FLUCONAZOLE- fluconazole tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
FLUCONAZOLE (UNII: 8VZV102JFY) (FLUCONAZOLE - UNII:8VZV102JFY)
Available from:
Bryant Ranch Prepack
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Fluconazole tablets are indicated for the treatment of: - Vaginal candidiasis (vaginal yeast infections due to Candida ). - Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, fluconazole tablets were also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia. - Cryptococcal meningitis. Before prescribing fluconazole tablets for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing fluconazole tablets to amphotericin B in non-HIV infected patients have not been conducted. Prophylaxis: Fluconazole tablets are 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 pr
Product summary:
Product: 63629-8054 NDC: 63629-8054-1 2 TABLET in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
63629-8054-1

FLUCONAZOLE- fluconazole tablet

Bryant Ranch Prepack

----------

Fluconazole Tablets, USP

Rx only

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-α,α -bis(1H-1,2,4-triazol-1-ylmethyl) benzyl

alcohol with an molecular formula of C

H F N O and molecular weight of 306.3. The structural

formula is:

Fluconazole USP is a white or almost white crystalline powder which is freely soluble in methanol,

soluble in alcohol and in acetone, sparingly soluble in isopropanol and in chloroform, slightly soluble

in water, very slightly soluble in toluene.

Each fluconazole tablet, USP intended 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:

croscarmellose sodium, dibasic calcium phosphate anhydrous, fd&c red no. 40 aluminum lake,

magnesium stearate, microcrystalline cellulose and povidone.

Fluconazole tablet meets USP Dissolution Test 2.

CLINICAL PHARMACOLOGY

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 (C

) 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

of 6.72 mcg/mL (range: 4.12 mcg/mL to 8.08 mcg/mL) and after single oral doses of 50 mg to 400

mg, fluconazole plasma concentrations and area under the plasma concentration-time curve (AUC) are

dose proportional.

The C

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.)

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 cerebrospinal fluid (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.

Tissue or Fluid

Ratio of Fluconazole

Tissue (Fluid)/Plasma

Concentration

Cerebrospinal fluid

0.5 to 0.9

Saliva

Sputum

Blister fluid

Urine

Normal skin

Nails

Blister skin

Vaginal tissue

Vaginal fluid

0.4 to 0.7

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

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

Independent of degree of meningeal inflammation.

*

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 adrenocorticotropic hormone (ACTH)-stimulated

cortisol response.

Pharmacokinetics in Children

In children, the following pharmacokinetic data {Mean (%cv)} have been reported:

Age Studied

Dose (mg/kg)

Clearance (mL/min/kg) Half-life (Hours)

C

(mcg/mL)

Vdss (L/kg)

9 Months to

13 years

Single-Oral

2 mg/kg

0.40 (38%)

N=14

2.9 (22%)

N=16

9 Months to

13 years

Single-Oral

8 mg/kg

0.51 (60%)

N=15

19.5

9.8 (20%)

N=15

5 to 15 years

Multiple IV

2 mg/kg

0.49 (40%)

17.4

5.5 (25%)

0.722 (36%)

5 to 15 years

Multiple IV

4 mg/kg

0.59 (64%)

15.2

11.4 (44%)

0.729 (33%)

5 to 15 years

Multiple IV

8 mg/kg

0.66 (31%)

17.6

14.1 (22%)

1.069 (37%)

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.

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 C

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 the AUC or C

. In addition, creatinine clearance (74 mL/min), the percent of drug

recovered unchanged in urine (0 to 24 hours, 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 to 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 to normal young male volunteers are due to the decreased kidney function

that is expected in the elderly.

max

Drug Interaction Studies (See PRECAUTIONS, Drug Interactions)

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 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 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 C

. There was a mean ± SD decrease in

fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and C

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.

Antacid: Administration of Maalox

(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.

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 C

compared to fluconazole given alone. There was a mean ± SD increase in

fluconazole AUC and C

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%).

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. (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 mean ± SD 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 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. (See PRECAUTIONS.)

Cyclosporine: Cyclosporine AUC and C

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, C

(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 C

increased 60% ±

48% (range: –5 to 133%). The C

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 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.

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, C

, and

half-life with a corresponding decrease in clearance. The mean ± SD theophylline AUC increased 21%

± 16% (range: –5 to 48%). The C

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. (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/day or greater significantly

increases plasma levels of terfenadine when taken concomitantly. (See CONTRAINDICATIONS and

PRECAUTIONS.)

Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with

quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with

QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and

quinidine is contraindicated. (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 C

following the administration of fluconazole. There was a mean ± SD increase in

tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide C

increased 11% ± 9% (range: –6

to 27%). (See PRECAUTIONS.)

Glipizide: The AUC and C

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 C

of 19% ± 23% (range: –11 to 79%).

(See PRECAUTIONS.)

Glyburide: The AUC and C

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 C

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.)

Tacrolimus: 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 C

. Following multiple doses of fluconazole, there was a 192%

increase in the cisapride AUC and a 154% increase in the cisapride C

. 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, 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, fluconazole increased the midazolam AUC and

by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the

midazolam AUC and C

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 C

midazolam were significantly higher after oral than IV administration of fluconazole. Oral fluconazole

increased the midazolam AUC and C

by 272% and 129%, respectively. IV fluconazole increased the

midazolam AUC and C

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.

Voriconazole: Voriconazole is a substrate for both CYP2C9 and CYP3A4 isoenzymes. Concurrent

administration of oral Voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral

fluconazole (400 mg on Day 1, then 200 mg Q24h for 4 days) to 6 healthy male subjects resulted in an

increase in C

and AUC of voriconazole by an average of 57% (90% CI: 20% to 107%) and 79%

(90% CI: 40% to 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects,

reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this

effect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended.

Close monitoring for adverse events related to voriconazole is recommended if voriconazole is used

sequentially after fluconazole, especially within 24 h of the last dose of fluconazole. (See

PRECAUTIONS.)

Tofacitinib: Coadministration of fluconazole (400 mg on Day 1 and 200 mg once daily for 6 days [Days

2 to 7]) and tofacitinib (30 mg single dose on Day 5) in healthy subjects resulted in increased mean

tofacitinib AUC and C

values of approximately 79% (90% CI: 64% to 96%) and 27% (90% CI: 12%

to 44%), respectively, compared to administration of tofacitinib alone. (See PRECAUTIONS.)

Microbiology

Mechanism of Action

Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-

α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of

normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible

for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to

fluconazole inhibition.

Res is tance

A potential for development of resistance to fluconazole is well known. Fungal isolates exhibiting

reduced susceptibility to other azoles may also show reduced susceptibility to fluconazole. The

frequency of drug resistance development for the various fungi for which this drug is indicated is not

known.

Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme

(lanosterol 14-α-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 minimum inhibitory concentration (MIC) is categorized as

Intermediate (16 mcg/mL to 32 mcg/mL), the highest fluconazole dose is recommended.

Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be

mediated by reduced sensitivity of the target enzyme to inhibition by the agent.

There have been reports of cases of superinfection with Candida species other than C. albicans, which

are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require

alternative antifungal therapy.

Antimicrobial Activity

Fluconazole has been shown to be active against most isolates of the following microorganisms both in

vitro and in clinical infections.

Candida albicans

Candida glabrata (Many isolates are intermediately susceptible)

Candida parapsilosis

Candida tropicalis

Cryptococcus neoformans

The following in vitro data are available, but their clinical significance is unknown. At least 90% of

the following fungi exhibit an in vitro MIC less than or equal to the susceptible breakpoint for

fluconazole (https://www.fda.gov/STIC) against isolates of similar genus or organism group. However,

the effectiveness of fluconazole in treating clinical infections due to these fungi has not been

established in adequate and well-controlled clinical trials.

Candida dubliniensis

Candida guilliermondii

Candida kefyr

Candida lusitaniae

Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be

mediated by reduced sensitivity of the target enzyme to inhibition by the agent.

There have been reports of cases of superinfection with Candida species other than C. albicans, which

are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require

alternative antifungal therapy.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods

and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

INDICATIONS AND USAGE

Fluconazole tablets are indicated for the treatment of:

1. Vaginal candidiasis (vaginal yeast infections due to Candida).

2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small

numbers of patients, fluconazole tablets were also effective for the treatment of Candida urinary

tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated

candidiasis, and pneumonia.

3. Cryptococcal meningitis. Before prescribing fluconazole tablets for AIDS patients with

cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing fluconazole

tablets to amphotericin B in non-HIV infected patients have not been conducted.

Prophylaxis: Fluconazole tablets are 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.

CLINICAL STUDIES

Cryptococcal meningitis: In a multicenter study comparing fluconazole (200 mg/day) to amphotericin B

(0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis

revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental

status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white

blood cell count of less than 20 cells/mm . Mortality among high risk patients was 33% and 40% for

amphotericin B and fluconazole patients, respectively (p=0.58), with overall deaths 14% (9 of 63

subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48). Optimal doses and regimens

for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be

determined. (Saag, et al. N Engl J Med 1992; 326:83-9.)

Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using the 150

mg tablet. In both, the results of the fluconazole regimen were comparable to the control regimen

(clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month

post-treatment evaluation.

The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal

candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida

(microbiologic eradication), was 55% in both the fluconazole group and the vaginal products group.

Fluconazole PO

150 mg tablet

Vaginal Product

qhs x 7 days

Enrolled

Evaluable at Late Follow-up

347 (77%)

327 (77%)

Clinical cure

239/347 (69%)

235/327 (72%)

Mycologic eradication

213/347 (61%)

196/327 (60%)

Therapeutic cure

190/347 (55%)

179/327 (55%)

Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months) and

achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when treated with a

150 mg fluconazole tablet administered orally. These rates were comparable to control products. The

remaining one-fourth of enrolled patients had recurrent vaginitis (>4 episodes/12 months) and achieved

57% clinical cure, 47% mycologic eradication, and 40% therapeutic cure. The numbers are too small to

make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients

with recurrent vaginitis.

Substantially more gastrointestinal events were reported in the fluconazole group compared to the

vaginal product group. Most of the events were mild to moderate. Because fluconazole was given as a

single dose, no discontinuations occurred.

Parameter

Fluconazole PO

Vaginal Products

Evaluable patients

With any adverse event

141 (31%)

112 (27%)

Nervous System

90 (20%)

69 (16%)

Gastrointestinal

73 (16%)

18 (4%)

With drug-related event

117 (26%)

67 (16%)

Nervous System

61 (14%)

29 (7%)

Headache

58 (13%)

28 (7%)

Gastrointestinal

68 (15%)

13 (3%)

Abdominal pain

25 (6%)

7 (2%)

Nausea

30 (7%)

3 (1%)

Diarrhea

12 (3%)

2 (<1%)

Application site event

0 (0%)

19 (5%)

Taste Perversion

6 (1%)

0 (0%)

Pediatric Studies

Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of fluconazole

(2 to 3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in immunocompromised children with

oropharyngeal candidiasis was conducted. Clinical and mycological response rates were higher in the

children treated with fluconazole.

Clinical cure at the end of treatment was reported for 86% of fluconazole-treated patients compared to

46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients had the infecting

organism eradicated compared to 11% for nystatin treated patients.

Fluconazole

Nystatin

Enrolled

Clinical Cure

76/88 (86%)

36/78 (46%)

Mycological eradication

55/72 (76%)

6/54 (11%)

The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for subjects

receiving fluconazole and 16% for subjects receiving nystatin. At 4 weeks after the end of treatment, the

percentages of patients with clinical relapse were 22% for fluconazole and 23% for nystatin.

CONTRAINDICATIONS

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 fluconazole to patients with

hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving

fluconazole at multiple doses of 400 mg/day or higher based upon results of a multiple dose interaction

study. Coadministration of other drugs known to prolong the QT interval and which are metabolized via

the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide, and quinidine are

contraindicated in patients receiving fluconazole. (See CLINICAL PHARMACOLOGY: Drug

Interaction Studies and PRECAUTIONS.)

WARNINGS

(1) Hepatic injury: Fluconazole should be administered with caution to patients with liver dysfunction.

Fluconazole has been associated with rare cases of serious hepatic toxicity, including fatalities

primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated

hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex, or age of the patient

has been observed. Fluconazole hepatotoxicity has usually, but not always, been reversible on

discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole

therapy should be monitored for the development of more severe hepatic injury. Fluconazole should be

discontinued if clinical signs and symptoms consistent with liver disease develop that may be

attributable to fluconazole.

(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.

(3) Dermatologic: Exfoliative skin disorders during treatment with fluconazole have been reported.

Fatal outcomes have been reported in patients with serious underlying diseases. Patients with deep

seated fungal infections who develop rashes during treatment with fluconazole should be monitored

closely and the drug discontinued if lesions progress. Fluconazole should be discontinued in patients

treated for superficial fungal infection who develop a rash that may be attributed to fluconazole.

Subjects without follow-up cultures for any reason were considered nonevaluable for mycological response.

(4) Potential for fetal harm: There are no adequate and well-controlled clinical trials of fluconazole in

pregnant women. Case reports describe a pattern of distinct congenital anomalies in infants exposed in

utero to high dose maternal fluconazole (400 mg/day to 800 mg/day) during most or all of the first

trimester. These reported anomalies are similar to those seen in animal studies. If fluconazole is used

during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be

informed of the potential hazard to the fetus. Effective contraceptive measures should be considered in

women of child-bearing potential who are being treated with fluconazole 400 mg/day to 800 mg/day

and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives)

after the final dose. Epidemiological studies suggest a potential risk of spontaneous abortion and

congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single

or repeated dose in the first trimester, but these epidemiological studies have limitations and these

findings have not been confirmed in controlled clinical trials. (See PRECAUTIONS: Pregnancy.)

PRECAUTIONS

General

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the

electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium

Channel current (Ikr). The QT prolongation caused by other medicinal products (such as amiodarone)

may be amplified via the inhibition of cytochrome P450 (CYP) 3A4. (See PRECAUTIONS: Drug

Interactions.) During post-marketing surveillance, there have been rare cases of QT prolongation and

torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients

with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities, and

concomitant medications that may have been contributory. Patients with hypokalemia and advanced

cardiac failure are at an increased risk for the occurrence of life-threatening ventricular arrhythmias and

torsade de pointes.

Fluconazole should be administered with caution to patients with these potentially proarrhythmic

conditions.

Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity

(prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination

should be avoided.

Fluconazole should be administered with caution to patients with renal dysfunction.

Adrenal insufficiency has been reported in patients receiving azoles, including fluconazole. Reversible

cases of adrenal insufficiency have been reported in patients receiving fluconazole.

When driving vehicles or operating machines, it should be taken into account that occasionally dizziness

or seizures may occur.

Single Dose

The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of

vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug

related adverse events with fluconazole (26%) versus intravaginal agents (16%) in U.S. comparative

clinical studies. (See ADVERSE REACTIONS and CLINICAL STUDIES.)

Drug Interactions: (See CONTRAINDICATIONS.) Fluconazole is a moderate CYP2C9 and

CYP3A4 inhibitor. Fluconazole is also a strong inhibitor of CYP2C19. Patients treated with

fluconazole, who are also concomitantly treated with drugs with a narrow therapeutic window

metabolized through CYP2C9 and CYP3A4, should be monitored for adverse reactions associated with

the concomitantly administered drugs. In addition to the observed /documented interactions mentioned

below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9,

CYP2C19, and CYP3A4 coadministered with fluconazole. Therefore, caution should be exercised

when using these combinations and the patients should be carefully monitored. The enzyme inhibiting

effect of fluconazole persists 4 to 5 days after discontinuation of fluconazole treatment due to the long

half-life of fluconazole. Clinically or potentially significant drug interactions between fluconazole and

the following agents/classes have been observed and are described in greater detail below:

Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of

of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is

fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Amiodarone: Concomitant administration of fluconazole with amiodarone may increase QT prolongation.

Caution must be exercised if the concomitant use of fluconazole and amiodarone is necessary, notably

with high-dose fluconazole (800 mg).

Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-

Nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after 1

week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.

Amphotericin B: 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 Candida 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.

Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of

astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and

rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is

contraindicated.

Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the

effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral

dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin.

There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Calcium channel blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine,

verapamil, and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the

systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is

recommended.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum

carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity.

Dosage adjustment of carbamazepine may be necessary depending on concentration

measurements/effect.

Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the

celecoxib C

and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may

be necessary when combined with fluconazole.

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. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug

Interaction Studies.)

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. Dose adjustment of warfarin may be necessary. (See

CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase

in serum bilirubin and serum creatinine. The combination may be used while taking increased

consideration to the risk of increased serum bilirubin and serum creatinine.

Cyclosporine: Fluconazole significantly increases 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. (See CLINICAL

PHARMACOLOGY: Drug Interaction Studies.) This combination may be used by reducing the

dosage of cyclosporine depending on cyclosporine concentration.

Fentanyl: One fatal case of possible fentanyl-fluconazole interaction was reported. The author judged

that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with 12

healthy volunteers, it was shown that fluconazole delayed the elimination of fentanyl significantly.

Elevated fentanyl concentration may lead to respiratory depression.

Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on

CYP3A4.

HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is

coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin

and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient

should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be

monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine

kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple-dose

hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of

fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole

dose regimen in subjects receiving concomitant diuretics.

Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is

responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with

losartan. Patients should have their blood pressure monitored continuously.

Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of

methadone may be necessary.

Non-steroidal anti-inflammatory drugs: The C

and AUC of flurbiprofen were increased by 23% and

81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen

alone. Similarly, the C

and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were

increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen

(400 mg) compared to administration of racemic ibuprofen alone.

Although not specifically studied, fluconazole has the potential to increase the systemic exposure of

other non-steroidal anti-inflammatory drugs (NSAIDs) that are metabolized by CYP2C9 (e.g., naproxen,

lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to

NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

Olaparib: Moderate inhibitors of CYP3A4 such as fluconazole increase olaparib plasma concentrations;

concomitant use is not recommended. If the combination cannot be avoided, reduce the dose of olaparib

as instructed in the LYNPARZA

(Olaparib) Prescribing Information.

Oral contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been

performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the

50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were

increased 40% and 24%, respectively. Thus, multiple-dose use of fluconazole at these doses is

unlikely to have an effect on the efficacy of the combined oral contraceptive.

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. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Phenytoin: Fluconazole increases the plasma concentrations of phenytoin. Careful monitoring of

phenytoin concentrations in patients receiving fluconazole and phenytoin is recommended. (See

CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with

pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can

lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole

and pimozide is contraindicated.

Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed

acute adrenal cortex insufficiency when a 3 month therapy with fluconazole was discontinued. The

discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased

metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be

carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with

quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with

QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and

quinidine is contraindicated. (See CONTRAINDICATIONS.)

Rifabutin: There have been reports that an interaction exists when fluconazole is administered

concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. 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. (See CLINICAL

PHARMACOLOGY: Drug Interaction Studies.)

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. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, C

approximately 55%, and decreases the clearance of saquinavir by approximately 50% due to inhibition

of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of

saquinavir may be necessary.

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. (See

CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the

metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage

adjustment of sirolimus depending on the effect/concentration measurements.

Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to

5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant

pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased

tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus

should be decreased depending on tacrolimus concentration. (See CLINICAL PHARMACOLOGY:

Drug Interaction Studies.)

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/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. (See CONTRAINDICATIONS and CLINICAL

PHARMACOLOGY: Drug Interaction Studies.) The coadministration of fluconazole at doses lower

than 400 mg/day with terfenadine should be carefully monitored.

Theophylline: Fluconazole increases the serum concentrations of theophylline. Careful monitoring of

serum theophylline concentrations in patients receiving fluconazole and theophylline is recommended.

(See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Tofacitinib: Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with

fluconazole. Reduce the dose of tofacitinib when given concomitantly with fluconazole (i.e., from 5 mg

twice daily to 5 mg once daily as instructed in the XELJANZ

[tofacitinib] label). (See CLINICAL

PHARMACOLOGY: Drug Interaction Studies.)

Triazolam: Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C

20% to 32%, and increases t

by 25% to 50 % due to the inhibition of metabolism of triazolam. Dosage

20% to 32%, and increases t

by 25% to 50 % due to the inhibition of metabolism of triazolam. Dosage

adjustments of triazolam may be necessary.

Vinca alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids

(e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect

on CYP3A4.

Vitamin A: Based on a case report in one patient receiving combination therapy with all-transretinoid

acid (an acid form of vitamin A) and fluconazole, central nervous system (CNS) related undesirable

effects have developed in the form of pseudotumor cerebri, which disappeared after discontinuation of

fluconazole treatment. This combination may be used but the incidence of CNS related undesirable

effects should be borne in mind.

Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring for

adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is

started within 24 h after the last dose of fluconazole. (See CLINICAL PHARMACOLOGY: Drug

Interaction Studies.)

Zidovudine:. Fluconazole increases the C

and AUC of zidovudine by 84% and 74%, respectively,

due to an approximately 45% decrease in oral zidovudine clearance. The half-life of zidovudine was

likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients

receiving this combination should be monitored for the development of zidovudine-related adverse

reactions. Dosage reduction of zidovudine may be considered.

Physicians should be aware that interaction studies with medications other than those listed in the

CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months

at doses of 2.5 mg/kg/day, 5 mg/kg/day, or 10 mg/kg/day (approximately 2 to 7 times the recommended

human dose). Male rats treated with 5 mg/kg/day and 10 mg/kg/day had an increased incidence of

hepatocellular adenomas.

Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in four strains

of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone

marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to

fluconazole at 1000 mcg/mL) showed no evidence of chromosomal mutations.

Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5 mg/kg,

10 mg/kg, or 20 mg/kg or with parenteral doses of 5 mg/kg, 25 mg/kg, or 75 mg/kg, although the onset

of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5 mg/kg,

20 mg/kg, and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20

mg/kg (approximately 5 to 15 times the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The

disturbances in parturition were reflected by a slight increase in the number of still born pups and

decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with

the species specific estrogen-lowering property produced by high doses of fluconazole. Such a

hormone change has not been observed in women treated with fluconazole. (See CLINICAL

PHARMACOLOGY.)

Pregnancy

Teratogenic Effects.

Potential for Fetal Harm: Use in pregnancy should be avoided except in patients with severe or

potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit

outweighs the possible risk to the fetus. A few published case reports describe a pattern of distinct

congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400 mg/day to 800

mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in

animal studies. Effective contraceptive measures should be considered in women of child-bearing

potential who are being treated with fluconazole 400 mg/day to 800 mg/day and should continue

throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose. If

fluconazole is used during pregnancy, or if the patient becomes pregnant while taking the drug, the

patient should be informed of the potential hazard to the fetus. Spontaneous abortions and congenital

abnormalities have been suggested as potential risks associated with 150 mg of fluconazole as a single

or repeated dose in the first trimester of pregnancy based on retrospective epidemiological studies.

There are no adequate and well-controlled studies of fluconazole in pregnant women. (See

WARNINGS: Potential for Fetal Harm.)

Human Data

Case reports describe a distinctive and rare pattern of birth defects among infants whose mothers

received high-dose (400 mg/day to 800 mg/day) fluconazole during most or all of the first trimester of

pregnancy. The features seen in these infants include brachycephaly, abnormal facies, abnormal

calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and

congenital heart disease. These effects are similar to those seen in animal studies.

Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in

infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first

trimester, but these epidemiological studies have limitations and these findings have not been confirmed

in controlled clinical trials.

Animal Data

Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses

of 5 mg/kg, 10 mg/kg, and 20 mg/kg and at 5 mg/kg, 25 mg/kg, and 75 mg/kg, respectively. Maternal

weight gain was impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose

based on body surface area [BSA] comparison), and abortions occurred at 75 mg/kg (approximately 4

times the 400 mg clinical dose based on BSA); no adverse fetal effects were observed.

In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal

weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal

effects at 5 mg/kg or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis

dilation) and delays in ossification were observed at 25 mg/kg and 50 mg/kg and higher doses. At doses

ranging from 80 mg/kg to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical dose based on

BSA), embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate, and

abnormal craniofacial ossification. These effects are consistent with the inhibition of estrogen

synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy,

organogenesis, and parturition.

Nursing Mothers

Fluconazole was present in low levels in breast milk following administration of a single 150 mg dose,

based on data from a study in 10 breastfeeding women who temporarily or permanently discontinued

breastfeeding 5 days to 19 months postpartum. The estimated daily infant dose of fluconazole from

breast milk (assuming mean milk consumption of 150 mL/kg/day) based on the mean peak milk

concentration (2.61 mcg/mL [range: 1.57 to 3.65 mcg/mL] at 5.2 hours post-dose) was 0.39 mg/kg/day,

which is approximately 13% of the recommended pediatric dose for oropharyngeal candidiasis.

(Labeled pediatric dose is 6 mg/kg/day on the first day followed by 3 mg/kg/day; estimated infant dose

is 13% of 3 mg/kg/day maintenance dose). There are no data on fluconazole levels in milk after repeated

use or after high-dose fluconazole. A published survey of 96 breastfeeding women who were treated

with fluconazole 150 mg every other day (average of 7.3 capsules [range 1 to 29 capsules]) for

lactation-associated candida of the breasts reported no serious adverse reactions in infants. Caution

should be exercised when fluconazole is administered to a nursing woman.

Pediatric Use

An open-label, randomized, controlled trial has shown fluconazole to be effective in the treatment of

oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL STUDIES.)

The use of fluconazole in children with cryptococcal meningitis, Candida esophagitis, or systemic

Candida infections is supported by the efficacy shown for these indications in adults and by the results

from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in

children (see CLINICAL PHARMACOLOGY) have established a dose proportionality between

children and adults. (See DOSAGE AND ADMINISTRATION.)

In a noncomparative study of children with serious systemic fungal infections, most of which were

candidemia, the effectiveness of fluconazole was similar to that reported for the treatment of

candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline

symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients had a mycologic

cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following

cessation of therapy.

The efficacy of fluconazole for the suppression of cryptococcal meningitis was successful in 4 of 5

children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or

serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of

cryptococcal meningitis in children.

The safety profile of fluconazole in children has been studied in 577 children ages 1 day to 17 years

who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE

REACTIONS.)

Efficacy of fluconazole has not been established in infants less than 6 months of age. (See CLINICAL

PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day to 6 months have been

treated safely with fluconazole.

Geriatric Use

In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer

patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was

no consistent difference between the older and younger patients with respect to individual side effects.

Of the most frequently reported (>1%) side effects, rash, vomiting, and diarrhea occurred in greater

proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%)

discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous

reports of anemia and acute renal failure were more frequent among patients 65 years of age or older

than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the

natural increase in the incidence of anemia and renal failure in the elderly, it is however not possible to

establish a casual relationship to drug exposure.

Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older

to evaluate whether they respond differently from younger patients in each indication. Other reported

clinical experience has not identified differences in responses between the elderly and younger

patients.

Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are

more likely to have decreased renal function, care should be taken to adjust dose based on creatinine

clearance. It may be useful to monitor renal function. (See CLINICAL

PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

ADVERSE REACTIONS

Fluconazole is generally well tolerated.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes

in renal and hematological function test results and hepatic abnormalities have been observed during

treatment with fluconazole and comparative agents, but the clinical significance and relationship to

treatment is uncertain.

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 fluconazole, 150 mg single dose. The overall incidence of side effects

possibly related to fluconazole 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.

In Patients Receiving Multiple Doses for Other Infections:

Sixteen percent of over 4000 patients treated with 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 fluconazole 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%.

Hepato-biliary: In combined clinical trials and marketing experience, there have been rare cases of

serious hepatic reactions during treatment with fluconazole. (See WARNINGS.) 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 and jaundice, have occurred among patients with no other identifiable risk factors. In

each of these cases, liver function returned to baseline on discontinuation of fluconazole.

In two comparative trials evaluating the efficacy of fluconazole 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 serum transaminase 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 fluconazole concomitantly with one or more

of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea

hypoglycemic agents.

Post-Marketing Experience

In addition, the following adverse events have occurred during post-marketing experience.

Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been

reported.

Body as a Whole: Asthenia, fatigue, fever, malaise.

Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.)

Central Nervous System: Seizures, dizziness.

Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis,

thrombocytopenia.

Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting.

Other Senses: Taste perversion.

Musculoskeletal System: myalgia.

Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo.

Skin and Appendages: Acute generalized exanthematous pustulosis, drug eruption including fixed drug

eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic

epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) (see

WARNINGS), alopecia.

Adverse Reactions in Children:

The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric

clinical trials are comparable to those seen in adults.

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 fluconazole 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.

Percentage of Patients With Treatment-Related Side Effects

Fluconazole

(N=577)

Comparative Agents

(N=451)

With any side effect

Vomiting

Abdominal pain

Nausea

Diarrhea

OVERDOSAGE

There have been reports of overdose with fluconazole accompanied by hallucination and paranoid

behavior.

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 3-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.

DOSAGE AND ADMINISTRATION

Dosage and Administration in Adults:

Single Dose

Vaginal candidiasis: The recommended dosage of fluconazole for vaginal candidiasis is 150 mg as a

single oral dose.

Multiple Dose

SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF

FLUCONAZOLE IS THE SAME FOR ORAL 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 fluconazole 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.

Oropharyngeal candidiasis: The recommended dosage of fluconazole for oropharyngeal candidiasis is

200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal

candidiasis generally resolves within several days, but treatment should be continued for at least 2

weeks to decrease the likelihood of relapse.

Esophageal candidiasis: The recommended dosage of fluconazole for esophageal candidiasis is 200 mg

on the first day, followed by 100 mg once daily. Doses up to 400 mg/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 two weeks following resolution of symptoms.

Systemic Candida infections: For systemic Candida infections including candidemia, disseminated

candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been

established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily

have been used.

Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and

peritonitis, daily doses of 50 mg to 200 mg have been used in open, noncomparative studies of small

numbers of patients.

Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is

400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg 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 to 12 weeks after the cerebrospinal fluid becomes

culture negative. The recommended dosage of fluconazole for suppression of relapse of cryptococcal

meningitis in patients with AIDS is 200 mg once daily.

Prophylaxis in patients undergoing bone marrow transplantation: The recommended fluconazole daily

dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg,

once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils

cells/mm ) should start fluconazole prophylaxis several days before the anticipated onset of

neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells/mm .

Dosage and Administration in Children:

The following dose equivalency scheme should generally provide equivalent exposure in pediatric and

adult patients:

Pediatric Patients

Adults

3 mg/kg

100 mg

6 mg/kg

200 mg

12 mg/kg

400 mg

Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns.

(See CLINICAL PHARMACOLOGY.) 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 fluconazole pharmacokinetics in full-

term newborns is available.

Oropharyngeal candidiasis: The recommended dosage of fluconazole 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.

Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of

fluconazole 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.

Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily

doses of 6 to 12 mg/kg/day have been used in an open, noncomparative study of a small number of

children.

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 to 12 weeks after the cerebrospinal fluid

becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with

AIDS, the recommended dose of fluconazole is 6 mg/kg once daily.

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 fluconazole, an initial loading dose of 50 mg to 400

mg should be given. After the loading dose, the daily dose (according to indication) should be based on

the following table:

Creatinine Clearance (mL/min)

Recommended Dose %

>50

≤50 (no dialysis)

Hemodialysis

100% after each hemodialysis

Patients on hemodialysis should receive 100% of the recommended dose after each hemodialysis; on

non-dialysis days, patients should receive a reduced dose according to their creatinine clearance.

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)

Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not

recommended.

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.)

Administration

Fluconazole tablets are administered orally. Fluconazole tablets can be taken with or without food.

HOW SUPPLIED

Product: 63629-8054

NDC: 63629-8054-1 2 TABLET in a BOTTLE

PATIENT INFORMATION

Fluconazole (floo-KON-a-zole) Tablets USP

This leaflet contains important information about fluconazole (floo-KON-a-zole) tablets. It is not meant

to take the place of your doctor's instructions. Read this information carefully before you take

fluconazole tablets. Ask your doctor or pharmacist if you do not understand any of this information or if

you want to know more about fluconazole tablets.

What Are Fluconazole Tablets?

Fluconazole is a tablet you swallow to treat vaginal yeast infections caused by a yeast called Candida.

Fluconazole tablets help stop too much yeast from growing in the vagina so the yeast infection goes

away.

Fluconazole tablets are different from other treatments for vaginal yeast infections because it is a tablet

taken by mouth. Fluconazole tablets are also used for other conditions. However, this leaflet is only

about using fluconazole tablets for vaginal yeast infections. For information about using fluconazole

tablets for other reasons, ask your doctor or pharmacist. See the section of this leaflet for information

about vaginal yeast infections.

What Is a Vaginal Yeast Infection?

It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much yeast starts to

grow in the vagina and this can cause a yeast infection. Vaginal yeast infections are common. About

three out of every four adult women will have at least one vaginal yeast infection during their life.

Some medicines and medical conditions can increase your chance of getting a yeast infection. If you are

pregnant, have diabetes, use birth control pills, or take antibiotics you may get yeast infections more

often than other women. Personal hygiene and certain types of clothing may increase your chances of

getting a yeast infection. Ask your doctor for tips on what you can do to help prevent vaginal yeast

infections.

If you get a vaginal yeast infection, you may have any of the following symptoms:

itching

a burning feeling when you urinate

redness

soreness

a thick white vaginal discharge that looks like cottage cheese

What To Tell Your Doctor Before You Start Fluconazole Tablets?

Do not take fluconazole tablets if you take certain medicines. They can cause serious problems.

Therefore, tell your doctor about all the medicines you take including:

diabetes medicines such as glyburide, tolbutamide, glipizide

blood pressure medicines like hydrochlorothiazide, losartan, amlodipine, nifedipine or felodipine

blood thinners such as warfarin

cyclosporine, tacrolimus or sirolimus (used to prevent rejection of organ transplants)

rifampin or rifabutin for tuberculosis

astemizole for allergies

phenytoin or carbamazepine to control seizures

theophylline to control asthma

cisapride for heartburn

quinidine (used to correct disturbances in heart rhythm)

amiodarone (used for treating uneven heartbeats 'arrhythmias')

amitriptyline or nortriptyline for depression

pimozide for psychiatric illness

amphotericin B or voriconazole for fungal infections

erythromycin for bacterial infections

olaparib, cyclophosphamide or vinca alkaloids such as vincristine or vinblastine for treatment of

cancer

fentanyl, afentanil or methadone for chronic pain

halofantrine for malaria

lipid lowering drugs such as atorvastatin, simvastatin, and fluvastatin

non-steroidal anti-inflammatory drugs including celecoxib, ibuprofen, and naproxen

prednisone, a steroid used to treat skin, gastrointestinal, hematological or respiratory disorders

antiviral medications used to treat HIV like saquinavir or zidovudine

tofacitinib for rheumatoid arthritis

vitamin A nutritional supplement

Since there are many brand names for these medicines, check with your doctor or pharmacist if you

have any questions.

are taking any over-the-counter medicines you can buy without a prescription, including natural or

herbal remedies

have any liver problems.

have any other medical conditions

are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor will

discuss whether fluconazole tablets are right for you. Women who can become pregnant

should think about using effective birth control while taking fluconazole tablets.

are breastfeeding. Fluconazole can pass through breast milk to the baby.

are allergic to any other medicines including those used to treat yeast and other fungal infections.

are allergic to any of the ingredients in fluconazole tablets. The main ingredient of fluconazole

tablets is fluconazole. If you need to know the inactive ingredients, ask your doctor or pharmacist.

Who Should Not Take Fluconazole Tablets?

To avoid a possible serious reaction, do NOT take fluconazole tablets if you are taking erythromycin,

astemizole, pimozide, quinidine, and cisapride (Propulsid

) since it can cause changes in heartbeat in

some people if taken with fluconazole tablets.

How Should I Take Fluconazole Tablets?

Take fluconazole tablets by mouth with or without food. You can take fluconazole tablets at any time of

the day.

Fluconazole tablets keep working for several days to treat the infection. Generally the symptoms start to

go away after 24 hours. However, it may take several days for your symptoms to go away completely.

If there is no change in your symptoms after a few days, call your doctor.

Just swallow 1 fluconazole tablet to treat your vaginal yeast infection.

What Should I Avoid while Taking Fluconazole Tablets?

Some medicines can affect how well fluconazole tablets work. Check with your doctor before starting

any new medicines within seven days of taking fluconazole tablets.

What Are the Possible Side Effects of Fluconazole Tablets?

Like all medicines, fluconazole tablets may cause some side effects that are usually mild to moderate.

The most common side effects of fluconazole tablets are:

headache

diarrhea

nausea or upset stomach

dizziness

stomach pain

changes in the way food tastes

Allergic reactions to fluconazole tablets are rare, but they can be very serious if not treated right away

by a doctor. If you cannot reach your doctor, go to the nearest hospital emergency room. Signs of an

allergic reaction can include shortness of breath; coughing; wheezing; fever; chills; throbbing of the

heart or ears; swelling of the eyelids, face, mouth, neck, or any other part of the body; or skin rash,

hives, blisters or skin peeling.

Tell your doctor or pharmacist if you experience skin rash, fever, swollen glands, increase in a type of

white blood cell (eosinophilia), and inflammation of internal organs (liver, lungs, heart, kidneys, and

large intestine) as they may be signs of a hypersensitivity reaction (Drug Reaction or rash with

Eosinophilia and Systemic Symptoms (DRESS)).

Fluconazole tablets have been linked to rare cases of serious liver damage, including deaths, mostly in

patients with serious medical problems. Call your doctor if your skin or eyes become yellow, your

urine turns a darker color, your stools (bowel movements) are light-colored, or if you vomit or feel like

vomiting or if you have severe skin itching.

In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes with skin

peeling have been reported. Tell your doctor right away if you get a rash while taking fluconazole

tablets.

Fluconazole tablets may cause other less common side effects besides those listed here. If you develop

any side effects that concern you, call your doctor. For a list of all side effects, ask your doctor or

pharmacist.

Cases of reversible adrenal insufficiency have been reported with fluconazole tablets. Tell your doctor

is you experience chronic, or long lasting fatigue, muscle weakness, loss of appetite, weight loss or

abdominal pain.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-

800-FDA-1088.

What to Do For an Overdose

In case of an accidental overdose, call your doctor right away or go to the nearest emergency room.

How to Store Fluconazole Tablets

Keep fluconazole tablets and all medicines out of the reach of children.

General Advice about Prescription Medicines

Medicines are sometimes prescribed for conditions that are mentioned in patient information leaflets.

Do not use fluconazole tablets for a condition for which it was not prescribed. Do not give fluconazole

tablets to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about fluconazole tablets. If you would like

more information, talk with your doctor. You can ask your pharmacist or doctor for information about

fluconazole tablets that is written for health professionals.

Please address medical inquiries to, (MedicalAffairs@zydususa.com) Tel.: 1-877-993-8779.

*The brand names mentioned are registered trademarks of their respective manufacturers.

Manufactured by:

Cadila Healthcare Ltd., India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev.: 03/19

FLUCONAZOLE 200MG TABLET

FLUCONAZOLE

fluconazole tablet

Product Information

Product T ype

HUMAN PRESCRIPTION

DRUG

Ite m Code

(S ource )

NDC:6 36 29 -8 0 54(NDC:70 710 -1140 )

Route of Administration

ORAL

Bryant Ranch Prepack

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

FLUCO NAZO LE (UNII: 8 VZV10 2JFY) (FLUCONAZOLE - UNII:8 VZV10 2JFY)

FLUCONAZOLE

20 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ANHYDRO US DIBASIC CALCIUM PHO SPHATE (UNII: L11K75P9 2J)

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

FD&C RED NO . 4 0 (UNII: WZB9 127XOA)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO VIDO NE K3 0 (UNII: U725QWY32X)

Product Characteristics

Color

PINK (light pink to pink)

S core

no sco re

S hap e

OVAL (mo dified o val)

S iz e

12mm

Flavor

Imprint Code

1140

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 29 -8 0 54-1

2 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/18 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 8 9 6 3

0 4/0 6 /20 17

Labeler -

Bryant Ranch Prepack (171714327)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

171714327

REPACK(6 36 29 -8 0 54) , RELABEL(6 36 29 -8 0 54)

Revised: 8/2019

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