Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4160
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Diflucan (Tablet)
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Dosage and Administration in Adults:<br/>Single Dose:<br/>Multiple Dose: SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient's response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse.<br/>Dosage and Administration in Children: The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature newborns. Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding DIFLUCAN pharmacokineticsin full-term newborns is available.<br/>Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse.<br/>Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used based on medical judgment of the patient's response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms.<br/>Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6���12 mg/kg/day have been used in an open, noncomparative study of a small number of children.<br/>Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient's response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10���12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily.<br/>Dosage In Patients With Impaired Renal Function: Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg)��(140-age)72��serum creatinine (mg/100 mL) Females: 0.85��above value Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K��linear length or height (cm)serum creatinine (mg/100 mL) (Where K=0.55 for children older than 1 year and 0.45 for infants.)<br/>Administration: DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN injection has been used safely for up to fourteen days of intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a maximum rate of approximately 200 mg/hour, given as a continuous infusion. DIFLUCAN injections in glass and Viaflex' Plus plastic containers are intended only for intravenous administration using sterile equipment. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is cloudy or precipitated or if the seal is not intact.<br/>Directions for Mixing the Oral Suspension: Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Note: Shake oral suspension well before using. Store reconstituted suspension between 86��F (30��C) and 41��F (5��C) and discard unused portion after 2 weeks. Protect from freezing.<br/>Directions for IV Use of DIFLUCAN in Viaflex' Plus Plastic Containers: Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product. CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. DO NOT ADD SUPPLEMENTARY MEDICATION. Preparation for Administration:
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DIFLUCAN' (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration, as a powder for oral suspension and as a sterile solution for intravenous use in glass and in Viaflex' Plus plastic containers. Fluconazole is designated chemically as 2,4-difluoro-��,��-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of CHFNO and molecular weight 306.3. The structural formula is: Fluconazole is a white crystalline solid which is slightly soluble in water and saline. DIFLUCAN tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone, croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate. DIFLUCAN for oral suspension contains 350 mg or 1400 mg of fluconazole and the following inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate, titanium dioxide, colloidal silicon dioxide, xanthan gum and natural orange flavor. After reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted suspension contains 10 mg or 40 mg of fluconazole. DIFLUCAN injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are packaged in glass and in Viaflex' Plus plastic containers. The Viaflex' Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146' Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability 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.
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Pharmacokinetics and Metabolism: The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose. 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. In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN (fluconazole) leads to a mean Cmax of 6.72��g/mL (range: 4.12 to 8.08��g/mL) and after single oral doses of 50���400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose proportional. Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating women resulted in a mean Cmax of 2.61��g/mL (range: 1.57 to 3.65��g/mL). 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, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations. A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing. A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing. 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 are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of DIFLUCAN may need to be reduced in patients with impaired renal function. A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response.<br/>Pharmacokinetics in Children: In children, the following pharmacokinetic data {Mean(%cv)} have been reported: Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg. In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later.<br/>Pharmacokinetics in Elderly: A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4+ 20.3 mcg���h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0���24 hr, 22%) and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject's terminal elimination half-life versus creatinine clearance compared with the predicted half-life���creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life���creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney function that is expected in the elderly.<br/>Drug Interaction Studies:<br/>Oral contraceptives: Oral contraceptives were administered as a single dose both before and after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women. There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6% (range:���47 to 108%) and levonorgestrel AUC increased 17% (range:���33 to 141%). In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol wereadministered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: -12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: -11 to 101%). Both of these increases were statistically significantly different from placebo. A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to 21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In this placebo-controlled, double-blind, randomized, two-way crossover study carried out over three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range 18���31%) and 13% (95% C.I. range 8���18%), respectively relative to placebo. Fluconazole treatment did not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to placebo dosing. The individual AUC values of norethindrone decreased very slightly (<5%) in 3 of the 21 subjects after fluconazole treatment.<br/>Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean��SD decrease in fluconazole AUC of 13%��11% (range:���3.4 to���31%) and Cmax decreased 19%��14% (range:���5 to���40%). However, the administration of cimetidine 600 mg to 900 mg intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers.<br/>Antacid: Administration of Maalox' (20 mL) to 14 normal male volunteers immediately prior to a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of fluconazole.<br/>Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean��SD increase in fluconazole AUC and Cmax of 45%��31% (range: 19 to 114%) and 43%��31% (range: 19 to 122%), respectively. These changes are attributed to a mean��SD reduction in renal clearance of 30%��12% (range:���10 to���50%).<br/>Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean��SD reduction in fluconazole AUC of 23%��9% (range:���13 to���42%). Apparent oral clearance of fluconazole increased 32%��17% (range: 16 to 72%). Fluconazole half-life decreased from 33.4��4.4 hours to 26.8��3.9 hours.<br/>Warfarin: There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to 13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as compared to the administration of warfarin alone. There was a mean��SD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7%��4% (range:���2 to 13%). Mean is based on data from 12 subjects as one of 13 subjects experienced a 2-fold increase in his prothrombin time response.<br/>Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily, orally for 3 days followed by 250 mg intravenously for one dose) both with and without the administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC. The mean��SD increase in phenytoin AUC was 88%��68% (range: 16 to 247%). The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin.<br/>Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks. There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and a significant reduction in apparent oral clearance following the administration of fluconazole. The mean��SD increase in AUC was 92%��43% (range: 18 to 147%). The Cmax increased 60%��48% (range:���5 to 133%). The Cmin increased 157%��96% (range: 33 to 360%). The apparent oral clearance decreased 45%��15% (range:���15 to���60%).<br/>Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were on a stable zidovudine dose for at least two weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The mean��SD increase in AUC was 20%��32% (range:���27 to 104%). The metabolite, GZDV, to parent drug ratio significantly decreased after the administration of fluconazole, from 7.6��3.6 to 5.7��2.2.<br/>Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean��SD theophylline AUC increased 21%��16% (range:���5 to 48%). The Cmax increased 13%��17% (range:���13 to 40%). Theophylline clearance decreased 16%��11% (range:���32 to 5%). The half-life of theophylline increased from 6.6��1.7 hours to 7.9��1.5 hours.<br/>Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36%��36% (range: 7 to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400-mg and 800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly.<br/>Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily for 7 days. In these three studies 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%) of placebo treated patients experienced symptoms consistent with hypoglycemia.<br/>Rifabutin: There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin.<br/>Tacrolimus: There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus.<br/>Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple doses of fluconazole, there was a 192%increase in the cisapride AUC and a 154% increase in the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days.<br/>Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study, subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2 to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing, fluconazoleincreased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam. A second randomized, double-dummy, placebo-controlled, cross-over study in three phases was performed to determine the effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400 mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The AUC and Cmax of midazolam were significantly higher after oral than IV administration of fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%, respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%, respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of midazolam.<br/>Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.<br/>Microbiology:<br/>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.<br/>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 The following in vitro data are available, but their clinical significance is unknown. Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8��g/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 DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy.<br/>Susceptibility Testing Methods:<br/>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��g 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.<br/>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 normaland 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 A. fumigatus. The clinical significance of results obtained in these studies is unknown.<br/>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��g/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 DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy.
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DIFLUCAN (fluconazole) is 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 DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. Coadministration of cisapride is contraindicated in patients receiving DIFLUCAN (fluconazole).
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DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100 or 200 mg of fluconazole are packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval shaped, packaged in a single dose unit blister. DIFLUCAN Tablets are supplied as follows: DIFLUCAN 50 mg Tablets: Engraved with "DIFLUCAN" and "50" on the front and "ROERIG" on the back. NDC 0049-3410-30 Bottles of 30 DIFLUCAN 100 mg Tablets: Engraved with "DIFLUCAN" and "100" on the front and "ROERIG" on the back. NDC 0049-3420-30 Bottles of 30NDC 0049-3420-41 Unit dose package of 100 DIFLUCAN 150 mg Tablets: Engraved with "DIFLUCAN" and "150" on the front and "ROERIG" on the back. NDC 0049-3500-79 Unit dose package of 1 DIFLUCAN 200 mg Tablets: Engraved with "DIFLUCAN" and "200" on the front and "ROERIG" on the back. NDC 0049-3430-30 Bottles of 30NDC 0049-3430-41 Unit dose package of 100<br/>Storage: Store tablets below 86��F (30��C).<br/>DIFLUCAN for Oral Suspension: DIFLUCAN for oral suspension is supplied as an orange-flavored powder to provide 35 mL per bottle as follows: NDC 0049-3440-19 Fluconazole 350 mg per bottleNDC 0049-3450-19 Fluconazole 1400 mg per bottle<br/>Storage: Store dry powder below 86��F (30��C). Store reconstituted suspension between 86��F (30��C) and 41��F (5��C) and discard unused portion after 2 weeks. Protect from freezing.<br/>DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are supplied in glass bottles or in Viaflex' Plus plastic containers containing volumes of 100 mL or 200 mL affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN injections in Viaflex' Plus plastic containers are available in both sodium chloride and dextrose diluents. DIFLUCAN Injections in Glass Bottles: NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL��6NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL��6<br/>Storage: Store between 86��F (30��C) and 41��F (5��C). Protect from freezing. DIFLUCAN Injections in Viaflex' Plus Plastic Containers: NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL��6NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL��6NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL��6NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL��6<br/>Storage: Store between 77��F (25��C) and 41��F (5��C). Brief exposure up to 104��F (40��C) does not adversely affect the product. Protect from freezing.
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There have been reports of overdosage with DIFLUCAN (fluconazole). A 42-year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behavior after reportedly ingesting 8200 mg of DIFLUCAN. The patient was admitted to the hospital, and his condition resolved within 48 hours. 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%. In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex and cyanosis; death was sometimes preceded by clonic convulsions.
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fluconazole
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Diflucan (Tablet)
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In Patients Receiving a Single Dose for Vaginal Candidiasis: During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience.<br/>In Patients Receiving Multiple Doses for Other Infections: Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.<br/>Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with DIFLUCAN. The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis andjaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of DIFLUCAN. In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serumtransaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking DIFLUCAN concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents.<br/>Adverse Reactions in Children: In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase.
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DIFLUCAN (fluconazole) is indicated for the treatment of: Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.
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Diflucan
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