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Diflucan.org


DIFLUCAN®
(Fluconazole

Tablets)
(Fluconazole Injection - for intravenous infusion only)
(Fluconazole for Oral Suspension)

DESCRIPTION
DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is
available as tablets for oral administration, as a powder for oral suspension and as a sterile
solution for intravenous use in glass and in Viaflex® Plus plastic containers.
Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl)
benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight 306.3. The
structural formula is: Fluconazole is a white crystalline solid which is slightly soluble in water and saline. DIFLUCAN tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone, croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate. DIFLUCAN for oral suspension contains 350 mg or 1400 mg of fluconazole and the following inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate, titanium dioxide, colloidal silicon dioxide, xanthan gum and natural orange flavor. After reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted suspension contains 10 mg or 40 mg of fluconazole. DIFLUCAN injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are
packaged in glass and in Viaflex® Plus plastic containers.
The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride
(PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.).
The amount of water that can permeate from inside the container into the overwrap is insufficient
to affect the solution significantly. Solutions in contact with the plastic container can leach out
certain of its chemical components in very small amounts within the expiration period, e.g.,
di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the
plastic has been confirmed in tests in animals according to USP biological tests for plastic
containers as well as by tissue culture toxicity studies.
CLINICAL

Pharmacokinetics and Metabolism
The pharmacokinetic properties of fluconazole are similar following administration by the
intravenous or oral routes. In normal volunteers, the bioavailability of orally administered
fluconazole is over 90% compared with intravenous administration. Bioequivalence was
established between the 100 mg tablet and both suspension strengths when administered as a
single 200 mg dose.
Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours
with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after
oral administration.
In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN
(fluconazole) leads to a mean Cmax of 6.72 µg/mL (range: 4.12 to 8.08 µg/mL) and after single
oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma
concentration-time curve) are dose proportional.
Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating
women resulted in a mean Cmax of 2.61 µg/mL (range: 1.57 to 3.65 µg/mL).
Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg
given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose
results in plasma concentrations close to steady-state by the second day. The apparent volume of
distribution of fluconazole approximates that of total body water. Plasma protein binding is low
(11-12%). Following either single- or multiple-oral doses for up to 14 days, fluconazole
penetrates into all body fluids studied (see table below). In normal volunteers, saliva
concentrations of fluconazole were equal to or slightly greater than plasma concentrations
regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum
concentrations of fluconazole following a single 150 mg oral dose were equal to plasma
concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole
concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.
A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing. A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing. Ratio of Fluconazole
Tissue or Fluid
Cerebrospinal fluid† * Relative to concurrent concentrations in plasma in subjects with normal renal function.
† Independent of degree of meningeal inflammation.
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately
80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose
is excreted in the urine as metabolites.
The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There
is an inverse relationship between the elimination half-life and creatinine clearance. The dose of
DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE
AND ADMINISTRATION
.) A 3-hour hemodialysis session decreases plasma concentrations
by approximately 50%.
In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once
daily for up to 14 days) was associated with small and inconsistent effects on testosterone
concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol
response.
Pharmacokinetics in Children
In children, the following pharmacokinetic data {Mean(%cv)} have been reported:
(Hours) (µg/mL)
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 Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was
76.4+ 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic
parameter values are higher than analogous values reported for normal young male volunteers.
Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine
clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%) and the
fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower
than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly
appears to be related to reduced renal function characteristic of this group. A plot of each
subject's terminal elimination half-life versus creatinine clearance compared with the predicted
half-life – creatinine clearance curve derived from normal subjects and subjects with varying
degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence
limit of the predicted half-life – creatinine clearance curves. These results are consistent with the
hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects
compared with normal young male volunteers are due to the decreased kidney function that is
expected in the elderly.
Drug Interaction Studies
Oral contraceptives: Oral contraceptives were administered as a single dose both before and
after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women.
There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the
administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6%
(range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%).
In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN
tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all
subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of
study treatment was random. Single doses of an oral contraceptive tablet containing
levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both
cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of
AUC for levonorgestrel compared to placebo was 25% (range: -12 to 82%) and the mean
percentage increase for ethinyl estradiol compared to placebo was 38% (range: -11 to 101%).
Both of these increases were statistically significantly different from placebo.

A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to
21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In
this placebo-controlled, double-blind, randomized, two-way crossover study carried out over
three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the
mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The
mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range 18-31%)
and 13% (95% C.I. range 8-18%), respectively relative to placebo. Fluconazole treatment did not
cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to
placebo dosing. The individual AUC values of norethindrone decreased very slightly (<5%) in 3
of the 21 subjects after fluconazole treatment.

Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours
after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration
of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean
± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased
19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg
intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of
DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in
24 healthy male volunteers.
Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to
a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of
fluconazole.
Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg
hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in
fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD
increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31%
(range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in
renal clearance of 30% ± 12% (range: –10 to –50%).
Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin
administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease
in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There
was a mean ± SD reduction in fluconazole AUC of 23% ± 9%
(range: –13 to –42%). Apparent oral clearance of fluconazole increased 32% ± 17% (range: 16 to
72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (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 DIFLUCAN 200 mg administered daily for 14 days as
compared to the administration of warfarin alone. There was a mean ± SD increase in the
prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2
to 13%). (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 DIFLUCAN 200 mg daily for 16 days) in 10 normal male
volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in
phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction
is unknown because of the intrinsically nonlinear disposition of phenytoin. (See
PRECAUTIONS.)
Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration
of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on
cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks.
There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and
a significant reduction in apparent oral clearance following the administration of fluconazole.
The 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%). (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, 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. (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 DIFLUCAN taken in doses of 400 mg
per day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
(See CONTRAINDICATIONS and PRECAUTIONS.)
Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral
hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three
placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a
single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily
for 7 days. In these three studies 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%)
of placebo treated patients experienced symptoms consistent with hypoglycemia. (See
PRECAUTIONS.)

Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide
(500 mg single dose) AUC and Cmax following the administration of fluconazole. There was
a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide
Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.)
Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased
following the administration of fluconazole in 13 normal male volunteers. There was a mean
± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of
19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.)
Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased
following the administration of fluconazole in 20 normal male volunteers. There was a 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. (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 Cmax. Following multiple
doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in
the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving
cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and
PRECAUTIONS.)
Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of
midazolam was examined in a randomized, 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 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. (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.
Microbiology

Mechanism of Action
Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 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.
Activity In Vitro and In Clinical Infections

Fluconazole has been shown to be active against most strains of the following microorganisms
both in vitro and in clinical infections.

Candida albicans
Candida glabrata
(Many strains are intermediately susceptible)*
Candida parapsilosis
Candida tropicalis
Cryptococcus neoformans
* In a majority of the studies, fluconazole MIC90
values against C. glabrata were above the susceptible breakpoint
(≥16µg/ml). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to
multiple azoles.
For an isolate where the MIC is categorized as intermediate (16 to 32 µg/ml, see Table 1), the
highest dose is recommended (see Dosage and Administration). For resistant isolates alternative therapy is
recommended.
The following in vitro data are available, but their clinical significance is unknown.
Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or
less against most (≥90%) strains of the following microorganisms, however, the safety and
effectiveness of fluconazole in treating clinical infections due to these microorganisms have not
been established in adequate and well controlled trials.

Candida 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 DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.

Susceptibility Testing Methods
Cryptococcus neoformans and filamentous fungi:
No interpretive criteria have been established for Cryptococcus neoformans and filamentous
fungi.
Candida species:
Broth Dilution Techniques
: Quantitative methods are used to determine antifungal minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida
spp. to antifungal agents. MICs should be determined using a standardized procedure.
Standardized procedures are based on a dilution method (broth)1 with standardized inoculum
concentrations of fluconazole powder. The MIC values should be interpreted according to the
criteria provided in Table 1.
Diffusion Techniques: Qualitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One
such standardized procedure2 requires the use of standardized inoculum concentrations. This
procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of
yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1.
Table 1: Susceptibility Interpretive Criteria for Fluconazole

Broth Dilution at 48 hours Disk Diffusion at 24 hours (Zone Diameters in mm) Antifungal agent * Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be interpreted using this scale. ** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for fluconazole.
The susceptible category implies that isolates are inhibited by the usually achievable
concentrations of antifungal agent tested when the recommended dosage is used. The
intermediate category implies that an infection due to the isolate may be appropriately treated in
body sites where the drugs are physiologically concentrated or when a high dosage of drug is
used. The resistant category implies that isolates are not inhibited by the usually achievable
concentrations of the agent with normal dosage schedules and clinical efficacy of the agent
against the isolate has not been reliably shown in treatment studies.
Quality Control

Standardized susceptibility test procedures require the use of quality control organisms to control
the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks
should provide the following range of values noted in Table 2. NOTE: Quality control
microorganisms are specific strains of organisms with intrinsic biological properties relating to
resistance mechanisms and their genetic expression within fungi; the specific strains used for
microbiological control are not clinically significant.
Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results

(Zone Diameter in mm) Candida parapsilosis ATCC 22019 Candida krusei ATCC 6258 Candida albicans ATCC 90028 Candida tropicalis ATCC 750 ---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies.
Activity In Vivo
Fungistatic activity has also been demonstrated in normal and immunocompromised animal
models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for
systemic infections due to Candida albicans.
In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to
fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was
active in a variety of animal models of fungal infection using standard laboratory strains of fungi.
Activity has been demonstrated against fungal infections caused by Aspergillus flavus and
Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal
models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary
infections in normal mice; one model of Coccidioides immitis intracranial infections in normal
mice; and several models of Histoplasma capsulatum pulmonary infection in normal and
immunosuppressed mice. The clinical significance of results obtained in these studies is
unknown.
Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis.
Concurrent administration of fluconazole and amphotericin B in infected normal and
immunosuppressed mice showed the following results: a small additive antifungal effect in
systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus
neoformans,
and antagonism of the two drugs in systemic infection with A. fumigatus. The
clinical significance of results obtained in these studies is unknown.
Drug Resistance
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 MIC is categorized as Intermediate (16 to 32 µg/mL), the highest fluconazole dose is recommended. Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. INDICATIONS AND USAGE
DIFLUCAN (fluconazole) is 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, DIFLUCAN was 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 DIFLUCAN (fluconazole) for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing
DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted.
Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. CLINICAL STUDIES
Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (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/mm3. Mortality
among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN 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
Evaluable at Late Follow-up Therapeutic cure 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 DIFLUCAN 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 Gastrointestinal With drug-related event Gastrointestinal Application site event
Pediatric Studies
Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of
DIFLUCAN (2-3 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
Mycological eradication* * Subjects without follow-up cultures for any reason were considered nonevaluable for mycological response.
The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for
subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end
of treatment the percentages of patients with clinical relapse were 22% for DIFLUCAN and 23%
for nystatin.
CONTRAINDICATIONS
DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to
fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity
between fluconazole and other azole antifungal agents. Caution should be used in prescribing
DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is
contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or
higher based upon results of a multiple dose interaction study. Coadministration of cisapride is
contraindicated in patients receiving DIFLUCAN (fluconazole). (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies
and PRECAUTIONS.)
WARNINGS
(1) Hepatic injury: DIFLUCAN has been associated with rare cases of serious hepatic
toxicity, including fatalities primarily in patients with serious underlying medical
conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to
total daily dose, duration of therapy, sex or age of the patient has been observed.
DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation
of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy
should be monitored for the development of more severe hepatic injury. DIFLUCAN
should be discontinued if clinical signs and symptoms consistent with liver disease develop
that may be attributable to DIFLUCAN.

(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.
(3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with
DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and
malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during
treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions
progress.
PRECAUTIONS
General

Some azoles, including fluconazole, have been associated with prolongation of the QT interval
on the electrocardiogram. 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.
Fluconazole should be administered with caution to patients with these potentially proarrhythmic
conditions.

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 DIFLUCAN (26%) versus intravaginal agents
(16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL
STUDIES
.)
Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and
CONTRAINDICATIONS.) Clinically or potentially significant drug interactions between
DIFLUCAN and the following agents/classes have been observed. These are described in greater detail below: Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Terfenadine Cisapride Astemizole Rifabutin Tacrolimus Short-acting benzodiazepines
Oral hypoglycemics:
Clinically significant hypoglycemia may be precipitated by the use of
DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia
in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the
metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of
these agents. When DIFLUCAN 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
.)
Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving
concomitant DIFLUCAN 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 DIFLUCAN and coumarin-type anticoagulants is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of
phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Cyclosporine: DIFLUCAN 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 DIFLUCAN and cyclosporine. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN.
Depending on clinical circumstances, consideration should be given to increasing the dose of
DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies
.)
Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful
monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and
theophylline is recommended. (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 DIFLUCAN 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. (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.
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
.)

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.
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. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
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. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies
.)
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
.)
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. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) 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 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, 5 or 10 mg/kg/day (approximately 2-7x the recommended human
dose). Male rats treated with 5 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
4 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 µg/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,
10 or 20 mg/kg or with parenteral doses of 5, 25 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, 20 and
40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg
(approximately 5-15x 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. Pregnancy Category C: Fluconazole was administered orally to pregnant
rabbits during organogenesis in two studies, at 5, 10 and 20 mg/kg and at 5, 25, and 75 mg/kg,
respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at
75 mg/kg (approximately 20-60x the recommended human dose); no adverse fetal effects were
detected. In several studies in which pregnant rats were treated orally with fluconazole during
organogenesis, maternal weight gain was impaired and placental weights were increased at
25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants
(supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and
50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-60x the
recommended human dose) to 320 mg/kg embryolethality in rats was increased and fetal
abnormalities included wavy ribs, cleft palate and abnormal cranio-facial 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.
There are no adequate and well controlled studies in pregnant women. There have been reports
of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more
months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis (an
unindicated use). The relationship between fluconazole use and these events is unclear.
DIFLUCAN should be used in pregnancy only if the potential benefit justifies the possible risk
to the fetus.
Nursing Mothers
Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of
DIFLUCAN in nursing mothers is not recommended.
Pediatric Use
An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the
treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL
STUDIES
.)
The use of DIFLUCAN 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 DIFLUCAN 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 DIFLUCAN 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 DIFLUCAN 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 DIFLUCAN 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 DIFLUCAN.
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
In Patients Receiving a Single Dose for Vaginal Candidiasis:
During comparative clinical studies conducted in the United States, 448 patients with vaginal
candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side
effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative
agents, the incidence was 16%. The most common treatment-related adverse events reported in
the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%),
nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or
greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion
(1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema
and anaphylactic reaction have been reported in marketing experience.
In Patients Receiving Multiple Doses for Other Infections:
Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of
7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due
to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.
Clinical adverse events were reported more frequently in HIV infected patients (21%) than in
non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected
patients were similar. The proportions of patients discontinuing therapy due to clinical adverse
events were similar in the two groups (1.5%).
The following treatment-related clinical adverse events occurred at an incidence of 1% or greater
in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%,
headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.
Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases
of serious hepatic reactions during treatment with DIFLUCAN. (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 DIFLUCAN.
In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of
cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT)
levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the
other. The overall rate of 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 DIFLUCAN 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 postmarketing experience.
Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has
been reported.
Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.)
Central Nervous System: Seizures, dizziness.
Dermatologic: Exfoliative skin disorders including Stevens-Johnson syndrome and toxic
epidermal necrolysis (see WARNINGS), alopecia.
Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis,
thrombocytopenia.
Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Gastrointestinal: Dyspepsia, vomiting.
Other Senses: Taste perversion.
Adverse Reactions in Children:
In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients,
ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to
1,616 days. Thirteen percent of children experienced treatment related adverse events. The most
commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea
(2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4%
of patients due to laboratory test abnormalities. The majority of treatment-related laboratory
abnormalities were elevations of transaminases or alkaline phosphatase.
Percentage of Patients With Treatment-Related Side Effects
Fluconazole
Comparative
With any side effect
OVERDOSAGE
There have been reports of overdosage with DIFLUCAN (fluconazole). A 42-year-old patient
infected with human immunodeficiency virus developed hallucinations and exhibited paranoid
behavior after reportedly ingesting 8200 mg of DIFLUCAN. The patient was admitted to the
hospital, and his condition resolved within 48 hours.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if
clinically indicated) should be instituted.
Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma
levels by approximately 50%.
In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex and cyanosis; death was sometimes preceded by clonic convulsions. DOSAGE AND ADMINISTRATION
Dosage and Administration in Adults:
Single Dose
Vaginal candidiasis: The recommended dosage of DIFLUCAN 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 DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND
SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of
twice the daily dose is recommended on the first day of therapy to result in plasma
concentrations close to steady-state by the second day of therapy.
The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis
should be based on the infecting organism and the patient's response to therapy. Treatment
should be continued until clinical parameters or laboratory tests indicate that active fungal
infection has subsided. An inadequate period of treatment may lead to recurrence of active
infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal
candidiasis usually require maintenance therapy to prevent relapse.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN 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 DIFLUCAN 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 50-200 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 10-12 weeks
after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN
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
DIFLUCAN daily dosage for the prevention of candidiasis of patients undergoing bone marrow
transplantation is 400 mg, once daily. Patients who are anticipated to have severe
granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis
several days before the anticipated onset of neutropenia, and continue for 7 days after the
neutrophil count rises above 1000 cells per cu mm.
Dosage and Administration in Children:
The following dose equivalency scheme should generally provide equivalent exposure in
pediatric and adult patients:
Pediatric
Patients Adults
* Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended.
Experience with DIFLUCAN 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 DIFLUCAN pharmacokinetics in full-term newborns is available.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment
should be administered for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage
of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up
to 12 mg/kg/day may be used based on medical judgment of the patient's response to therapy.
Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at
least 2 weeks following the resolution of symptoms.
Systemic Candida infections: For the treatment of candidemia and disseminated Candida
infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a
small number of children.
Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended
dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once
daily may be used, based on medical judgment of the patient's response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal
meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily.
Dosage In Patients With Impaired Renal Function:
Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust
single dose therapy for vaginal candidiasis because of impaired renal function. In patients with
impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose
of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication)
should be based on the following table:
Creatinine Clearance (mL/min)
Percent of Recommended Dose
≤50 (no dialysis) Regular dialysis 100% after each dialysis These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg) × (140-age) 72 × serum creatinine (mg/100 mL) Females: 0.85 × above value Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K × linear length or height (cm) serum creatinine (mg/100 mL) (Where K=0.55 for children older than 1 year and 0.45 for infants.) Administration
DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN injection
has been used safely for up to fourteen days of intravenous therapy. The intravenous infusion of
DIFLUCAN should be administered at a maximum rate of approximately 200 mg/hour, given as
a continuous infusion.
DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for
intravenous administration using sterile equipment.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
Do not use if the solution is cloudy or precipitated or if the seal is not intact.
Directions for Mixing the Oral Suspension
Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely.
To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and
shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The
concentrations of the reconstituted suspensions are as follows:
Fluconazole Content per Bottle
Concentration of Reconstituted Suspension

Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers
Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The
inner bag maintains the sterility of the product.
CAUTION: Do not use plastic containers in series connections. Such use could result in air
embolism due to residual air being drawn from the primary container before administration of
the fluid from the secondary container is completed.
To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due
to moisture absorption during the sterilization process may be observed. This is normal and does
not affect the solution quality or safety. The opacity will diminish gradually. After removing
overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard
solution as sterility may be impaired.
DO NOT ADD SUPPLEMENTARY MEDICATION.
Preparation for Administration:
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
HOW
SUPPLIED
DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100 or 200 mg of fluconazole are packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval shaped, packaged in a single dose unit blister. DIFLUCAN Tablets are supplied as follows: DIFLUCAN 50 mg Tablets: Engraved with "DIFLUCAN" and "50" on the front and "ROERIG" on the back. NDC 0049-3410-30 DIFLUCAN 100 mg Tablets: Engraved with "DIFLUCAN" and "100" on the front and "ROERIG" on the back. NDC 0049-3420-30 NDC 0049-3420-41 Unit dose package of 100 DIFLUCAN 150 mg Tablets: Engraved with "DIFLUCAN" and "150" on the front and "ROERIG" on the back. NDC 0049-3500-79 Unit dose package of 1 DIFLUCAN 200 mg Tablets: Engraved with "DIFLUCAN" and "200" on the front and "ROERIG" on the back. NDC 0049-3430-30 NDC 0049-3430-41 Unit dose package of 100
Storage:
Store tablets below 86°F (30°C).
DIFLUCAN for Oral Suspension: DIFLUCAN for oral suspension is supplied as an
orange-flavored powder to provide 35 mL per bottle as follows:
Fluconazole 350 mg per bottle Fluconazole 1400 mg per bottle
Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are
formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are
supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or
200 mL affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN
injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose
diluents.
DIFLUCAN Injections in Glass Bottles:
NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6

Storage:
Store between 86°F (30°C) and 41°F (5°C). Protect from freezing.
DIFLUCAN Injections in Viaflex® Plus Plastic Containers:
NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6
NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6

Storage:
Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does
not adversely affect the product. Protect from freezing.
Rx only

REFERENCES
1. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal
Susceptibility Testing of Yeasts; Approved Standard-Second Edition. CLSI Document M27-A2, 2002 Volume 22, No 15, CLSI, Wayne, PA, August 2002. 2. Clinical and Laboratory Standards Institute. Methods for Antifungal Disk Diffusion Susceptibllity Testing of Yeasts; Approved Guideline. CLSI Document M44-A, 2004 Volume 24, No. 15 CLSI, Wayne, PA, May 2004. 3. Pfaller, M. A., Messer,S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and Diekema1, D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and Resistance to Voriconazole among 13,338 Clinical Isolates of Candida spp. Tested by Clinical and Laboratory Standard Institute-Recommended Broth Microdilution Methods. 2007. Journal of Clinical Microbiology. 45:70–75. LAB-0099-10.0 Revised March 2008

Source: http://diflucan.org/Diflucan.pdf

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The World Anti-Doping Code PROHIBITED LIST STANDARD The official text of the Prohibited List shall be maintained by WADA and shall be published in English and French. In the event of any conflict between the English and French versions, the English version shall prevail. This List shall come into effect on 1 January 2005.

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expand new drug markets for TB endTB aims to find shorter, less toxic and more effective treatments for multidrug-resistant TB 5 Approach through access to new drugs, a clinical trial, 6 Countries and advocacy at country and global levels. 7 Country requirements Only 11% of multidrug-resistant tuberculosis (MDR-TB) patients get