DIFLUCAN®
`
`(Fluconazole Tablets)
`
`(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.
`
`Fluconazole is designated chemically as 2,4-difluoro-,1-bis(1H-1,2,4-triazol-1-ylmethyl)
`benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3. The
`structural formula is:
`
`N
`
`N
`
`OH
`
`C
`
`N
`
`CH2
`
`N
`
`N
`
`CH2
`
`F
`
`N
`
`F
`
`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.
`
`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.
`
`Reference ID: 4173680
`
`Page 1 of 35
`
`ACRUX DDS PTY LTD. et al.
`
`EXHIBIT 1516
`
`IPR Petition for
`
`U.S. Patent No. 7,214,506
`
`

`

`Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours
`with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after
`oral administration.
`
`In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN
`(fluconazole) leads to a mean Cmax of 6.72 g/mL (range: 4.12 to 8.08 g/mL) and after single
`oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma
`concentration-time curve) are dose proportional.
`
`The Cmax and AUC data from a food-effect study involving administration of DIFLUCAN
`(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, DIFLUCAN may be taken
`without regard to meals. (see DOSAGE AND ADMINISTRATION.)
`
`Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating
`women resulted in a mean Cmax of 2.61 g/mL (range: 1.57 to 3.65 g/mL).
`
`Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg
`given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose
`results in plasma concentrations close to steady-state by the second day. The apparent volume of
`distribution of fluconazole approximates that of total body water. Plasma protein binding is low
`(11-12%). Following either single- or multiple oral doses for up to 14 days, fluconazole
`penetrates into all body fluids studied (see table below). In normal volunteers, saliva
`concentrations of fluconazole were equal to or slightly greater than plasma concentrations
`regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum
`concentrations of fluconazole following a single 150 mg oral dose were equal to plasma
`concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole
`concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.
`
`A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal
`tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours
`following dosing.
`
`A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal
`fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following
`dosing.
`
`Tissue or Fluid
`Cerebrospinal fluid†
`Saliva
`Sputum
`Blister fluid
`Urine
`Normal skin
`
`Reference ID: 4173680
`
`Ratio of Fluconazole
`Tissue (Fluid)/Plasma
`Concentration*
`0.5-0.9
`1
`1
`1
`10
`10
`
`Page 2 of 35
`
`

`

`1
`Nails
`2
`Blister skin
`1
`Vaginal tissue
`0.4-0.7
`Vaginal 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:
`
`Age
`Studied
`
`9 Months-
`13 years
`
`9 Months-
`
`13 years
`
`5-15 years
`
`5-15 years
`
`5-15 years
`
`Dose
`(mg/kg)
`
`Single-Oral
`2 mg/kg
`
`Single-Oral
`8 mg/kg
`
`Multiple IV
`2 mg/kg
`
`Multiple IV
`4 mg/kg
`
`Multiple IV
`8 mg/kg
`
`Clearance
`(mL/min/kg)
`
`Half-life
`(Hours)
`
`0.40 (38%)
`N=14
`
`0.51 (60%)
`N=15
`
`0.49 (40%)
`N=4
`
`0.59 (64%)
`N=5
`
`0.66 (31%)
`N=7
`
`25.0
`
`19.5
`
`17.4
`
`15.2
`
`17.6
`
`Cmax
`(g/mL)
`
`2.9 (22%)
`N=16
`
`9.8 (20%)
`N=15
`
`5.5 (25%)
`N=5
`
`11.4 (44%)
`N=6
`
`14.1 (22%)
`N=8
`
`Vdss
`(L/kg)
`
`
`
`___
`
`
`
`___
`
`0.722 (36%)
`N=4
`
`0.729 (33%)
`N=5
`
`1.069 (37%)
`N=7
`
`
`
` 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.
`
`Reference ID: 4173680
`
`Page 3 of 35
`
`

`

`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.
`
`Reference ID: 4173680
`
`Page 4 of 35
`
`

`

`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.
`
`Reference ID: 4173680
`
`Page 5 of 35
`
`

`

`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.)
`
`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 torsades 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 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.)
`
`Reference ID: 4173680
`
`Page 6 of 35
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`

`

`Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased
`following the administration of fluconazole in 13 normal male volunteers. There was a mean
`± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of 19% ± 23%
`(range: –11 to 79%). (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%,
`
`Reference ID: 4173680
`
`Page 7 of 35
`
`

`

`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 Cmax and AUC of voriconazole by an average of 57%
`(90% CI: 20%, 107%) and 79% (90% CI: 40%, 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: Co-administration of fluconazole (400 mg on Day 1 and 200 mg once daily for 6
`days [Days 2-7]) and tofacitinib (30 mg single dose on Day 5) in healthy subjects resulted in
`increased mean tofacitinib AUC and Cmax values of approximately 79% (90% CI: 64% – 96%)
`and 27% (90% CI: 12% – 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.
`
`Resistance
`
`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.
`
`Reference ID: 4173680
`
`Page 8 of 35
`
`

`

`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 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 DIFLUCAN (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
`
`* In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint
`
`(≥16 mcg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance
`to multiple azoles. For an isolate where the MIC is between 16 to 32 mcg/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. At least
`90% of the following fungi exhibit an in vitro MIC less than or equal to the susceptible
`breakpoint for fluconazole 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
`
`Reference ID: 4173680
`
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`

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`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:
`The interpretive standards for fluconazole against Candida species are applicable only to tests
`performed using Clinical and Laboratory Standards Institute (CLSI) broth dilution reference
`method M27 for MIC read at 24 hours or disk diffusion reference method M44 for zone diameter
`read at 24 hours.1-3
`
`Dilution Techniques:
`Quantitative methods are used to determine antifungal MICs. These MICs provide estimates of
`the susceptibility of Candida spp. to antifungal compounds. The MICs should be determined
`using a standardized test method at 24 hours1,2 (broth dilution). 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 antifungalcompound. The zone size should
`be determined using a standard test method.3 This procedure uses paper disks impregnated with
`25 mcg of fluconazole to test the susceptibility of yeasts to fluconazole. The disk diffusion
`interpretive criteria are provided in Table 1.
`
`Table 1: Susceptibility Interpretive Criteria for Fluconazole against Candida species
`
`Broth Microdilution at 24 hours
`(MIC in mcg/mL)
`Intermediate
`(I)
`
`Susceptible
`(S)
`
`Resistant
`(R)
`
`Disk Diffusion at 24 hours*
`(Zone Diameters in mm)
`Susceptible
`Intermediate
`Resistant
`(S)
`(I)
`(R)
`
`C. albicans
`≤13
`14-16
`≥17
`≥8
`4
`≤2
`C. glabrata
`-
`≥64
`≤32
`-
`14
`≥15
`C. parapsilosis
`≤13
`14-16
`≥17
`≥8
`4
`≤2
`C. tropicalis
`≤13
`14-16
`≥17
`≥8
`4
`≤2
`* 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.
`
`Reference ID: 4173680
`
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`

`

`A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the
`pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of
`infection. A report of Intermediate (I) indicates that the result should be considered equivocal,
`and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test
`should be repeated. This category implies possible clinical applicability in body sites where the
`drugs are physiologically concentrated or when a high dosage of drug is used. This category also
`provides a buffer zone that prevents small uncontrolled technical factors from causing major
`discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial is not
`likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations
`usually achievable at the infection site; other therapy should be selected.
`
`Quality Control
`
`Standardized susceptibility test procedures require the use of laboratory controls to monitor and
`
`ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques
`of the individuals performing the tests.1-3 Standardized fluconazole powder should provide the
`following range of MIC values noted in Table 2. For the diffusion technique using the 25 mcg
`disks, the criteria in Table 2 should be achieved.
`
`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
`
`QC Strain
`
`Macrodilution
`(MIC in mcg/mL)
`@ 48 hours
`
`Microdilution
`(MIC in mcg/mL)
`@ 24 hours
`
`Microdilution
`(MIC in mcg/mL)
`@ 48 hours
`
`Candida parapsilosis ATCC
`22019
`Candida krusei ATCC 6258
`Candida albicans ATCC
`90028
`Candidia albicans ATCC
`---*
`0.25-1.0
`24433
`26-37
`---*
`---*
`1.0-4.0
`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.
`
`Disk Diffusion
`(Zone Diameter in
`mm)
`@ 24 hours
`22-33
`---*
`28-39
`
`2.0-8.0
`16-64
`0.25-1.0
`
`0.5-4.0
`8.0-64.0
`---*
`
`1.0-4.0
`16-128
`---*
`
`Reference ID: 4173680
`
`Page 11 of 35
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`

`

`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 p