study resulted in increased plasma concentrations of terfenadine. The manufacturer of fluconazole has stated that concomitant administration of terfenadine and fluconazole in a daily dosage of 400 mg or greater has been contraindicated and it was recommended that patients be carefully monitored if lower fluconazole dosages (i.e., less than 400 mg daily) were administered in patients receiving terfenadine.

Cisapride

Concomitant administration of fluconazole and cisapride may result in increased plasma cisapride concentrations and has rarely been associated with adverse cardiac events including torsades de pointes. In a placebo-controlled, randomized, multiple-dose study in individuals receiving fluconazole (200 mg daily), initiation of cisapride (20 mg 4 times daily) after 7 days of fluconazole therapy resulted in a 102-192% increase in the AUC and a 92-153% increase in peak plasma concentrations of cisapride. In addition, administration of fluconazole to individuals receiving cisapride (20 mg 4 times daily for 5 days) resulted in a significant increase in the QT interval corrected for rate. The manufacturer of fluconazole states that concomitant administration of fluconazole and cisapride is contraindicated.

Drugs Affecting Gastric Acidity

Studies in fasting, healthy adults indicate that GI absorption of fluconazole is not affected substantially by concomitant administration of drugs that decrease gastric acid output or increase gastric pH. When a single 100-mg oral dose of fluconazole was administered 2 hours after a single 400-mg oral dose of cimetidine, the area under the plasma concentration-time curve (AUC) of fluconazole was decreased 13% and peak plasma fluconazole concentrations were decreased by 21%1, 61, 68, 91; these effects were not considered clinically important. Administration of antacids containing aluminum hydroxide or magnesium hydroxide either with or immediately prior to a single 100-mg oral dose of fluconazole had no effect on absorption or elimination of the antifungal agent.

Oral Contraceptives

Concomitant administration of fluconazole and oral estrogen-progestin contraceptives reportedly does not produce clinically important effects on the pharmacokinetics of the contraceptives. In healthy premenopausal women receiving oral contraceptives and 50-mg oral doses of fluconazole given once daily for 10 days, the mean increase in AUCs of ethinyl estradiol and levonorgestrel was 6 (range: -47 to 108%) and 17% (range: -33 to 141%), respectively. In addition, in a controlled study in healthy women receiving oral contraceptives concomitantly with 200-mg oral doses of fluconazole or placebo for 10 days, AUCs of both levonorgestrel and ethinyl estradiol were increased substantially in women receiving oral fluconazole compared with those receiving placebo; mean increases in AUCs of ethinyl estradiol and levonorgestrel were 38 (range: -11 to 101%) and 25% (range: -12 to 82%), respectively. However, in some women ethinyl estradiol and levonorgestrel concentrations decreased by 47 and 33%, respectively. The manufacturer suggests that decreases in ethinyl estradiol and levonorgestrel concentrations may be the result of random variation. While limited data indicate that fluconazole may inhibit metabolism of ethinyl estradiol and levonorgestrel, there is no evidence that fluconazole is an inducer of ethinyl estradiol and levonorgestrel metabolism.

Phenytoin

Concomitant administration of fluconazole and phenytoin has resulted in increased plasma phenytoin concentrations and AUCs and has resulted in phenytoin toxicity. In one study in healthy adults, minimum plasma concentrations of phenytoin increased 128% and the AUC for phenytoin increased 75% during concomitant fluconazole administration; fluconazole pharmacokinetics were not affected. It has been suggested that such alterations in phenytoin pharmacokinetics result from fluconazole-induced inhibition of metabolism of the anticonvulsant. Plasma phenytoin concentrations should be monitored carefully and dosage of the anticonvulsant adjusted accordingly whenever fluconazole is initiated or discontinued. Phenytoin and fluconazole should be used concomitantly with caution.

Sulfonylurea Antidiabetic Agents

Administration of fluconazole in individuals receiving tolbutamide, glyburide, or glipizide has resulted in increased AUCs and peak plasma concentrations and reduced metabolism of the antidiabetic agent. The mean increase in AUC or peak plasma concentrations of tolbutamide, glyburide, or glipizide reported in healthy adults receiving concomitant fluconazole is 26-49 or 11-19%, respectively. Clinically important hypoglycemia may be precipitated by concomitant use of oral hypoglycemic agents and fluconazole, and at least one fatality has been reported from hypoglycemia in a patient receiving glyburide and fluconazole concomitantly. In several individuals, symptoms consistent with hypoglycemia occurred; oral glucose therapy was necessary in a few cases. If fluconazole is used concomitantly with tolbutamide, glyburide, glipizide, or any other oral sulfonylurea antidiabetic agent, blood glucose concentrations should be monitored carefully and dosage of the antidiabetic agent adjusted as necessary.

Theophylline

Concomitant administration of theophylline and fluconazole increases serum theophylline concentrations. In a study in healthy adults, administration of a single dose of IV aminophylline (6 mg/kg) after 14 days of oral fluconazole (200 mg daily) resulted in a 21 or 13% increase in the mean AUC or peak plasma concentration of theophylline, respectively, and a mean decrease of 16% in theophylline clearance; the half-life of theophylline increased from 6.6 to 7.9 hours. The manufacturer recommends that serum theophylline concentrations be monitored carefully in patients receiving fluconazole.

Thiazide Diuretics

In healthy adults receiving 100-mg doses of fluconazole, concomitant administration of 50-mg doses of hydrochlorothiazide resulted in a 14% increase in peak fluconazole plasma concentrations, a 43% increase in fluconazole's AUC, and plasma fluconazole concentrations that were approximately 1-2 mcg/mL higher compared with results obtained when the antifungal agent was given alone. It has been suggested that the thiazide diuretic decreased renal clearance of fluconazole by about 20%; however, adjustment of fluconazole dosage does not appear to be necessary during combined therapy with the drugs.

Acute Toxcicity

Limited information is available on the acute toxicity of fluconazole in humans. In mice and rats receiving very high dosages of fluconazole, decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex, and cyanosis occurred.

There were no fatalities in mice and rats receiving fluconazole doses of 1 g/kg or less. At higher doses (1-2 g/kg), death occurred 1.5 hours to 3 days after the dose; in some cases, death was preceded by clonic seizures.

Hallucinations and paranoid behavior developed in a patient with human immunodeficiency virus (HIV) infection who reportedly ingested 8.2 g of fluconazole. The patient was hospitalized, and these manifestations resolved within 48 hours. If acute overdosage of fluconazole occurs, supportive and symptomatic treatment should be initiated. If indicated, the stomach should be emptied by gastric lavage. Elimination of fluconazole can be facilitated by hemodialysis; plasma concentrations of the drug generally are decreased 50% by a 3-hour period of hemodialysis.

Mechanism of Action

Fluconazole usually is fungistatic in action. Fluconazole and other triazole-derivative antifungal agents (e.g., itraconazole, terconazole) appear to have a mechanism of action similar to that of the imidazole-derivative antifungal agents (e.g., butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole).

Like imidazoles, fluconazole presumably exerts its antifungal activity by altering cellular membranes resulting in increased membrane permeability, leakage of essential elements (e.g., amino acids, potassium), and impaired uptake of precursor molecules (e.g., purine and pyrimidine precursors to DNA). Although the exact mechanism of action of fluconazole and other triazoles has not been fully determined, the drugs inhibit cytochrome P-450 14-a-desmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol. It appears that this may occur because a nitrogen atom (N-4) in the triazole molecule binds to the heme iron of cytochrome P-450 14-a-desmethylase in susceptible fungi.

Unlike some imidazoles (e.g., clotrimazole, econazole, miconazole, oxiconazole) that suppress ATP concentrations in intact cells and spheroplasts of C. albicans, fluconazole does not appear to have an appreciable effect on ATP concentrations in the organism. It is unclear whether this effect is related to the in vivo antifungal effects of the drugs.

Fluconazole generally is fungistatic against Candida albicans when the organism is in either the stationary or early logarithmic phase of growth.

Fluconazole and other triazoles (e.g., itraconazole) have a high affinity for fungal P-450 enzymes and only a weak affinity for mammalian P-450 enzymes and are more specific inhibitors of fungal cytochrome P-450 systems than many imidazoles (e.g., ketoconazole).

The drug does not appear to have any effect on cholesterol synthesis in mammalian liver homogenates. In an in vitro study using rat Leydig cells, fluconazole concentrations of 10 mcg/mL caused less than a 30% inhibition of basal testosterone production whereas the same concentration of ketoconazole caused a 95% inhibition. Further study is needed to fully evaluate whether fluconazole affects P-450 enzyme systems and steroid synthesis in humans.

While there is some evidence that fluconazole has only a minimal inhibitory effect on microsomal cytochrome P-450 systems, other evidence suggests that the drug may have a potent inhibitory effect. Results of an in vitro study using rat liver indicate that fluconazole may act as a potent inducer of some hepatic cytochrome P-450 enzymes systems involved in drug metabolism, acting as an enzyme inhibitor at low concentrations and an inducer at high concentrations.

Unlike most imidazoles (e.g., ketoconazole), fluconazole appears to have only minimal, if any, effects on human steroid synthesis, including production of cholesterol, testosterone, and estrogen in dosages up to 400 mg daily. Results of in vitro studies using human polymorphonuclear leukocytes (PMNs) obtained from healthy individuals indicate that exposure of PMNs to fluconazole concentrations of 1-50 mcg/mL does not appreciably affect PMN function, including chemotaxis, phagocytosis, and oxidative metabolism, and does not interfere with intracellular killing of C. albicans blastoconidia.

The drug also does not affect lymphocyte proliferation in vitro. Spectrum Fluconazole is active against many fungi, including yeasts and dermatophytes. Fluconazole does not appear to have antibacterial activity.

In Vitro Susceptibility Testing

Like imidazole derivatives and other triazole derivatives, results of in vitro fluconazole susceptibility tests are method dependent, and MIC values vary depending on the culture medium used, incubation temperature, pH, and inoculum size. In addition, currently available in vitro tests do not necessarily reflect the in vivo susceptibility of many fungi (especially Candida). Consequently, in vivo animal models of fungal infections may provide a more accurate assessment of the antifungal effectiveness of fluconazole than currently available in vitro susceptibility tests.

While fluconazole is less active on a weight basis in vitro than many other antifungal agents (e.g., itraconazole, ketoconazole, miconazole), the drug often is as or more active than these agents in vivo.

The reasons for the current lack of correlation between results of in vitro and in vivo tests are unclear. It has been suggested that substances contained in media used for in vitro susceptibility testing, especially complex media, may antagonize fluconazole. Other factors also probably contribute to the apparent poor correlation between in vitro and in vivo results.

Optimal methods for antifungal agent in vitro susceptibility testing have been difficult to identify and are still being investigated. The National Committee for Clinical Laboratory Standards (NCCLS) has recommended standardized procedures for reference broth dilution antifungal susceptibility testing that can be used to test in vitro susceptibility of yeasts (e.g., Candida, Cryptococcus neoformans) to fluconazole.

The reference method has not been used for testing the in vitro susceptibility of the yeast forms of dimorphic fungi (e.g., Blastomyces dermatitidis, Histoplasma capsulatum) or filamentous fungi (e.g., Aspergillus, Pseudallescheria boydii, Rhizopus, Sporothrix schenckii). Criteria regarding specific MICs that would indicate in vitro susceptibility or resistance to fluconazole are being established.

Experience to date indicates that, when the NCCLS reference broth dilution procedure is used to evaluate susceptibility to fluconazole, the majority of yeasts tested have MICs of 0.25-32 mcg/mL. It has been suggested that when the NCCLS reference procedure is used to test susceptibility of Candida isolates with a fluconazole MIC of 8 mcg/mL or less can be considered susceptible and those with an MIC of 64 mcg/mL or greater be considered resistant to the drug. Candida with a fluconazole MIC of 16-32 mcg/mL may be considered to have dose-dependent susceptibility, and fluconazole doses of 400 mg daily or higher may be required to treat infections caused by these strains.

These suggested MIC guidelines are principally based on experience with oropharyngeal candidiasis or invasive candidal infections in nonneutropenic patients and their clinical relevance in other settings is uncertain.

These MIC interpretive guidelines do not apply to C. krusei, an organism considered to be intrinsically resistant to fluconazole.

Fungi

When results of in vitro susceptibility tests are compared, fluconazole appears to be less active than ketoconazole against most susceptible organisms since MICs of fluconazole reported for C. albicans, C. neoformans, and H. capsulatum generally are 4-16 times higher than those reported for ketoconazole. However, results of studies using the drugs in various animal models of fungal infections indicate that, despite higher MIC values in vitro, the in vivo effectiveness of fluconazole is equal to or, in many cases, greater than the in vivo effectiveness of ketoconazole.

This difference may occur because results of fluconazole in vitro susceptibility tests are affected to a greater extent than those of ketoconazole and/or because pharmacologic differences between the drugs (e.g., fluconazole's higher oral bioavailability and lower protein binding) affect the in vivo effectiveness of the drugs. In vitro, fluconazole is active against some strains of Candida, including some strains of C. albicans, C. dubliniensis, C. guilliermondii, C. kefyr (formerly C. pseudotropicalis), C. glabrata (formerly Torulopsis glabrata), C. parapsilosis, C. lusitaniae, and C. tropicalis. C. krusei are intrinsically resistant to fluconazole and many strains of C. glabrata also are resistant to the drug. (See Resistance.)

In vitro, susceptible strains of C. albicans, C. guilliermondii, C. parapsilosis, and C. tropicalis usually are inhibited by fluconazole concentrations of 0.03-8 mcg/mL. When the NCCLS standardized procedure was used to test in vitro susceptibility of clinical isolates of C. dubliniensis obtained from patients with or without human immunodeficiency virus (HIV) infection, most strains were inhibited by fluconazole concentrations of 0.125-1 mcg/mL, but some strains had reduced susceptibility to the drug and required fluconazole concentrations of 8-32 mcg/mL for in vitro inhibition.

Fluconazole has in vitro activity against some strains of Cryptococcus neoformans. In vitro, some strains of C. neoformans are inhibited by fluconazole concentrations of 0.125-12.8 mcg/mL. Fluconazole is active in vitro against some strains of Histoplasma capsulatum. A wide range of fluconazole MICs has been reported for this organism. In some in vitro studies, MICs of fluconazole reported for H. capsulatum were 0.125-4 mcg/mL; however, in other studies, MICs ranged from 16-250 mcg/mL. In addition, some amphotericin B-susceptible strains of H. capsulatum with fluconazole MICs exceeding 1000 mcg/mL have been reported. Some strains of Blastomyces dermatitidis are inhibited in vitro by fluconazole concentrations of 2.5-10 mcg/mL, but other strains require concentrations of 20-80 mcg/mL for in vitro inhibition.

Fluconazole is inactive against Malassezia pachydermatis in vitro, and generally is inactive against Aspergillus in vitro. Scopulariopsis, including S. acremonium and S. brevicaulis, generally are resistant to fluconazole in vitro.

 In Vivo Susceptibility Testing

In vivo studies using various animal models (e.g., mice, rats, rabbits) and standard laboratory strains of fungi indicate that oral or IV fluconazole has fungistatic activity against a variety of fungal infections. Activity of the drug against fungi in these in vivo studies was generally evaluated based on increased survival rate and reduction of fungal burden in the animals' organs.

The manufacturer states that the clinical importance of results obtained in these studies is unknown. Fluconazole has been active in vivo in both normal and immunosuppressed mice, rats, and rabbits against systemic and local infections caused by C. albicans, including endophthalmitis, endocarditis, pyelonephritis, and intestinal, vaginal, and disseminated candidiasis; in several studies, fluconazole was at least as effective as amphotericin B (alone or combined with flucytosine) and more effective than ketoconazole in vivo against these infections.

Fluconazole also has been effective in vivo in animals against systemic C. parapsilosis infections.

Although fluconazole was active in vivo in mice against infections caused by C. tropicalis or C. glabrata, the drug was less effective against these infections than amphotericin B; neither fluconazole nor amphotericin B were effective in reducing tissue concentrations of C. krusei in these mice.

Fluconazole has been effective in vivo in mice and rabbits against infections caused by C. neoformans, including meningitis and pulmonary infections. The drug generally has been effective against systemic infections, including pulmonary infections, caused by H. capsulatum in normal and immunosuppressed mice, and was as effective as or less effective than amphotericin B.

Fluconazole also generally has been effective in mice against systemic infections, including intracranial infections, caused by C. immitis; pulmonary infections in mice caused by Blastomyces dermatitidis; and infections in mice caused by Paracoccidioides brasiliensis.

Results of in vivo testing of fluconazole activity against Aspergillus have been conflicting. In some in vivo studies in normal or immunosuppressed mice or rabbits, high dosages of the drug (60-120 mg/kg daily) were effective against infections caused by A. flavus and A. fumigatus. However, in at least one in vivo study in mice, fluconazole was ineffective against experimental aspergillosis. In in vivo models of dermatomycoses, fluconazole has been effective against pityriasis (tinea) versicolor caused by Malassezia furfur (Pityrosporum orbiculare or P. ovale) and infections caused by Trichophyton or Microsporum canis.

Resistance

Resistance to fluconazole can be produced in vitro by serial passage of Candida albicans in the presence of increasing concentrations of the drug. Some Candida species are intrinsically resistant to fluconazole (e.g., C. krusei), and many strains of C. glabrata are resistant to the drug. In addition, strains of Candida with decreased in vitro susceptibility to fluconazole have been isolated with increasing frequency.

Fluconazole-resistant strains of C. albicans, C. glabrata, C. lusitaniae, C. norvegensis, C. parapsilosis, and C. tropicalis have been isolated from patients receiving fluconazole.

Strains of Cryptococcus neoformans with decreased susceptibility to fluconazole also have been isolated from patients receiving the drug. Prolonged or intermittent use of oral fluconazole in immunocompromised patients has been suggested as a major contributing factor to the emergence of fluconazole resistance in Candida. In one study evaluating the in vitro susceptibility of Candida isolates obtained from patients with candidemia, 72% of the isolates obtained from patients who had received prior fluconazole therapy had decreased in vitro susceptibility to fluconazole (MIC greater than 8 mcg/mL) compared with only 12% of isolates obtained from patients who had not previously received fluconazole.

There is evidence that decreased in vitro susceptibility to fluconazole may correlate with clinical failure in the treatment of candidal infections (e.g., esophageal candidiasis) in HIV-infected patients. Emergence of fluconazole-resistant strains of C. albicans also have been reported rarely in immunocompetent patients receiving the drug.

Several mechanisms for decreased susceptibility to fluconazole have been suggested, including reduced intracellular accumulation of the drug as the result of defective lipids or sterols in the fungal cell membrane or active efflux of the drug or mutation of fungal 14-a-desmethylase leading to diminished affinity for the enzyme. In one in vitro study, fluconazole-resistant strains of C. albicans reverted to susceptible phenotypes when grown without the presence of fluconazole.

Fluconazole-resistant fungi also may be cross-resistant to other azole antifungal agents (e.g., ketoconazole, itraconazole).

While the clinical importance is unclear, fluconazole-resistant strains of C. albicans that were cross-resistant to amphotericin B have been isolated from a few immunocompromised individuals, including leukemia patients and HIV-infected individuals. In addition, a few isolates of Cryptococcus neoformans with decreased susceptibility to fluconazole have shown cross resistance to amphotericin B.

Pharmacokinetics

Absorption

The pharmacokinetics of fluconazole are similar following IV or oral administration. The drug is rapidly and almost completely absorbed from the GI tract, and there is no evidence of first-pass metabolism. Oral bioavailability of fluconazole exceeds 90% in healthy, fasting adults; peak plasma concentrations of the drug generally are attained within 1-2 hours after oral administration.

Results of a few limited studies indicate that oral bioavailability of fluconazole in adults with human immunodeficiency virus (HIV) infection appears to be similar to that reported for healthy adults. The rate and extent of GI absorption of fluconazole are not affected by food.

The manufacturer states that the commercially available fluconazole suspensions are bioequivalent to the 100-mg fluconazole tablets. Unlike some imidazole-derivative antifungal agents (e.g., ketoconazole), GI absorption of fluconazole does not appear to be affected by gastric pH. In one patient with achlorhydria who received 100-mg oral doses of fluconazole once daily, plasma concentrations of the drug 2 hours after a dose were similar to those reported at the same time interval in healthy adults.

Studies in healthy, fasting adults indicate that peak plasma concentrations, areas under the concentration-time curves (AUCs), time to peak plasma concentrations, and elimination half-life of fluconazole are not affected substantially by concurrent administration of drugs that increase gastric pH. Peak plasma fluconazole concentrations and AUCs increase in proportion to the dose over the oral dosage range of 50-400 mg.

Steady-state plasma concentrations of fluconazole are attained within 5-10 days following oral doses of 50-400 mg given once daily. The manufacturer states that when fluconazole therapy is initiated with a single loading dose equal to twice the usual daily dosage and followed by the usual dosage given once daily thereafter, plasma concentrations of the drug reportedly approach steady state by the second day of therapy. In healthy, fasting adults who received a single 1-mg/kg oral dose of fluconazole, peak plasma concentrations of the drug averaged 1.4 mcg/mL.

Following oral administration of a single 400-mg dose of fluconazole in healthy, fasting adults, peak plasma concentrations average 6.72 mcg/mL (range: 4.12-8. mcg/mL). In adults with coccidioidal meningitis who received oral fluconazole in a dosage of 50 or 100 mg daily, peak serum concentrations of the drug ranged from 2.5-3. or 4.5-8 mcg/mL, respectively, and were attained in 2-6 hours; serum concentrations averaged 1.2 or 3.1 mcg/mL, respectively, at 24-27 hours after a dose. In healthy adults receiving 50- or 100-mg doses of fluconazole given once daily by IV infusion over 30 minutes, serum concentrations of the drug 1 hour after dosing on the sixth or seventh day of therapy ranged from 2.14-2.81 or 3.86-4.96 mcg/mL, respectively.

In children 9 months to 13 years of age, oral administration of a single 2- or 8-mg/kg dose of fluconazole resulted in mean peak plasma concentrations of 2.9 or 9.8 mcg/mL, respectively. In a multiple-dose study in children 5-15 years of age, IV administration of 2-, 4-, or 8-mg/kg doses of fluconazole resulted in mean peak plasma concentrations of 5.5, 11.4, or 14.1 mcg/mL, respectively. In a limited study in premature neonates who received 6-mg/kg doses of fluconazole IV every 72 hours, peak serum concentrations of the drug ranged from 3.7-10.2 mcg/mL after the first dose and from 6-17.8 mcg/mL after the third dose (day 7).

Distribution

Fluconazole is widely distributed into body tissues and fluids following oral or IV administration. Studies in mice using IV doses of radiolabeled fluconazole indicate that the drug is evenly distributed throughout body tissues. In adult humans with normal renal function, concentrations of the drug attained in urine and skin may be 10 times higher than concurrent plasma concentrations; concentrations attained in saliva, sputum, nails, blister fluid, blister skin, and vaginal tissue are approximately equal to concurrent plasma concentrations. Concentrations attained in vaginal secretions following administration of a single 150-mg oral dose reportedly are about 40-86% of concurrent plasma concentrations.

Fluconazole concentrations in prostatic tissue reportedly average about 30% of concurrent plasma concentrations. In adults with bronchiectasis who received a single 150-mg oral dose of fluconazole, sputum concentrations of the drug in samples obtained at 4 and 24 hours after the dose averaged 3.7 and 2.23 mcg/mL, respectively, and were approximately equal to concurrent plasma concentrations.

Studies in rabbits indicate that high concentrations of fluconazole are attained in the cornea, aqueous humor, and vitreous body following IV administration; these concentrations were higher in inflamed than uninflamed eyes.

Fluconazole, unlike some azole-derivative antifungal agents (e.g., itraconazole, ketoconazole), distributes readily into CSF following oral or IV administration; CSF concentrations of fluconazole may be 50-94% of concurrent plasma concentrations regardless of the degree of meningeal inflammation. In adults with coccidioidal meningitis who received an oral fluconazole dosage of 50 or 100 mg daily, CSF concentrations of the drug in samples obtained 0.5-8 hours after a dose averaged 0.7-2.23 or 3.5-5.3 mcg/mL, respectively. The apparent volume of distribution of fluconazole approximates that of total body water and has been reported to be 0.7-1 L/kg. In a limited study, the estimated volume of distribution at steady state of fluconazole was slightly lower in HIV-infected adults than in healthy adults.

Unlike some azole-derivative antifungal agents (e.g., itraconazole, ketoconazole, miconazole), which are highly protein bound, fluconazole is only 11-12% bound to plasma proteins. It is not known whether fluconazole crosses the placenta in humans. The drug crosses the placenta in rats, and concentrations in amniotic fluid, placenta, fetus, and fetal liver are approximately equal to maternal plasma concentrations. Fluconazole is distributed into human milk in concentrations similar to those attained in plasma.

Following administration of a single 150-mg oral dose in nursing women, peak plasma fluconazole concentrations were 2.61 mcg/mL (range: 1.57-3.65 mcg/mL)

Elimination

The plasma elimination half-life of fluconazole in adults with normal renal function is approximately 30 hours (range: 20-50 hours). In one study, plasma elimination half-life of the drug was 22 hours after the first day of therapy and 23.8 and 28.6 hours after 7 and 26 days of therapy, respectively. In a limited, single-dose study in HIV-infected adults, the plasma elimination half-life of fluconazole averaged 32 hours (range: 25-42 hours) in those with absolute helper/inducer (CD4+, T4+) T-cell counts greater than 200mm and 50 hours (range: 32-69 hours) in those with CD4+ T-cell counts less than 200mm. In other single-dose studies in a limited number of HIV-infected adults with CD4+ T-cell counts less than 200mm, the plasma elimination half-life of the drug averaged 35-40 hours (range 22-75 hours).

The mean plasma half-life of fluconazole in children 9 months to 15 years of age has ranged from about 15-25 hours. In a limited study in premature neonates who received IV fluconazole once every 72 hours, the plasma half-life decreased over time, averaging 88 hours after the first dose and 55 hours after the fifth dose (day 13). In patients with impaired renal function, plasma concentrations of fluconazole are higher and the half-life prolonged; elimination half-life of the drug is inversely proportional to the patient's creatinine clearance. In addition, there is limited evidence that elimination of the drug may be impaired in geriatric patients. The elimination half-life of fluconazole reportedly is not affected by impaired hepatic function. In healthy adults, fluconazole is eliminated principally by renal excretion.

Renal clearance of the drug averages 0.27 mL/minute per kg in adults with normal renal function. In a limited, single-dose study, renal clearance of fluconazole averaged 0.79 L/hour in healthy adults, 0.58 L/hour in HIV-infected adults with CD4+ T-cell counts greater than 200mm, and 0.2 L/hour in those with CD4+ T-cell counts less than 200mm. Approximately 60-80% of a single oral or IV dose of fluconazole is excreted in urine unchanged, and about 11% is excreted in urine as metabolites.

Small amounts of the drug are excreted in feces. Fluconazole is removed by hemodialysis and peritoneal dialysis. The amount of the drug removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate). A 3-hour period of hemodialysis generally decreases plasma concentrations of the drug by 50%. In 2 adults with fungal peritonitis undergoing continuous ambulatory peritoneal dialysis (CAPD) and receiving an oral fluconazole dosage of 100 mg/kg daily, concentrations of the drug in peritoneal dialysis fluid ranged from 2.3-9 mcg/mL and concurrent plasma concentrations ranged from 3.2-9 mcg/mL.

Chemistry and Stability

Chemistry

Fluconazole, a synthetic triazole derivative, is an azole antifungal agent. The drug is structurally related to imidazole-derivative azole antifungal agents (e.g., butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole) since it contains a 5-membered azole ring attached by a carbon-nitrogen bond to other aromatic rings. However, imidazoles have 2 nitrogens in the azole ring (imidazole ring) and fluconazole and other triazoles (e.g., itraconazole, terconazole) have 3 nitrogens in the ring (triazole ring).

Replacement of the imidazole ring with a triazole ring apparently results in increased antifungal activity and an expanded antifungal spectrum of activity. In addition to this triazole ring, fluconazole contains a second triazole ring and thus is a bistriazole derivative. Presence of these triazole rings may contribute to fluconazole's resistance to first-pass metabolism and the drug's low lipophilicity and protein binding.

However, other structural modifications to bistriazole derivatives also affect these characteristics since itraconazole, which also is a bistriazole, is highly lipophilic and protein bound and undergoes extensive hepatic metabolism. Presence of a halogenated phenyl ring increases antifungal activity of bistriazole derivatives and the 2,-difluorophenyl derivative (fluconazole) has an aqueous solubility suitable for IV formulation. Fluconazole occurs as a white crystalline powder and is slightly soluble in water, having an aqueous solubility of 8 mg/mL at 37°C.

The drug has a solubility of 25 mg/mL in alcohol at room temperature. Fluconazole has a pKa of 1.76 at 24°C in 0.1 M sodium chloride.

Fluconazole injections are sterile, iso-osmotic solutions of the drug in a sodium chloride or dextrose diluent; each mL contains 2 mg of fluconazole and either 9 mg of sodium chloride or 56 mg of dextrose. The injections have an osmolarity of 300-315 mOsm/L; the pH ranges from 4-8 in the sodium chloride diluent and from 3.5-6.5 in the dextrose diluent.

Stability

Fluconazole tablets should be stored in tight containers at a temperature less than 30°C; fluconazole powder for oral suspension should be stored at a temperature less than 30°C. After reconstitution, refrigeration of fluconazole oral suspension is not necessary and freezing of the suspension should be avoided.

The manufacturer states that the reconstituted suspension is stable for 14 days when stored at 5-30°C and any unused suspension should be discarded after this period. Commercially available fluconazole injection provided in glass bottles should be stored at 5-30°C and protected from freezing.

Fluconazole injection provided in Viaflex® Plus plastic containers should be stored at 5-25°C and protected from freezing; brief exposure of the drug in Viaflex® Plus containers to temperatures up to 40°C will not adversely affect the injection. Commercially available fluconazole injection in glass or plastic containers is stable for 24 or 18 months, respectively, following the date of manufacture.

The Viaflex® Plus plastic containers are fabricated from specially formulated polyvinyl chloride (PVC). The amount of water that can permeate from inside the container into the overwrap is insufficient to substantially affect the solution. Solutions in contact with the plastic can leach out some of its chemical components in very small amounts (e.g., bis(2-ethylhexyl)phthalate BEHP, DEHP in up to 5 ppm) within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

Additives should not be introduced into the glass or Viaflex® Plus containers of commercially available fluconazole injection.

Preparations

Fluconazole Oral For suspension 50 mg/5 mL Diflucan®, Pfizer 200 mg/5 mL Diflucan®, Pfizer Tablets 50 mg Diflucan®, (with povidone) Pfizer 100 mg Diflucan®, (with povidone) Pfizer 150 mg Diflucan®, (with povidone) Pfizer 200 mg Diflucan®, (with povidone) Pfizer Fluconazole in Dextrose Parenteral Injection, for IV 2 mg/mL (200 or 400 mg) in Diflucan® in Iso-osmotic infusion only 5.6% Dextrose Dextrose Injection, (in Viaflex® Plus [Baxter]) Pfizer Fluconazole in Sodium Chloride Parenteral Injection, for IV 2 mg/mL (200 or 400 mg) in Diflucan® in Iso-osmotic infusion only 0.9% Sodium Chloride Sodium Chloride Injection, (in glass and Viaflex® Plus [Baxter]) Pfizer

 
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