Fluconazole drug interactions

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


List of drug interactions


Oral hypoglycemics

Coumarin-type anticoagulants

Phenytoin

Cyclosporine

Rifampin

Theophylline

Terfenadine

Cisapride

Astemizole

Rifabutin

Tacrolimus

Short-acting benzodiazepines

Oral contraceptives

Cimetidine

Antacid

Hydrochlorothiazide

Warfarin

Zidovudine

Tolbutamide

Glipizide

Glyburide

Midazolam

Azithromycin

Complete List of Drug Interactions









Oral hypoglycemics

Clinically significant hypoglycemia may be precipitated by the use of Fluconazole with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined Fluconazole and glyburide use. Fluconazole reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When Fluconazole is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary.
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.

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Coumarin-type anticoagulants

Prothrombin time may be increased in patients receiving concomitant Fluconazole and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving Fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving Fluconazole and coumarin-type anticoagulants is recommended.

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Phenytoin

Fluconazole increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving Fluconazole and phenytoin is recommended.
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 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.

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Cyclosporine

Fluconazole may significantly increase cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving Fluconazole and cyclosporine. <br 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%).

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Rifampin

Rifampin enhances the metabolism of concurrently administered Fluconazole. Depending on clinical circumstances, consideration should be given to increasing the dose of Fluconazole when it is administered with rifampin.
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 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.

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Theophylline

Fluconazole increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving Fluconazole and theophylline is recommended.
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.

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Terfenadine

Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200-mg daily dose of Fluconazole failed to demonstrate a prolongation in QTc interval. 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. The combined use of Fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. The coadministration of Fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored.
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.

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Cisapride

There have been reports of cardiac events, including torsade de pointes in patients to whom Fluconazole and cisapride were coadministered. A controlled study found that concomitant Fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The combined use of Fluconazole with cisapride is contraindicated.
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.

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Astemizole

The use of Fluconazole in patients concurrently taking astemizole or other drugs metabolized by the cytochrome P450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when coadministering Fluconazole. Patients should be carefully monitored.

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Rifabutin

There have been reports of uveitis in patients to whom Fluconazole and rifabutin were coadministered. Patients receiving rifabutin and Fluconazole concomitantly should be carefully monitored.
There have been published reports that an interaction exists when Fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin.

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Tacrolimus

There have been reports of nephrotoxicity in patients to whom Fluconazole and tacrolimus were coadministered. Patients receiving tacrolimus and Fluconazole concomitantly should be carefully monitored.
There have been published reports that an interaction exists when Fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus.

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Short-acting benzodiazepines

Following oral administration of midazolam, Fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of Fluconazole than with Fluconazole administered intravenously. If short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with Fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored.
Fluconazole tablets coadministered with ethinyl estradiol- and levonorgestrel-containing oral contraceptives produced an overall mean increase in ethinyl estradiol and levonorgestrel levels; however, in some patients there were decreases up to 47% and 33% of ethinyl estradiol and levonorgestrel levels. The data presently available indicate that the decreases in some individual ethinyl estradiol and levonorgestrel AUC values with Fluconazole treatment are likely the result of random variation. While there is evidence that Fluconazole can inhibit the metabolism of ethinyl estradiol and levonorgestrel, there is no evidence that Fluconazole is a net inducer of ethinyl estradiol or levonorgestrel metabolism. The clinical significance of these effects is presently unknown.
Physicians should be aware that interaction studies with medications other than those listed here have not been conducted, but such interactions may occur.

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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, ten-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 18–31%) 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.

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Cimetidine

Fluconazole 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 Fluconazole 200 mg) did not affect the bioavailability or pharmacokinetics of Fluconazole in 24 healthy male volunteers.

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Antacid

Fluconazole 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 Fluconazole 200 mg) did not affect the bioavailability or pharmacokinetics of Fluconazole in 24 healthy male volunteers.

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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 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%).

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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 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.

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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.

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Tolbutamide

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.

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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 mean ± SD increase in AUC of 49%± 13% (range: 27 to 73%) and an increase in Cmax of 19%± 23% (range: −11 to 79%).

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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 mean ± SD 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.

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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, 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.

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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.

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Complete List of Drug Interactions

Major Interactions

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Moderate Interactions

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Minor Interactions

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Adapted from the FDA Package Insert.


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