Fluconazole (fluconazole 150 mg) Dailymed

Description

Fluconazole, the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration. Fluconazole is designated chemically as 2,4-difluoro-benzyl alcohol with a molecular formula of C13H12F2N6O and molecular weight 306.3. The structural formula is: Fluconazole, USP is a white crystalline solid which is slightly soluble in water and saline. Each tablet, for oral administration, contains 50 mg, 100 mg, 150 mg or 200 mg of fluconazole, USP. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake, magnesium stearate, microcrystalline cellulose, povidone and sodium lauryl sulfate.

Clinical Pharmacology

Pharmacokinetics And Metabolism

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 to 50 hours) after oral administration. In fasted normal volunteers, administration of a single oral 400 mg dose of fluconazole leads to a mean Cmax of 6.72 mcg/mL (range: 4.12 to 8.08 mcg/mL) and after single oral doses of 50 mg to 400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose proportional. The Cmax and AUC data from a food-effect study involving administration of fluconazole tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food. Therefore, fluconazole may be taken without regard to meals. (See

DOSAGE AND ADMINISTRATION

.) Administration of a single oral 150 mg tablet of fluconazole to ten lactating women resulted in a mean Cmax of 2.61 mcg/mL (range: 1.57 to 3.65 mcg/mL). Steady-state concentrations are reached within 5 to 10 days following oral doses of 50 mg to 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% to 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.

*

Relative to concurrent concentrations in plasma in subjects with normal renal function.

Independent of degree of meningeal inflammation.Tissue or FluidRatio of Fluconazole Tissue (Fluid)/Plasma Concentration

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Cerebrospinal fluid

0.5 to 0.9Saliva1Sputum1Buler fluid1Urine10Normal skin10Nails1Buler skin2Vaginal tissue1Vaginal fluid0.4 to 0.7In 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 fluconazole may need to be reduced in patients with impaired renal function. (See

DOSAGE AND ADMINISTRATION

.) A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. In normal volunteers, fluconazole 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.

Pharmacokinetics in Children

In children, the following pharmacokinetic datahave been reported: Age StudiedDose (mg/kg)Clearance (mL/min/kg)Half-life (Hours)Cmax (mcg/mL)Vdss (L/kg)9 Months to 13 yearsSingle-Oral 2 mg/kg0.40 (38%) N = 14252.9 (22%) N = 16-9 Months to 13 yearsSingle-Oral 8 mg/kg0.51 (60%) N = 1519.59.8 (20%) N = 15-5 to 15 yearsMultiple IV 2 mg/kg0.49 (40%) N = 417.45.5 (25%) N = 50.722 (36%) N = 45 to 15 yearsMultiple IV 4 mg/kg0.59 (64%) N = 515.211.4 (44%) N = 60.729 (33%) N = 55 to 15 yearsMultiple IV 8 mg/kg0.66 (31%) N = 717.614.1 (22%) N = 81.069 (37%) N = 7Clearance 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 6 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.

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 mcgh/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 to 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-lifecreatinine 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-lifecreatinine 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.

Drug Interaction Studies

Oral Contraceptives Oral contraceptives were administered as a single dose both before and after the oral administration of fluconazole 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 fluconazole. 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 fluconazole tablets or placebo for two, 10-day periods. The treatment cycles were one month apart with all subjects receiving fluconazole 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 were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of fluconazole, 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% to 31%) and 13% (95% C.I. range 8% to 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.

Cimetidine Fluconazole 100 mg was administered as a single oral dose alone and 2 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 meanSD 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 4-hour period (from 1 hour before to 3 hours after a single

Antacid Administration of Maalox

1

(20 mL) to 14 normal male volunteers immediately prior to a single dose of fluconazole 100 mg had no effect on the absorption or elimination of fluconazole.

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Maaloxis a registerd trademark of Novartis Consumer Health Inc.

Hydrochlorothiazide Concomitant oral administration of 100 mg fluconazole and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a meanSD 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 meanSD reduction in renal clearance of 30%12% (range: -10% to -50%).

Rifampin Administration of a single oral 200 mg dose of fluconazole 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 meanSD 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 33.44.4 hours to 26.83.9 hours. (See

PRECAUTIONS

.)

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 fluconazole 200 mg administered daily for 14 days as compared to the administration of warfarin alone. There was a meanSD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7%4% (range: -2% to 13%). (See

PRECAUTIONS

.) Mean is based on data from 12 subjects as one of 13 subjects experienced a 2-fold increase in his prothrombin time response.

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 fluconazole 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC. The meanSD 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. (See

PRECAUTIONS

.)

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 meanSD 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%). (See

PRECAUTIONS

.)

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 2 weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The meanSD 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 7.63.6 to 5.72.2.

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 meanSD 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 6.61.7 hours to 7.91.5 hours. (See

PRECAUTIONS

.)

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 fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. (See

CONTRAINDICATIONS

and

PRECAUTIONS

.)

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 fluconazole 100 mg daily for 7 days. In these three studies 22/46 (47.8%) of fluconazole treated patients and 9/22 (40.1%) of placebo treated patients experienced symptoms consistent with hypoglycemia. (See

PRECAUTIONS

.)

Tolbutamide

In 13 normal male volunteers, there was significant increase in tolbutamide (500 mg single dose) AUC and Cmax following the administration of fluconazole. There was a meanSD increase in tolbutamide AUC of 26%9% (range: 12% to 39%). Tolbutamide Cmax increased 11%9% (range: -6% to 27%). (See

PRECAUTIONS

.)

Glipizide

The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased following the administration of fluconazole in 13 normal male volunteers. There was a meanSD increase in AUC of 49%13% (range: 27% to 73%) and an increase in Cmax of 19%23% (range: -11% to 79%). (See

PRECAUTIONS

.)

Glyburide

The AUC and Cmax of glyburide (5 mg single dose) were significantly increased following the administration of fluconazole in 20 normal male volunteers. There was a meanSD increase in AUC of 44%29% (range: -13% to 115%) and Cmax increased 19%19% (range: -23% to 62%). Five subjects required oral glucose following the ingestion of glyburide after 7 days of fluconazole administration. (See

PRECAUTIONS

.)

Rifabutin

There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See

PRECAUTIONS

.)

There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. (See

PRECAUTIONS

.)

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. (See

CONTRAINDICATIONS

and

PRECAUTIONS

.)

Midazolam

The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, crossover 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, fluconazole increased 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, crossover 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. (See

PRECAUTIONS

.)

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.